Human freedom and the brain.

ACADEMIC LECTURE Human freedom and the brain Hans Helmut Kornhuber Department of Neurology, Ulm University, Ulm, Germany Abstract: Freedom of will does exist, it is self-leadership of man based on reason and ethos. Evidence comes from truth. Determinism cannot be proved since if you try, you mean to prove a truth; but there is no truth without freedom. By contrast for freedom there are many pieces of evidence e.g. science, arts, technology. Freedom utilizes creative abstract thinking with phantasy. Freedom is graded, limited, based on nature, but not developed without good will. We perceive reliably freedom by self-consciousness and in other persons as long as we are sober. Freedom needs intelligence, but is more, it is a creative and moral virtue. The basis for freedom is phylogenesis and culture, in the individual learning and experimenting. Factors in the becoming of freedom are not only genes and environment but also self-discipline. But the creativity of free will is dangerous. Man therefore needs morale. Drives and feelings become humanized, cultural interests are developed. There is a humane nobility from long good will. The cerebral basis of intelligence is in the sum of the association areas, the basis of will and conscience in the prefrontal fields. This rational motivation system is superimposed on the limbic system. Voluntary movement needs the basal ganglia. When they search for motor programs the Bereitschaftspotential increases slowly, this is no proof against freedom. Since freedom is real; we can help people to become more free. A cause of deterioration is self-corruption. Free will is the top human ability; weÕve got always to work on. 1. When we want to understand the relation of freedom and the brain we need a concept of freedom; this today is confused. Usually only the external, the economic and political freedom is considered. It is clear that freedom in these fields is important, but this external freedom of the social state with rule of the law and democracy would not exist – after all it is created by man – if man would not have internal freedom. The essence of this, however, is freedom of the will. For if it were so as Schopenhauer claimed that man may perhaps do what he wants, but he cannot decide what he wants, he would be unfree. This freedom of the will has been challenged. Does it really exist? Of course we are not totally free, after all we are living beings with needs on energy and so on but we are not puppets either determined by unconscious processes of our brain. The ancient Greeks believed in freedom (1). Perhaps because, coming from the North and being a nation of conquerors first and then, living on beautiful coasts became masters of the sea, a nation with great physicians, mathematicians, geographers, historians, artists, poets and philosophers with an undogmatic religion in which the people were near to the gods – there even were sons of gods among the people in ancient times as they believed – and perhaps just because their philosophers, first of all Herakleitos (2), had discovered nature as a self-organizing system and at the same time that man is able to understand the logos of nature by research which was a great gain in freedom. Man is free by creativity was summarized by Sophokles in his famous chorus in the Antigone. It is not by accident that people who were so free in thinking also invented democracy. In the bible we find a lot on god’s freedom but little on freedom of the will, by contrast the bible is full with omnipotency of god and his providence which was interpreted by priests who at the same

time were the rulers of the people. Freedom of the will appears only in the gospel of John and this as freedom by truth. This gospel is a late book of the bible, written hundreds of years after Christ under the influence of Greek philosophy. Religious authors that were influenced by the older part of the bible denied freedom, first of all Mohammed. Spinoza (3) too belongs to this line of thought; although he was writing on nature, he knew little of it. And despite the fact that he later criticized the origin of it, he was trained in Hebrew theology. Hegel already has seen this (4). In the medieval ages fortunately the Greek philosophy was rediscovered and integrated into the teaching of the church. Albertus Magnus and Thomas Aquinas acquired the wisdom of Platon and Aristotle as a treasure of Christianity. Most of all the Franciscans (5) believed in freedom and defended it against the Islam. They believed more in the Sermon on the Mount than in Paulus. Duns Scotus saw that will is in all parts of mental activity, and Johannis Petrus Olivi wrote: the will is a king. In the Renaissance Pico della Mirandola (6) pointed toward creativity as the essence of free will including its influence on the becoming of the character. By contrast Luther (7) threw Aristotle and the freedom of will away, although on the other hand by his translation of the bible and by introducing songs in the language of the people he actually did a lot for education. In Luther¢s teaching as in that of the apostle Paulus man has only the freedom to accept the grace of god. Another consequential opponent of freedom in modern times was Schopenhauer (8,9). In his teaching there is really no will, but he renamed drive into will, although will is very different from drive. A drive is a primitive function, existent already in fishes, it has causes in genes and in vital needs of the organism, by contrast will is a high cortical function, fully developed only in man, it has well considered reasons and values and its basis is not only nature but also culture. Schopenhauer localized the focus of what he called will into the genitalia; in this point the Freudists followed him. Schopenhauer, however, although he denied free will, maintained the responsibility of man – a point that is forgotten today by Roth and Singer. The fundamental importance of the freedom of the will was rediscovered in modern times by Immanuel Kant (10). He distinguished between freedom in the negative sense (Nietzsche (11) called this freedom from ... it means freedom from oppression etc.) and freedom in the positive sense (Nietzsche called it freedom to ... which means the ability to do good deeds). Kant believed, because he was impressed by Newton’s physics that in the nature there may be no freedom. In order to save freedom he divided the world in an empirical part without freedom and a mental–moral world with freedom. How these two worlds were connected remained open. In reality there is freedom in nature and this in the realm of life in the stages of evolution; the problem is a cybernetic one of creative information processing in higher nervous systems. Max Planck (12) thought that considered from outside, man is unfree, but from inside free. This contradiction, however, does not exist. As long as we are sober outside and inside perceptions are in agreement. For instance we realize it when we are very tired, and one sees this also from outside. But the idea of the determination of everything by god was in the twentieth century still so strong that Einstein did not accept accidents in nature. He said: God does not play dice. But others believed just this to be freedom, when quantum physics came. Pascual Jordan believed erroneously that chance is freedom. There are of course a lot of accidents in nature, and they may contribute to freedom

2009 The Authors Journal Compilation 2009 John Wiley & Sons A/S Acta Neuropsychiatrica 2009: 21 (Supplement 2): 1–72

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when phantasy is asked, but they are not its essence. The problem was that in Plancks and Einstein’s time modern Philosophy since Decartes, Kant and Laplace despite enlightment was still under biblical-religious prejudice: nature had acquired a quality of omnipotence and predestination. The concept of freedom was therefore quasi metaphysical, it was an all–or–nothing concept. But nature is really full of grades and modes of freedom (and despair): a worm has not the freedom of a dog to feel what his master wants, and in deep depression a brave man may be so hopeless that he thinks of suicide. Freedom is not a mechanical or metaphysical problem, but a cybernetic fact, a result of higher information processing by systems in learning systems. Freedom of the will consists neither of accidents nor of behavior at pleasure, but it is the ability of self-leadership towards the good. Why to the good? Because the evil is destructive. But just because freedom rests on nature and culture, we can analyse it, and can help people to become more free. The essence is higher, creative information processing, it is a matter of innovations and decisions by rational and moral principles. By the way: the task of physicians is to promote freedom. In ancient Greece there were three concepts of freedom: first, Eleutheria, freedom from suppression, second, Arete´, which means virtue and third Sophrosyne that is prudence or reasonableness of the will. Herakleitos (13) said: Sophrosyne is the most important virtue. Hesiodos, besides Homeros the second early teacher of the Greeks, wrote: Before virtue the gods have set sweat (14). So the Greeks knew that we can and must do something for freedom. In short, it was clear since the ancient times that ethos belongs to freedom of will. 2. Freedom is not an illusion as recently claimed by some (15). That man has freedom of will indeed is easy to see from the following example (16): anyone who seriously denies freedom means to tell truth by this, however, he contradicts himself because without reasoned will and its freedom to invent methods for research there is no truth. It takes creative thinking in order to discover truth. Without the creative abilities of our brain there is for instance an intestinal motion but no reasoned will. At this point scepticists doubt, that there is any truth at all. But on court of law such scepticism does not exculpate an engineer when his bridge breaks down because of bad construction. Not only science, but also technology, medicine, arts, and law are created by means of freedom of the will. There are so many discoveries of facts which converge from different fields of research that fundamental scepticism regarding the ability of man for truth is unrealistic, even if these discoveries are only approximations. Furthermore from disturbances of freedom such as obsessive–compulsive disease one cannot conclude on total lack of freedom in healthy adults. 3. Of course freedom of the will does not mean to jump out of nature. Real freedom is based on nature (17), it is relative, has grades, different domains, it is changeable and yet it is a global ability. Man is more free than an ape, a sober man more free than a drunken, an adult more free than an infant. But a monkey is also more free than a worm. Freedom is based not only on reason, but has a vital basis in blood supply, and it needs information and communication and therefore senses and a motor system. In the realm of life many steps of the evolution were necessary before the freedom of man appeared. For instance an insect that must wait for the sun to warm up is in this domain less free than a mammal with regulated production of heat. Regarding the tendency of nature to select intellectual and creative abilities there are many examples from social insects to the exploratory behavior in young ravens, the use of tools in many species and the learning of social hunting by dolfins. Wolf Singer and Gerhard Roth (18) erroneously claim that our freedom is an illusion. Under pathological conditions it is true, that there occur illusions of freedom, for instance in mania or in intoxication with LSD. Some intoxicated jump from the balcony because they have the illusion that they are able to fly. Drunkenness causes an illusion of freedom and results in many accidents.

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The conclusion is that realistic perception of freedom is essential for life (19), and this is true for both self-perception and judgement regarding other’s freedom. For instance we are not allowed to give our car key to a drunken friend. Man has instincts indeed, but he learns in childhood and youth to regulate them by precaution, by postponement, by integration. In this process also the feelings are humanized. Of course man is, even when adult, not completely free, for instance he cannot change his genes; and he displays when different impulses interfere, instinctive actions of displacement behavior; and some need help when trying to give up bad habits. 4. Because freedom is creative it is also dangerous. Homo sapiens invents weapons, he defrauds ingeniously and he has done such terrible deeds as atomic bombing on civil cities. Therefore he needs morals beyond the monkey group order and care for the young, and he must adapt his rules to the changing conditions of culture. Freedom can be learned only by cooperation of the youth and other persons of good will. Man has the task to develop himself as well to help others, because without the care of others he would not be a man. Among the discoveries of Charles Darwin the role of competition for the origin of species is overemphasized. Darwin himself stated in his book on the descent of man that for the becoming of living beings within a species the role of cooperation and mutual help is more important than competition. Unfortunately this point is suppressed in today’s discussion. There would not have been a development towards man without cooperation: the evolution of reliable will occurred in social hunting. There are shining examples of helpfulness in all cultures: in the west Herakles and Jesus, in the Far East Konfucius. Egoism is infantile; a mature man is expected to be fair to everybody. It was not a good idea to proclaime egoism as the basis of economy. In short, the evolution of freedom leads to new duties beyond the individual. 5. What is the basis of freedom in man? First of all phylogenesis, when the apes were forced to live in the savannah, they became hunters in groups; this gave an advantage for the survival of reliable individuals in dangerous situations. The apes then needed larger groups and therefore better communication. Language evolved two million years ago in Homo habilis (20); he had a Wernicke area in the temporal lobe. Thus a primitive language was an early step towards Homo sapiens. Homo habilis had only half as much brain as we do, only a little more than apes. Language is important but not the essence of man. The Neanderthals had of course elaborate language, and they even had 200 grams more brain than we do (on average), but after 200 000 years they had the same primitive weapons as before. Although they of course were masters in the use of fire, they did not develop the art of cooking and therefore retained a massive dentition with very strong chewing muscles. The Neanderthals, as far as we know, did not develop arts, while the modern man who came to Europe 40 000 before Chr. had better weapons every 2000 years and created perfect art for instance expressive natural paintings. The difference in creativity probably came from the fact that the modern man had a larger frontal lobe whereas the Neanderthals had a small shallow forehead (21); they had more of brain in the posterior lobes and therefore had probably a good orientation. The climate was not the cause of the difference; it is true that there were cold times, but the Neanderthals had developed in Europe from Homo erectus, thus they were better adapted to the cold than Homo sapiens sapiens who came from Africa. Secondly, freedom is based on culture, on many discoveries and their tradition, on knowledge, law, morals and many inventions beginning with the mastery of the fire which was the sign of man from the beginning. Thirdly, however, freedom comes in the individual child and youth from education and learning from experience, partly from examples among family members or teachers, partly however from experimenting and experience with his own will and conscience,


and this is the factor which is forgotten today. Chimpanzees are able to learn sign language if the teaching starts early in childhood – not word language because they lack the Wernicke area for rapid auditory regulation of the phonemes –, but they never develop language by themselves. By contrast, children without hearing often develop sign language by themselves, without an example (22). Thus, the difference is in creativity. The variance of the great personality factors – such as emotional stability, agreeableness, conscientiousness or openness to experience, in all of which is creative will, comes only to 40 % from heredity, 10–15 % from familiar influences, but on the average almost half comes from something what the psychologists erroneously call ’’external factors not shared with the family’’ (23). In these factors of cause is the own will of the child and the young; for instance development of intellectual interests, choice of good or bad friends etc. There is no "Nu¨rnberg funnel’’ to bring knowledge and ethos into a man without his own will. What is learned and what remains depends on internal motivation and own activity. What the behaviorists wanted with conditioning tends toward a herd-being. Although it is necessary to set limits to bad behavior, indoctrination of freedom is impossible. You can only promote germs of freedom and bring the meaning of freedom to shining by a good example and love; this is socratic education. What happens in this is like a springing spark as described by Platon (24). Free learning is based on interest, on insight, on truth, on trust, on sense. Because of the influence of man upon his own becoming there are the enormous differences of personalities much bigger than in other species. This individuality even influences higher animals, for instance dogs, when they live in company with humans for a longer time. Most people have enough intelligence; intelligence is inherited more than half. The larger differences come from the will: on the one hand the fair, helpful, brave, creative, on the other hand different modes of self-corruption but, of course, also many disadvantaged by disease, lack of education, poisons, some even before birth (25). 6. The behaviorist manifest (26) threw not only will and his freedom away, but also consciousness. This ideology acted behind the fence of three concepts: stimulus, response and adaptation. But consciousness is not an epiphenomenon, it is important. A patient who regains consciousness after a head trauma can compensate many defects by active training. He may recover even from severe aphasia, if he had sung in his youth so that the language came with the melodies in his right hemisphere, he then can reconstruct speech by singing. But if he does not regain consciousness after the trauma, there is no repair even if he stays alive for a long time. The level of consciousness in the brain is the cerebral cortex. If we have a lesion in the retina, we see it as a dark scotoma; the retina is a part of the brain, and the optic nerve is not a peripheral nerve but a tract of the brain. However, if we have a lesion of the optic cortex, we do not see it. Even if the whole visual cortex is suddenly lost on both sides by a vascular insult and therefore the patient is blind, he does not see it, and it takes days or weeks until he realizes that something is wrong with his vision, but still he cannot see it. The further forward toward the frontal lobe the lesion, the longer the time until the patient gains insight, and with lesions of the prefrontal cortex, the anosognosia often remains permanently (27), what makes therapy much more difficult. Consciousness thus does not live behind the brain but it is produced by the activity of the brain, especially the cortex and it is a very important factor for freedom. 7. But now an important point: in the brain there are two motivation systems, the old one in the hypothalamus (28) and limbic system deep in the brain and the new in the frontal cortex, more specifically in its youngest part, the prefrontal cortex (29). The old motivation system is conservative; in comparison with the monkeys there is little change. But this old system is in a mature man under the leadership of the new so that the drives and feelings are humanized at least in people of good will. An example: Gerhard Roth (30) claims that man is a puppet of the activity of a

small nucleus in the limbic system, the amygdala. In monkeys this nucleus is important for the anxious perception of bad voices or furious faces of fellow monkeys. If in an adult rhesus monkey the amygdala is destroyed on both sides, the animal looses fear, becomes more trusty and therefore he is much-liked in the group. But in man after bilateral damage of this nucleus there is almost perfect compensation so that these persons live normal and have normal feelings (31). The leading function of the frontal cortex is the result of normal becoming of a human personality in an environment with protection in childhood, challenges in youth and responsibility when adult. But in a spoiling social environment the opposite is possible, namely that a demanding limbic system abuses the intelligence of the cortex to become an accomplice for bad deeds. This self corruption to hedonism with intimidation of the conscience may occur in a welfare state as well as under totalitarian pressure. In the prefrontal cortex there is a division of function (32): creative thinking and planning depends on the cortex on the frontal pole and on the convexity of the frontal lobe, by contrast the conscience depends on the orbital cortex. Unilateral lesions in the frontal lobe are better compensated than left temporal lesions, but bilateral lesions in the prefrontal cortex cause severe defects of behavior, and the feelings become shallow. Extensive bilateral lesions either in the prefrontal cortex or in the sub cortical fibres toward and from it cause changes of personality, reduction of initiative and productive thinking so that the patients often are not able to carry on a self-guided life (33). Lesions of the orbital cortex can change a good person into an unreliable fellow. Of course the prefrontal cortex does his leading activity not alone but by the help of older centers among them the centers for attention in the anterior part of the cingulate gyrus and in the parietal cortex. By the way the intelligence does not depend solely on the frontal lobe; intelligence is correlated with the volume of all association areas (34) of the brain that are those areas of the cortex which are not devoted to primary sensory or motor functions. It is the sum of these association areas that is characteristic for the higher development of the brain in the evolution of mammals. The brain works cooperatively as a whole, but all information is transmitted to the frontal lobe, and the prefrontal cortex has its own information system (35) and influences not only the perception and the motor system but also the selection of events in the stream of consciousness for storage in long-term memory by its influence on the hippocampus (36). The prefrontal cortex also influences – besides the circadian rhythm – the deep nuclei which by transmitters like dopamine, serotonin, noradrenalin and acetylcholine regulate our wakefulness, mood, readiness for learning, etc. How is it possible that the activity of the prefrontal cortex within the system of the brain makes us more free? Information processing power of the prefrontal cortex and its influence on the rest of the brain we are not in captivity of the drives and of the things anymore. We are able to make models of the world (37), consider them – independent of their presence – from different points of view, change them and check how they fit to the situation and to our perspective, and we use thereby a system of abstract concepts, symbols, principles and theories to reach coherence, meaning and transsubjective understanding. And we can transmit the results of this free thinking to our motivation system making it more free by inhibition of destructive tendencies – lesions of the orbital cortex disinhibit reckless and obscene drives – and by enabling it to earn happiness from good-willed work; of course within limits, we still need sleep, water and so on. The cooperation of the prefrontal cortex gives us exact phantasy, exact because such a complex system as our brain would be lost in absurdities, if our ideas would not be checked on the real world. This holds also for our behavior with persons. We transcend ourselves and have understanding and empathy with our fellow men but also with animals like dogs; this understanding is now called "theory of mind’’. The prefrontal


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cortex enables us in the realm of needs, interests, striking perceptions and so on to clear our will, to develop our self, to make decisions and to keep course in view of distractors and self-chosen bindings and values. This leading cortex enables us also to gain insight of ourself, to set goals for our own development and to correct ourself by experience. In this connection we have feelings like regret, shame, sorrow and internal freedom, all of which are not illusions. 8. Because of the activity of the two motivation systems in man there are not only conflicts between drives but also between drives and the longterm goals of the will with well-founded self-binding. Therefore to freedom also belongs that a person when drifting or in conflicts comes to pure terms with himself and his people. Furthermore creativity misleads some to phony behavior. 9. The execution of our decisions belongs also to freedom, thus the ability to willed motor activities. It is more difficult for information systems engineers to build up a good robot automat with smoothly regulated movements and target acquisition than to compose a nice music by a computer. Usually external stimuli play a role for our movements, in this case the task is more simple for the motor cortex since it is an association area of the tactile area (38) which is juxtaposed to it, and it also gets visual and auditory information via premotor fields. But to produce a voluntary movement without all external stimuli is more difficult, and for this an older part of the brain is still necessary, the basal ganglia (39). One can see this in the disturbances of voluntary movements caused by diseases of the basal ganglia such as the Parkinson syndrome or athetosis. In Parkinson¢s disease there is akinesia: the patients cannot start walking although they don¢t have paresis and although the motor cortex is intact. In athetosis the patients cannot move the arm which is contracted in a bizarre position although there is no paresis and the motor cortex is intact. But if the athetotic hand is touched by the other hand without pulling, just by skin contact the contracted arm can follow the other hand as with magnetic force: this shows the influence of the tactile cortex on the motor cortex what makes the help of the basal ganglia unnecessary when an external stimulus leads the movement. The command for voluntary movements of man does not come from the basal ganglia which don’t have either consciousness nor will, but from the frontal cortex (40), – and this command may precede the movement by several seconds in a variable way, but the electrical signal is small and its occurrence is variable in time so that it cannot easily be averaged and recorded so far. What we can measure regularly is the Bereitschaftspotential (41) (the subject of much discussion today) and in its production the basal ganglia (42) participate together with a fronto-medial area the supplementary motor area (SMA) (43). The Bereitschaftspotential is pretty small too – about 1/100 to 1/10 of the spontaneous alpha-rhythm of the electroencephalogram – but with averaging by means of backward analysis (44), triggered with the beginning of the muscle contraction over many equal simple finger movements we can measure it. After the decision to participate in this experiment the frontal cortex delegates the execution of the series of movements to the basal ganglia. After the slow Bereitschaftpotential another sharp potential (called motor potential) can be recorded from the scalp which is a sign of the firing of the pyramidal cells of the motor cortex whose nerve fibres go directly to the motor neurons of the spinal cord that activate the muscles. This activity of the cortical pyramidal cells – 60 milliseconds before the beginning of the muscle activity of the forearm – is still much smaller than the Bereitschaftspotential, but we can measure it (45) because it is in fixed temporal relation to the start of the movement. The basal ganglia however when after the command of the frontal lobe preparing the movement work much slower than the cortex, they increase the activity slowly in the course of about one second and signal about 200 milliseconds before the movement to the cortical consciousness (46) that they are ready so that it can be checked by the frontomedial SMA

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whether the time is suitable for the moment. This sequence of events is not in contradiction to freedom, for the movement is initiated by a cortical command and its execution in an acceptable moment of time is again controlled by consciousness. The supervisory function of the SMA regarding the suitable time for movement is underlined by two lesion syndromes of this frontomedial area: one is a diminished spontaneity of movements, another is a disinhibition of hand movements, the ’’alien hand’’ (47) which makes movements initiated by the basal ganglia that appear alien to the patient. When 40 years ago I was searching together with my doctoral student Lu¨der Deecke for signs of will in the brain (48) – at that time the human person was investigated by the physiologists only as a passive system by external stimuli and recording of evoked cerebral potentials – and when I found the Bereitschaftspotential, it was soon clear to me that this potential can not be the command signal. Therefore I gave him the name Bereitschaftspotential (readiness potential) and this proper term was taken over from the German language into the English (49). You can see with the method of backward analysis, which had to be designed and developed for this discovery, also the effort of the frontal lobe when learning (50) or the delegation of tasks for execution from the frontal lobe to posterior parts of the brain (51) when the experimental situation is asking for this, since the time resolution of electrical or magnetic recording is much better than that of the imaging methods that are based on movement of blood in the vessels. By the opponents of freedom it is often mentioned that in the cerebral process of volition unconscious events are participating. This argument shows little understanding of the brain since most of the billions of processes in the brain are unconscious. Consciousness requires a high neuronal coordination, and the consciousness is narrow. The flow of information in the peripheral sensory channels has to be condensed by at least about 1:10 000 (52) before reaching consciousness. Thus consciousness can deal only with the most important events. However, the unconscious and the consciousness closely cooperate and consciousness controls the important events, among them always volition. In the large brain with its enormous knowledge stored in memory the initiative for thinking perhaps does not always come from the frontal lobe. The brain sometimes makes suggestions on its own initiative which suddenly come to consciousness as ideas, especially when we have tried before to solve a problem or to remember something, but these events do not come from the absolute unconscious (like discharges in the autonomic nervous system) they are prepared by previous conscious thinking. All this is not a sign of lack of freedom but of the great richness of information processing in the brain. We are when mentally healthy not manipulated by such spontaneity, rather we check what the brain is offering. It is not the condition of normal men but a sign of mental disease if someone looses the freedom to control his thoughts or actions. By the way just the discovery of the Bereitschaftspotential potential in 1964, which was the first physiological sign of will in the brain gave the psychologists the courage to do research again on volition, for between 1945 and 1965 all research on the will ceased (53) because of the influence of Freudism after the Second World War; the research on will is now in full blossom again (54). 10. This is my answer to Gerhard Roth¢s argument against freedom from the Bereitschaftspotential. Roth is a zoologist who most of the time has worked on salamanders. He claims that the human personality is almost completely programmed at age three (55), that is during a time when no memory on personal events is preserved. This is a grotesque misjudgement about the becoming of man, for the reasonable human will evolves in the child beginning from age three and in the youth under the cooperation of his own conscience, and the will continues to learn throughout life. Wolf Singer (56) has another argument against freedom, he claims that in the brain there is no location where decisions can be made.


The neurons, so his opinion, make a thunderstorm and then we do something. But so chaotic is our behavior not. The neurons normally behave well coordinated except in dreams, when they are activated at random from an old brain stem nucleus for training. A neuronal thunderstorm, however, is characteristic for epilepsy. It is probably true that in the brain there are no ’’grandmotherneurons’’, that means that there is no single nerve cell which is specialized for recognition of our grandmother; the brain works always in a cooperative manner, so that many cells act together in variable combinations. But this is true also for perception as for volition. However, that we have perception has not been doubted even by the sceptics. All higher forms of life would be impossible without perception. Thus the ideas of both of the opponents of freedom are unrealistic, and it is an astonishing sign of disorientation and sensationalism that they are propagated by the media. I would rather like to comment these events with irony and humor if our situation were not so serious. 11. Therefore a last point: we are living in a time of enhanced seduction to hedonism. The consumption of drugs, the alcoholism of women since 1968, the cerebral damage in children before birth due to alcohol and cigarette smoking during pregnancy are increased and consequently the fetal alcohol syndrome and the attention deficit – hyperactivity disorder (57). The consumption of illegal drugs increased in Germany from 1965 to 1971 sixty fold, the high dose alcoholism of woman from 1968 to 1990 more than tenfold (58,59). In addition in the last years came obesity of the children due to lack of movement as well as insulin resistance even before birth due to alcohol, a risk factor for high blood pressure, diabetes and early dementia. A flood of dementia is impending if nothing is done for prevention. And there is a high level of aggression, mobbing and violence among youth and against teachers with all sorts of crime. A similar situation is now in the financial world where reckless rating agencies and investment banking have caused a huge damage to global economy. In this situation indoctrination of general inability for accountability of man is damaging indeed. Man is a potentially noble being who has always to work on his freedom. Today in addition we have to help the developing countries to gain more freedom because freedom is an important factor of development, and this helps to stop devastation of the earth. There is a lot of talk on prevention but it is difficult to organize it (except for a health levy on alcohol and cigarettes the revenues of which should go to the health system). An example: our most common disease is high blood pressure but we do not feel it and therefore only half of the cases is diagnosed, only half of the diagnosed cases is treated, and only half of the treated cases is sufficiently treated. The method to wait until the patients come to the doctors does not work in this case. To go to the patients to measure their blood pressure without annoying them is difficult. It does work however by means of their children. When in 1978 in Ulm the measurement of blood pressure was introduced into the schools (59), all participants were enthusiastic: the teachers because the children liked this practical method, the children were proud because they found many cases of high blood pressure in their families, also the doctors because they could earlier and more effectively treat the disease. Unfortunately this inexpensive method (it does not need a new bureaucracy) is not yet in general use. Since high blood pressure causes stroke and dementia, prevention preserves freedom. 12. In conclusion, man is born for freedom of the will but he must develop it. This freedom is the highest ability of man, more than speech and intelligence: it is the comprehensive virtue to make life worth living by doing good deeds and finding happiness of meaning. Freedom is never complete, always in danger but we can and must do something for it, among other things by helping one another. There is, independently of the class, a human nobility that comes from long good will. But we should behave worthy of this high gift and not abuse it to ruin the beauty of earth.

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30. Roth, G. Fu¨hlen, Denken, Handeln. Wie das Gehirn unser Verhalten steuert. Frankfurt: Suhrkamp, 2001. 31. Anderson AK & Phelps EA. Is the human amygdala critical for subjective experience of emotion? J Cognit Neurosci 2002;14:709–720. 32. Kleist, K. Kriegsverletzungen des Gehirns in ihrer Bedeutung fu¨r die Hirnlokalisation und Hirnpathologie. Leipzig: Barth, 1934. Regard M. The perception and control of emotion: Hemispheric differences and the role of the frontal lobes. Habilitationsschrift: Zu¨rich, 1991. Stuss DT, Alexander MP, Floden D et al. Fractionation and localisation of distinct frontal lobe processes: Evidence from focal lesions in humans. In: Stuss DT, Knight RT. (eds.): Principles of frontal lobe function.New York: Oxford, 2002:392–407. 33. Freeman WJ, Watts JW. Psychosurgery: Intelligence, emotion and social behavior following prefrontal lobotomy for mental disorders. Springfield: Thomas, 1942. 34. Haier RJ, Jung RE, Yeo RA, Head K, Alkire MT. Structural brain variation and general intelligence. NeuroImage 2004;23:425–433. 35. Petrides M. Specialized systems for the processing of mnemomic information within the primate frontal cortex. Phil Trans Roy Soc (Lond.) Biol Sci 1996;351:1455–1462. 36. Kornhuber HH. Neural control of input into longterm memory: limbic system and amnestic syndrome in man. In: Zippel HP. (ed.): Memory and transfer of information. New York: Plenum Press, 1973. 37. Shallice T. Specific impairments of planning. Phil Trans Roy Soc Lond (Biol.) 1982;298:199–209. 38. Kornhuber HH. Cerebral cortex, cerebellum and basal ganglia: an introduction to their motor functions. In: Schmitt FU., Worden FG. (eds.): The Neurosciences. Third Study Program, Cambridge Mass.: MIT Press, 1974:267–280. 39. Kornhuber HH. A reconsideration of the cortical and subcortical mechanisms involved in speech and Aphasia. In: Desmedt JE. (ed.): Progr Clin Neurophysiol. Vol. 3, Basel: Karger, 1977:28–35. 40. Kornhuber HH, Deecke L. Wille und Gehirn. Bielefeld, Edition Sirius, 2007, p. 32. 41. Kornhuber HH, Deecke L. Hirnpotentiala¨nderungen bei Willku¨rbewegungen und passiven Bewegungen des Menschen: Bereitschaftspotential und reafferente Potentiale. Pflu¨gers Arch Physiol 1965;284:1–17. 42. Cunnington R, Windischberger C, Deecke L, Moser C. The use of single event fMRI and fuzzy clustering analysis to examine haemodynamic response time courses in supplementary motor and primary motor cortical areas. Biomed Technik 1999;44 (Suppl. 2):116–119. 43. Deecke L, Kornhuber HH. An electrical sign of participation of the mesial ’’supplementary’’ motor cortex in human voluntary finger movement. Brain Res 1978;159:473–476.

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44. Deecke L, Kornhuber HH. Human freedom, reasoned will, and the brain: the Bereitschaftspotential story. In: Jahanshahi M, Hallet M. (eds.): The Bereitschaftspotential. New York: Kluwer Academic/Plenum Publ., 2003:283–320. 45. Deecke L, Scheid P, Kornhuber HH. Distribution of readiness potential, pre-motion positivity and motor potential of the human cerebral cortex preceding voluntary finger movements. Exp Brain Res 1969;7:158–168. 46. Libet B, Gleason CA, Wright EW, Pearl DK. Time of conscious intention to act in relation to onset of cerebral activity (readiness potential). Brain 1983;106:623–642. 47. Scepkowski LA, Cronin-Colomb A. The alien hand: cases, categorisations, and anatomical correlates. Behav Cognit Neurosci Rev 2003;2:261–277. 48. see 41. 49. Jahanshahi M, Hallet M. (eds.): The Bereitschaftspotential. Movementrelated cortical potentials. New York: Kluwer Plenum, 2003. 50. Lang W, Lang M, Kornhuber A, Deecke L, Kornhuber HH. Human cerebral potentials and visuomotor learning. Pflu¨gers Archiv Eur J Physiol 1983;399:342–344. Lang W, Lang M, Kornhuber A, Kornhuber HH. Electrophysiological evidence for right frontal lobe dominance in spatial visuo-motor learning. Arch Ital Biol 1986;124:1–13. Lang M, Lang W, Uhl F, Kornhuber A. Patterns of event related potentials in paired associative learning tasks: Learning and directed attention. In: Maurer K. (ed): Topographic brain mapping in EEG and evoked potentials. Heidelberg: Springer, 1989:323–325. 51. Kornhuber HH. Attention, readiness for action, and the stages of voluntary decision. Exp Brain Res 1984; Suppl. 9:420–429. 52. Kornhuber HH. Wahrnehmung und Informationsu¨bertragung. In Die Psychologie des 20. Jahrhunderts. Band VI (Stamm RA & Zeier H eds.), Kindler, Zu¨rich, 1978:783–798. 53. Heckhausen H. Perspektiven einer Psychologie des Wollens. In: Heckhausen H, Gollwitzer PM, Weinert FE. (Hg.): Jenseits des Rubikon: Der Wille in den Humanwissenschaften. Berlin, Heidelberg: Springer-Verlag, 1987:121–142. 54. Heckhausen H, Gollwitzer RM, Weinert FE (eds.) Jenseits des Rubikon. Der Wille in den Humanwissenschaften, Berlin: Springer, 1987. 55. Roth, G. (2001): see 30. 56. see 15 57. see 25 58. Kornhuber HH, Fu¨chtner J. More than tenfold increase of alcoholism in women since 1968. Neurol Psychiat Brain Res 1992;1:46–48. 59. Kornhuber HH. Pra¨ventive Neurologie. Nervenarzt 1983;54:57–68.


MAIN THEME: PERSONALITY DISORDERS Neurobiological underpinnings of personality disorders Hans-Peter Kapfhammer Clinic of Psychiatry, Medical University of Graz, Graz, Austria Introduction: Modern psychiatry favours a multifactorial model of personality and personality disorder stressing close interactions of neurobiological and psychosocial influences. Currently, categorical and dimensional models are being passionately discussed for revisions of diagnostics of personality disorders in future systems of classification. This revision may have important consequences. A traditional categorical approach to study neurobiological factors in the aetiopathogenesis of personality disorder has been meeting many difficulties so far. To conceptually and methodologically differentiate character as the result of a complex process of social learning, and temperament as the neurobiological fundament of any personality may be considered a first step out of this dilemma. The well-known psychobiological model of personality by Cloninger et al. (1) conceptualise temperament according to four basic dimensions of personality, novelty seeking, harm avoidance, reward dependence, and persistence. Individual tendencies in various dimensions may form the neurobiological underpinnings of typical personality and personality disorder. A major system of neurotransmitter has been linked to each dimension of temperament in theoretical terms leading to differential psychopharmacological hypotheses in the case of a discrete personality disorder. Although some empirical findings support some clinical utility of this model, the neurobiological hypotheses have not been empirically validated (5). Another methodological approach is about to identify some endophenotypes in major dimensions of personality being linked to underlying genotypes that influence the traits and dimensions of personality disorders, as well as susceptibility to major psychiatric illnesses. Clinical dimensions of personality disorders that lend themselves to the study of corresponding endophenotypes include affective instability, impulsivity, aggression, emotional information processing, cognitive disorganisation, social deficits, and proneness to psychosis (4). Research data on the neurobiology of personality disorders: For the time being, research data on the neurobiology of personality disorders may best be presented within the framework of DSM-IV clusters of personality disorders (2). Each cluster may be conceptualised in terms of discrete dimensions that might turn out as promising endophenotypes (Table 1). Cluster A Neurobiological research in cluster A first and foremost refers to schizotypal personality disorder within a concept of schizophrenia spectrum disorders. Here it focuses on pathological alterations within the cognitive–perceptive organisation and underlines typical socio–affective deficits, neurocognitive dysfunctions, psychotic-like disturbances of perception and thinking. 1) Patients with schizotypal personality disorders are basically hampered in the processing of important social information that essentially forms a theory of mind. Deficits in social perception can be reliably measured by neuropsychological tests. The deficits seem to be more subtle than in schizophrenic patients, but importantly

Table 1. Endophenotypes in personality disorders (5). DSM-IV Cluster

Dimensions

Cluster A disorders

social deficits psychotic-like perceptual distortions cognitive impairment

Cluster B disorders

impulsivity aggression affective instability emotional information processing

Cluster C disorders

anxiety / behavioral inhibition compulsivity

contribute to the clinically well-known eccentricity and profound interpersonal difficulties of schizotypal patients. In various neuropsychological performances combined with neuroimaging methods (PET, SPECT, fMRI), schizotypal patients take a medium position between normal control persons and schizophrenic patients. In tests measuring executive functions, learning or working memory, they less activate dorsolateral prefrontal cortex than control persons, but significantly stronger than schizophrenic patients, and in addition activate other areas of the anterior frontal cortex (BA 10) for compensation. They show structural reductions in the temporal lobe in an amount as schizophrenic patients do, but less pronounced reductions in the frontal cortex, whereas schizophrenic patients demonstrate major volume reductions in both cerebral regions. 2) Dopamine system may play a decisive role in the susceptibility to psychotic-like symptoms of perceptions and thoughts. Measures of HVA, the end-metabolite of dopamine in CSF positively correlate with psychometric scores of perceptual and cognitive distortions. In pharmacologic challenges, e.g. with amphetamine, schizotypal patients show a stronger response than control persons, but a less pronounced response than schizophrenic patients do. Their mitigated response may be in line with neuroimaging findings of reduced striatal volumes that are considered a protective factor against full-blown state of psychosis. Molecular–genetic investigations hint to a probably important polymorphism of COMT underlining the basic influence of dopamine system on the one hand, linking to major neurocognitive functions as working memory on the other that quite likely are regulated, however, by various other neurotransmitter systems as e.g. norepinephrine. Cluster B Essential characteristics of this cluster of personality disorders affect impulsivity, aggression, emotional regulation and emotional information processing. Neurobiological research is more or less exclusively based on borderline personality disorder. Affective instability and impulsivity turned out to be as basic personality dimensions in BPD demonstrating a relative stability in time. In addition, a tendency to dissociation under psychosocial stress and trauma is considered another typical personality dimension marking a special mode of emotional and cognitive information processing. Affective instability comprises an increased general emotional responsivity with reduced thresholds for emotional stimuli on the one hand, and high intensity of emotional expression and heavily reduced recovery to initial levels of affectivity on the other. Affective instability in


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BPD may contribute to the frequent cycles of easily escalating aversive affects combined with embarrassing feelings of interior tension, often leading to self-destructive behavioural acts as suicide attempt, self-harm, bulimic attack, episodic excess consumption of alcohol and drugs. There seems to be a close interconnection between affective instability and impulsivity. 1) Emotional dysregulation and impulsivity hint to disordered neuronal circuits of limbic over-activation and prefrontal cortical under-control. Various results from functional and structural neuroimaging studies may be interpreted under the hypothesis of a reduced ’’top-down’’ regulation or under the hypothesis of an increased ’’bottom-up’’ regulation. Both aspects of neuronal regulation may be linked to genetic predisposition and aversive and traumatic experiences during early social development as well. Various neurotransmitter systems are involved from this perspective. 2) A close relation of serotonergic dysfunction and impulsivity contributing to clinical states of anger and reactive aggression is established on several methodological levels of investigation, as e.g. neuroendocrine / neurochemical provocation tests, radio-labelled binding studies in peripheral thrombocytes, functional neuroimaging methods combined with pharmacological challenges, and molecular– genetic investigations. Serotonergic dysfunction seems to be especially related to the mode of impulsivity that mediates the significantly increased risk of suicide during the long-term course of BPD. 3) During emotional turmoil patients with BPD very often show various dissociative symptoms in an impressing way. Both the heterogeneous clinical phenomenology of dissociation and the underlying neurobiological mechanisms seem to be highly complex and are most favourably discussed within the context of trauma and post-traumatic processing. Cluster C Anxiousness, anxiety, harm avoidance, behavioural inhibition, and compulsivity define the core traits of cluster C personality disorders. Again, neurobiological research is primarily focused on one variant of cluster C, i.e. anxious-avoidant personality disorder, whereby the main methodological approach is in accordance with social phobia, generalized type. Implicitly, an identity of generalized social phobia and anxious-avoidant personality disorder is assumed from a nosological point of view. Besides, empirical investigations of anxiousness as a general dimension of personality seem to be of clinical relevance. 1) A general biological preparedness to anxious affects refers to a close functional interface of brain stem, limbic, and cortical structures. The amygdale seems to be the control centre of fear, panic and anxiety reactions and plays a basic role in the encoding and regulation of fear-based memories. Two neuronal circuits are at disposal to react adaptively in the face of menacing dangers. These circuits are closely interconnected differing, however, regarding velocity and cognitive differentiation of information processing. Various systems of neurotransmitters and neuropeptides are involved in the regulation of fear and anxiety, among which the GABAergic, noradrenergic, sertonergic und glutamatergic systems play a major role. In neuroimaging findings an amygdalar over-activity with a concomitantly insufficient modulation by the prefrontal cortex is stressed. Besides, other important centres as insula (visceral-autonomic perception), anterior cingulated cortex (emotional evaluation) or dorsolateral prefrontal cortex (working memory, response selection, response preparation) take part in the mediation of fear reactions. 2) Molecular–genetic investigations stress some interesting links to a general disposition of anxiety. Some results identified a susceptibility gene on chromosome 4q21 that is near a locus encoding neuropeptide Y. Glutamic acid decarboxylase-gene 1, Dopamine D2 receptor gene, and a COMT-polymorphism may also play a significant role in anxiety responsivity. A significant association between the general dimensions of neuroticism and trait-anxiety on the one hand, and a short-allele variant of

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serotonin-transporter-gene has been stressed. Carriers of shortallele show enhanced amygdale-mediated reactions to the presentation of fearful faces in fMRI. This short-allele polymorphism may play a major role in decoupling the amygdalar circuit from important modulating influences by the prefrontal cortex and the anterior cingulated cortex. Future research projects will focus more closely on genetic dispositions and stressors of the social environment playing together in critical periods of early development. 3) In special line with the neurobiology of generalized social phobia a sensitization both of the amydalar fear/panic system and an anxiety-mediating system via the bed nucleus of stria terminalis may be important. Both reaction systems must be considered within a long-term development of a presumably genetically determined temperament of behavioural inhibition, shyness and avoidance throughout the stages of childhood, adolescence and early adulthood. From a perspective of neurotransmitter systems, major alterations in the dopamine system are involved among dysfunctions in other neurotransmitter systems. 4) So far, it is still a matter of controversy whether neurobiological findings in obsessive–compulsive disorder may directly apply to compulsive personality disorder, in direct analogy of generalized social phobia and anxious-avoidant personality disorder. Neurobiology-based consequences for the treatment of personality disorders:The clinical importance of results derived from neurobiological investigations of personality disorders may be assessed in some promising psychopharmacological approaches to the treatment of personality disorders. Empirical data from a series of randomized controlled trials meanwhile allow some tentative recommendations of differential psychopharmacology for the psychiatric practitioner (Table 2). Table 2. Psychopharmacological approaches with some empirical evidence of efficacy in distinct symptom clusters of personality disorders (2,3) Cognitive–perceptive ''Psychosis-like symptoms'' atpyical antipsychotics Symptoms Dissociative symptoms no EbM-recommendation opiate-antagonists: effects shown only in open trials with depersonalisation Impulsivity 1. topiramate 2. SSRI (fluoxetine; male patients) valproate (female patients; consider: gender-specific side effects) 3. atypical antipsychotics to avoid: benzodiazepines, tricyclics, polypharmazy Emotional Affektive instability 1. SSRI (fluvoxamine) Dysregulation 2. valproate Depressive mood 1. atypical antipsychotics (without major (olanzapine) depression) 2. MAO-inhibitors to avoid: tricyclics, carbamazepine Anger, hostility, 1. topiramate, valproate irritability 2. atypical antipsychotics Anxiety 1. atypical antipsychotics 2. SSRI, SSNRI 3. MAO-inhibitors to avoid: long-term use of benzodiazepines

References: 1. Cloninger CR, Svrakic DM, Przybeck TR. A psychobiological model of temperament and character. Arch Gen Psychiatry 1993;50:975–990.


2. Kapfhammer HP. Perso¨nlichkeitssto¨rungen – Diagnostische Konzepte, Neurobiologie, Pharmakotherapie. Psychiatrie Psychotherapie 2008;4:37–57 3. Rinne T, Ingenhoven T. Pharmacotherapy of severe personality disorders: A critical review. In: van Luyn B, Akhtar S, Livesley WJ (eds.) Severe personality disorders. Cambridge University Press, Cambridge, 2007, pp. 137–163. 4. Siever LJ. Endophenotypes in the personality disorders. Dialogues Clin Neurosci 2005;7:139–151 5. Whittle S, Allen NB, Lubman DI, Yu¨cel M. The neurobiological basis of temperament: Towards a better understanding of psychopathology. Neurosci Biobehav Rev 2006;30:511–525

Causes, diagnoses and treatment of post-traumatic stress disorder Dragica Kozaric´-Kovacˇic´ Department of Psychiatry, Dubrava University Hospital, Referral Center for Stress-related Disorders of the Croatian Ministry of Health and Social Welfare, Regional Center for Psychotrauma, Zagreb, Croatia Post-traumatic stress disorder (PTSD) is an anxiety disorder that can develop after experiencing or witnessing a life-threatening event, such as accident, disaster, war trauma, violence or abuse (family, sexual, physical, and/or psychological), or any situation that seriously threatens the integrity of a person. The disorder, however, does not develop in every person exposed to traumatic experience. Stress results from an interaction between the mind and the body. The brain is the organ that determines reaction to stress as it decides on what is stressful and controls biological and physiological responses to stress. These responses vary from one person to another due to differences in their biological, genetic, environmental, and psychological characteristics, as well as their personal history. Stress causes neuroanatomical and neurochemical changes in the brain. Early traumatic experience (eg, abuse or severe neglect in childhood) may affect the brain structures and functions so as to make a person vulnerable to negative stressful events and more prone to later development of PTSD or other anxiety-related disorders. A particular genetic profile also plays a role in vulnerability or resilience to stress. For example, individuals with a short ss allele of serotonin transporter are more vulnerable to depression and PTSD, especially if they had early traumatic experience. A long-term dysregulation of cortisol and noradrenalin, the main stress mediators, favors the development of different anxiety disorders, including PTSD. Stress-induced changes in hippocampus (atrophy), amygdales (volume reduction), and prefrontal cortex are also frequent findings in patients with these disorders. The neurobiological changes in the brain, which result from dysregulation of noradrenergic, serotoninergic, dopaminergic, and other neurotransmitter systems, provide the basis for psychopharmacologic treatment of patients with PTSD. The evaluation of different biomarkers might facilitate a goal of the modern medicine, a proper treatment for an individual patient at a given stage of disease. This is especially important in PTSD, a disorder with complex clinical picture, diverse symptoms, and different comorbidities. PTSD was officially proposed as separate diagnosis in DSM-III, although the clinical consequences of trauma were recognized since ancient times. After its identification in DSM-III, the neurobiology of chronic PTSD has been area of increasing investigation. Earlier the psychoanalytic model of explanation and treatment mostly prevailed. Epidemiological studies show high prevalence of PTSD in general population and specific groups exposed to the traumatic events (survivors of war trauma, natural disasters, terrorist attacks, etc.). Trauma and its consequences affect significantly individual health and functioning, and whole society. The diagnosis of PTSD

may have several subtypes, including psychotic symptoms, depending upon pre-existing psychiatric disorder, trauma severity and duration, comorbidity, post-trauma social environment, etc. The role of trauma as an etiological factor in other psychiatric disorders and symptoms remains to be clarified. Complex neurobiological changes triggered by such a traumatic and stressful experience may explain a wide range of PTSD symptoms and provide the rationale for psychopharmacological treatment. Selective serotonin-reuptake inhibitors make the firstline treatment of PTSD. Clinical experience has shown that they are more effective than noradrenalin-reuptake inhibitors or tricyclic antidepressants. Antipsychotic drugs, especially atypical ones, have been shown effective in PTSD patients with psychotic characteristics or refractoriness to other treatments. Mood stabilizers seem to reduce mostly autonomous overreactions to stress, whereas the evidence for effectiveness of monoamine oxidase inhibitors is largely inconclusive. Other groups of medications, such as serotonin agonists and antagonists, new antidepressants, dual inhibitors of serotonin- and noradrenalin-reuptake, anticonvulsants, and opiate antagonists are also sometimes used in PTSD treatment. However, as shown in the present article, most clinical studies performed to date to investigate the effectiveness of different psychopharmacological agents in the therapy of PTSD have serious limitations in terms of small sample size, lack of blinding and randomization, and small effect size. More rigorously designed, comparative studies are needed to determine the usefulness, efficacy, tolerability, and safety of particular psychopharmaceutical drugs in the treatment of this therapeutically and functionally challenging disorder. One group of medications is often not enough for the treatment of all the PTSD symptoms, especially in cases where PTSD is comorbid with depression, alcoholism, borderline personality disorder, or psychotic, panic, or other disorders. Irrespective of the different mechanisms of action of drugs used in the treatment of PTSD, the final goal is always the same – to reduce distress, reinforce the psychological defense system, and restore the functioning of the person. However, evidence from controlled clinical trials showing the effectiveness of pharmacotherapy in PTSD is still unsatisfactory.

Anxiety disorders: causes, diagnosis and treatment Jrgen Deckert Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wrzburg, Germany Causes: Anxiety disorders are complex disorders. Environmental and genetic factors equally contribute to their pathogenesis. In the first half of the last century, on the basis of Freud’s concept of anxiety neurosis, environmental factors such as life events in childhood and adolescence have been stressed as pathogenetic factors. They include separation from parents or spouses by death or divorce, experiences of physical or sexual violence and physical illness. Based on Klein’s observation that some forms of anxiety neurosis can be successfully treated by antidepressants, biological factors have been given more attention in the second half of the last century. Twin and family studies provide evidence for a major contribution of genetic factors. Linkage and association studies point to candidate loci such as chromosomes 13q and 22q as well as candidate genes such as serotonergic and noradrenergic genes. Genomewide association studies, due to their hypothesis-free approach, will help to identify new genes and new pathophysiological pathways. The contribution of each factor, however, will be minor and explain only a few percent of the variance. Research efforts such as the DFG-funded special research network TRR58 on ’’Fear, Anxiety and Anxiety Disorders’’ utilizing endophenotypes (imag-


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ing genomics, pharmacogenomics) as well as animal models (knockout mice) will enhance our understanding of the complex interplay between environmental and genetic factors in the context of fear and anxiety networks including among others the amygdale and the prefrontal cortex. Diagnosis: Anxiety disorders like other mental disorders are defined as categories. IDC-10 and DSM-IV differentiate panic disorder with and without agoraphobia, generalized anxiety disorder, social phobia and specific phobia. Sometimes and in particular in the American literature post-traumatic stress disorder and obsessive-compulsive disorder are also added to the anxiety disorders although they show clearly distinct features from the other core anxiety disorders. Diagnosing an anxiety disorder warrants careful exclusion of somatic disorders imitating anxiety disorders. These include hyperthyreosis, certain arrhythmias, epilepsies and vestibular disorders among others. In addition to a careful physical examination therefore an electrocardiogram, an electroencephalogramm and a routine blood test including thyroid parameters should be performed. Depending on the results further tests such as a 24hour electrocardiogram, a 24 hour electroencephalogram, a cCT and/or a cMRT and a drug screening may become necessary. Occasionally, a real comorbidity may exist between anxiety disorders and certain somatic disorders such as arrythmias and asthma bronchiale. As anxiety may be a symptom also in other mental disorders, unias well as bipolar depressive disorders and somatoform disorders in particular have to be considered as alternative diagnoses. As with somatic disorders there may be true comorbidity with these disorders and also secondary substance abuse disorders which will effect treatment strategies. Structured interviews such as the SCID or the CIDI may be helpful in differentiating them. Rating scales such as the HAMAS or the PAS allow to semiquantitatively define the severity of the anxiety disorder. In addition to establishing the categorical diagnosis it is important to define personality, cognitive and coping features of the individual patient as they will be important in designing an individually tailored therapy. Equally important are informations on the present life situation and the personal history (life events) in particular with regard to the nature of relations to family members as they are also important for designing the therapy. Treatment: As in some anxiety disorders such as panic disorder the patient has a somatic concept of the disorder based on its predominantly somatic symptoms, the first and most important treatment step is to develop a common psychosomatic concept of the etiopathogenesis of the disorder. Helpful models are the stressvulnerability and the anxiety circle models. The need to spend enough time for this step cannot be overstressed. Once this has been achieved, the therapy of choice in the treatment of anxiety disorders today is cognitive behavioural therapy. Numerous studies have proven its efficacy and numerous manuals for the individual anxiety disorders have been developed. The core element seems to be exposure to the fear inducing subject, object or situation. Research efforts such as the BMBF-funded PanicNet focus on the question if this is indeed so, and if yes, which form of exposure is more effective. Exposure in sense in generalized anxiety disorder or in sensu in agoraphobia. Modifications with a greater focus on cognitive strategies and a gradual exposure have to be applied in the elderly and the case of true comorbidity with certain somatic disorders. Cognitive behavioural therapy may be administered as more intensive individual therapy or as less intensive group therapy. The latter may be a good complement in particular in the case of social phobia. In some instances, e.g. blood-injury phobia additional treatment elements may be necessary. Psychodynamic therapy elements may be helpful in secondary prevention. Among pharmacological approaches, treatment with selective serotonergic antidepressants is considered the treatment of choice. As, however, they may cause a worsening of symptoms prior to

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symptom reduction, their medication must be preceded by a careful information of the patient of their undesired effects. In general, in comparison with the treatment of depressions, uptitration should be slower and the maintenance dose lower. In particular in the case of comorbidity with depression, sedating antidepressants may be helpful. The use of benzodiazepines should be restricted to emergency situations because of their liability to the development of abuse and dependence. High-potency typical antipsychotics should not be administered because of the risk of tardive dyskinesia. A matter of controversy over the years has been the comparative efficacy and the combination of cognitive behavioural psychotherapy and pharmacotherapy with antidepressants. While convictions are strong, data are few. Those which exist seem to indicate that while pharmacotherapy has a faster, psychotherapy has a longerlasting effect. The combination, if necessary in severe cases, seems to have advantages by combining a faster effect without compromising a long-lasting effect. Questions like these are topics of discussion of committees for treatment guidelines such as the S3guideline currently being developed in Germany. Nevertheless, there seems to be emerging a consensus that while effective in many cases, cognitive behavioural therapy with exposure as core element may have to be complemented in severe cases by other therapy elements individually tailored to the individual patient. References: 1. Zwanzger P, Deckert J Angsterkrankungen – Ursachen, Klinik, Therapie. Nervenarzt 2007;78:349–360. 2. Domschke K, Deckert J Genetik der Angsterkrankungen, Nervenarzt 2007;78:825–35.

On psychodynamics of personal value-judgements – Nietzsche¢s theory of resentment and its reception by Karl Jaspers and Kurt Schneider Matthias Bormuth Institute of Medical Ethics and History of Medicine, University of Tbingen, Tbingen, Germany Abstract: A hundred years ago when Karl Jaspers was introducing psychological understanding to psychiatry the founder of the school of Heidelberg spoke of Friedrich Nietzsche as one of the ’’greatest’’ psychologists. Especially his theory of resentment with its core thesis unconscious prejudices were influencing our behaviour was able to illuminate the complex structure of human will. Taking into account this horizon of psychiatric history of ideas the presentation wants to persecute the following three questions: 1) Why the postulate which Nietzsche was giving on cultural prejudices of our thoughts, feelings and acts was so provocative so that many of the classical thinkers of psychological understanding were taking it up according to the needs of their disciplines sociology, psychology, psychiatry and philosophy? 2) What were the results of this inspiring theory which could be especially seen in the works of Karl Jaspers and Kurt Schneider? In other words: What were the aspects in which they agreed in their reception of Nietzsche and what were the points in which the two psychiatrists of the school of Heidelberg differed in the way they took the theory of resentment into account for their psychological understanding? 3) What could be the actual significance of the historical fact that Nietzsche and in his footsteps Max Weber were taking deep influence on psychiatric thinking around 1900? Introduction: A hundred years ago when Karl Jaspers was introducing psychological understanding to psychiatry the founder of the school of Heidelberg spoke of Friedrich Nietzsche as one of the ’’greatest’’ psychologists (1,2). Especially his theory of resentment with its core thesis unconscious prejudices were influencing our thoughts, feelings and acts was able to illuminate the complex structure of human will. The freedom was not only dependent on natural reasons but had also to be thought as


influenced by its biographical and cultural conditions. With the help of Nietzsche¢s viewpoint on personal value-judgements it was possible to put into perspective the biological determinism which was the leading trend of psychiatry at that time. At the same time arises the question which psychodynamic meaning the cultural and biographical impressions do have when being related to personal value-judgements of the scientist. That the young Jaspers took an eye on Nietzsche whether the philosopher stood academically in the twilight of his late mental illness and whether the most of the psychiatrists just took his works as pathographic material (3,4) is astonishing and can only be understood by the influence of Max Weber (5). The methodological teacher of Jaspers who was one of the founders of cultural sciences had introduced the theory of resentment as an important element of scientific understanding (6). He himself was inspired by the American psychologist and philosopher William James who had already established the interdisciplinary dialogue between natural and cultural sciences. His Gifford-lectures The variety of religious experiences were counting on Nietzsche¢s insight that unconscious motives of biographical and cultural kind were influencing the personal value-judgements (7). The third inspiration which was forcing Jaspers to be keenly aware of Nietzsche was Max Scheler with his impressing little work On Resentment and moral judgement (8) and the greater essay Resentment in the Structure of Morals (9). From Scheler it is not far to Kurt Schneider who had written his philosophical dissertation Pathopsychological Tribute to the Psychological Phenomenology of Love and Sympathy (10) under his observation and who felt at the same time as a psychiatric scholar of Jaspers. The study was published in 1921 in a psychiatric journal unrolling his theory of understanding in case studies and keeping relatively distant to Nietzsche. Taking into account this horizon of psychiatric history of ideas the presentation wants to persecute the following three questions: 1) Why the postulate which Nietzsche was giving on cultural prejudices of our thoughts, feelings and acts was so provocative and touching so that many of the classical thinkers of psychological understanding were taking it up according to the needs of their disciplines sociology, psychology, psychiatry and philosophy? 2) What were the results of this inspiring theory which could be especially seen in the works of Karl Jaspers and Kurt Schneider? In other words: What were the aspects in which they agreed in their reception of Nietzsche and what were the points in which the two psychiatrists of the school of Heidelberg differed in the way they took the theory of resentment into account for their psychological understanding? 3) What could be the actual significance of the historical fact that Nietzsche and in his footsteps Max Weber were taking deep influence on psychiatric thinking around 1900? Historical outline: In order to be able to understand the meaning which Nietzsche had for cultural sciences and psychiatry one cannot hinder firstly to speak of Charles Darwin. As it has often been said and written – especially in this year of his remembrance – the private scholar Darwin was bringing a revolution to scientific thinking by inventing the theory of evolution. For by his sharp and deep insights the great hypothesis of the Creator was crashing down and the human being seemed to be just by accident a chain link in the development of living beings in the same way forced to obedience to natural laws of selection in the struggle for existence as every other animal. Freud¢s enthusiastic cry which claimed in the year 1875 Darwin to be the ’’most modern saint’’ (11) of natural sciences can be taken as a significant example for the mood in which the disenchantment of the world – to speak with Max Weber – had set most scientists of the time. Whether the young Nietzsche also showed himself deeply impressed by the thoughts of Darwin speaking in the year 1877 of the possibility that he might have the opportunity to meet the famous scientist in England he was really shocked by the disenchanting result of the theory of evolution (12). In

opposite to Freud he spoke of the ’’horrible consequence of the Darwinism’’ which was responsible for the great loss of absolute values (13). Very clearly Nietzsche recognized that the theory of evolution implicitly was showing the philosophical pattern of biological perspectivism. This form of bringing higher ideas down to relativism by showing their natural genealogy was also the reason why Darwin himself was driven to the decision as he wrote in his autobiography My life to give up his religious believe of a creating God and to interpret the Christian ethics only as a useful tool in the struggle for existence (14). But Nietzsche was taking a sceptical view on the ’’genealogy of human being’’ of which Darwin spoke in On the Origin of Man (15) because the standpoint of the book seemed to him to be taken from the position of biology. Therefore he was criticising his close friend Paul Reé who showed himself totally inspired by Darwin while searching for a natural origin of moral emotions (16). Nietzsche took an alternative path. According to his book Genealogy of Morality he was searching for the ’’real history of morality’’. This historical investigation was supposed to be totally different from the biological perspective of the Darwinian ’’genealogist of morality’’ whether her character should not be less disenchanting. On the contrary: Nietzsche¢s hermeneutical ambition which wanted to bring the ’’hardly readable hieroglyphs of the moral history of mankind’’ to a clear sense also was following a radical claim of criticism in order to destroy illusionary thoughts on godly values (16). The only difference to Darwins approach was that the higher ideas should be shown in their nakedness as psychologically born out of the certain interests to be used as moral weapons against stronger enemies in the cultural struggle for existence. In other words: Nietzsche wanted to amplify the biological viewpoint of Darwin by the cultural dimension being even more ambitious in disenchanting the Christian god and his absolute morality by scientific arguments. This special reception of Darwin can be seen in Nietzsche¢s core statement of anthropology. It can also be found in the Genealogy of Morality where Nietzsche declares that man is an ’’animal without definite determination’’ and that therefore his behaviour cannot be understood alone by interpreting him in terms of instincts which give other animals a definite structure: ’’Man is more sick, more insecure, more irritable, less determined as any other animal, no doubt, – he is the sick animal.’’ (16) Man as a cultural being which is privileged by a widely opened horizon of possible thoughts, feelings and actions is even able to draw extreme decisions, so one has the relatively free choice for suicide or a meaningful conduct of life. According to Nietzsche these opposite patterns of behaviour bring strongly and exemplarily to evidence that man is able to live in a consequent – joyful or desperate – search for a higher meaning of life. This view was not part of the perspective of the biological utilitarism of Darwin and his time forcing Nietzsche to a polemic aphorism: ’’Does one have a why to live one can endure every how. – Man does not pursuit happiness; only English men do so.’’ (17) The anthropological viewpoint that man is an ’’animal without definite determination’’ was taken by Karl Jaspers as a premise of his psychology of understanding. Therefore he saw the philosopher as an outstanding philosopher of exposing human value-judgements who was able like nobody else to demonstrate how human ideas were rooted in biographical and cultural interests (18). The theory of resentment can be seen as a special history of exposing. Therefore the Christian idea of altruism and justice are shown as results of the unconscious wish to fight successfully as a poor slave against the powerful roman oppressors by postulating these ideals (16). Jaspers was fascinated like Weber, James and Scheler before him by this outline of deep psychology although for him Nietzsche¢s interpretation of the genealogy of Christian ideas was just one possible interpretation of this moral phenomenon.


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The attraction of Nietzsche and his theory of resentment since 1900 can be summed up as follows: His critical genealogy of morality has to be seen in the tradition of scientific disenchantment which strongest impulse was Darwin¢s theory of evolution. The special attention which Nietzsche found in the humanities and cultural sciences was a result of the complexity of his horizon of thinking. The perspective of biological functionality is combined by him with the anthropological viewpoint of man as an ’’animal without definite determination’’. This means: A human being is able to create higher ideals in order to compensate personal weaknesses in the struggle for existence. Therefore the disenchantment of the world and the human necessity of developing moral ideas were both part of his anthropological thinking. Therefore his theory of resentment was so attractive to liberal thinkers which were not living anymore in peace with the traditional believes but were still convinced that one still must have a viewpoint beyond biology. Nietzsche¢s reception by Jaspers and Kurt Schneider: Now we want to answer more closely the question how this theory of resentment which claimed to expose the Christian morality by psychological means was adapted in the fields of cultural sciences and psychiatry around 1900. While Freud – forced by his atheistic believe – was driving the strategy of exposing forward showing psychoanalytically that all religious believe and moral values were wishful projections of powerless people beaten by misery (19). Max Weber, William James, Jaspers and Kurt Schneider were reading Nietzsche differently. The cultural scientist Weber was judging the theory or resentment as a revolutionary insight into the unconscious roots of human thought, feeling and acts which could find different interpretations according to the cultural horizons of the understanding person. Against Freud and his school he was claiming that human beings could not be caught in the net of one single theory which demands to bring exclusively the explanation for the human psychodynamics of creating meaning in life (6). The view which William James developed in his famous lecture The Variety of Religious Experiences on Nietzsche can be read as close to Weber¢s sight. The pragmatic psychologist and philosopher also took the evidence of unconscious prejudices for granted declaring that they were rooted also in patterns of character, biology, biography and cultural surroundings. Therefore the critical interpretation of the Christian ressentiment was just one possibility for him. Also it could be thinkable that the ideal of altruism and justice was held up by a strong personality in an impressing life conduct of holiness (7). Jaspers is taking the perspective of Weber and James in general by pointing out how important the theory of resentment is for all psychology of understanding and by focussing their criticism that the narrow view on Christian morality is just one possible way of understanding next to other interpretations of the genealogy of Christian ideas. As a concrete correction of Nietzsche¢s standpoint he mentions Max Scheler and his impressing essay On Resentment and Moral Value-judgement (1, 8). In later years his philosophical studies deepen his psychiatric reception. Nietzsche is seen by Jaspers as a psychologist of suspicion who sheds twilight of psychological genesis on all values of absolute meaning. Although he estimates like Weber and James the plurality of perspectives he ends up with a more conservative idea of Nietzsche. So Jaspers claims that the relativity of all value-judgements were not the ultimate opinion of Nietzsche. He postulates that the attitude of exposing everything is just the outside of the deeper search for something like a hidden god or a form of transcendence which both cannot be expressed in cultural terms of a certain ’’Weltanschauung’’. Consequently Jaspers is interpreting Nietzsche¢s radical criticism of Christianity psychologically as an unconscious notion of hating himself (18). Also Kurt Schneider is holding in his philosophical dissertation a more conservative position than Weber or James. In opposite to Jaspers he is not showing any sympathy with Nietzsche¢s thinking

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of plurality. On the contrary: He is criticising this modern attitude with Max Scheler. Taking the Christian phenomenology of altruism and sympathy for granted Schneider gives some casuistic demonstrations so that one may recognize the pathological aspects in each of them. According to this program Schneider draws the consequence and neglects any need of the genetic understanding as Jaspers proclaims it as necessary. So he keeps a greater distance to Nietzsche pointing out that psychology should be limited by the ’’static understanding’’ which means pure description of psychic experiences (10). The relatively close views which Jaspers and Schneider take in their receptions of Nietzsche¢s theory of understanding reflect also their personal and scientific dialogue which was initiated by changing words of sympathy in this topic. So Schneider asked in January 1921 Jaspers successfully whether he could dedicate to him his philosophical dissertation on the Christian ideals which had led to Nietzsche¢s analysis on resentment (20). How much Jaspers who was already famous as a psychiatrist and now on his way to establish himself in Heidelberg as a philosopher was estimating Schneider as a coming psychiatrist can be seen by the sentence of Nietzsche which he quoted in his answer: ’’I listen for resonance but all I hear is affirmation.’’ Also he seemed to have known already by intuition that Schneider would step later in his footpath by leading the psychopathologic school of Heidelberg: ’’The greatest joy of a working spirit is in thinking of the work which the others will do in later times.’’ (16) Maybe not just by accident this quotation is taken out of the works of Hippolyte Taine. Hence with the French historian of culture one can close the circle of arguments which connects Darwin and Nietzsche since Taine was combining the biological and historical viewpoint on human freedom (20). Current dimension: At the end it has to be asked what may be the current use of such a short outline of history of ideas which wants to show how the beginning of the psychiatric school of Heidelberg is connected to Nietzsche¢s theory of resentment? Without doubt: a person with a historical interest could be satisfied with this depiction since it may give him some new ideas and more details on their genealogy. But this antiquarian interest – to speak with Nietzsche – will surely not be enough for one who is taking the viewpoint of a conference of neuropsychiatry. The only way the critical function of writing psychiatric history may be useful is in provoking methodological suggestions. These are bound to the question which implication the psychological understanding as a tool of cultural sciences could have in contrast to the common opinion all knowledge should certainly be ’’objective’’ which means not bound to the historical change of subjective standpoints and personal value-judgements. The presentation started with the historical fact that especially the theory of resentment belongs to a tradition of enlightenment which was mainly pushed by the theory of evolution and whose aim was the disenchantment of the world. Darwin was destroying by his biological genealogy the religious belief that man is a determined entity because human beings were shown as being just a chain link in the series of changeable animals. Nietzsche was more than just Darwin¢s successor. In taking away the deep conviction that there are absolute values by developing his genealogy of morality he did something different in the field of the humanities. He could lift the perspective beyond the horizon of biology and open the eyes for the fact that man created ideas in order to have cultural weapons in the struggle for existence. In other words: The biological perspectivism of Darwin as well as the historical perspectivism of Nietzsche lead to the deeper insight that human freedom is limited and relative since it is depending on nature and history. Hereby Nietzsche¢s insights can be seen as a critical addition to the biological viewpoint. The notion that man and his morality are relative and changeable according to their genealogy does also affect the status of cultural


understanding itself. Jaspers was still taking for granted that the psychological approach admitted to take a standpoint above the changing of the moral standards of the time. He was not fully aware of the insight of Nietzsche¢s theory of human resentment which meant that all scientific understanding is impressed by unconscious prejudices. His believe was still that there is a scientific objectivity even in describing psychopathological phenomena. Only as philosopher of existence Jaspers was reflecting on the impossibility to bypass the problem of moral plurality and historical perspectivism in cultural life. Therefore he was giving some deep considerations in the last edition of the General Psychopathology concerning the fact that the borderline between disease and health is often drawn by subjective notions (1). One can say: The late Jaspers is taking into account the dilemma of valuejudgements which arises in every understanding science. But he was relegating the problem from the core of psychiatry when postulating that it were just a question of private and existential interest not worthwhile to be discussed as a matter of serious science. Kurt Schneider took the same decision even stronger and banished all forms of genetic understanding since his beginnings from the psychopathological approach to disease. For him the reflections on moral plurality and historical perspectivism which Jaspers gave in the General Psychopathology were not necessarily part of the book. Schneider remained with his first intuition that it would have been the right decision not to trespass the border of static understanding. According to his teacher Max Scheler and in contrast to Nietzsche he was assuming that there is a sphere of absolute values. Therefore the theory of resentment was just acceptable for him in the revised version of Scheler. And hence it is not surprising that Schneider was cultivating since his early years in Cologne the friendship with Nicolai Hartmann, a philosopher who also had developed a philosophy of absolute values which cannot be touched by natural or historical conditions. Accordingly Schneider was taking psychiatry all in all as an objective science whose subjective aspects could only be managed partly by a close form of psychopathological descriptions. All cultural aspects were out of bounds for the serious scientist. Nietzsche¢s insight that personal value-judgements influence our way of understanding caused Schneider to the ascetic decision to close up the path of understanding from any genealogical perspective. The fact that Jaspers was taking Nietzsche more deeply into account by following his disenchanting genealogy of moral convictions can be seen as a result of the influence of Max Weber. His reception of the theory of resentment was radical in terms of cultural sciences. The insight into the historical changes of moral judgements led Weber to a methodological demand: All sciences like history, sociology or psychiatry which were ambitious of human understanding should reflect that their premises are changing their character according to their time and to their object of interest. For him not only the limits between animal and man were relative like Darwin showed in the biological evolution. And for Weber not only the moral standards of human societies were changeable as the historical genealogy showed. Also he considered for the epistemic status of cultural sciences that the moral dimensions of understanding are opened, not bound by objectivity once for all times. Weber was aware that these methodological considerations were marginal in times of cultural continuity. Their useful meaning could be seen only in decades of cultural crisis when revolutionary changes were disturbing and reorganizing the public patterns of value-judgements. Thus only then the demand for reflecting the moral standards could make sense in order to get to know how their unconscious influence had already impressed the scientific forms of understanding in a new way. Therefore all work of cultural sciences could normally be done without a constant reflection of the last values in which the process of understanding has its unseen anchorage. Only in times when the structure and

color of the unreflected values are changing – so the opinion of Weber – the cultural sciences should react with a reflection of their unconscious prejudices. This means that the new standards of personal value-judgements and their influence on the process of understanding have to be enlightened: ’’Then science has to be prepared to change its standpoint and its rational instruments.’’ (6) This reflection of the historical genealogy of cultural sciences can be seen as an original consequence of the disenchanting approaches Darwin and Nietzsche made in the different and also correlated fields of biological and historical genealogy of man and morals. My remarks will close with a question which arises as a result of the actual observation that today, a time of increasing changes in value-questions, quite many people tend to a biological viewpoint in the scientific discussion of freedom (22,23). The alternative path in the cultural crisis to try to come to deeper reflection of the new standpoints and terms of the understanding sciences is seldom entered. It seems as if one turned down a decisive possibility of scientific enlightenment of the freedom of man which Nietzsche called the ’’animal without definite determinations’’. Max Weber was a great and classical exception and his classical texts still have the intellectual power to stir up our methodological thoughts like they did a hundred years ago when Jaspers read his epistemic textbook of science called Wissenschaftslehre His close reading of Weber and at the same his cautious way of taking unlike him the theory of resentment into account of his psychological approach show his deep ambivalence towards changing morals in the scientific field. Personally Jaspers was arguing with the idea of existential judgements which were at no means to enlighten by science. Kurt Schneider was even more cautious. He was looking for philosophical shelter in the horizon of absolute values which Scheler and Hartmann were holding up in their ethical thinking. They both did not take the risk which Weber took to bring cultural sciences and personal value-judgements into a serious. Why is such an attitude so seldom? With Nietzsche one could speak of a very understandably resentment against the chaotic tendencies of life which all biological and all historical and cultural thinking cannot overcome. Modern philosophers especially Nietzsche have opened our eyes for this ambivalent viewpoint. Aware of this deep fear Max Weber wanted to strengthen the opposite attitude of human curiosity by quoting Goethe¢s drama Faust. The passage he took out of a longer monolog of Faust is situated at the end of his methodological essay on scientific "objectivity’’: "…der neue Trieb erwacht, / Ich eile fort, ihr ew¢ges Licht zu trinken, / Vor mir den Tag und hinter mir die Nacht, / Den Himmel u¨ber mir und unter mir die Wellen.’’ (’’… the new drive is awaking,/I hurry to drink their eternal light,/In front the day and night behind,/Above the sky and waves beneath.’’) (6) These metaphoric words underline the enthusiasm and the slight ambivalence which result out of the decision to risk the adventure of inventing the human world into a nameless region where new moral standards have to be set scientifically according to the changing world. Although Jaspers and Schneider were inspired by Weber they were too cautious and conservative to take Weber¢s Faustian attitude. Maybe this attitude is a fruit of their medical ethics which is bound to pragmatic help. As a pure philosopher Jaspers opened up for the horizon of changing criteria of cultural sciences which is connected with Nietzsche¢s theory of resentment. Taking the risk of valuejudgements in a psychiatric approach of understanding is necessary in terms of research in order to gain the possible state of the art in a world of changing views and values. One can sum up: Taking Nietzsche and Weber seriously one can claim: Psychiatry has to be a biological and a cultural science at the same time. References: 1. Jaspers K. General Psychopathology. Baltimore. Johns Hopkins University Press, 1998.


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2. Bormuth M. Life Conduct in Modern Times. Karl Jaspers and Psychoanalysis. New York. Springer 2006. 3. Bormuth M. Einsicht und Willen. Karl Jaspers als Pathograph Nietzsches. In: Kunst und Krankheit. Studien zur Pathographie (M Bormuth, K Podoll and C Spitzer, eds.). Go¨ttingen. Wallstein 2007, pp. 11–26. 4. Hilken S, Bormuth M. u. Schmidt-Degenhard M. Psychiatrische Anfa¨nge der Pathographie. In: Kunst und Krankheit. Studien zur Pathographie (M Bormuth, K Podoll and C Spitzer, eds.). Go¨ttingen. Wallstein 2007, pp. 27–56. 5. Bormuth M. Lebensfu¨hrung in der Moderne. Karl Jaspers und Max Weber. In: Existenz in Kommunikation. Zur philosophischen Ethik von Karl Jaspers (B Weidmann, ed.), Wu¨rzburg. Ko¨nigshausen und Neumann, pp. 119–150. 6. Weber M. The Methodology of Social Sciences. New York 1949. 7. James W. The Variety of Religious Experiences. New York 2004. 8. Scheler M. U¨ber Ressentiment und moralisches Werturteil. Zeitschrift fu¨r Pathopsychologie 1912;1:268ff. 9. Scheler M. Das Ressentiment im Aufbau der Moralen. Frankfurt. Klostermann 2004. 10. Schneider K. Pathopsychologische Beitra¨ge zur psychologischen Pha¨nomenologie von Liebe und Mitgefu¨hle. Zeitschrift fu¨r die gesamte Neurologie und Psychiatrie 1921;65:109–140. 11. Freud S. Jugendbriefe an Eduard Silberstein. Frankfurt. S Fischer, 1989:1871–1881. 12. Nietzsche F. Briefe Januar 1875-Dezember 1879. Sa¨mtliche Briefe. Kritische Studienausgabe Vol. 5. Mu¨nchen. De Gruyter 1986. 13. Nietzsche F. Nachgelassene Fragmente. Sa¨mtliche Werke. Kritische Studienausgabe Vol 7. Mu¨nchen. De Gruyter 1980:1869–1874 14. Darwin Ch. Mein Leben. Die vollsta¨ndige Autobiographie. Frankfurt. Insel, 2008. 15. Darwin Ch. Die Abstammung des Menschen. Frankfurt S. Fischer 2008. 16. Nietzsche F. Die Genealogie der Moral. Sa¨mtliche Werke. Kritische Studienausgabe Vol 5. Mu¨nchen. De Gruyter 1980. 17. Nietzsche F. Go¨tzen-Da¨mmerung. Sa¨mtliche Werke. Kritische Studienausgabe Vol 6. Mu¨nchen. De Gruyter 1980. 18. Jaspers K. Nietzsche. Einfu¨hrung in das Versta¨ndnis seines Philosophierens. Berlin. De Gruyter 1950. 19. Freud S. Die Zukunft einer Illusion, Wien. Verlag der Psychoanalyse, 1927. 20. Jaspers K. Ausgewa¨hlte Korrespondenzen Vol 1 (M Bormuth and D v. Engelhardt, Eds.). Tu¨bingen. Preprint, 2009. 21. Nietzsche F. U¨ber Nutzen und Nachteil der Historie fu¨r das Leben. Unzeitgema¨ße Betrachtung. Sa¨mtliche Werke. Kritische Studienausgabe Vol 1. Mu¨nchen. De Gruyter 1980. 22. Bormuth M. Between Freedom and Necessity. Karl JaspersÕ contribution to brain research. Felsefe de Yeditepe. A reviewed Yearbook 2006;5:pp. 54–69. 23. Bormuth M. Ambivalenz der Freiheit. Suizidales Denken im 20. Jahrhundert. Go¨ttingen. Wallstein 2008.

The role of diagnosis in psychiatric forensic examination Vera Folnegovic´-malc1, ulijano Ljubicˇic´2 & Varda Robert1 1 University Department of Psychiatry, Psychiatric Hospital Vrapcˇe, Zagreb, Croatia Department for Psychiatry, 2University Hospital Centre Rijeka, Cambierieva, Rijeka, Croatia Although we do take into account the psychic status of the forensic examinee and his co-relation with his environment, especially

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regarding an injured person (and possible victimization action), his family and material status, possible earlier criminal acts committed, in each and every psychiatric forensic examination, no matter if it is mental competence, testatory capability, ability to stand trial or working capability, we are most certainly obliged to establish a psychiatric diagnosis, or, if there isn’t one, i.e. when an examinee is mentally healthy, we are to state Sine morbo psychico (i.e. without a mental disorder). It is of utmost importance to underline that although the diagnosis is important, it is not the only determining component for the judgment of mental competence. The official classification of mental disorders in the Republic of Croatia is the World Health Organization’s ICD-10 (1), and there is another, American classification – the DSM-IV (2). It is quite justified to ask why there are two official classifications of mental disorders that are used all over the world, and which one of the two is better. It is important to stress that the ICD-10 was from the very beginning constructed by medical doctors who, in that same medical fashion and tradition were working for physicianstherapists. It was primarily constructed on medical criteria and it is better adjusted for the implementation in practical medicine. On the other hand, the DSM-IV was primarily done by statisticians. The first incentive for drafting a classification was population census in 1840 in which a category ’’idiocy/insanity’’ was included. Already 40 years afterwards, i.e. in 1880 during the population census there existed 7 diagnostic categories from the field of neuropsychiatry. The primary goal of that classification was motivated statistically, whilst the motivation of the classification of the World Health Organization was primarily medical. According with different aims of these classifications, there are some very important differences between them. ICD-10 has far better structural validity, while DSM-IV has better predictive validity. For forensic sciences in psychiatry as a medical-forensic discipline ICD-10 is more appropriate, but, as DSM-IV is in some chapters more detailed than ICD-10, it is those very fields where DSM-IV should be used. As neither of the two classifications was not maked primarily for forensic use, one recommends usage of psychiatric and forensic textbooks so that each and every forensic examination could be founded on reviewed sources which are compatible with recent classifications. In somatic medicine as a rule we use the term disease, while in psychiatry we use the term psychiatric diagnosis or psychiatric disorder. The reason for that is that psychiatric disorders do not fulfill criteria for them to be named diseases for in most instances we are unaware of etiology and pathophysiology, and often not even prognosis or specific therapy. Luckily, in forensic examination it is not the diagnosis that is crucial, but there are other important factors. Only in cases of severe mental retardation or highly advanced dementia and acute psychotic state (schizophrenic or schizoaffective or manic), a person is considered without mental competence and without ability to stand a trial. As one finds high comorbidity with other psychiatric disorders and/or somatic diseases, forensic examination becomes even more complicated. Comorbidity of psychosis, dementia and posttraumatic stress disorder with alcoholism and drug dependence is very frequent, and personality disorders complicate the situation even worse. Those are all factors that make a forensic expert work difficult in finding the right decision. It is important to keep by the rules, the conclusion is to be founded on medical record and in cases where one can’t examine an examinee or if there are no enough relevant date, conclusion ’’non-liquet’’ is the most appropriate one.


MAIN THEME: MULTIPLE SCLEROSIS Immunopathogenesis of multiple sclerosis Vesna Brinar Department of Neurology, University hospital ''Zagreb'', Croatia Abstract: Immunopathogenesis of multiple sclerosis is a complex process involving T cell mediated autoimmunity at initial stage of disease. A long standing view that Th1 cells are critical for early inflammatory development of lesions is challenging by recent findings that Th1 helper cells with Th17 phenotype are even more important. A complex autoimmunity of MS is further complicated with evidence that CD8 cells, regulatory T cells, clonal expansion of B cells, cells of myelin lineage, antibodies and complement, as well as process intrinsic to central nervous system contribute to the tissue destruction. Although there are a lot of evidences about inflammatory phase of MS, far less is known about mechanisms involved in degenerative phase of disease. It is not known weather quantitative, or qualitative differences in inflammatory response contributes to destruction of the tissue, or as it was shown experimentally demyelination may sometimes occur independent of T cells. Understanding of immunopathogenesis of MS especially regarding various stages of disease is necessary for clinicians in choosing optimal therapy of MS in individual patients. Influences of immunomodulatory treatment on various stages of MS immunopathogenesis are presented. Key words: immunology, multiple sclerosis, immunologic basis for treatment MS is regarded as autoimmune T cells mediated disease, characterized with multiphocal demyelination and axonal damage of central nervous system (CNS), based on a complex genetic background (1). Although it is accepted that activation of Cd4 cells and their differentiation into Th1 phenotype is a driving force in early phase of MS, but also important in the long-term evolution of disease, other components of immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells contribute to the lesion formation. Th1 cells were for a long time regarded as critical for development of demyelination in MS but recent data obtained from animal models as well as from MS patients indicate that T helper cells with Th17 phenotype may be even more important for inflammation. It was found that IL-17 mRNA is more abundant in blood and CSF of MS patient and IL23 critical for development of Th17 cells is higher in myeloid dendritic cells from patients with multiple sclerosis (5). CD8+ cells also contribute to development of lesion in MS. In contrast to CD4+ cells that are found only at the edge of MS plaque, CD8+ cells are present also in perivascular regions. Besides this CD8+ cells recognize myelin proteins in MS patients with higher frequency than in healthy individuals, and myelin proteins are regarded, although it is not yet proved with certain, as specific target in MS. Therefore it is speculated that lesions in multiple sclerosis are initiated by CD4+, but amplification and damage is mediated by CD8+. This is supporting by data that CD8+ cells can directly attach and damage axons (3,6) While in the past the role of B cells and the production of oligoclonal IgG in the brain and cerebrospinal fluid in patients with MS were mainly viewed as an epiphenomenon, more recent pathological findings in MS point to the important role of B cells in MS pathology. There are more and more evidences indicating that in MS, similar to other autoimmune diseases like rheumatoid

arthritis, B cells aggregate into lymphoid-like structures. In MS such B cell ectopic lymphoid structures are found in intrameningeal follicles and in white matter. B cells are often infected with Epstein Barr (EBV) virus (7). These findings could explain continuous B cell and T cell activation in patients with severe SPMS and PMS. Although there is a lot of yet unsolved questions related on various B-cell-related mechanisms (e.g. B cell effectors and regulatory functions and others) it is clear that clonal expansion of B cells, and their antibody products, contributes to the hallmark of inflammation in the CNS in MS patients (7, 8). Function of dendritic cells (DCs) in T cell response is also very important and influences the outcome of inflammatory response in MS. In EAE model myeloid DCs (CD 11b CD11c, CD45) are associated with presentation of antigen to active and to naı¨ ve T cells and therefore they may contribute to antigen spreading, and amplifying the inflammatory process, but also they contribute to maturation of Th17 cells (9). In multiple sclerosis diffuse distribution of activated microglia was found, challenging that maybe such activation represent one of initial steps in lesion development and that it also may be answer to the fact that there is diffuse lesion of normal appearing white matter (10). Formation of acute inflammatory lesions in MS is possible by breakdown of blood-brain barrier (BBB).Such lesions are commonly clinically silent, and are ten times more frequent, than clinically presenting symptoms. Disruption of BBB lasts for about a month and than resolves leaving the area of inflammatory damage. The outcome of such acute lesion is determined by immunological and genetic vulnerability factors of the central nervous system predicting also heterogeneity of MS (2, 3). Beside acute inflammatory component degenerative process also exists in MS and contributes to the progression of disability. Although it is possible that degenerative process is independent of active immunological process, immune mechanism may contribute to its development. The cause of axonal damage is well established but the question is if immunological or non-immunological mechanisms are involved in mediation of the process. It is not yet known weather qualitative or quantitative difference in inflammatory response contribute to the degeneration of axons and neurons in CNS of MS patient. Based on pathological findings existence of four different pathological patterns are generally accepted (3).The types one and two are characterized with pronounced inflammation, but in type two deposits of complement and antibodies are dominant, indicating that in this type of disease myelin damage is mediated by antibody (3). This is also evident by an increase in intrathecally synthesized immunoglobulin G, indicating a clonal expansion of B cells. Besides, immunoglobulin G may be specific for causative agents in MS. Although such agent is not yet found, some studies showed that oligoclonal bands are directed against two different proteins of Epstein Barr (EBV) virus (11). On the other side antibody against MOG (myelin ologodendrocyte glycoprotein) can increase demyelination in marmoset EAE (12), and it was suspected that the same happened in MS patients (13), but it was not definitively confirmed (14). An increase of inflammatory response could be due to various infiltrating cells, among them also regulatory cells but it could be also due to the processes associated with local CNS environment. Some studies point to the importance of various chemokines and their receptors in augmentation of CNS inflammation. Chemokine receptor CCL2 has been identified as potent chemo attractant of


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monocytes and dendritic cells, and it is assumed that its induction in astrocytes occurs by innate or adaptive activation (15). Experimentally was shown that over expression of chemokines receptors CCL2 in CNS may lead to minimal inflammation despite of substantial demyelination. This indicate that at least in some patients with MS initial step in the formation of lesion may be independent of immune cells, that means non immunologically driven(15). The final pathway for axonal damage is probably calcium influx and mitochondrial collapse, probably with contribution of glutamate excitoxicity (16). Involvement of a CD4+ T cell-mediated process as an initial in development of MS is consistent with the association of genetic risk with HLA class II molecules. Many studies confirmed that HLA class II genes have the largest risk for multiple sclerosis. In Western Europe these are HLA DRB genes of HLA DR-15 haplotype (17). The most important question how and why autoimmune process starts in previously healthy individual is still questioned. Earlier standing that clonal depletion of self reactive T cells in thymus maintains the immunologic self tolerance was rejected by finding that potentially pathogenic autoreactive T cells are also present in the periphery of healthy individuals (18,19) . This point that some other regulatory mechanism must exist to prevent autoreactive T cells to start immune disorders (20). According to experimental findings the regulatory T cells play a key role in the control of self antigen reactive T cells and in the induction of peripheral tolerance (18). It was also found that autoreactive T cells in patients with autoimmune diseases are more easily activated compared to the same cells in healthy individuals (18). Recently it was found that CD4+ and CD25+ T cells prevent activation and effectors function of T cells. Although both subsets DCD4+ and CD25+ T cells are present at the same frequency in healthy individuals and in patients with MS, in MS patients CD 4+ and CD25+ T cells show primary regulatory defect of function. They are not able o suppress the proliferate response of CD4, CD25, +T cells target as it was possible with the same subset of healthy individual (19). In MS it is not clear if Treg cells exert their effects in the periphery or at the site of disease, in the target organ, but regulatory T cells are definitively important part of complex autoimmunity in MS (20). All this point to the conclusion that autoimmune disturbance in MS is characterized by the complex interplay of autoreactive T cells, B cells, antibodies, T regulatory cells complement as well as processes intrinsic to the CNS itself . These factors are also important in determining the stages of tissue damage and heterogeneity of the disease. Another question is how to clinically apply results of scientific immunological studies? It is clear that immunological studies are fundamental for understanding the basic process that is ongoing in MS, and provide basis for development of pathogenetically adequate and effective therapy in MS. Influence of interferons beta on induction of anti-inflammatory cytokines IL 10 as well as inhibition of T-cells traffic by blocking metalloproteinases, and increasing a tissue inhibitor to matrix metalloproteinases is well known and correlate with reduction of disease activity (21). Changes in the BBB permeability or local increase in expression of adhesion molecules contribute to disease activity. Interactions between endothelia cells and monocyte in acute MS lesions are well documented. It was shown that therapy with interferon beta in MS increases soluble vascular cell-adhesion molecules and causes reduction of endothelial adhesion cells thereby minimize the lymphocyte traffic into the CNS. Recently was documented and confirmed by studies in MS patients, that monoclonal antibody directed at integrin alpha 4 (natalizumab) have special effect on adhesion cells resulting in profound reduction of disease activity (22).

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Therapy with sphingosine-1 phosphate (SP1) receptor agonist (fingolimod) traps the lymphocytes in the lymph nodes and prevents their migration to peripheral tissue. Although the effectiveness of this medication is still studied results showed impressive reduction of disease activity pointing also to the importance of lymphocyte trafficking in the development of MS. (23) A treatment that remove mononuclear cells by monoclonal antibody to CD 52 (alemtuzumab) also produce a profound reduction in inflammatory activity, and indicates importance of CD4 and CD8 cells in CNS inflammation in MS (24). The exact function of B cells is not quite known, although it was shown that antibodies to myelin proteins contribute to demyelination. A trial with monoclonal antibody specific to CD 20 (Rituximab) showed a rapid reduction of acute disease activity shown by MRI, and is important for understanding the role of B cells in MS (25). Reduction of activity in MS was also found with another monoclonal antibody- daclizumab. Explanation of such therapeutic goal is observation that daclizumab treated patients showed marked reduction of CD4 and CD25, FOX 3 type 1 regulatory cells (Tr1 cells) (26). Conclusion: In MS inflammation is disregulated and inflammatory cells, pro-inflammatory cytokines, plasma proteins and cytotoxic agents predominate. Immunological studies suggested putative pathogenetic factors that may be important in the therapy of multiple sclerosis. Manipulations of immune response based on known pathogenesis of multiple sclerosis evolved in development of present immunomodulating treatment, but further researches and applications of new studies of even more effective therapies are ongoing. An ideal therapy in the future would bring the immune system into balance by increasing anti-inflammatory agents and restorative molecules. References: 1. Martin R, McFarland HF, McFarlinDE, Immunological aspects of demyelinating disorders. Ann Rev Immunol 1992:579–621. 2. McFarland H & Martin R. Multiple sclerosis: a complicated picture of autoimmunity. Nature Immunology, 2007;9:913– 919. 3. Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez Z, Lassman H. Heterogeneity of multiple sclerosis;implications for the pathogenesis of demyelination. Ann Neurol 2000;47;707–17 4. Zamvill SS, Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Ann Rev Immunol 1990:8:579–621 5. Matusevicius D, Kivisakk P, Navikas V, Soderstrom M, Fridrickson S, Link H. Interleukin 17-mRNA expression in blood and CSF mononuclear cells is augemented in multiple sclerosis. Mult Scler 1999;5:1001–104 6. Brisebois M, Zehntner SP, Estrada J, Owens T, Fournier S. A pathogenic role of CD8+ cells in spontaneous model of demyelinating disease. J Immunol 2006;177:2403–2411. 7. Serafini B, Rosicarelli B, Franciotta D, Magliozzi R, Reynolds R, Cinque P, Andreoni L, Trivedi P, Salvetti M, Faggioni A, Aloisi F. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med 2007;204:2899–2912 8. Franciotta D, Salvetti M, Lolli F, Serafini B, Aloisi F. B cells and multiple sclerosis. Lancet Neurology 2008;7:852–58 9. Bailey SL, Schreiner B, McMahon EJ. CNS myeloid DCs presenting endogenous myelin peptides preferentially polarize CD4+ Th17 cells in relapsing EAE. Nat Immunol 2007;8:172– 180. 10. Allen IV, McQuaid S, Mirakhur M, Nevin G. Review: Pathological abnormalities in the normal appearing white matter in multiple sclerosis. Neurol Sci 2001;22:141–144.


11. Cepok S, Zhou D, Srivastava R, Nessler S, Stei S, Bu¨ssow K, Sommer N, Hemmer B. Identification of Epstein Barr virus protein as putative targets of the immune response in multiple sclerosis. J Clin Invest 2005;115:1352–1360. 12. Genain CP, Nguyen MH, Letvin NL, Pearl R, Davis RL, Adelman M, Lees MB, Linington C, Hauser SL. Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J Clin Invest 1995;96(6):2966–2974. 13. Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, Dilitz E, Deisenhammer F, Reindl M. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003;349(2):139–145. 14. Zadro I, Brinar V, Horvat G, Brinar M. Clinical relevance of antibodies against myelin oligodendrocyte glycoprotein in different clinical types of multiple sclerosis. Clin Neurol Neurosurg 2007;109(1):23–26. Epub 2006 June 5. 15. Rebenko-Moll NM, Lui L, Cardona A, Ransohoff RM. Chemokines, mononuclear cells and nervous system: heaven (or hell) is in details. Curr Opin Immunol 2006;18: 683–689. 16. Pitt D,Werner P, Raine CS. Glutamate excitoxicity in a model of multiple sclerosis. Nat Med 2000;6:67–70. 17. Barcellos LF, Oksenberg JR, Begovich AB, Martin ER, Schmidt S, Vittinghoff E, Goodin DS, Pelletier D, Lincoln RR, Bucher P, Swerdlin A, Pericak-Vance MA, Haines JL, Hauser SL. Multiple Sclerosis Genetics Group: HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course. Am J Hum Genet 2003;72: 710–766. 18. Pete M, Fujuta K, Kitze B, Whitaker JN, Albert E et al. Myelin basic protein-specific T lymphocyte lines from MS patients and healthy individuals. Neurology 1990;45:540–548. 19. Sakaguchi S. Natural arising CD4+ regulatory T cell immunologic self tolerance, and negative control of immune responses. Ann Rev Immunol 2004;22:531–562. 20. Hafler D, Slavik JM, Anderson DE, OÕConnor KC, De Jager P, Baecher-Allan C. Multiple Sclerosis Immunological Reiews 2005;208–231. 21. Stu¨ve O, Dooley NP, Uhm JH, Antel JP, Francis GS, Williams G, Yong VW. Interferon beta 1b decrease the migration of T lymphocytes in vivo: effects on matrix metalloproteinase-9. Ann Neurol 1996;40:853–863. 22. Kappos L, Bates D, Hartung HP, Havrdova E, Miller D, Polman CH, Ravnborg M, Hauser SL, Rudick RA, Weiner HL, OÕConnor PW, King J, Radue EW, Yousry T, Major EO, Clifford DB. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 2007;6(6):431–441. 23. OÕConnor P, Comi G, Montalban X, Antel J, Radue EW, de Vera A, Pohlmann H, Kappos L. FTY720 D2201 Study Group:Oral fingolimod (FTY720) in multiple sclerosis: two-year results a phase II extension study. Neurology 2009:72(1):73–79. 24. Coles AJ, Compston AD. Monoclonal antibody treatment exposes three mechanisms underlying clinical course of multiple sclerosis. Ann Neurol 1999;46:296–304. 25. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, LangerGould A, Smith CH. HERMES Trial Group:B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358(7):676–688. 26. Bielekova B, Howard T, Packer AN, Richert N, Blevins G, Ohayon J, Waldmann TA, McFarland HF, Martin R. Effect of anti CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis. Arch Neurol 2009;66(4):493–499.

Importance of neurophysiological investigations in the diagnosis of multiple sclerosis Osman Sinanovic´ Department of Neurology, University Clinical Center Tuzla, School of Medicine, University of Tuzla, Tuzla, Bosni and Herzegovina Introduction:Evoked potentials (EPs) are the electric responses of the nervous system (cortical response) to motor or sensory stimulations. Visual, acoustic or auditory (or auditory brain stem) and somatosensory evoked potentials (or responses) (VER/

(a)

1a

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4 µV 300 ms Fig. 1. a) Visual evoked potential. b) Norma visual evoked potential. c) Normal visual evoked potential.


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4µV 300 ms

Fig. 5. Normal median nerve sormatosensory evoked potentials. Fig. 2. Prolongation of Ploo latency in patient with multiple Sclerosis.

Fig. 3. Avditory evoked potential.

Fig. 6. Normal posterior tibial nerve somatosensory evoked potentials.

200 µV 10 ms

Fig. 4. Abnormality of avditory evoked potentials in patient with multiple sclerosis. VEP, AER/AEP or ABER/ABEP, SSER/SSEP) are reliable diagnostic tests that yield reproducible results today in routine clinical practice. These tests provide sensitive, quantitative extensions of the clinical neurological examination. They primarily afford numerical data, but sometimes the absence of wave or an abnormal configuration of its potentials also provides useful information (1,2). Visual evoked responses (VER/VEP) make it possible to measure the conduction of impulses through the optical nerve pathways.

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The electrodes convey every cerebral response to an optical stimulus. The results of several repetitions are then added up or computer averaged (Fig. 1a). With a healthy eye, a response to stimulus occurs after 100 to 120 milliseconds (Fig. 1b,c). A characteristic delay of this response can indicate the presence of MS (Fig. 2), and the VEP can provide important diagnostic information regarding the functional integrity of the visual system (3). Acoustic or auditory evoked responses potentials (AER/AEP) help a specialist to detect disturbances of the sensory pathway in the auditory or acoustic nerve, as well as disturbances of the cerebellum and of the centripetal pathways. A click stimulus is presented to each ear by earphone and the electrical potential is measured over the corresponding occipital area (Figs 3 & 4). This method of investigation is especially important if no disturbances of cerebral function have been previously clinically identified. Somatosensory evoked responses (SSER/SSEP) measure sensitivity to touch (tactile sensitivity) on specific parts of the body, usually of the hands and feet, and their conduction of impulses to the brain. The stimulus is applied with light electrical impulses either on the


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(c)

(b)

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Fig. 7. Follow up of VEPs of multiple sclerosis patient. anklebone of the foot above the course of the tibial nerve (a tibial SSER/SSEP) or on the inner side of the wrist joint above the median nerve or ulnar nerve (Figs 5 & 6). The measurement is related to the corresponding area of the brain. Sometimes it is also necessary to measure responses during impulse conduction, over the spinal cord, which is sometimes referred to as fractionated SSER/SSEP. Magnetic evoked responses differ from the previously discussed forms of evoked response in that the nerve cells themselves are directly stimulated. Superficial electrodes are used to assess muscular responses on the muscles of the arm or leg, depending on the arm or leg function for which the brain area under stimulus is responsible. The time between the stimulation of the brain cells and the muscle response is measured. Stimuli are also applied over the region of neck vertebrae or of the lumbar vertebrae in order to distinguish between conduction in the brain and conduction in the spinal cord. Evoked potentials and multiple sclerosis: These tests can be helpful in making the diagnosis of multiple sclerosis (MS) and other disorders. In MS, signal transmission can slow down and the signal becomes weak. Evoked potentials are used to show abnormalities in the function of nerve pathways that can be caused by MS. The numerous disorders have been shown to have different abnormalities of visual (VEPs) and auditory evoked potentials (AEPs), and among them multiple sclerosis (MS), Parkinson’s disease (PD) and brainstem vascular lesions (BSVLs) (1–4). However, they are most often used in providing additional evidence in support of diagnosis of MS (5). The current diagnostic criteria for MS consider only VEP findings because this particular EP study has been shown to be the most useful (6.7). The VEP is used to identify impaired transmission along the optic nerve pathways, which is a fairly common early finding in MS, even in someone who has never been aware of any visual symptoms (2,8,9). Age number of clinical studies attest to the sensitivity of the VEP in revealing demyelinating lesions in the

optic nerve (ON) – about 90% of patients who have clear history of ON have abnormal VEPS (2). In some studies, the proportion is closer to 100%, and VEP was more sensitive than magneting resonance imaging (MRI) (2,10). MS is the most common form of central demyelination, characterized pathologically by widespread occurrence in the central nervous system of patches of demyelination followed by gliosis. Clinically, dissemination of lesions in time and space are the characteristics of the condition (1). EPs are very useful in establishing evidence of subclinical disease in pathways not known to be affected, so contributing to the clinical criteria of disease disseminated in time and space (11.12). They are also useful in evaluation of clinical course during time and treatment (2), and can provide not only diagnostic but also prognostic information during evaluation of MS patients (6,7) (Fig. 7). Abnormal VEP parameters in MS patient are typical finding in MS patients, and incidence of VEP abnormalities ranges from a high 96% to a low 47% (Fig. 3)(2,6,11). According to Chiappa and Hill (2), in 26 clinical series, published in seventies and early eighties, encompassing about 1950 patients with all MS classifications, the average abnormality rate found was 63%. There have been a large number of studies of AEPs in patients with MS. Of 1006 patients with varying classifications of MS from some of these studies in eighties, 466 (46%) had abnormal AEPs. Differences in definitions of MS (and diagnostic criteria), patient populations, and techniques account for the variations between studies (2,11). Moreover, many types of EPs can help in assisting the diagnosis of multiple sclerosis (12,13,14), and can assist in predicting progression and in a follow up of MS patients (13,15– 18). In conclusion, VEP studies, being the sole diagnostic tool for EP studies according to the new diagnostic criteria for MS, bear more important for follow up of clinical course of MS (including VEP and AEP) and in the field of differential diagnosis (8,11,19),


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although there is debate (20) on the diagnostic value of other EP studies in MS. References: 1. Misulis EK. Spehlmann’s Evoked Potential Primer. Butterworth-Heinemann: Boston, 1994. 2. Chiappa HK, Hill AR. Pattern-Shift Visual Evoked Potentials: Interpretation. In: Chiappa HK (ed). Evoked Potentials in Clinical Medicine. Lippincot-Raven Publishers: Philadelphia, 1997:95–146. 3. Odom JV, Bach M, Barber C, Brigell M, Marmor MF, Patrizia Tormene A, Holder GE. Visual evoked potentials standard (2004). Doc Ophtal 2004;108: 115–123. 4. Barbato L, Rinalduzzi S, Laurenti M, Ruggieri S, Accornero N. Electroencephalogr Clin Neurophysiol 1994;2:169–172. 5. Ellis JS. Clinical Neurology: Essential Concepts. Butterwort Heinemann: Oxford, 1998. 6. Weinstock-Guttman B, Baier M, Stockton R et al. Pattern reversal visual evoked potentials as a measure of visual pathway pathology in multiple sclerosis. Mult Scler 2003; 9(5):529–534. 7. Fischer C, Andre-Obadia N, Mauguiere F. Diagnostic criteria of multiple sclerosis: electrophysiological criteria. Rev Neurol (Paris) 2001:157(8–9 Pt 2):974–980. 8. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1):121–127. 9. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, OÕConnor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ’’McDonald Criteria’’. Ann Neurol 2005;58(6):840–846. 10. Miller DH, Newton MR, van der Poel JC, du Boulay EP, Halliday AM, Kendall BE, Johnson G, MacManus DG, Moseley IF, McDonald WI. Magnetic resonance imaging of the optic nerve in optic neuritis. Neurology 1988;38(2):175–179. 11. Sinanovic´ O. Visual and auditory evoked potentials in multiple sclerosis, Parkinson’s disease and brain steam vascular lesions. Radovi (Akademije nauka Bosne i Hercegovine). Knjiga 3. 2004;101–112. 12. Sinanovic´ O. Multipla skleroza: hocú da znam. PrintCom d.o.o.: Tuzla, 2008. 13. Drislane FW. Use of evoked potentials in the diagnosis and follow-up of multiple sclerosis. Clin Neurosci 1994, 2(3– 4):196–201. 14. Walsh P, Kane N, Butler S. The clinical role of evoked potentials. J Neurol Neurosurg Psychiatry 2005;76 (Suppl 2):ii16–22. 15. Alshuaib WB. Progression of visual evoked potential abnormalities in multiple sclerosis and optic neuritis. Electromyogr Clin Neurophysiol 2000;40(4): 243–252. 16. Fraser C, Klistorner A, Graham S, Garrick R, Billson F, Grigg J. Arch Neurol 2006;63(6):847–850. 17. Sater RA, Rostami AM, Galetta S, Farber RE, Bird SJ. Serial evoked potential studies and MR imaging in chronic progressive multiple sclerosis. J Neurol Sci 1999;171:79–83. 18. Turker H, Terzi M, Bayrak O, Cengiz N, Onar M, Us O. Visual evoked potentials in different diagnosis of multiple sclerosis and neeurobehcet’s disease. Tohoku J Exp Med 2008;216(2):109–116. 19. Djuricic V, Djuricic S, Jolic M. Diagnostic value of multimodal evoked potential in patients with multiple sclerosis. Int Cong Ser 2005; 1278: 160–162.

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20. Rico A, Audoin B, Franques J, Eusebio A, Reuter F, Malikova I, Ali Cherif A, Pouget J, Pelletier J, Attarian S. Motor evoked potentials in clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 2009;15(3): 355– 362.

Clinical and neurochemical characteristics of pediatric multiple sclerosis – CSF analysis as knowledge base for differential diagnosis and pathophysiology Kevin Rostasy1 & Hansotto Reiber2 1 Department of Pediatrics IV, Division of Pediatric Neurology, Inborn Errors of Metabolism and Developmental Neurology, Medical University of Innsbruck, Innsbruck, Austria 2Neurochemistry Laboratory, Department of Neurology, Georg-August University Gçttingen, Germany Abstract: Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system affecting young adults. Although adults and children share important features of the disease, they also differ in some clinical, radiological and laboratory aspects. This review focuses on the neuroimmunological findings in the cerebrospinal fluid of children with MS pointing out that there is already at earliest time of clinical manifestation a neuroimmunological pattern, which differs only in intensity of the humoral immune response but not in frequency and does not support a neuroimmunological difference between early onset from adult onset MS. The humoral immune response with intrathecal IgG and IgM class response and the polyspecific production of antibodies against a wide range of antigens (MRZ antibody response) further helps to differentiate childhood MS from ADEM as the main differential diagnostic challenge. Introduction: Adult MS patients have a relapsing- remitting (80%) and less frequently a primary- progressive course of the disease (20%) (1). Children with MS have also a predominantly relapsing– remitting course. No reports on a primary-progressive course below the age of 10 years do exist. Even between 10 and 16 years of age a primary-progressive course of the disease is exceedingly rare (2). Children with MS have a longer disease duration until they enter a phase of secondary-progression compared to adults (2,3). Children with MS reach an expanded disability status scale (EDSS) 4 after a much longer time than adults (20.2 vs. 10.7 years), but are still significantly younger (median 31.6 years) than adults (median 41.1 years) when they suffer from significant disability (2,3). When children enter the phase of secondary progression they appear to follow the same time course as adults (3). Children more often than adults present initially with more than one functional system involved (4). In a cohort of 132 patients reported by Pohl and colleagues 67% of children with MS had a polysymptomatic manifestation (5). Cerebellar and brainstem symptoms in pediatric MS are more and pyramidal symptoms less frequent than in adults with MS (2,5). Children with MS have a higher relapse rate in the first 2 years, which in general correlates with a faster disease progression, than in adults (6). Before the age of 10 years a male preponderance exists. During and after puberty (between 15 and 16 years) several studies report a rise in the female/male ratio to 2.1:1 to 2.4:1, which is slightly higher compared to adults with MS (2,5). Of particular diagnostic relevance is the observation that children with MS often do not meet the McDonald MRI criteria for dissemination in space at the time of their first exacerbation or their MS diagnosis (7). This underscores the importance of other diagnostic features such as the presence of oligoclonal bands for an accurate diagnosis also in view of the broad differential diagnosis in pediatric MS. The most frequently considered differential diagnosis is acute dissem-


inated encephalomyelitis (ADEM). Clinical and neuroradiological features often do not permit a discrimination at the initial presentation. Although ADEM is regarded to be a monophasic disease, reports demonstrate the existence of biphasic or multiphasic variants in children. ADEM presents rarely with oligoclonal IgG in cerebro-spinal fluid (CSF). Other important neuroimmunological diseases, which need to be considered, are neuromyelitis optica (NMO), the group of clinical isolated syndromes (e.g. transverse myelitis, opticus neuritis) in addition to rare neurometabolic diseases (e.g. Leber’s hereditary optic neuropathy (LHON)). Most CSF studies in MS have been performed in adults. Little is known about the natural evolution from childhood to adulthood MS of CSF parameters such as albumin, protein, intrathecal IgGand IgM- or a measles, rubella and varicella antibody synthesis – an important but still underappreciated feature of a chronicneuroinflammatory disease. We therefore studied the CSF of the first available lumbar puncture of 9 groups of MS patients with onset of MS between 7 and 30 years (n = 186) and compared our findings with a large cohort of non-inflammatory controls (n = 4100). Data were evaluated numerically and graphically in CSF/serum quotient diagrams (9). As an extension of an earlier report (9,10) for the statistical purpose the intrathecal IgG and IgM synthesis was interpreted with reference to the Qmean + 2 SD as upper border of the reference range for blood derived proteins in CSF instead of the diagnostically more specific border Qlim = Qmean + 3 SD. This improved the sensitivity for detection of an intrathecal IgM synthesis. This new CSF statistics tool which counts frequencies of increased values and also calculates mean intensities for comparison of groups and compensates for the age related difference of the barrier function in groups of different mean age was reported earlier in this journal (11). Our results were as follows: The increase of the mean albumin quotient QAlb (2.8–5.3 x 10–3) is age-related normal. Oligoclonal IgG was detected in all age groups with a frequency of 95–100%. The mean amount of intrathecal IgG in CSF increased with age of onset (IgGloc(mean) = 12–40 mg/L) (Reiber H, Teut M, Pohl D, Rostasy K M, Hanefeld F. Pediatric Multiple sclerosis: Age related differences and time course of the neuroimmunological response in CSF; unpublished results). Frequency of intrathecal IgM (QIgM > Qmean (IgM) + 2 SD) was higher but intensity (mean of IgMloc (mean) was lower in early onset patients. There was no uniform tendency for increase or decrease of IgM intensity in the disease course of the single patient. The correlation of intrathecal IgM synthesis with the clinical course of the disease showed that the presence of intrathecal IgM at time of first clinical manifestation in pediatric MS correlates with a slower progression of the disease (Stauch C, Rauchenzauner M, Pohl D, Hanefeld F, Reiber H, Rosta´sy KM. Intrathecal IgM synthesis in children with MS correlates with slow progression rate; unpublished results). This is in contrast to adult MS patients in whom the presence of oligoclonal IgM is associated with the onset of new relapses and an earlier conversion to secondary progression (12,13). A certain confusion in the field comes from the interpretation of oligoclonal IgM in the CSF. In contrast to the established method of oligoclonal IgG, the existence of ’’oligoclonal’’ IgM as detected after isoelectric focusing is questioned by several groups (Reiber, personal communication). A second source of biased results comes from interpretations of intrathecal IgM by the linear IgM Index (14). As shown recently the linear evaluation of an Index is unsuitable for statistical comparison of groups (11). The polyspecific, intrathecal production of antibodies against a wide range of antigens, a diagnostic hallmark in adults, was also found in children with MS. Frequencies of intrathecal measles and VZV antibody synthesis are similar in pediatric and adult MS patients, also in the disease course the intrathecal antibody

synthesis does not diminish detected by serial analysis of the single patient. Conclusions: Although MS in childhood is characterized by important clinical differences, the findings in CSF of children with MS have all the hallmarks of a chronic-neuroinflammatory Bcell driven disease. Oligoclonal bands as detected by isoelectric focussing and the presence of measles, rubella and/or varicela antibodies are already present in children and of utmost importance do not represent a transient phenomena but a persisting immune response. The main difference between pediatric and adult MS patients is the intensities but not the frequencies of the intrathecal IgG and IgM synthesis. Gender-related changes (pre- to post-puberty) from 1:1 to 1:2 (m:f) and median cell counts in CSF increase with age in MS. Differences between pediatric and adult MS are explained as normal age-related development but not as different neuroimmunological pathomechanism. The neuroimmunological response in the CSF characterized the presence of oligoclonal IgG and the polyspecific response with MRZ antibodies is detected already in the earliest phase of pediatric MS and is therefore a diagnostically important difference to ADEM and other diseases. References: 1. Amato MP, Ponziani G, Bartolozzi ML, Siracusa G. A prospective study on the natural history of multiple sclerosis: clues to the conduct and interpretation of clinical trials. J Neurol Sci 1999;168:96–106. 2. Simone IL, Carrara D, Tortorella C, Liguori M, Lepore V, Pellegrini F, Bellacosa A, Ceccarelli A, Pavone I, Livrea P. Course and prognosis in early-onset MS. Comparison with adult-onset forms. Neurology 2002;59:1922–1928. 3. Renoux C, Vukusic S, Mikaeloff Y, et al. The natural history of MS with Childhood onset. NEMJ 2007;356:2603–2613. 4. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med 2000;343:938–952. 5. Pohl D, Hennemuth J, von Kries R, Hanefeld F. Pediatric Multiple Sclerosis and Acute Disseminated Encephalomyelitis in Germany: Results of a nationswide survey. Eur J Pediatr 2007;166:405–412. 6. Gorman MP, Healy BS, Polgar-Turcsanyi M, Chitnis T. Increased Relapse Rate in Pediatric-Onset compared With Adult-Onset Multiple Sclerosis. Arch Neurol 2009;66:54–59. 7. Hahn CD, Shroff MM, Blaser SI, Banwell BL. MRI criteria for multiple sclerosis. Evaluation in a pediatric cohort. Neurology 2004;62:806–808. 8. Reiber H, Ungefehr S, Jacobi C. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Mult Scler 1998;4:111–117. 9. Reiber H, Peter JB. Cerebrospinal fluid analysis – diseaserelated data patterns and evaluation programs. J Neurol Sci 2001;184:101–122. 10. Reiber H. Basic CSF diagnostic in neuroimmunological diseases. Acta Neuropsychiatrica 2008;20(S1):9–10. 11. Reiber H, Albaum W. Statistical evaluation of intrathecal protein synthesis in CSF/Serum quotient diagrams. Acta Neuropsychiatrica 2008;20(S1):48–49. Free download of the CSF Statistics Tool from www.COMED-com.de. 12. Villar LM, Masjuan J, Gonza´lez-Porque´ P, Plaza J, Sa´daba MC, Roldań E, Bootello A, Alvarez-Cermenõ JC. Intrathecal IgM synthesis predicts the onset of new relapses and a worse disease course in MS. Neurology 2002;59:555–559. 13. Villar LM, Masjuan J, Gonzalez-Porque P, Plaza J, Sa´daba MC, Roldań E, Bootello A, Alvarez-Cermenõ JC. Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis. Ann Neurol 2003;53:222–226. 14. Sharief MK, Thompson EJ. Intrathecal immunglobulin M synthesis in multiple sclerosis. Brain 1991;114:181–195.


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Urogenital dysfunction in patients with multiple sclerosis David B. VoduÐek Division of Neurology, University Medical Centre, Ljubljana, Slovenia Abstract: The occurrence of urogenital dysfunction as an isolated early symptom in multiple sclerosis (MS) is rare, but the prevalence thereof becomes high with progression of disease. Lower urinary tract dysfunction may add to the cause of death (particularly through urinary infections), but both urinary and sexual dysfunction significantly affect quality of life of patients. Both storage and evacuation of urine may be affected by MS, and ultimatively the functional diagnosis can only be made by urodynamic testing. As upper urinary tract affection is, however, rare (and can be prevented by timely ultrasound imaging), a first stage diagnostics in the MS center by the neurologist and specialized nurse is appropriate. History, urine tests and post void residual urine determination (preferably by ultrasound) should provide necessary data for treatment of infections, and also symptomatic management of frequency, urgency and incontinence by bladder training, anticholinergics, and intermittent self catheterization (as indicated); the referral to urologist may be reserved for patients who fail first line treatment. Treatment in the late stages of MS is as yet little researched, but eventually a suprapubic catheter is the preferred method of bladder emptying. Sexual dysfunction should be actively sought in MS patients (in men erectile and ejaculation dysfunction, in women deficient lubrication and genital hyper- or hyposensitivity are frequent). Clinical examination contributes little to clarification of neurogenic sexual dysfunction, but defines the extent of other deficits due to MS, which may be relevant for sexual counseling (spasticity, sensory loss). Sildenafil has been demonstrated to be effective in treatment of men, but not in women. Other management options exist, and the doctor and nurse in the MS center should be proactive in providing first line counseling and management. Lower urinary tract dysfunction: Introduction: The prevalence of urinary symptoms in any mixed patient group with multiple sclerosis is high; in a conservative estimate it is at least as high as that of lower limb dysfunction, and the MRI incidence of spinal cord lesions (c. 75%) (1). The estimates vary in different studies and it seems evident that the prevalence depends on the state of progression of disease; lower urinary tract dysfunction is a rare sole initial symptom (2% have been reported by Goldstein et al 1982, but also lower and higher numbers have been quoted) (2). In advanced multiple sclerosis, neurogenic bladder disease probably affects all patients. Even in patients who are urologically asymptomatic and have a relatively short disease duration (mean 5 years) urodynamic abnormalities have been demonstrated in 52% (3). Urogenital symptoms are recognised to have significant adverse effect on the quality of life in MS patients (4). Lower urinary tract dysfunction is furthermore a potentially serious (although not yet fully defined) health risk to patients. In a study of causes of death in USA, symptomatic urinary tract infection was considered as a contributing cause in 8.4% of cases; terminal renal insufficiency was, however, not found to be a notable cause of mortality (5). Neural Control of Micturition Voluntary micturition is a behaviour pattern which starts with relaxation of striated urethral sphincter. The micturition center in the pons co-ordinates micturition as such, but areas rostral to the brainstem (the hypothalamus and other parts of the brain including the frontal cortex) are responsible for the timing of the start of micturition. The pontine micturition center (PMC) co-ordinates the activity of motor neurons of the urinary bladder and the urethral sphincter (both nuclei located in the sacral spinal cord), receiving afferent input via the periaqueductal grey. This brainstem control of lower urinary tract function is organized as a on-off switching circuit that

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maintains a reciprocal relationship between the urinary bladder and urethral outlet. Without PMC and its spinal connections coordinated bladder/sphincter activity is not possible. Thus patients with such lesions demonstrate bladder sphincter discoordination (dyssynergia). Patients with lesions above the pons do not show detrusor-sphincter dyssynergia, they, however, suffer from urge incontinence (due to bladder overactivity), may demonstrate noninhibited sphincter relaxation and furthermore an inability to delay voiding to an appropriate place and time. Urodynamic abnormalities in MS: Urodynamic abnormalities were found in all MS patients complaining of lower urinary tract symptoms by Bemelmans et al. (3), but in other populations up to 30% of symptomatic patients have no demonstrable abnormalities (6). Typically, the most common urodynamic abnormality is neurogenic detrusor overactivity without bladder outlet obstruction (62%), than neurogenic detrusor overactivity with detrusor sphincter dyssynergia (25%), than detrusor underactivity (20%) (7). Lower urinary tract symptoms and urodynamic abnormalities may worsen during the course of the disease and regular reviews of lower urinary tract status have been recommended (8). Correlation of lower urinary tract abnormalities, clinical picture and MRI: Female patients have been said to be more commonly affected than males, but this as well as other correlations (age at onset, type of MS, etc.) are controversial. In both sexes urgency, frequency, nocturia and pain are common. More common in men are: hesitation, weak urine flow and incomplete bladder emptying. Incontinence is more frequent in women. In principle, the lesions responsible for LUT dysfunction may be anywhere along the neuraxis, as the neural LUT control matrix is widely spread throughout the brain and spinal cord. MS plaques may conceivably even cause a ’’lower motor neuron type’’ LUT dysfunction if affecting lower sacral cord segments (9). A correlation between lower urinary tract complaints and spinal cord cross sectional area as defined my MRI has been demonstrated. There is no good evidence for association of urinary symptoms and MRI changes in the brain (10). With progression of disease (particularly it seems with increasing spinal cord involvement) there is worsening of lower urinary tract dysfunction. There may be worsening of detrusor overactivity, but particularly of the efficiency of detrusor contractions (bladder emptying). The worsening urinary problems are complicated / exacerbated by progressive loss of ambulation, spasticity and cognitive impairment. Lower urinary tract dysfunction is accompanied by recurrent urinary tract infections, but rarely by upper urinary tract involvement and only exceptionally by renal failure. Indeed, renal failure seems to be no more common than in the general population (11). Diagnostics: In addition to overall assessment of the clinical picture and the neurological deficit, a careful history of lower urinary tract symptoms is mandatory. The use of a validated questionnaire is promoted (12) It is useful if the patient fills in a voiding diary. Examination of the anogenital region including assessment of the anal sphincter tone, sensation of touch and pinprick, the bulbocavernosus and anal reflex (bilaterally) is traditionally a part of the overall neurological examination, but is often neglected. In the experience of the author, such examination is not only occasionally helpful (because of detection of some unexpected abnormality), but also convincing the patient that the neurologist is taking his/her complaints seriously. As for investigations, no general consensus guidelines exist; in practice, in a MS patient developing LUT symptoms usually no additional diagnostics are performed to determine the neurological lesion responsible (i.e., imaging or neurophysiological testing). The practice related to an urological (urogynecological) consultation varies in different centers. Several tests are available to the clinician


to asses the function of LUT; the more simple testing is practiced within many MS centers, but few neurological departments have an uroneurological unit providing the availability of a full urodynamic investigation. Residual urine cannot be reliably ascertained from history. It can be measured after a normal void by an ’’in-out’’ catheterisation, or by a hand held ultrasound scanner. (It is important to note that the residual urine may not reflect detrusor contractility, because urine may be emptied by straining or pressure on the abdominal wall). Measurement of post void residual urine is particularly important before prescribing an anticholinergic drug for frequency, urgency and urge incontinence, as residual urine may in itself trigger uninhibited detrusor contractions (and certainly exacerbate the clinical situation in patients with neurogenic detrusor overactivity). Residual urine may occur only after introduction of an anticholinergic drug (as a common side effect), and may be the reason why the drug seems to be non-effective. It is accepted that the determination of the post void residual urine is required in neurological patients with LUT symptoms. Uroflowmetry non-invasively measures urinary flow and provides information on urine flow vs. time (the uroflow ’’curve’’). Maximum and mean flow rates as well as the voided volume can be established. A ’’poor’’ flow may be due to detrusor failure or bladder outlet obstruction. The measurement is only valid if the voided volume exceeds 150 ml, which may be a problem in neurological patients. Combined with ultrasound measurement of post void residual urine uroflow is a screening test to exclude serious bladder outflow obstruction. (Outflow obstruction may be deleterious to the upper urinary tract and needs further diagnostics). Cystometry records bladder pressure in relation to its volume. It is an invasive test which provides data on detrusor function and also sensation in the bladder. In the filling phase of the ’’micturition cycle’’ (filling cystometry) the test assesses the storage capability of the bladder. In the voiding phase (voiding cystometry) the relationship between detrusor pressure and uroflow its recorded, and the ’’mechanics’’ of micturition is assessed. With concomitant imaging and/or electromyographic recording of external sphincter activity detrusor – (external) sphincter dyssynergia can be demonstrated. Ureteric reflux and the site of neurogenic bladder outlet obstruction can be best visualised by videourodynamics. The role of cystometry (and videocystometry) in the investigation of neurological patients with bladder dysfunction has been promoted by urologists, because it is only through these investigations that detrusor sphincter dyssynergia can be diagnosed (13). The International Consultation on Incontinence Consensus recommends that patients with suspected neurogenic LUT dysfunction should receive comprehensive urodynamic evaluation (including videourodynamics, if possible) to establish the state and function of LUT (14). Because upper urinary tract involvement is rare in MS patients it has been argued that urodynamic testing is not necessary for first line symptomatic management of lower urinary tract dysfunction, but post void residual urine determination is (1). This is in opposition to the general urological opinion, but urological consultation is as a rule difficult to obtain for the large numbers of MS patients. It needs to be pointed out that no prospective study has investigated the cost benefit of invasive urodynamics vs. simpler diagnostics (post void residual, upper urinary tract ultrasound). Thus, particularly for MS patients, the simple pragmatic approach can be advocated (6), and more invasive procedures are reserved for the patient with refractory problems. In determining upper urinary tract dilatation ultrasound scanning has largely overtaken intravenous urography. No definite study on the value/necessity of a particular battery of tests of urinary tract function in MS patients has been performed yet. Management: The treatment of patients with MS is coordinated by the neurologist; same should hold for treatment of their urogenital symptoms, i.e., this treatment should also be coordinated by the

neurologist or the neurorehabilitation physician. Referral to urology is often impractical for first line management, and neurological teams engage more and more in solving simple early urogenital problems themselves, and only refer to urology if first line treatment fails. In managing MS patients with LUT dysfunction a specially educated nurse (’’continence advisor’’) is very helpful. Treating LUT symptoms Some patients with hesitation, difficulty in initiating voiding and poor emptying may stimulate their bladder by suprapubic vibration. A practical device is commercially available (1). Scheduled voiding (bladder training) may be an adequate treatment for patients with mild symptoms of frequency and urgency, or hyposensitive bladders. Complete and regular emptying of the bladder may be all that is necessary to alleviate frequency, urgency, incontinence and bladder discomfort. If bladder training and scheduled voiding do not suffice, a simple algorithm for the management of frequency, urgency and incontinence can be followed: clean intermittent catheterisation should be introduced if the value of the post void residual is above 100 ml; if symptoms persist, an anticholinergic drug should be added. More selective muscarinic antagonists may be preferable if dry mouth or cognitive side effects occur (dariphenacine, soliphenacine). Clean intermittent selfcatheterisations may become necessary after introduction of the anticholinergic drug because of appearance of significant residual urine is a side effect of the drug treatment (1). In patients with post void residual urine above 100 ml the bladder should be regularly emptied by clean intermittent self catheterisation. This can be achieved by the patient or sometimes by the caregiver. Motivation, cognition and adequate manual dexterity are necessary conditions. In patients with bothersome day or night time frequency desmopresine has been shown to be of symptomatic benefit providing patients with up to 6 hours of freedom from frequency (15). Desmopresine in a dose of 10–20 lg should only be used once in any 24 hours period; it should not be used regularly because of the danger of hyponatremia; it should not be used in patients over 65years of age. Patients with resistant neurogenic detrusor overactivity should be referred to an urologist interested in treating neurological patients. Botulinum toxin infiltration of detrusor has been shown to be effective in treating frequency, urgency and urgency incontinence. The beneficial effects of this therapy have a median duration of 13 months. Many patients need to start intermittent self catheterisation after botulinum injections (due to the inability of the detrusor to empty the bladder) (16). It is necessary to note that botulinum toxin A is not yet licensed for the use in bladder. Intrasphincteric injections of botulinum toxin may improve urinary retention, but this type of therapy is still investigational (17). Further therapies are being explored. It has been known for several decades that electrical stimulation can inhibit the overactive detrusor (also in patients with multiple sclerosis), but only uncontrolled and small studies have confirmed the efficacy of such therapy. Electrical stimulation can be applied by surface electrodes placed in the lumbosacral dermatomes, or by intravaginal or intrarectal electrode plugs (18). The invasive and much more expensive sacral nerve neuromodulation has been reported as inducing clinical and urodynamic improvement at 46 months follow up in MS patients (19). Recently repetitive transcranial magnetic stimulation of the motor cortex for 5 consecutive days over 2 weeks in MS patients complaining of lower urinary tract symptoms has been demonstrated to ameliorate the voiding phase of the micturition cycle (20). Treating LUT infections Urinary tract infections are common symptoms of lower urinary tract dysfunction in MS patients, usually caused by incomplete emptying. They should be treated aggressively as they aggravate weakness, spasticity and may even


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foster new inflammatory activity and relapses of MS. Optimal treatment of retention is primarily important; intermittent selfcatheterisation to completely empty the bladder on a regularly basis may have to be instituted. If urinary tract infections continue an urologic evaluation is warranted to look for foreign bodies or bladder deformities (kidney and bladder stones are particularly common since certain types of bacteria my cause them). Chronic antibiotic use should be discouraged; this practice will almost certainly lead to infections with resistant bacteria. The strategy is to use intermittent or alternating courses of antibiotics (nitrofurantoin or trimethoprine). In patients with indwelling catheters asymptomatic bacteriuria should be expected and tolerated. Treating LUT dysfunction in advanced MS In the highly disabled MS patient with limited mobility, cognitive impairment, loss of manual dexterity and increased spasticity clean intermittent self catheterisation (even with the aid of the caregiver) may become difficult, and an indwelling catheter becomes a necessity. Usually a urethral catheter connected to a leg bag is introduced first but should be promptly replaced by a suprapubic catheter (1). Use of urethral catheters on a long term basis causes urethral trauma and several other complications. The suprapubic catheter is as a rule introduced by the urologist. The catheter tract becomes epitelised in 6–8 weeks post-puncture; at that point the catheter can be changed for the first time and than subsequently at 3-month intervals (the regular change of catheter can be performed by a nurse). Upper urinary tract complications such as hydronephrosis, reflux and pyelonephritis have been reported in up to 19% of 180 patients (21); several other studies reported lower incidence of these serious complications. An indwelling catheter per se does not protect the upper urinary tract. In advanced multiple sclerosis repeated post void residual urine measurements and ultrasound of kidneys and bladder are necessary. It has been stressed that management in advanced MS is based on tradition rather than on evidence (22). Permanent catheterisation is the method of choice for treating urinary problems in advanced MS, but the long term consequences are often neglected (catheter blockage, stones, infection; long term catheterisation is risk factor for developing bladder cancer). Haematuria is to be considered as a warning sign that must lead to further investigation. Sexual Dysfunction Introduction: Sexual excitement and satisfaction from adequate stimuli are a normal component of a fulfilled life. To the neurologist, sexual behavior involves a series of neurally controlled phenomena occurring in a hormonally defined milieu. Sexuality depends also on psychosocial factors, but the neurologist’s interest is necessarily focused more on physiological aspects; nevertheless, the perspective of partnership and social issues should not be forgotten. Sexual dysfunction, such as lack of libido (in both sexes), erectile dysfunction and disturbances of ejaculation (in men), and deficient lubrication, dyspareunia, and problems with orgasm (in women), is not uncommon in the general population (23), but much more common in MS (24). Sexual functioning needs to be addressed in patients since it is a major determinant of quality of life, and may be responsive to treatment. Neurophysiology of the sexual response: Any lesion involving neural tissue relevant for sexual responses may cause dysfunction, as also may lesions of other neural structures more generally involved in control of behaviour. Thus, forebrain areas regulate the initiation and the execution of sexual behavior; the medial preoptic area integrates sensory and hormonal signals, and the amygdala and other nuclei play a role in the execution and reward aspects of sexual function. Desire or sexual interest (libido) is enhanced by sexual activity itself, exciting circumstances, new sexual partners, hypomania, and certain focal brain lesions

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(particularly of the frontal and temporal lobes). Sexual interest may be lowered by lack of opportunity, age, certain addictive or sedative drugs, malnutrition, debilitating illness, depression, and certain focal brain lesions. Sexual excitement results from sensory stimuli or sexual ideation. Sensory information from the glans and the skin of the penis and clitoris is conveyed through bilateral branches of the pudendal nerve (the dorsal nerves of penis/clitoris). Genital afferents synapse in the spinal cord via interneurons with both somatic and autonomic motoneurons; those afferents destined for supraspinal structures travel in the anterolateral funiculus. ’’Erotically colored’’ sensations from the genital region are conveyed by the spinothalamic pathways, and patients with selective damage to these tracts may complain of anorgasmia and ejaculatory failure. Orgasmic sensation is blocked by bilateral anterolateral lesions of the spinal cord (25). Both thalamic and cortical areas receive sensory input from the genitals. Somatosensory input from other body parts (’’erogenic zones’’) may – subject to somatic and individual psychological factors and dependent on context – also lead to sexual excitement. Adequate sexual excitation can be achieved by stimuli delivered through cranial nerves, and mental imagery. Sexual excitement leads to a complex response of the autonomic nervous system, and a particular behavioral response. Blood flow in the penile artery, or the corresponding artery in the clitoris, increases. The smooth muscle of the cavernosal sinuses in the penile corpora relax, and the helicine arterioles branching from cavernosal arteries selectively shunt blood flow to the lacunar spaces of the cavernosal bodies, filling them with blood. Subtunical venules are compressed so that corporeal venous return is restricted, resulting in increasing intracorporeal pressure. The pressure stabilizes at approximately systolic blood pressure, resulting in penile (and clitoral) tumescence and rigidity. Continued sacral parasympathetic activity maintains this erection (26). In women, parasympathetic activity causes clitoral erection, engorgement of the labia, and vaginal lubrication. The lubrication during sexual arousal is due to transudation through the vaginal wall. Another source is secretion from paraurethral glands (emptying into the urethra). Increased vaginal blood flow, lubrication, and erection of cavernous tissue in the clitoris and around the outer part of the vagina are the female homologues of the male erectile response; the response is dependent on innervation and a normal estrogen level (27). In the periphery, the main proerectile transmitter is nitric oxide, which is co-localized with vasoactive intestinal peptide and acetylcholine; the main antierectile neurotransmitter is norepinephrine (28). Erections can still occur in men after lesions of sacral cord and pelvic nerves. This is due to the ’’alternative’’ proerectile sympathetic pathway mediated through the thoracolumbar cord and the hypogastric nerve. The ’’reflex’’–’’psychogenic’’ dichotomy of the genital sexual response can be seen in both genders (29). Orgasm can be separated conceptually (but not easily physiologically) from emission and ejaculation. Anorgasmia is very rare in otherwise normal men (30), but 13 percent of women between the ages of 18–26 years have never achieved orgasm, with the incidence declining to a minimum of 3 percent in women between the ages of 51 and 64 years (31). Physiological inhibitory influences on the sexual response also exist. A center in the rostral ventral medulla (in the region of nucleus paragigantocellularis) seems to mediate tonic inhibition of sexual reflexes by a direct serotoninergic pathway descending to spinal centers (32). Sexual dysfunction due to MS: Disturbances of sexual function are common in patients with multiple sclerosis, regardless of gender (25). Most such disturbances seem to relate to spinal cord involvement by the disease and are often associated with urinary symptoms and lower limb involvement. Sexual dysfunction has also been correlated with destructive lesions in the pons, as


detected by magnetic resonance imaging, in patients with relapsing–remitting multiple sclerosis (33). Changes in sexual function are rare at the onset of multiple sclerosis. Erectile dysfunction may be an initial symptom (34), and it becomes more common with increasing spinal cord involvement. In men with established MS it is a frequent problem, with estimates of its prevalence varying between 35 and 80 percent (35). Interest in resuming sexual activity persists in 75 percent of patients (36). Spontaneous improvement in erectile function sometimes occurs. In men with multiple sclerosis problems with ejaculation are also frequent (37,38) and are often coupled to the erectile dysfunction. Anorgasmia has been correlated with evidence on magnetic resonance imaging of brainstem and corticospinal abnormalities as well as with total area of lesions (39). In women, decreased lubrication and sensory disturbances involving the genital region (hypoesthesia, hyperesthesia, and different types of pain) are common (40). Sacral-segment dysesthesias may be so severe that patients are unable to bear direct genital or nongenital contact. Electrodiagnostic data – cortical evoked potentials of the dorsal nerve of the clitoris (41) – as well as measurement of vibratory thresholds in the clitoris (42) suggest that pudendal somatosensory input is necessary for female orgasmic function, and that this may be disturbed even in early, mild multiple sclerosis. To compensate for such a loss, more direct stimulation of the anterior vaginal wall is recommended. Some patients with multiple sclerosis experience decreased libido; this problem has not been studied in depth, however, and emotional and cognitive disturbances may be contributory. Increased sexual desire occasionally constitutes a problem. Other symptoms related to multiple sclerosis, such as fatigue, depression, cognitive dysfunction, spasticity in the lower limbs, urinary and bowel disturbances, and the use of aids to manage incontinence, can inhibit sexuality, as can paroxysmal motor and sensory disturbances triggered by sexual intercourse. Examination: The breadth of the history and clinical examination will be tailored by the individual physician’s interests and practice habits; inquiry about sexual function should, however, be obligatory and not reserved for the male patient. The history should include details of patient’s sexual expectations, needs, and behavior. Before diagnosing dysfunction of sexual organs, the level of actual desire should be established. Men should be asked about erectile function (the occurrence of nocturnal erections, morning erections, and erections evoked by genital, visual, auditory, or psychogenic stimuli), and women about vaginal lubrication. The nature of ejaculation should be determined. Finally it should be clarified whether the patient can achieve orgasm. In some circumstances it may be helpful to interview the patient’s partner. Formal questionnaires can be used to obtain standardized information on male sexual function (43). These questionnaires mostly focus on erectile dysfunction (the persistent inability to develop and maintain an erection sufficient for satisfactory sexual activity) (44). The impact on quality of life is covered by another inventory (45). Questionnaires have also been formulated to assess sexual function in women, for instance the female sexual function index (46). Formal questionnaires are not necessary for assessment of individual patients (47). Clinical examination contributes little to clarification of neurogenic sexual dysfunction, but defines the extent of other deficits due to MS, which may be relevant for sexual counseling (spasticity, sensory loss). Sexual or neurophysiological function tests have no major role in clinical practice; abnormalities can be demonstrated, but they do not, as a rule, influence decisions on therapy. In a study of women with multiple sclerosis, for instance, latency of pudendal (and tibial) somatosensory evoked potentials failed to predict the extent of sexual dysfunction (48). Management: Sexual dysfunction associated with neurological disease often increases patientsÕ distress. Discussion with patients and partners about their sexual life should be part of any

rehabilitation strategy. In all instances, drug regimens should be reviewed for possible effects on sexual function. Sexual education, counseling, and specific suggestions about therapeutic methods are important, and should be provided by the treating physician. The development of drug treatments by the oral and intracavernous routes has revolutionized the outlook for men with erectile failure. Specific phosphodiesterase-5 inhibitors have been developed to treat erectile dysfunction, the first being sildenafil, which has now been used by several million men. The selective inhibitors of type 5 cyclic guanosine monophosphate phosphodiesterase augment the nitric oxide–mediated relaxation pathway in penile tissues by increasing available cyclic guanosine monophosphate in the corpus cavernosum. These medications therefore do not cause erection but enhance the response to sexual arousal. Sildenafil is an effective treatment for erectile dysfunction in men with multiple sclerosis (36). Sildenafil (25, 50, or 100 mg) is taken orally 1 hour before intended sexual activity. (Significant effects have been reported between 30 minutes and 4–6 hours after taking the medication.) Treatment should be begun with 25 mg or 50 mg, and the same dose taken several times before it is increased. Dose-finding studies have demonstrated a dose–response curve. Sildenafil can be used repeatedly, and if used once or twice per week there should be no fear of tachyphylaxis (49). Other phosphodiesterase inhibitors probably have similar effects also in MS men, although no formal studies have been performed. The most common adverse events of sildenafil are headache, flushing, and dyspepsia. Temporary visual symptoms (mainly color-vision disturbances) may occur with higher doses (100 mg). Adverse effects are mostly transitory and of minor intensity. No evidence was found of effects on the myocardium or the conduction system. Evaluation of functional capacity is necessary in patients with coronary artery disease, who need to know the risks of physical (and sexual) activity. Patients who can exercise to 4.5 metabolic equivalents without angina or hypotension can probably safely use sildenafil (50). Recommendations for the use of sildenafil in patients with cardiovascular disease have been published (50). Phosphodiesterase-5 inhibitors are contraindicated in combination with vasodilator drugs of the nitro type and nitric oxide donors, but a cardiologist can change such drug regimens in suitable patients with erectile difficulties requiring treatment. Phosphodiesterase-5 inhibitors should not be used in patients with retinitis pigmentosa. They are contraindicated in men with hypotension (blood pressure below 90/50 mmHg). Intrapenile injections of papaverine have been used in the treatment of erectile dysfunction in men with multiple sclerosis (51) and other neurogenic conditions. The required dosage of papaverine was lower than in vascular disease, and erection lasted longer and was of better quality. Priapism and prolonged erection were the most common acute complications but were dose related. Prostaglandin E1 (alprostadil) is now the preferred drug for self-injection therapy in erectile dysfunction. Intracavernous injection should be taught under medical supervision before self-administration is attempted by the patient or his partner. The effect is very rapid and may last for 2–4 hours. Local bleeding, pain and fibrosis may develop in the corpora cavernosa, leading to loss of effectiveness. This treatment is obviously contraindicated in patients taking anticoagulants or with hematological malignancies. Priapism as an adverse drug reaction usually has a good prognosis with conservative treatment. Painless priapism of less than 6 hours duration should be treated at first by cooling (52). If present for more than 6 but less than 24 hours, intracavernous injection of an alpha-adrenergic agonist such as metaraminol is recommended. In painful priapism or with failure of conservative methods, penile puncture should be performed, at which time a cavernosal blood sample should be obtained to assess cavernosal hypoxia.


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A vacuum device can provide rigidity adequate for sexual intercourse (penetration) in a high percentage of patients, but many find it inconvenient. The most common complications are bruises, petechiae, and skin edema. The constriction band should not stay in place for longer than 30 minutes; major complications such as severe erosion, and cellulitis have been associated with prolonged wearing of the band (53). The use of a constriction band (on its own) may help patients who can obtain an erection, albeit not a durable one; the same restrictions concerning the duration of application should be observed. In cases of anejaculation/anorgasmia, vibratory stimulation may be helpful. Premature (or rapid) ejaculation has been associated with myelopathy, but also with behavioral, psychological, and partner-related issues. Counseling on the use of particular techniques may lead to improvement (54). Use of antidepressants (serotoninergic agents such as clomipramine, or selective serotonin reuptake inhibitors such as sertraline or paroxetine) may be successful (55). Vibratory stimulation and dildos may be helpful in patients with genital sensory disturbances. Treatment of lack of sexual arousal and anorgasmia in women is difficult; no drug treatment is effective. Sildenafil has been well tolerated in women with lack of sexual arousal and multiple sclerosis, with few benefits or side effects. There was an effect on lubrication, but quality of life did not improve significantly although some women opted to continue on the drug after conclusion of the study (48). In women with dysesthetic or painful sensations in the genitalia that are not alleviated by improving lubrication, antiepileptic drugs such as gabapentin, pregabalin, and carbamazepine may be helpful. Conclusion: Urogenital dysfunction is common in MS patients and should be looked for, as patients may hesitate to offer information. Looking after MS patients in a MS centre with a specialised nurse provides a good solution for early detection and appropriate counseling. Diagnostics should be coordinated by the neurologist. In sexual dysfunction as a rule no further diagnostics is necessary. In patients with LUT dysfunction simple measurement of post void residual urine (preferably by the specialised nurse in the MS center) along with analysis of a voiding diary may suffice for first line treatment – symptom oriented management. Providing for proper bladder emptying is of paramount importance for alleviating symptoms and preventing infections. Ideally, the MS center would cooperate with an interested urologist, to whom complex cases should be referred. References: 1. Kalsi V, Fowler CJ. Therapy Insight: bladder dysfunction associated with multiple sclerosis. Nature Clinical Practice Urology 2005;2:492–501. 2. Goldstein I, Siroky MB, Sax DS, et al. Neurourologic abnormalities in multiple sclerosis. J Urol 1982;128:541–545. 3. Bemelmans BLH, Hommes OR, Van Kerrebroeck PEV, Lemmens WAJG, Doesburg WH, Debruyne FMJ. Evidence for early lower urinary tract dysfunction in clinically silent multiple sclerosis. J Urol 1991;145:1219–1224. 4. Nortvedt MW, Riise T, Myhr KM, Landtblom AM, Bakke A, Nyland HI. Reduced quality of life among multiple sclerosis patients with sexual disturbance and bladder dysfunction. Mult Scler 2001;7(4):231–235. 5. Redelings MD, McCoy L, Sorvillo F. Multiple sclerosis mortality and patterns of comorbidity in the United States from 1990 to 2001. Neuroepidemiology 2006;26:102–107. 6. Wyndaele JJ, Kovindha A, Madersbacher H, Radziszewski P, Ruffion QA, Schursch B, Igawa Y, Sakakibara R. Neurologic urinary and faecal incontinence. In Incontinence (P Abrams, L Cardozo, S Khoury, and A Wein Eds.). Health Publications Ltd./ Editions 21, Paris 2009, pp 797–960. 7. Litwiller SE, Frohman EM, Zimmern PE. Multiple sclerosis and the urologist. J Urol 1999;161:743–757.

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8. Ciancio SJ, Mulchnik SE, Rivera VM, Boone TB. Urodynamic pattern changes in multiple sclerosis. Urology 2001;57:239– 245. 9. Rodi Z, Vodusˇ ek DB, Denisˇ licˇ M. Clinical uro-neurophysiological investigation in multiple sclerosis. Eur J Neurol 1996;3:574–580. 10. Lycklama a` Nijeholt G, Barkhof F. Differences between subgroups of MS: MRI findings and correlation with histopathology. J Neurol Sci. 2003;206:173–174. 11. Lawrenson R, Wyndaele JJ, Vlachonicolis I, Farmer C, Glickman. Renal failure in patients with neurogenic lower urinary tract dysfunction. Neuropepidemiology 2001;20:138–143. 12. Rotar M, Trsinar B, Kisner K, Barbic M, Sedlar A, Gruden J, Vodusek DB: Correlations between the ICIQ-UI short form and urodynamic diagnosis. Published Online: Mar 3 2009, DOI: 10.1002/nau.20689. 13. Barbalias GA, Nikiforidis G, Liatsikos EN. Vesicourethral dysfunction associated with multiple sclerosis: clinical and urodynamic perspectives. J Urol 1998;160:106–111. 14. Hosker G, Rosier R, Gajewski J, Sand P. Dynamic testing. In Incontinence (P Abrams, L Cardozo, S Khoury, and A Wein Eds.). Health Publications Ltd./ Editions 21, Paris 2009:413– 522. 15. Hilton P, Hertogs K, Stanton SL. The use of desmopressin (DDAVP) for nocturia in women with multiple sclerosis. J Neurol Neurosurg Psychiatry 1983;46:854–855. 16. MacDonald R, Monga M, Fink HA, Wilt TJ. Neurotoxin treatments for urinary incontinence in subjects with spinal cord injury or multiple sclerosis: A systematic review of effectiveness and adverse effects. J Spinal Cord Med 2008;31:157–165. 17. Gallien P, Reymann JM, Amarenco G, Nicolas B, de Se`ze M, Bellissant E. Placebo controlled, randomised, double blind study of the effects of botulinum A toxin on detrusor sphincter dyssynergia in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 2005;76:1670–1676. 18. Primus G, Kramer G. Maximal external electrical stimulation for treatment of neurogenic or non-neurogenic urgency and/or urge incontinence. Neurourol Urodyn 1996;15:187–194. 19. Chartier-Kastler E, Richard F, Denys P, Perrigot M, Bussel B, Chatelain C. S3 sacral neuromodulation in patients with chronic refractory miction disorders. Presse Me´d 1997;26:466–467. 20. Centonze D, Petta F, Versace V, Rossi S, Torelli F, Prosperetti C, Rossi S, Marfia GA, Bernardi G, Koch G, Miano R, Boffa L, Finazzi-Agro E. Effects of motor cortex rTMS on lower urinary tract dysfunction in multiple sclerosis (In Process Citation). Mult Scler 2007;13:269–271. 21. Amarenco G, Bosc S, Boiteau F. Urologic complications of multiple sclerosis. 180 cases. Presse Me´d 1996;25:1007–1010. 22. De Ridder D, Ost D, Van der Aa F, Stagnaro M, Beneton C, Gross-Paju K, Eelen P, Limbourg H, Harper M, Segal JC, Fowler CJ, Nordenbo A. Conservative bladder management in advanced multiple sclerosis. Mult Scler 2005;11:694–699. Review. 23. Addis IB, Van Den Eeden SK, Wassel-Fyr CL, et al. Sexual activity and function in middle aged and older women. Obstet Gynecol 2006;107:755–764. 24. McCabe MP. Exacerbation of symptoms among people with multiple sclerosis: impact of sexuality. Arch Sex Behav 2004;33:593–601. 25. Beric A, Light JK. Anorgasmia in anterior spinal cord syndrome. J Neurol Neurosurg Psychiatry 1993;56:548–551. 26. Smith EM, Bodner DR. Sexual dysfunction after spinal cord injury. Urol Clin North Am 1993;20:535–542. 27. Lundberg PO. Physiology of female sexual function and effect of neurologic disease. In Neurology of Bladder, Bowel, and Sexual Dysfunction. (CJ Fowler Ed.). Boston, ButterworthHeinemann 1999, p 33.


28. Giuliano FA, Rampin O, Benoit G, et al. Neural control of penile erection. In Impotence. (A Melman, ed.). Urol Clin North Am 1995;22: pp 747–766. 29. Sipski ML, Alexander CJ, Rosen RC. Physiological parameters associated with psychogenic sexual arousal in women with complete spinal cord injuries. Arch Phys Med Rehabil 1995;76:811–818. 30. Brindley GS, Gillan P. Men and women who do not have orgasms. Br J Psychiatry 1982;140:351–356. 31. Janus SS, Janus CL. The Janus Report on Sexual Behavior. New York, John Wiley & Sons, 1993. 32. Marson L. Central nervous system control. In Textbook of Erectile Dysfunction (C Carson, R Kirby, I Goldstein, Eds.). Oxford, Isis Medical Media, 1999, p. 73. 33. Zivadinov R, Zorzon M, Locatelli L, et al. Sexual function in multiple sclerosis: a MRI, neurophysiological and urodynamic study. J Neurol Sci 2003;210:73–76. 34. Betts CD. Bladder and sexual dysfunction in multiple sclerosis. In Neurology of Bladder, Bowel, and Sexual Dysfunction. (CJ Fowler Ed.). Boston, Butterworth-Heinemann 1999, p 289. 35. Ghezzi A, Zaffaroni M, Baldini S, et al. Sexual dysfunction in male multiple sclerosis patients in relation to clinical findings. Eur J Neurol 1996;3:462. 36. Fowler CJ, Miller JR, Sharief MK, et al. A double blind, randomised study of sildenafil citrate for erectile dysfunction in men with multiple sclerosis. J Neurol Neurosurg Psychiatry 2005;76:700–705. 37. Valleroy M, Kraft G: Sexual dysfunction in multiple sclerosis. Arch Phys Med Rehabil 1984;65:125–128. 38. Minderhoud JM, Leemhuis JG, Kremer J, et al. Sexual disturbances arising from multiple sclerosis. Acta Neurol Scand 1984;70:299–306. 39. Barak Y, Achiron A, Elizur A, et al. Sexual dysfunction in relapsing-remitting multiple sclerosis: magnetic resonance imaging, clinical, and psychological correlates. J Psychiatry Neurosci 1996;21:255–258. 40. Shaughnessy L, Schuchman M, Ghumra M, et al. Sexual dysfunction in multiple sclerosis. In Sexual and Reproductive Neurorehabilitation. (M Aisen. Ed.). Totowa, NJ, Humana Press, 1997, p 169. 41. Yang CC, Bowen JR, Kraft GH, et al. Cortical evoked potentials of the dorsal nerve of the clitoris and female sexual dysfunction in multiple sclerosis. J Urol 2000;164:2010– 2013. 42. Hulter BM, Lundberg PO. Genital vibratory perception threshold (VPT) measurements in women with sexual dysfunction and/or sexual pain disorders. Eur J Sexual Health 2006;15 (Suppl. S33). 43. Rosen RC, Riley A, Wagner G, et al. An international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49:822. 44. NIH Consensus Development Panel on Impotence. Impotence. JAMA 1993;270:83–90. 45. Wagner TH, Patrick DL, McKenna SP, et al. Cross-cultural development of a quality of life measure for men with erection difficulties. Qual Life Res 1996;5:443–449. 46. Rosen R, Brown C, Heiman J, et al. The Female Sexual Function Index (FSFI): a multidimensional self-report instrument for the assessment of female sexual function. J Sex Marital Ther 2000;26:191–208. 47. Lue TF. Editorial comment. J Urol 1996;156:552. 48. Dasgupta R, Wiseman OJ, Kanabar G, et al. Efficacy of sildenafil in the treatment of female sexual dysfunction due to multiple sclerosis. J Urol 2004;171:1189–1193. 49. Salonia A, Rigatti P, Montorsi F. Sildenafil in erectile dysfunction: a critical review. Curr Med Res Opin 2003;19:241–262.

50. Zusman RM, Morales A, Glasser DB, et al. Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 1999;83:35C. 51. Betts CD, Jones SJ, Fowler CG, et al. Erectile dysfunction in multiple sclerosis. Brain 1994;117:1303–1310. 52. Lundberg PO. Priapism. Review. Scand J Sexol 2000;3:13–24. 53. Rivas D, Chancellor M. Complications associated with the use of vacuum constriction devices for erectile dysfunction in the spinal cord injured population. J Am Paraplegia Soc 1994;17:136–139. 54. Singer C. Erectile and ejaculatory disturbances: overview of diagnosis and treatment. In Sexual Dysfunction: A NeuroMedical Approach. (C Singer, WJ Weiner, Eds.). Armonk, NY, Futura, 1994, p 45. 55. Kandeel FR, Koussa VK, Swerdloff RS. Male sexual function and its disorders: physiology, pathophysiology, clinical investigation, and treatment. Endocr Rev 2001;22:342–388.

Immunotherapy of multiple sclerosis Sven G. Meuth, Stefan Bittner & Heinz Wiendl Department of Neurology, University of Wrzburg, Wrzburg, Germany Abstract:Multiple sclerosis (MS) is regarded as a prototypic inflammatory autoimmune central nervous system disorder causing neurological disability in young adults. Recommended basic immunomodulatory therapies of MS are currently interferon beta and glatiramer acetate. Both have proven to be clinically and paraclinically effective and clinical evidence suggests that treatment should be initiated as early as possible. However, despite the fact that therapeutic options for MS have significantly been widened over the past decade there is still tremendous activity in the search for new treatment options for MS. One important development in the field is reflected by the substantial number of promising results for oral therapies. Various phase III clinical trials are currently being initiated or are already underway evaluating the efficacy of a variety of orally administered agents, including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid. It is hoped that these oral therapies for MS further broaden our armament for MS therapy. Introduction: Multiple sclerosis (MS) is the most common neurological cause of disability in young adults with a lifetime risk of one in 400. MS is considered as an autoimmune inflammatory disorder of the central nervous system (CNS) which is influenced by environmental factors and susceptibility genes (1,2). Both temporal and spatial dissemination of lesions in the CNS is needed to clinically diagnose MS. The risk for developing clinically definite MS (CDMS) is highest when asymptomatic white-matter lesions in the brain can be found by MRI (3). But also patients with an isolated clinical deficit as for example optic neuritis (clinically isolated syndrome; CIS) are at risk of developing MS in the course of time. In one follow-up study, the 10-year risk of developing CDMS was 39%, the 20-year risk was 49%, the 30-year risk was 54% and the 40-year risk was 60% (4). The diagnostic criteria for MS (McDonald criteria) take these findings into consideration and allow diagnosing MS even before a second clinical event. Instead MRI evidence of dissemination of CNS lesions in time and space is sufficient for the diagnosis of MS (5,6). The presence of oligoclonal bands doubles the risk for having a second attack while not influencing the development of disability (7). In the course of years, the majority of MS patients develop progressive neurological disabilities. About 50% of MS patients will use a cane to support walking within 10 years and the disease course of most MS patients will develop into a secondary progressive form of the disease displaying substantial residual clinical deficits (8,9). The disease activity in early phases of the


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disease is apparently a strong predictor for the timing of disability as irreversible deficits may accumulate with each disease exacerbation. Therefore CIS and RRMS though not classified as progressive forms of MS strongly contribute to progressive persistent clinical impairment. This concept is the reason to initiate MS treatment at the earliest time point possible. The therapeutic approaches to the various forms of MS (CIS, RRMS, SPMS, PPMS) have been changed profoundly over the last decade and several novel disease-modifying therapies have been established (10–12). The current treatment strategies of the various subforms of MS will be discussed in the following paragraphs. Furthermore we describe a number of new, oral substances including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid currently tested in clinical trials. These substances are awaited to broaden our armament for MS therapy. Treatment of clinically isolated syndromes: Interferon beta: The effect of interferon beta (IFN) on the progression time from CIS to CDMS has been investigated in three multicenter, double-blind, placebo-controlled trials: The Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial in 2000 (13), the Early Treatment Of Multiple Sclerosis (ETOMS) trial in 2001 (14) and the Betaferon/Betaseron in Newly Emerging Multiple Sclerosis For Initial Treatment (BENEFIT) trial in 2006. 383 patients with a first demyelinating event were enrolled in the CHAMPS study. In addition, patients had to exhibit two ore more asymptomatic lesions on MRI to be included into the study (13). The treatment group received intramuscular IFN beta-1a 30 lg once a week. The interim analysis showed a significant lower cumulative probability of the development of CDMS in the IFN beta than in the placebo group after 3 years (OR 0.56; 95% CI 0.38–0.81; P = 0.002). Therefore the trial was stopped and assessment of both outcome measures (development of CDMS and changes in findings on MRI of the brain) revealed that treatment benefit was also seen in patient subgroups based on age, gender and baseline brain MRI parameters. The beneficial effect of IFN beta-1a when initiated at the first clinical demyelinating event in patients with MRI evidence of subclinical demyelination in the brain was observed in patients with different manifestations (spinal cord syndromes, brainstem-cerebellar syndromes and optic neuritis) (15). The CHAMPIONS study (Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurological Surveillance) was initiated as a 5-year open-label extension of the CHAMPS study in order to assess the long-term efficacy of early treatment with IFN beta. 53% of patients enrolled in CHAMPIONS (203/383; n = 100, initial treatment group; n = 103, delayed treatment group). The median time to start IFN beta-1 treatment in the delayed treatment group was 29 months. The cumulative probability of development of CDMS was significantly reduced in the initial treatment group (5 year incidence 36 ± 9%) in comparison to the delayed treatment group (49 ± 10%; P = 0.03) (16). In the ETOMS study, 309 patients were recruited but four clinically silent white matter lesions (or only three if one of them was enhancing after administration of gadolinium) were required for this study (14). Half of the patients received subcutaneous IFN beta-1a at 22 lg once a week and half placebo. Progression to CDMS was observed in fewer patients in the IFN group than in the placebo group (OR 0.61; 95% CI 0.37 – 0.99; P = 0.045), the time point at which 30% of patients had developed CDMS was significantly later in the treatment group and the number of relapse rates per year were significantly lower. MRI readout revealed fewer new lesion formations in the IFN group. In the BENEFIT study 468 patients were recruited after their first demyelinating event and two clinically silent brain MRI lesions. Half received subcutaneous IFN beta-1b 250 lg e.o.d. and half placebo (17). 45% of the placebo patients progressed to CDMS

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and 85% fulfilled the McDonald criteria after 2 years. The treatment group showed significantly delayed conversion to CDMS (OR 0.50; 95% CI 0.36 – 0.70; P < 0.0001) and to McDonald criteria MS (OR 0.54; 95% CI 0.43 – 0.67; P < 0.00001). A post-randomisation follow-up of all patients over an additional 3 years which was completed by 392 patients (84%) showed that the risk of progression of disability was reduced by 40% (18). Any patient with a high risk for converting into CDMS may therefore be considered as suitable for IFN beta treatment. It is nevertheless still challenging to sort out those CIS patients who will develop CDMS and this question has been addressed by a number of studies. The majority of patients with CIS and additional asymptomatic white-matter lesions as assessed by MRI will convert into CDMS (19–23). The Optic Neuritis Treatment Trial (ONTT) showed that the number of brain lesions in patients with monosymptomatic optic neuritis is a strong marker to identify patients with a high risk of developing CDMS (24). Nearly 90% of patients with CIS and an abnormal MRI in the beginning were found to progress into CDMS in a 14-year prospective study (3) in contrast to only 21% of the patients with normal baseline MRI. The disease course after 20 years of follow-up was relapsingremitting in 58% while 42% had further progressed into SPMS. A moderate correlation between T2 lesion volume at all time-points and 20-years EDSS was found (r(s) values 0.48 to 0.67; P < 0.001 and MSFC z-score (r(s) values (–0.50) to (–0.61); P < 0.001) (25). There are several reasons to initiate therapy with IFN beta without unnecessary retardation (26). First, pathological events in the beginning of the disease are a strong predictor for the timing of disability and axonal damage caused by inflammation is an early feature of MS. Moreover, the inflammatory process in RRMS proceeds continuously and is not restricted to phases with clinical symptoms. Finally, the activity of the immune system may be influenced more easily in the beginning of the disease and it may be more difficult to deal with later on. Therefore, an early immunomodulatory therapy is the most effective strategy at the moment to control and limit the progression of disease (27). Surrogate markers like MRI will help to identify those patients with CIS who will profit most from early treatment with IFN beta. Glatiramer acetate: The data of a randomized, placebo-controlled phase III study concerning the effect of glatiramer acetate have not been published so far. However, the study was recently completed and communications at a number of meetings suggest that the beneficial influence of GA on disease progression from CIS to CDMS might be comparable to the effect of the interferons. Approval of GA for CIS has been granted recently. Treatment of relapsing-remitting MS: Various agents are currently approved by the FDA (US Food and Drug Administration) for the treatment of RRMS: Three different IFN beta formulations (subcutaneous IFN beta-1b, Betaferon/Betaseron/Extavia; intramuscular IFN beta-1a, Avonex; subcutaneous IFN beta1a, Rebif), glatiramer acetate (Copaxone), and mitoxantrone (Novantrone). However, there is still an intent discussion about which disease-modifying drug should be chosen. Interferon beta: While clearly effective in MS in a number of clinical trials, the exact mode of action of the interferons is still a matter of debate and various biological activities have been described so far. Among others, interferons inhibit the proliferation of leukocytes, hamper antigen presentation, shift the cytokine production towards an anti-inflammatory Th2 phenotype and reduce the T cell migration capacity across the blood-brain barrier by down-regulation the expression of adhesion molecules and matrix metalloproteinases (28–30). The first class I trial (multicenter, randomized, double-blind, placebo-controlled) in RRMS demonstrated clinical efficacy of IFN beta-1b (31–33). 372 patients with a maximal EDSS of 5.5 and at least two exacerbations in the previous 2 years were included


into the study. One third received 1.6 million international units (MIU; 50 lg) of subcutaneous IFN beta-1b, one third 8 MIU (250 lg) IFN beta-1b and one third placebo. The annual exacerbation rate was investigated after 2 years and was significantly lowered in both treatment groups compared with the placebo group (annual exacerbation rate placebo: 1.27; 1.6 MIU: 1.17 and 8 MIU: 0.84. Statistical evaluation: 1.6 MIU vs. placebo, P = 0.0101; 8 MIU vs. placebo, P = 0.0001; 8 MIU vs. 1.6 MIU, P = 0.0086). These results might suggest a dose-dependent effect of IFN beta-1b treatment as well, but this was not a primary outcome measure in the design of the study. Evaluation of MRI (T2) revealed that IFN beta-1b patients had significantly lower lesion loads than patients treated with placebo. The 8-MIU treatment also reduced the confirmed 1-point EDSS progression rate but statistical significance was not reached for this parameter (29%, P = 0.016). The effect of intramuscularly administered IFN beta-1a treatment was studied in a multicenter, randomized, placebo-controlled study (34–36). 301 patients with an EDSS of 1.0 to 3.5 were included who in addition suffered from at least two clinical events in the last 3 years. Dosage was 6 MIU (30 lg) of intramuscular IFN beta-1a once weekly vs. placebo. The primary outcome measure in this study was time to sustained progression of at least 1.0 point on the EDSS scale. The trial was stopped earlier than anticipated in the beginning and therefore only 57% of the patients enrolled (172 patients) completed 2 years of IFN beta-1a treatment. Study medication resulted in a significantly delayed time to sustained EDSS progression (-37%, P = 0.02). The Kaplan-Meier estimate of the percentage of patients with EDSS progression by the end of the 2 years was 34.9% in the placebo group vs. 21.9% in the treatment group. IFN beta-1a treated patients also had a significantly reduced number of disease exacerbations (P = 0.03) and a significantly lower number of gadolinium-enhanced lesions in the brain on MRI (-33%, P = 0.05) compared with the place group. The annual exacerbation rate over 2 years was reduced from 0.90 in the placebo-arm to 0.61 in the IFN beta-1a-arm. An interesting finding was that the reduction in the attack rate in the therapy group didn’t reach statistical significance in the first year (-9.6%) but the reduction in patients after 2 years was significantly lower (32%, P = 0.002). This result suggests that the beneficial effect of IFN beta-1a might be delayed. However, patients who fully completed the 2 years already had a similar reduction in the attack rate in the first year (-29%) which on the other hand suggests that the 2-year completers do not represent the study cohort as a whole. Anyhow, IFN beta-1a clearly showed a significant effect in RRMS in this clinical trial as it reduced the accumulation of permanent physical disability, frequency of exacerbations and disease activity measured by gadloinium-enhanced lesions on brain MRI. The effect of IFN beta-1a administered subcutaneously was investigated in the Prevention of Relapses and Disability by IFN beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study. PRISMS was a much larger multicenter, randomized, doubleblind, placebo-controlled trial (Class I) in 560 RRMS patients with a maximal EDSS score of 5.0 and additionally at least two relapses in the previous 2 years (37.38). Patients were divided into three groups: Subcutaneous IFN beta-1a at 22 lg (6 MIU) or 44 lg (12 MIU) three times a week or placebo. The relapse rate after 2 years was significantly reduced with both doses of IFN beta-1a than with placebo treatment (mean number per patient: 1.82 for 22 lg, 1.73 for 44 lg and 2.56 with placebo). Risk reduction was calculated as 27% (95% CI 14 – 39) for 22 lg and 33% (95% CI 21 – 44) for 44 lg. MRI assessment revealed significant improvement in the IFN beta-1a treatment group when compared to the placebo arm (median number of T2 active lesions -78%, P < 0.0001 and volume of T2 lesions -14.7%, P < 0.0001). Moreover, the confirmed 1-point EDSS progression rate was also significantly reduced (-30%, P < 0.05) by IFN beta-1a medication. Taken

together this study further underlines the therapeutical value of IFN beta in RRMS patients. Additionally, this clinical trial demonstrates that IFN beta can significantly lower both the T2 disease burden as well as the confirmed 1 –point EDSS progression. This study was continued for another 2 years and named therefore PRISMS-4. The former placebo-treated patients were now rerandomized double-blindly to one of the two treatment groups receiving either a low or high dosage of IFN beta-1a (39). This extensions study can be discussed because a bias can not be excluded based on previous drop-outs and the re-randomization. Nevertheless, this extension phase showed both a clinical and a benefit on MRI level for IFN beta-1a. The PRISMS-4 study shows that patients still benefit from treatment in the third and fourth year although the first 2 years of therapy were associated with the greatest reduction in relapse rate and MRI burden. A dosedependent effect after 4 years was only seen for some clinical and MRI outcomes but not for others. The OWIMS (Once Weekly Interferon for MS Study) trial IFN beta-1a was administered subcutaneously in a dosage of 22 lg or 44 lg in comparison with placebo. After 48 weeks, a benefit on MRI level was confirmed for IFN beta-1a at 22 lg in RRMS but no significant clinical effect was observed (40). IFN beta therapy often causes side effects. The most common are flu-like symptoms, elevation of liver enzymes and lymphopenia (32,34,38). These side effects, however, are generally mild and rarely last longer than some months after statement of treatment. Therapy can therefore be continued in most cases. Subcutaneous injection of IFN beta can also cause reactions at the injection site and side effects of IFN beta are observed more often at higher doses. The use of auto-injectors as well as training of patients to correctly inject IFN beta and concomitant anti-inflammatory medication can reduce these problems and therefore increase the compliance of patients. In summary, IFN beta is effective in RRMS both on a clinical and on MRI level and IFN beta therapy may be considered in any patient with RRMS. Glatiramer acetate: Glatiramer acetate is a random polypeptide consisting of four different amino acids (glutamic acid, lysine, alanine and tyrosine) in a specific molar ratio. So far, its immunological mechanisms of action are still not fully unravelled but some of them seem to be distinct from those of the interferons. It is suspected that GA treatment leads to a shift from a Th1 to a Th2 phenotype, induces antigen specific T suppressor cells that may cross-react with putative autoantigens in the CNS and that it also directly inhibits antigen presentation (29,41). In a large, multicenter, randomized, double-blind and placebocontrolled trial with 251 RRMS patients half of them received 20 mg subcutaneous glatriamer acetate daily and half placebo. To be enrolled patients had to have an EDSS score between 0 and 5.0 and they had to have suffered from at least two clinical attacks in the previous 2 years. The study was initiated for 2 years with an extension phase of another third year (42). The relapse rate over 2 years was significantly lower in GA treated patients (-29%, P = 0.007). MRI parameters were not investigated in this clinical trial. However, a second short duration trial specifically addressed MRI findings upon GA treatment (14). 249 RRMS patients with a maximal EDSS score of 5.0 and at least one gadolinium-enhancing lesion on baseline MRI were enrolled and the treatment group showed a significant reduction in the total number of enhancing lesions (-35%, P = 0.001). Interestingly, the treatment effect only occurred after 6 months of treatment. This delay indicates that GA rather has a long-term immunomodulatory effect and rather no immediate immunosuppressive effect or effect on the blood-brain barrier. In an open-label extension trail all patients were assigned to GA for another 9 months. A reduction of 54% in the mean number of enhancing lesions for the previous placebo treated patients and an additional reduction of 25% for those always


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treated with GA was reported. These data suggest a sustained effect of glatiramer acetate over the period of one and a half years based on MRI parameters (43). A recent study concerning the long-term clinical efficacy as well as long-term safety profile of GA over 22 years was published in 2008. A lower relapse rate and a slower EDSS progression was found in this open-label observational study in RRMS patients (44). However, the study cohort is self-selected and therefore a bias of this study towards treatment effects can not be excluded. GA therapy generally causes only mild side effects and injection site reactions are usually minimal (45). In summary, GA reduces clinical relapses in patients with RRMS and therefore can be recommended for treatment of these patients. Treatment of secondary progressive MS: Patients with SPMS are still a great challenge in terms of therapeutic treatment. It must be taken into account that the degree of disability and the inflammatory activity as determined by the annual relapse rate may vary widely in these patients. A successful therapeutic approach to patients with SPMS must therefore be personalized and especially weigh carefully between the expected clinical benefit and the adverse effects of the chosen therapy which might potentially occur. Interferon beta: Effect of IFN beta treatment in SPMS patients has been tested in several large, randomized, placebo-controlled trials. One trial in Europe and one in North America investigating IFN beta-1b in SPMS have been reported. 718 patients with and EDSS of 3.0 to 6.5 were enrolled in the European trail. Patients also had to have either two relapses or more than a 1.0 point increase in the EDSS score in the previous 2 years. Half were treated with the standard dose of IFN beta-1b and half received placebo (46). IFN beta-1b treated patients had a significantly reduced 1-point EDSS progression rate (-33%, P = 0.0008) than placebo-treated patients and a significant improvement was also found concerning clinical and MRI attack rates and the volume of white-matter disease assessed by MRI. Subgroup analysis of patients with our without clinical attacks in the 2 years prior to study initiation or analysis of those patients who did or did not have attacks during the study all demonstrated similar therapeutical effects of IFN beta-1b. However, patients with an EDSS of at least 6.0 profited less and the North American trial failed to show any difference in time to confirmed progression of EDSS scores between both IFN beta-1b treatment groups and the placebo group (47). A retrospective analysis was conducted to unravel the reason for the discrepancy between the European and the North American trial (48) and it was found out that the European patients were situated in an earlier phase of SPMS and that their disease was more active both pre-study (number of relapses, MRI data) as well as during the study (EDSS score, number of relapses, MRI data). This indicates that IFN beta is more effective in the relapsing phase of the disease course. The Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) trial which tested the effect of subcutaneous IFN beta-1a in SPMS similarly failed to find a statistically significant reduction in the confirmed 1-point EDSS progression rate (49). Patients were post hoc separated into those with or without relapses and this analysis showed a beneficial therapeutic effect on the confirmed 1-point EDSS progression rate in the patient subgroup with attacks (P = 0.027). Such a reanalysis however gives raise to criticism about the validity of the results. The data would once more support the concept that IFN beta is most effective in patients with a residual inflammatory activity in early phases of SPMS. The IMPACT trial investigated the effect of intramuscular IFN beta-1a in 436 patients with SPMS and an EDSS score of 3.5–6.5 (50). Patients either received 60 lg IFN beta-1a (twice the FDAapproved dose for RRMS) or placebo by intramuscular injection

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once a week over 2 years. The MS Functional Composite (MSFC) which includes quantitative tests of ambulation (timed 25-foot walk), arm function (nine-hole peg test) and cognition (paced auditory serial addition test) was chosen as a primary outcome measure. IFN beta-1a led to a significant amelioration of MSFC scale (P = 0.033) and this was mostly due to improvement in the nine-hole peg test. No difference was found in EDSS score. Patients treated with IFN beta-1a had significantly fewer relapses (P = 0.008) and it is therefore appropriate to consider IFN beta for treatment in SPMS patients who still experience relapses but not in those patients without clinical attacks. IFN beta-1b was approved for the treatment of SPMS patients in the US by the FDA and the European agency (EMEA) also approved IFN beta-1b and subcutaneous IFN beta-1a for SPMS with superimposed relapses. The efficacy of IFN-beta in patients with SPMS who do not experience relapses any more is unclear at the moment. Treatment of primary progressive MS: Primary progressive MS appears to be different from relapsing-remitting MS in terms of pathology and clinical appearance. So far, treatments for RRMS have failed in PPMS and neither the interferons nor glatiramer acetate have shown to be effective in this subform of MS and therefore can not be recommended (51,52). Oral disease modifying treatments for MS: Cladribine: The adenosine deaminase-resistant nucleoside analogue cladribine accumulates – after phosphorylation into the active triphosphate deoxynucleotide – in lymphocytes and monocytes causing DNA damage and subsequent cell death (53,54). Since 1993 the substance is approved for the treatment of hairy cell leukemia. Smaller placebo-controlled trials in chronic progressive MS (55,56) and RRMS patients (57) demonstrated that cladribine delays disease progression, nearly completely eliminates gadoliniumenhanced T1 lesions and stabilizes T2 lesion volume. Anyhow, a multicenter, double-blind, placebo controlled trial of cladribine in 159 patients with SPMS and PPMS showed no significant clinical benefit after 1 year (0.7 mg/kg, 2.1 mg/kg vs. placebo) (58–60). Side effects included upper respiratory tract infarctions, muscle weakness and injection site reactions. Since cladribine reduced the number and volume of gadolinium-enhanced T1-weighted brain lesions and overall T2 lesion load, there is a discrepancy between those MRI endpoints and the observed clinical effects (60). Meanwhile the substance is available as an oral formulation and a randomized, double-blind, placebo controlled phase III trial (1290 RRMS patients) has been initiated (CLARITY). The outcome parameters include relapse rate, EDSS progression and MRI activity and results from this trial are expected in 2009. Furthermore two other phase III trials investigate the substance in CIS patients (ORACLE) and pre-treated RRMS patients (ONWARD). Teriflunomide: Teriflunomide belongs to a group of malononitrilamide agents blocking the mitochondrial enzyme dihydroorotatedehydrogenase, is an analogue of leflonomide (known from the therapy of rheumatoid arthritis) and inhibits T and B cell proliferation by energy reduction (61,62). Teriflunomide has been found to display beneficial effects on the EAE model probably by suppression of TNFa and IL2 (63,64). Results from a clinical phase II trial testing teriflunomide (7 or 14 mg/day vs. placebo over 36 weeks) in patients with RRMS and SPMS have recently been published (65). The primary endpoint of the study was met since subjects receiving verum of either dose had significantly less active MS lesions and a reduced number of new lesions on MRI. Furthermore EDSS progression was delayed (high dose group) and a trend towards reduction in relapses was observed. Besides respiratory tract infections and headache the substance was well tolerated. Anyhow, serious side effects (e.g. toxic liver necrosis and pancytopenia) have been described in


patients with rheumatoid arthritis. Therefore final appraisal of the substance has to wait for the results of an ongoing phase III trial investigating the safety and efficacy of the drug in MS. Laquinimod: Laquinimod (ABR-215062, SAIK-MS) is a novel orally active immunomodulator which is approximately 20 times more potent than its ’’ancestor’’ roquinimex (linomide), at least in EAE (66). The synthetic compound is characterized by a convincing oral bioavailability and it mediates immunoregulatory properties without general immunosuppressive actions. In a number of different animal models mimicking autoimmune or inflammatory diseases the sustained inhibitory activity of the immune system could be shown (67–69). In clinical phase II studies of MS linomide significantly reduced active MRI lesions, but a phase II trial had to be halted due to unexpected severe side effects (e.g. serositis and myocardial infarction) (70,71). Two phase I studies indicated that laquinimod is well tolerated and results from a double-blind, randomized, multicenter proof-of principle study testing 0.1 mg/day and 0.3 mg/day vs. placebo in 180 patients with RRMS have recently been published (72). A significant difference between laquinimod 0.3 mg/day and placebo was observed for the primary outcome measure, i.e. the mean cumulative number of active MRI lesions (5.24 vs. 9.44, respectively; 44% reduction). This effect was even more pronounced in those patients with at least one active lesion at baseline (52% reduction). Clinical outcome parameters (relapse rate, disability) were not different between the groups. Based on these data laquinimod has a good potential to become a safe and effective oral treatment in MS. The substance is currently tested in a large phase III trial. Fingolimod: The orally available compound FTY720 (fingolimod, 2-amino-2-(2-(4-octylphenyl)ethyl)-propan-1,3-diole) is derived from the fungus Isaria sinclairii and exhibits profound and unique immunoregulatory effects by targeting sphingosine-1phosphate (S1P) receptors (73). After in vivo phosphorylation FTY720 forms FTY720P which leads to internalization of the SIP1 receptor, resulting in a rapid and reversible inhibition of lymphocyte egress from peripheral lymph nodes, which prevents auto reactive T cells from sites of autoimmune inflammation (74). Further effects were demonstrated on dendritic, endothelial and glia cells (75–77). The therapeutic potency of this agent has already been demonstrated in acute and chronic EAE models (78,79). The results of an international, double-blind, placebo-controlled phase II study involving 281 subjects with active RR-MS have recently been released (80). The participants received one of two doses of oral FTY720 (1.25 mg/day or 5 mg/day, respectively) or placebo for 6 months. Both dosages of FTY720 significantly reduced the number of Gd-enhancing lesions and led to a 45% reduction in the annualized relapse rate. The 18-month extension phase of the trial included a switch of the placebo group to verum and demon stared sustained efficacy. Side effects included colds, sinusitis, mild headaches and gastrointestinal disorders. The underlying mechanism of drug action however warrants extensive safety analysis, especially with longer periods of administration. Two large phase III studies of FTY720 in MS are currently launched (2006). One study is testing the safety and efficacy of two doses (1.25 mg/day and 0.5 mg/day) against placebo (FREEDOMS I and II study), the other assesses the efficacy of FTY720 in a headto-head design against an active comparator (IFNß-1a i.m. once weekly; TRANSFORMS study). Results are expected in 2009. In these trials, two fatal cases of viral encephalitis were recently reported (www.reuters.com/article/CHMMFG/idUSL058 6762720080605). Fumaric acid: Oral application of fumaric acid esters (BG12, fumarate) represents an other strategy to induce beneficial immune modulation by enhancing Th2-driven responses in MS (81). An exploratory, prospective, open-label study of fumaric acid esters was conducted in patients with RR-MS. In this small trial

including 10 subjects, a reduction of relapse rate and volume of gadolinium-enhancing lesions as assessed by MRI was observed after 12 weeks (82). However, 3 patients discontinued treatment during the first 3 weeks of the study and several patients experienced mild to moderate gastrointestinal discomfort. A double-blind, placebo-controlled phase II study was performed to further test the safety and effectiveness in controlling disease course and development of MS brain lesions. In January 2006, the product sponsor announced that the study met its primary endpoint by reducing the number of active MRI lesions with 6 month of treatment (http://www.FDA.org). Details about the secondary outcome measures have not been released so far. Conclusion: Both IFN beta and GA have proven efficacy in RRMS and represent first line treatment choices for those patients. Additionally, SPMS patients with superimposed relapses will profit from those treatments. IFN beta and GA still remain the most recognized therapeutic options for MS treatment but many novel treatment strategies are currently tested in clinical trials and some of them are expected to be approved in the following years, among them oral therapies. Various phase III clinical trials are currently being initiated or are already underway evaluating the efficacy of a variety of orally administered agents, including cladribine, teriflunomide, laquinimod, fingolimod and fumaric acid. Results from these studies are awaited from both, clinicians and patients, and promising new candidates will help to further improve therapeutic possibilities in MS treatment. Re´fe´rences: 1. Compston A & Coles A. Multiple sclerosis. Lancet 2002;359:1221–1231. 2. Kieseier BC, Hemmer B, & Hartung HP. Multiple sclerosis– novel insights and new therapeutic strategies. Curr Opin Neurol 2005;18:211–220. 3. Brex PA, Ciccarelli O, OÕRiordan JI, Sailer M, Thompson AJ, & Miller DH. A longitudinal study of abnormalities on MRI and disability from multiple sclerosis. N Engl J Med 2002;346:158–164. 4. Rodriguez M, Siva A, Cross SA, OÕBrien PC, & Kurland LT. Optic neuritis: a population-based study in Olmsted County, Minnesota. Neurology 1995;45:244–250. 5. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, & Wolinsky JS. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127. 6. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, OÕConnor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, & Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the ‘‘McDonald Criteria’’. Ann Neurol 2005;58:840–846. 7. Tintore M, Rovira A, Rio J, Tur C, Pelayo R, Nos C, Tellez N, Perkal H, Comabella M, Sastre-Garriga J, & Montalban X. Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology 2008;70:1079–1083. 8. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, & Ebers GC. The natural history of multiple sclerosis: a geographically based study. 2. Predictive value of the early clinical course. Brain 1989;112 (Pt 6):1419– 1428. 9. Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, & Ebers GC. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989;112 (Pt 1):133–146.


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JOINT MEETING OF THE PULA CONGRESS WITH ALPS-ADRIA NEUROSCIENCE SECTION: GENDER DIFFERENCES IN NEUROLOGIC AND PSYCHIATRIC DISORDERS Are there gender differences in neurologic and psychiatric disturbances? Vida Demarin & Vlasta Vukovic´ University Department of Neurology, Sestre Milosrdnice University Hospital, Reference Center for Neurovascular Disorders and Reference Center for Headache of the Ministry of Health and Social Welfare of the Republic of Croatia, Vinogradska 29, Zagreb, Croatia Sex differences in human behavior have led to the hypothesis that sex differences in brain anatomy and physiology contribute to these behavioral differences. Furthermore, sex differences have an influence on the prevalence of certain neurological and psychiatric diseases. Some genetic diseases are different in women than in men. In many of these disorders, affected females show severe involvement of the nervous system with mental retardation. Sex-linked disorders include oral-facial-digital dysplasia type I, polycystic kidney-berry aneurysm disease, CHILD syndrome(congenital hemidysplasia with ichthyosiform erythroderma and limb defects), X-linked chondrodysplasia puncata 2, Aicardi syndrome, Rett syndrome, X-linked Kennedy spinobulbar atrophy, Lesch-Hyhan syndrome and certain metabolic encephalopathies. Headaches, overall, are more frequently present in women. The prevalence of migraine is 12–18% in women and 3–6% in men; in early childhood prevalence of migraine is equal among sexes, however in puberty the prevalence increases in females. On the contrary, cluster headache is 4 times more likely to occur in men over all ages. Studies have shown that there is a correlation between headaches, namely migraine with aura, and stroke which is of great importance if we take into consideration the fact that the prevalence of migraine is far greater in women than in men. One population based study examined the correlation between chronic unspecified headache and stroke and found that the risk of stroke in men who have had headaches during the past year is 4 times higher than in those without headaches, whereas that risk was only 2 times higher in men with headaches during the past 5 years. Among women, there was also a direct but statistically nonsignificant association between headache and the risk of stroke, thus the authors have concluded that chronic headache is an independent predictor of stroke among men and that it may be a marker of the underlying disease process leading to acute stroke seeing how the connection was strongest during a 1-year follow-up. In a study including 3610 women with active migraine, 39.7% had migraine with aura; compared with women with no migraine history, these women had increased hazard ratios for stroke: 1.91 for ischemic stroke, 2.08 for myocardial infarction, 1.74 for coronary revascularization, 1.71 for angina, and 2.33 for death due to ischemic cardiovascular disease (68). A similar study failed to find a correlation between migraine without aura or ordinary headache and ischemic or hemorrhagic stroke, but found a connection between migraine with aura and

stroke; these women had a 1.71 times increased risk of ischemic stroke, even in women 55 years of age and younger. However, this is an increase in relative risk; in terms of absolute risk this means only 3.8 additional cases per year per 10 000 women (69). Women aged 15–49 years with probable migraine with aura have a 1.5 increased risk for stroke, and women who use oral contraceptives or smoke have even a seven-fold increased risk for stroke compared with women with probable migraine with aura who are non-smokers or do not use oral contraceptives. Sub-analysis from the Women’s Health Study revealed that women who have active migraine without aura do not have an increased risk for any cerebrovascular events, but women with active migraine with aura have a 2 fold increased risk for major cardiovascular disease and stroke compared with women with no migraine. Since migraine has a complex pathophysiology, especially migraine with aura, which include vascular mechanisms, connection between migraine and stroke may have similar background. The incidence and prevalence rates for epilepsy are higher in men (3.4%) than in women (2.8%). Women with epilepsy have a greater risk for syndromes associated with infertility, such as hypothalamic-pituitary disruption, polycystic ovary-like syndrome and anovulatory cycles. Catamenial seizures are influenced by cyclical hormonal changes na doccur in one third to one-half of women with epilepsy. Multiple sclerosis is the leading cause of neurologic disability in young adults. Multiple sclerosis is more common in women than in men, by a ratio of at least 2:1. Possible hormonal factors, maternal factors and X-linked gene factors are thought to be responsible for this sex preference. The majority of patients present with a relapsing-remitting disease, while a minority presents with a primary or secondary progressive disease. Several peripheral diseases are more common in women. Idiopathic facial nerve palsy has a slightly higher incidence in women particularly of childbearing age, so do mononeuropathies in pregnancy (median, ulnar nerve). Pregnancy also appears to worsen episodes of weakness in patients with multifocal motor neuropathy. Acute neuropathies of the lower ectremity may develop during labor from injury at the spinal root, lumbosacral plexus or peripheral nerve. Connective tissue diseases and autoimmune disorders are more prevalent in women such as Sjo¨gren’s syndrome (peripheral neuropathy), rheumatoid arthritis and systemic lupus erithematosus. Takayasu arteritis is a large-vessel vasculitis (aorta and major branches) which has a sex ratio women:men = 9:1 and is more commonly found in Asia. Giant cell arteritis is more common in women, affecting patients over 50 years of age. Typical presentations include headache, amaurosis fugax, muscle and joint aches and pains. Muscular dystrophy has several forms; Duchenne muscular dystrophy and Becker muscular dystrophy are allelic X-linked recessive disorders; boys become symptomatic for Duchenne


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dystrophy at approximately 5 years of age, become wheelchair bound at 10–12 years and die by the age of 20. In 5–10% a female carrier of an altered dystrophin gene will develop myopathic features similar to but milder than those that develop in boys. Myasthenia gravis is an autoimmune disorder in which polyclonal antibodies are directed against the nicotinic acetylcholine receptor of skeletal muscles. . Female predominance is slight before puberty but becomes marked during and after puberty (female:male incidence = 14:1). Polymyositis and dermatomyositis are inflammatory disorders that affect striated and cardiac muscles and are more prevalent in women. Dermatomyositis and to a lesser extent polymyositis carry an increased risk of cancer, which can occur before, at the time of, or years after the diagnosis is established. It is a well known fact that genetic pre-disposition has great influence on risk for stroke and several genes for certain risks factors were identified. However lately a study has established that heritability of ischemic stroke is greater in women than in men: stroke in female family members was more frequent if other female family members previously suffered from it, while male family members were less likely to suffer from stroke. This difference was statistically significant even if traditional risk factors that could explain these gender differences were taken into consideration. In some studies, women presented with a profile of higher baseline risk factors. A study evaluating the prevalence of risk factors in patients with myocardial infarction and their association with recurrent ischemic events (including myocardial infarction, stroke and coronary death) showed that women have more risk factors, and the risk of recurrent ischemic events in women increased with hypertension, diabetes and hypercholesterolemia, but for men, no increase in risk was detected with any risk factor. Another study in patients undergoing coronary artery bypass graft surgery showed that risk factors significantly differ among sexes: women have more frequently hypertension and intracranial artery stenosis while men more frequently had hyperlipidemia, peripheral vascular disease, abdominal aortic aneurysm, severe carotid stenosis and severe aortic atherosclerosis. A study evaluating risk factors in middle aged (45–65 years) stroke patients showed that women significantly more often had diabetes, hypertension and hypercholesterolemia while men more often had a history of ischemic heart disease, smoking and alcohol consumption (6). Male stroke patients are more likely to have a history of ischemic heart disease, whereas female stroke patients are more likely to have hypertension and atrial fibrillation (AF); some studies found diabetes more commonly in women, others in men. Men are more likely to smoke cigarettes, or to have been smokers previously in their lives than women. A study designed to identify risk factors for cryptogenic stroke revealed that low levels of high density lipoprotein (HDL) cholesterol and high factor VII activity were more frequently present in women while low level of plasma folate, hypertension and current smoking for the risk factors for stroke in men. One study showed that women more often suffer from cardioembolic strokes and men from atherothrombotic and lacunar strokes. A study from Spain showed that women more often suffered from aphasic disorders, visual field disturbances and dysphagia than men, and women who survived stroke were more disabled at discharge. Study from Israel showed no gender differences in clinical presentation or imaging studies, and the in-hospital mortality rate among women was higher. Early arrival to an emergency facility is one of the major requirements for treatment with thrombolysis, yet a study from Germany found that women have a 10% lower chance of being admitted within the first 3 hours than men and this chance is further decreased in older women; however. In the time window between 0 and 3 hours, men compared to women had elevated mortality but were approximately three times as likely to have good

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functional outcomes. However, women were significantly more likely to benefit from rtPA compared with men in a therapy window between 0 and 6 hours. Similarly, the PROACT-2 study of intra-aerterial stroke thrombolysis with prourokinase has shown that women have 20% absolute benefit compared with men (10% absolute benefit) (34). In contrast to these studies, a study from Switzerland has shown no differences between sex and recanalization or outcome after 3 months in patients treated with intraarterials thrombolysis. Observations from these studies need to be proved in future studies, sex may be an important factor for selection for thrombolysis especially in patients presenting at later time from symptom onset. Out of patients with atrial fibrillation, women have higher annual rates of ischemic stroke than men (3.5% women, 1.8% men); however, there was no significant difference by sex in 30-day mortality or annual rates of hemorrhage (1% of both minor and major hemorrhage within one-years follow-up) (36). The authors of this study have concluded that the female sex is an independent risk factor for thromboembolism which goes in favour of introducing anticoagulant therapy in women with AF. Another study has shown gender-related differences in patients with AF. Women were older, had a lower quality of life, more often had heart failure with preserved left ventricular systolic function, less frequently underwent electrical cardioversion and achieved rhythm control, and had a higher level of risk for stroke. However, prescription of oral anticoagulants was identical in both genders (65%) and so was the mortality. Yet another study, which examined gender-related differences in warfarin treatment of patients with AF, showed that women were older than men, had more risk factors, experienced more overall (major and minor) hemorrhages and had a higher rate of thromboembolism. Epidemiological data have shown that the risk of death 1 year after stroke is somewhat lower in women than men, especially among elderly patients. Case fatality (deaths caused by cerebrovascular diseases among cases of acute stroke) for both ischemic stroke and all types of stroke combined was higher in men than in women, as was case mortality (deaths attributable to any cause among cases of acute stroke); however there was no difference in mortality caused by SAH. It has been observed that women are more prone for a hypercoagulable state than men early after injury. Possibly underlying mechanisms such as coagulation status is an important factor in patients with stroke as well. Differences in coagulation parameters have been observed between men and women: women with diabetes mellitus have abnormalities in euglobulin clot lysis time and increased plasminogen activator inhibitor-1. Elevated levels of factor VIIa are associated with an increased risk of recurrent cardiac events in post infarction women but not in men while Ddimers are more predictive in men for cardiac events. These observations indicate possible gender-related differences in the pathophysiologic mechanisms of recurrent cardiac events. The existing literature provides conflicting evidence concerning the risks of carotid endarterectomy (CEA) in women as compared with men. The initial NASCET and ECST studies have found that asymptomatic women benefit, in terms of postoperative results, from CEA less than asymptomatic men or symptomatic patients in general, however recent studies have shown that these differences are not clear enough to suggest that women shouldn’t be surgically treated. A recent study on 3422 CEA patients has shown that women were at higher risk for a postoperative TIA or stroke and for postoperative stroke or mortality. This difference was visible only in asymptomatic women while there was no gender association for postoperative stroke or mortality for patients who were symptomatic. The authors of this study have concluded that although the combined TIA or stroke and stroke or mortality rates are higher in asymptomatic women as compared with men in the postoperative period, CEA is still appropriate in both women who are asymptomatic and women who are symptomatic but only if the


postoperative TIA, stroke, and mortality rates are appreciably lower than in the natural history of medical management of these patients. Subgroup analysis in a study evaluating CEA in asymptomatic patients showed that women had a lower risk of ipsilateral ischemic stroke on medical treatment and a higher operative risk than did men, whereas CEA was beneficial in symptomatic severe carotid stenosis. Another study found no difference in 30-day surgical mortality after CEA. A study done on a sample of 6038 CEA patients (out of which 35% were women), there was no significant difference in the perioperative risk of stroke or death, however, after a 2-year follow-up, women were more likely to have a stroke yet less likely to die. Another study, which evaluated the perioperative risks of over 1200 CEA patients (out of which 39% were women) during a 21year period, found that survival rates at 1.5 and 8 years were higher for asymptomatic and symptomatic women compared with men, thus concluding that CEA does not carry a higher level of risk for women. Yet another study, examined the data collected over a period of 8 years, evaluating the outcome of 1298 CEA patients, and found that women were more likely to be asymptomatic than men but that there was no gender-difference in the frequency of postoperative cardiac (2.5% women, 1.5% men) or neurological events (1.6% women, 2.1% men); the postoperative stroke rate was 1.5% with no significant difference between men and women, and late recurrent stenosis developed in 1.5% of women and 0.8% of men, once again showing no significant gender-difference. References: 1. Morovic´ S, Kesic´ MJ, Vukovic´ V, Lovrencˇic´-Huzjan A, Trkanjec Z, Sˇkaric´-Juric´ T, Budisˇ ic´ M, Antic´ S, Demarin V. Vertebral Arteries-Morphologic And Hemodynamic Differences Between Men And Women. European Journal of Neurology 2005;12(suppl. 2):52–53. 2. Touze E, Rothwell PM. Heritability of ischemic stroke in women compared with men: a genetic epidemiological study. Lancet Neurol 2007:6(2):125–33. 3. Lovrencˇic´ Huzjan, Arijana; Kesic, Miljenka Jelena; Vukovic, Vlasta; Morovic´, Sandra; Zavoreo, Iris; Roje Bedekovic´, Marina; Demarin, Vida. Presence of increased stiffness of the common carotid artery in women with higher body mass index. Cerebrovascular Disease 2003;16(suppl. 2):3. 4. Jurasˇ ic´ MJ, Lovrencˇic´ Huzjan A, Bedekovic´ MR, Demarin V. How to monitor vascular aging with an ultrasound. J Neurol Sci 2007, Feb 21 (Epub ahead of print). 5. Kurth T, Everett BM, Buring JE, Kase CS, Ridker PM, Gaziano JM. Lipid levels and the risk of ischemic stroke in women. Neurology 2007;68(8):556–562. 6. Kurth T, Kase CS, Berger K, Gaziano JM, Cook NR, Buring JE. Smoking and risk of hemorrhagic stroke in women. Stroke 2003;34(12):2792–2795. 7. Demarin V, Lovrencˇic´-Huzjan A, Trkanjec Z, Vukovic´ V, Vargek-Solter V, Sˇeric´ V, Lusˇ ic´ I, Kadojic´ D, Bielen I, Tusˇ kanMohar L, Aleksic´-Shihabi A, Dikanovic´ M, Hat J, DeSyo D, Lupret V, Berosˇ V. Recommendations for stroke management 2006 update. Acta Clin Croat 2006;45:219–285. 8. Holroyd-Leduc JM, Kapral MK, Austin PC, Tu JV. Sex differences and similarities in the management and outcome of stroke patients. Stroke 2000;31(8):1833–1837. 9. Di Cario A, Lamassa M, Baldereschi M, Pracucci G, Basile AM, Wolfe CD, Giroud M, Rudd A, Ghetti A, Inzitari D. Sex differences in the slinical presentation, resource use, and 3month outcome of acute stroke in Europe: data from a mulitcenter multinational hospital-based registry. Stroke 2003;34(5):1114–1119. 10. Mattos MA, Summer DS, Bohannon WT, Parra J, McLafferty RB, Karch LA, Ramsey DE, Hodgson KJ. Carotid endarterectomy in women: challenging the results from ACAS and NASCET. Ann Surg 2001;234(4):438–446.

11. Akbari CM, Pulling MC, Pomposelli FB Jr, Biggons GW, Campbell DR, Logerfo FW. Gender and carotid endarterectomy: does it matter? J Vasc Surg 2000;31(6):1103–1108. 12. Fang MC, Singer DE, Chang Y, Hylek EM, Henault LE, Jensvold NG, Go AS. Gender differences in the irsk of sichemic stroke and peripheral embolism in atrial fibrillation: an AnTicoagulation and Risk factors In Atrial Fibrillation (ATRIA) study. Circulation 2005;112(12):1687–1691. 13. Dagres N, Nieuwiaat R, Vardas PE, Andresen D, Levy S, Cobbe S, Kremastinos DT, Breithardt G, Cokkinos DV, Crijns HJ. Gender-related differences in presentation, treatment, and outcome of patients with atrial fibrillation in Europe: a report from the Euro Heart Survey on Atial Fibrillation. J Am Coll Cardiol 2007;49(5):572–577. 14. Gomberg-Maitland M, Wenger NK, Feyzi J, Lengyel M, Volgman AS, Petersen P, Frison L, Halperin JL. Anticoagulation in women with non-valvular atrial fibrillation inthe stroke prevention using an oral thrombin inhibitor (SPORTIF) trials. Eur Heart J 2006;27(16):1893–1894. 15. Lovrencˇic´-Huzjan A, Bosnar M, Huzjan R, Demarin V. Frequency of different risk factors for ischemic stroke. A one year survey on patients admitted to Neurology Department University Hospital ’’Sestre milosrdnice’’. Acta clin Croat 1999;38:159–163. 16. Mastorakos G, Sakkas EG, Xydakis AM, Creatsas G. Pitfalls of the WHIs: Women’s Health Initiative. Ann N Y Acad SCI 2006;1092:331–340. 17. Jousilahti P, Tuomilehto J, Rastenyte D, Vartiainen E. Headache and the risk of stroke: a prospective observational cohort study among 35,056 Finnish men and women. Arch Intern Med 2003;163(9):1058–1062. 18. Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Migraine and rick of cardiovascular disease in women. JAMA 2006;296(3):283–291. 19. Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST). Lancet 1998;351:1379–1387. 20. Sarac TP, Hertzer NR, Mascha EJ, OÕHara PJ, Krajewski LP, Clair DG, Karafa MT, Ouriel K. Gender as a primary predictor of outcome after carotid endarterectomy. J Vasc Surg 2002;35(4):748–753. 21. Kapral MK, Wang H, Austin PC, Fang J, Kucey D, Bowyer B, Tu JV. Sex differences in carotid endarterectomy outcomes: results from the Ontario Carotid Endarterectomy Registry. Stroke 2003;34(5):1120–1125.

Gender differences in migraine L. Battistin & F. Maggioni Neurologic Clinic, Department of Neurosciences. University of Padua, Italy Migraine is a common, episodic, temporarily disabling neurological disease. Epidemiological studies can identify groups of people at higher risk of disease, and the distribution of disability, as a prelude to devising interventions to reduce disease burden. The examination of the epidemiological studies performed in the Western Countries shows that the 1-year prevalence of migraine is 18% in women compared with 6% in men in the general population. There are, however, important differences considering the different classes of age. Migraine’s prevalence in the pediatric age group was well studied. At the age of 7 years, prevalence ranges from 1.2% to 3.2%. Between 7 and 15 years of age, prevalence ranges from 4% to 11%. Some studies show that migraine prevalence is higher in boys than girls at an age included between 3 and 5 years and at 5 to 7 years of age. Prevalence is equal in boys and girls aged 7–11 years and is higher in girls after


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11 years. The female to male ratio for migraine prevalence increases from menarche until approximately age 42, where it reaches its peak, 3.3:1. Migraine occurs during the reproductive years in 27% of women between 20 to 49 years of age. The predominance of this disorder and its social, functional, and economic consequences make migraine an important matter in particular in women’s health. The hormonal milieu has a substantial effect on migraine in women. An understanding of these hormonal influences in the various stages of life in females is essential to the management and migraine prevention. Race and geographic region contribute to variation in migraine prevalence but the difference between genders is almost the same. A population-based study in the United States compares the prevalence of migraine among Caucasians, African-Americans, and Asian-Americans. After adjusting for socio-demographic covariates, prevalence of migraine was lowest in Asian-Americans (women 9.2%, men 4.8%), intermediate in African-Americans (women 16.2%, men 7.2%), and highest in Caucasians (women 20.4%, men 8.6%). These results mirror the meta-analytic finding that prevalence is lowest in Asia and Africa, with considerably higher prevalence in Europe, Central and South America, and North America. Migraine prevalence decreases with advancing age in the general population and the difference between genders decreases too. In particular, women with natural menopause often show improvement in their migraines; therefore, it decreases, perhaps owing the gradual onset of ovarian failure and the declining provocative influence of hormonal cycling, but also due to non specific beneficial effects of aging on migraine.

Special gender issues in psychiatry Ilsemarie Kurzthaler & Barbara Sperner-Unterweger Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Austria Abstract: Significant gender differences exist in the course, manifestation and treatment of mental illness. Regardless of specific diagnosis age is one of the key factors in gender differences. Such differences between the sexes exist not only concerning origin and perpetuation of specific psychiatric diseases, they are also available and notable in specific fields of pharmacological and psychotherapeutically treatment. That review should sensitize clinicians for their responsibility to provide individualized, optimally effective, genderspecific care to patients suffering from mental diseases in some special topics. It should be a short overview considering some important gender details illustrated in concern with the epidemiological background, the symptoms and general used psychiatric treatment strategies of some frequent psychiatric diagnoses. Introduction: It is well known, that significant gender differences exist in the course, manifestation and treatment of mental illness. Regardless of specific diagnosis age is one of the key factors in gender differences. In child mental health services patients are preponderantly male (1). Around time of puberty that fact changes and after adolescence, virtually most major psychiatric disorders – except substance abuse, schizophrenia, and impulse control disorders – become substantially more prevalent in females than in males (2). That turning point in female to male ratio in psychiatric violability is caused by an active growth and/or pruning of neurons during that stage of life. However, genes alone do not explain the sex differences in vulnerability to illness. Genetic disposition elicits individual environment and experience modulates gene expression. Gender specific hormonal effects profoundly influence the neuronal development and after all the final steady state that is achieved individually. Male as well as female hormone concentration rises sharply during puberty. Gonadal steroid receptors are expressed in areas of the cerebral cortex that mediate cognition and affect (3).

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Stressful life events have been postulated as a fact to vulnerable individuals for processing psychiatric diseases. Women, in general, act as caretakers and pay more than men ‘‘the price of caring’’ in all areas of life (4,5). In women, the monthly fluctuation in gonadal hormone levels account for a reduced effectively protection against the potentially harmful effects of stress axis hormones (6). After suffering traumata, women are twice as likely as men to develop a posttraumatic stress syndrome. Additionally the anatomically women’s strong interhemispheric brain connections may facilitate the generalization of past stressors and the invocation of traumatic memories more easily than the less well connected hemispheres in men’s brains (7). Such differences as do exist between the sexes concerning origin and perpetuation of specific psychiatric diseases are also available and notable in specific fields of pharmacological treatment. The side effect profile in male and female as well as the efficacy of ‘‘standard’’ treatment medication often differs. The same dose of medication applied to women works less well than for men (8). Thus, the optimal dose range of a therapeutic medication may not be the same for women and for men. Bodies of women contain more adipose tissue than that of men per unit of body weight, which is fundamentally linked to psychotherapeutic drug response. Antipsychotics, antidepressants and anxiolytics are all lyophilise drugs and therefore on the one hand they will be retained longer in female bodies after treatment discontinuation and on the other hand they can also be released unexpectedly from fat stores during rapid weight loss and in the following causing untoward side effects. Blood flow to the brain is another remarkable factor in genderspecific psychopharmacological treatment. It is, to a large extent, under hormonal control and in females it shows a higher speed with speed varies during the menstrual cycle (9). Therefore in females psychotropic agents reach their brain targets faster. Nevertheless, also the activity of liver enzymes, that catabolise drugs and turn them into other molecules before they can be eliminated, depends on gender. One also must be aware of complications induced by induction of enzymes generated by an agent that may enhance or reduce the activity of another one. Women with psychiatric problems are receiving several medications than men because they more often suffer from concomitant illnesses. By the way they may also be taking contraceptives or hormone replacement therapies. Thus, drug interactions are more frequently encountered in women and, correspondingly, so are adverse reactions (9). By the way females and males cope with side effects in a very different way. For example drugs that induce weight gain are especially problematic in women as well as drugs that cause hypotension with a potentially accident risk in elderly women at high risk of osteoporosis. That review should sensitize clinicians for their responsibility to provide individualized, optimally effective, gender-specific care to patients suffering from mental diseases in some special topics. It should be a short overview considering some important gender details illustrated in concern with epidemiological background, symptoms and general used psychiatric treatment strategies of some frequent psychiatric diagnoses. Gender specific psychiatric epidemiology Child and adolescent psychiatric disorders The prevalence of one or more psychiatric disorders in childhood and adolescence increases with age. Roberts et al 1998 describes mean prevalence of 10.2% for preschool children, 13.2% for preadolescents and 16, 5% for adolescents. Boys more often feature so-called externalising disorders such as conduct disorder. They show hyper arousal –motor activity, impulsivity and hypervigilance – a syndrome mediated through noradrenalin (NA) at the locus coeruleus, the hypothalamic pituitary axis and the adrenal glands.


In contrast girl appears preferentially to show dissociative response, characterised by avoidance and depression, which is also brain stem-mediated by NA via the hypothalamic-pituitary axis. By adolescents the adult pattern of psychiatric disorders is emerging, raising speculation of puberty and social changing or both as causal Adult psychiatric disorders In adults, virtually all major psychiatric disorders become more prevalent in females than in man with exception substance abuse, schizophrenia and impulse control disorders. Schizophrenia A recent meta-analysis of the literature from the past two decades reported that the incidence risk ratio for men relative to women is between 1.31 and 1.42 (10). Rates of new-onset schizophrenia reach a peak between ages 15 and 24 years in men, and for women, the peak occurs between ages 20 and 29 years. 15% of the female schizophrenic patients do not develop the illness until their mid- or late 40 years on the opposite for male patient’s onset of the illness after the age of 40 years is rare. At least in the first 15 years after onset women show a more favourable premorbid history and outcome (9). Relatives of women suffering from schizophrenia are more likely to develop the illness compared with relatives of men with schizophrenia (11). Concerning symptomatology females tend to experience more affective and positive symptoms and fewer negative than males. Additionally, women who present initially with the illness after 45 years of age typically suffer fewer negative symptoms than agematched women with early-onset schizophrenia (12). Female patients are also less likely to have structural brain abnormalities such as increased ventricle size and decreased hippocampal volume (13). Depression In literature a female-to-male ratio of 1.68: 1 for major depression , with a life time prevalence of major depressive disorders of 21.3% in women and 12.7% in men (14). Women appear to be more likely to become depressed in response to interpersonal difficulties within their close family networks, and men appear more likely to become depressed in response to occupational difficulties (15). For dysthymia the prevalence is twice as high in women, with lifetime rates of 5.4% for women and 2.6% for men (16). The rate of depression in women is higher for atypical depression and for seasonal affective disorder (SAD) (17). As a prior history of an anxiety disorder increases the risk of developing major depression and dysthymia the female preponderance for those illnesses might be determined primarily by the gender difference in the prevalence of anxiety disorders (18). Bipolar Disorder Bipolar disorder occurs equally frequently in males and females. However, there are significant gender differences in its course and manifestation. Depressive and dysphoric manic episodes are more frequent in women than in men suffering from that disorder, whereas the number of manic episodes is higher in male patients (19). Female patients with bipolar disorder are approximately two times as likely as male patients to experience rapid cycling. The number of cycles is equal in both sexes. Concerning comorbidity, the relative risk of alcohol and substance use disorder is significant higher in females with bipolar disorder (20). Seasonal affective disorder Women have a six time higher risk to develop a seasonal affective disorder (SAD). However, SAD may occur in children, it tends to arise around puberty, worsen through adolescence, and become severe around the third decade of life.

For premenopausal women with SAD, symptoms typically include subjective dysphoria, hypersomnia, severe fatigue, increased appetite and carbohydrate graving (21). Anxiety disorders Anxiety disorders, all in all, are more prevalent in women than in men with a higher risk to experience comorbid depression (22). Whereas Panic with agoraphobia and generalized anxiety disorder (GAD) are two or three times more common in females than in men, social phobia is three to four times as common in women than in men. The rates of generalized anxiety disorder are equal in both sexes between the ages of 24 and 34 years, but with an increase in females over 34 years of age compared to age matched males. The prevalence of GAD in young people (15–24 years of age) is 1,5% (male) vs. 2.5% (female) and after 45 years of age we see an increase to 3.6% (male) vs. 10,3% (female) (23,24). Although both sexes appear to have an equal prevalence of OCD, more obsessions related to foot and weight with a high comorbidity of anorexia are described in female patients in comparison to male patients. Alcohol and substance abuse The prevalence rate of alcoholism in men has been estimated at more than twice that in women, but the prevalence rate in women is raising and in young women it appears even to be higher. When drinking an equal amount of alcohol per unit of body weight, females become more intoxicated compared to males. Thus, although heavy drinking is defined to consist of more than four drinks a day in men – in women as little as one and one-half drinks a day may constitute heavy drinking. The alcohol-related medical complicationes develop more quickly in women with higher relative mortality rates (25). The rates of hallucinogen and opiat abuse are also higher in the male population, however, the abuse of cocain and amphetamines seems equal in both sexes. Concerning consume habbits women are less likely to inject cocain they prefer to smoke or sniff it. Gender specific treatment aspects of mental illnesses Schizophrenia Some, but not all studies suggest that, compared with men, women show a better response to psychopharmacological treatment before menopause (9). Teaching women with schizophrenia about methods for birth control and strategies for avoiding unwanted sexual assault is one of the most important aspects of treatment. Schizophrenic patients are at increased risk for still-birth, preterm delivery and low-birth-weight babies. Additionally their newborns are at increased risk cardiovascular congenital anomalies as well as for sudden infant death syndrome (26). Depression Whether there are gender –based differences in response rates for different antidepressants is a subject of controversy till now (12). In providing psychopharmacological treatment to women of reproductive age, it is important to keep in mind the possibility of pregnancy. For women who are planning to conceive and continued use of medication during pregnancy is necessary, choosing an antidepressant that is safe during pregnancy may prevent the need to switch medication after conception. Females are also at increased risk for depression during approximately the first 4–8 weeks after delivery, and that increased risk is particularly true for women with history of a depression. Therefore a prophylaxis with an antidepressant drug, begun 1– 2 days after delivery, may decrease the likelihood of an episode of postpartum-onset major depressio (27). Bipolar Disorder Gender specific differences in presentation, clinical course, physiology, concomitant medications, and reproductive phase of life are all factors that should be considered when choosing treatment options for bipolar disorder in women (28). For women whose mood consistently deteriorates premenstrual, it is helpful to measure blood levels of medication both premenstrual


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and in the week post menses, as serum levels of mood stabilizers may fluctuate across the menstrual cycle (29). Alcohol and substance abuse Societal stigmatisation, fear loosing custody of their children and because a woman‘s drinking or drug use pattern is greatly influenced by that of her partner, it is essential to treat women in a non – judgmental and supportive manner. Gender and suicide Rates of suicide in general, are higher in males than in females with an increase in males, particularly, in the younger age group (30). In contrast suicide rates in women have remained stable with even a decrease in the older population. Social factors, linked to changes in gender roles seem the most likely explanation. Rates of deliberate self-harm (DSH) are usually higher in females compared to males but in women that behaviour is more often based on non-suicidal motivation than in men. Men tend to use violent means of both suicide and DSH more often than females do (31). Treatment compliance of male patients seems poorer than that of female patients. Gender differences in verbal abilities and the reluctance of many males to share emotional problems may make some of the usual talking therapies less attractive to some males. Treatment programmes that have more of a practical emphasis, perhaps focused on problem – solving, could prove more successful in engaging males at risk. Gender-specific suicide mortality in medical doctors The estimated relative risk of male doctors vs. general population varies from 1.1 to 3.4 and that of female doctors 2.5 to 5.7. When compared to other academics the relative suicide mortality varied 1.5 to 3.8 in males and 3.7 to 4.5 in females (32). Gender issues in psychotherapy Gender as a concept encompasses culturally determined cognitions, attitudes, and belief systems about females and males. It varies across cultures, changes through historical time and differs in terms of who makes the observations and judgements (33). Therefore, gender influences the patient’s choice of caregiver, the convenience between caregiver and patient and the sequence and content of the clinical material presented. Mostly it also affects the diagnosis, treatment selection, length of treatment and even the outcome (34). Gender Identity and Gender Role Gender identity the internalized sense of maleness or femaleness and the knowledge of one’s biological sex with all the psychological attributes. Its development depends on many influences such as identification with parents and their attitudes, expectations and behaviours as well as cultural factors (35). However, gender roles show enormous differences in dependence of existing societies. In all cultures the mother remains as the primary caregiver during early childhood, therefore she becomes the primary identification figure for both boys and girls at that time of lifespan. As girls grow up, that same sex-identification must not shift. On the contrary boys to consolidate their masculine identity have to change and develop identification with the male figure. That complex factor of separating from early attachments to establish a male identity may be responsible for the higher incidence of gender identity disorders in male (36). The self- concept and identity in adolescence shows differences in individual definition between the sexes. Males generally define themselves in terms of individual achievement and work and females more often in relational term (37). Gilligan also found that in mid- adolescence girls show in relationships a conflict between selfish solution and solutions that are selfless involving self-sacrifice. At that time females are about twice as likely as males to have a depressive episode. Gender and choice of therapist Some patients make gender priority in choosing a therapist, as well as some therapists make gender-based recommendations for clients

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regarding the choice of a therapist. That is mainly the case in victims of sexual abuse or other sexual troubles and adolescents because at that life stage sexual issues are so pressing, embarrassing and intrusive and gender conflicts can interfere with therapeutic progress. However, misunderstandings caused by a different gender-oriented therapist can be avoided that way. Therapeutic Process Gender belongs to a number of factors that can establish a basis of an insufficient attention to transference issues. Out of that discussion of particular material might be encouraged or inhibited. Transference can occur at any phase of the treatment interaction, in any treatment modality and can be seen at any patient (38). In couples, group and family therapy transference issues are extra multiple and more complex and during course of treatment attention must be paid to that fact regardless of whether the therapist is male or female. Because gender affects trust and even compliance, in other modes of treatment, as well as in psychotherapy change in therapist based on gender might be helpful in some situations. Psychotherapy treatments and outcome The specific literature shows that gender has not been well studied in that case till now. There is empirical evidence on both sides of the efficacy argument for a gender effect in treatment, with most studies concluding that there is none (39). Acknowledgments References: 1. Gardner W, Pajer KA, Kelleher KJ, Scholle SH, & Wassermann RC. Child sex differences in primary care clinicians‘ mental health care of children and adolescents. Archives of Pediatrics & Adolescent Medicine 2002;156:454–459. 2. Seeman MV. Gender issues in Psychiatry. Focus.psychiatryonline.org; winter 2006; IV, No.1. 3. Martin R, Guerra B, Alonso R, Ramirez CM, & Diaz M. Estrogen activates classical and alternative mechanism to orchestrate neuroprotection. Current Neurovascular Research 2005;22:287–301. 4. Schuster TL, Kessler RC, Aseltine RH, Jr: Supportive interactions, and depressed mood. Am J Community Psychol 1990;18:423–438. 5. Williams K. Has the future of marriage arrived? A contemporary examination of gender, marriage, and psychological well-beeing. Journal of Health and Social Behaviour 2003;44:470–487. 6. De Bellis MD, Keshavan MS, Beers SR, Hall J, Frustaci K, Masalehdan A, Noll J, & Boring AM: Sex differences in brain maturation during childhood and adolescence. Cerebral Cortex 2001;11:552–557. 7. Piefke M, & Fink GR. Recollections of one’s own past: The effects of aging and gender on the neural mechanism of episodic autobiographical memory. Anat Embryol (Berl) 2005;20:1–16. 8. Fankhauser MP: Psychiatric disorders in women: psychopharmacologic treatments. Journal of the American Pharmaceutical Association 1997;6:667–678. 9. Seeman MV. Gender differences in the prescribing of antipsychotic drugs. American Journal of Psychiatry 2004;161: 1324–1333. 10. Aleman A, Kahn RS, SeltenJP: Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch Gen Psychiatry 2003;60:565–571. 11. Castle DJ,Murray RM: The neurodevelopmental basis of sex differences in schizophrenia. Psychol Med 1991;21:565–575. 12. Burt VK, Hendrick VC: Gender issues in the treatment of mental illness, chapter 9 in Clinical Manual of Women’s Mental Health. Washington, DC, American Psychiatric publishing, 2005, pp 147–180.


13. Cowell PE, Kostianovsky DJ, Gur RC, et al: Sex differences in neuroanatomical and clinical correlations in schizophrenia. Am J Psychiatry 1996;153:799–805. 14. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, & Kendler KS. Lifetime and 12month prevalence of DSM-III-R psychiatric disorders in the United States: results from the National Comorbidity survey. Archives of General Psychiatry 1994;51:8–19. 15. Kendler KS, Thornton LM, & Prescott CA. Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. American Journal of Psychiatry 2001;158:587–593. 16. Kessler RC, McGonagle KA, Swartz M, et al: Sex and depression in the National Comorbidity Survey.I: lifetime prevalence, chronicity and recurrence. J Affect Disord 1993;29:85–96. 17. Rosenthal NE, Sack DA, Gillin JC; Lewy AJ, Goodwin FK, Davenport Y, Mueller PS, Newsome DA, & Wehr TA. Seasonal affective disorder: a description of the syndrome and preliminary findings with light therapy. Archives of General Psychiatry 1984;41:72–80. 18. Parker G, & Hadzi-Pavlovic D. Is any female preponderance in depression secondary to a primary female preponderance in anxiety disorder? Acta Psychiatrica Scandinavica 2001;103:252– 256. 19. Leibenluft E. Women with bipolar illness: clinical and research issues. American Journal of Psychiatry 1996;153:63–173. 20. Frye MA, Altshuler LL, Mc Elroy SL, Suppes T, Keck PE, Denicoff K, Nolen WA, Kupka R, Leverich GS, Pollio C, Grunze H, Walden J, & Post RM. Gender differences in prevalence risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. American Journal of Psychiatry 2003;160:883–889. 21. Levitan RD, Kaplan AS, Brown GM, Vaccarino FJ, Kennedy SH, Levitt AJ, Joffe RT. Hormonal and subjective response to intravenous im-chlorophenylpiperazine in women with seasonal affective disorders. Archives of General Psychiatry 1998;55:244–249. 22. Pigott TA. Anxiety disorders in women. The Psychiatric Clinics of North American 2003;26:621–672. 23. Halbreich U. Anxiety disorders in women: a developmental and life-cycle perspective. Depression and Anxiety 2003;17:107–110. 24. Burt VK, Rasgon N: Special considerations in treating bipolar disorder in women. Bipolar disord 2004;6:2–13. 25. Greenfield SF, Manwani SG, & Nargiso JE. Epidemiology of substance use disorders in women. Obstetrics and Gynecological Clinics of North America 2003;30:413–446. 26. Jablensky AV, Morgan V, Zubrick SR, et al: Pregnancy, delivery, and neonatal complications in a population cohort of women with schizophrenia and major affective disorder. Am J psychiatry 2005;162:79–91. 27. Wisner KL & Wheeler SB. Prevention of recurrent major postpartum major depression. Hospital & Community Psychiatry 1994;45:1191–1196. 28. Burt VK, & Rasgon N. Special considerations in treating bipolar disorder in women. Bipolar Disorder 2004;6:2–13. 29. Tondo L & Baldessarini RJ. Rapid cycling in women and men with bipolar manic –depressive disorder. American Journal of Psychiatry 1998;155:1434–1436. 30. Cantor CH. Suicide in the western world. In International Handbook of Suicide and Attempt Suicide (K. Hawton and K. Van Heeringen, Eds). Chichester: John Wiley & Sons, 2000, pp. 9–28. 31. Hawton K. Sex and suicide. British Journal of Psychiatry 2000;177:484–485.

32. Lindemann S, Laä¨ra¨ E, Hakko H, & Lo¨nnquist J. A systematic review on gender –specific suicide mortality in medical doctors. British Journal of Psychiatry 1996;168:274–279. 33. Worell J & Remer P. Feminist perspectives in therapy: An empowerment model for women. New York, Willey & Sons, 1992. 34. Nadelson CC, Notmann MT and McCarthy MK: Gender issues in Psychotherapy, Oxford University Press. 2005 35. Hines M & Green R. Human hormonal and neural correlates of sex typed behaviours. In Review of Psychiatry. Washington, DC: American Psychiatric Press Inc. 1991, pp 536–555. 36. American Psychiatric Association. Diagnostic and Mental Disorder, 3rd Edition (revised). Washington, DC: American Psychiatric Association, 1987. 37. Gilligan C. Adolescent development reconsidered. In New directions for child development: Adolescent social behaviour and health (C. Irwin, Ed.). San Francisco: Jossey-Bass 1987, pp 63–92. 38. Horner A. The role of the female therapist in the affirmation of gender in male patients Journal of the American Academy of Psychoanalysis 1992;20:599–610. 39. Huppert JD, Bufka LF, Barlow DH, Gorman JM, Shear MK, & Woods SW. Therapists, therapist variables, and cognitivebehavioural therapy outcome in a multicenter trial for panic disorder. Journal of Consulting and Clinical Psychology 2001;69:747–755.

Gender differences in epilepsy Snjezˇana MiÐkov University Department of Neurology, Sestre milolsrdnice University Hospital Vinogradska 29, Zagreb, Croatia Epilepsy is disorder of the central nervous system resulting in unprovoked seizures that happen more than once. Epilepsy affects children and adults, men and women, and persons of all races, religions, ethnic background and social classes. Individuals in certain populations are at higher risk. Epidemiological studies of epilepsy indicate that the overall incidence of epilepsy is slightly higher in male than in female subjects. For individual seizure types various sex ratios have been reported (1–5). In two population based studies, gender differences in idiopathic generalized epilepsy were identified. In the outpatient study these differences were due to juvenile absence epilepsy and juvenile myoclonic epilepsy. It seems that women more frequently than man have idiopathic generalized epilepsy. The reason behind this difference is not established, but it is likely that sex hormones may play a role in the development of idiopathic generalized epilepsy. If this assumption is true, the gender difference would be more pronounced before menopause, and indeed, the female preponderance in idiopathic generalized epilepsy was highest for the age group 15–50 years and decline with age (6–8). Symptomatic, localization reacted epilepsy was more frequent among men than among women, and this may reflect differences of structural damage of the brain and subsequent seizures. The gender difference was greatest in the age group 30–59 years (the age group with a high risk of traumatic brain injury), men also may be more vulnerable to seizure associated brain damage. It seems that nonsymptomatic epilepsy (both idopathic and criptogenic generalized) more often occurs in women in contrast to symptomatic location-related epilepsy which has preponderance in men (9). Most studies in the literature find a female preponderance in psychogenic non-epileptic seizures (PNES) with the proportion of women of 75%. Men were significantly older than women at both attack onset and presentation at the NES clinic. In most pediatric series there is no sex imbalance. High rates of concomitant


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psychopathology in patients with PNES are frequently reported (10). Both males and females with epilepsy have low bone marrow density (BMD) than controls. There are important gender differences in BDM. Males with longer duration of epilepsy (>6 years of epilepsy) experience the largest reduction in BDM compared to controls. Most studies in epilepsy have examined bone health and fractures and found evidence of increased bone turnover or a variable relationship to fractures. In women phenitoin and carbamazepine are associated with increased bone turnover suggesting that these antiepileptics may have long term effect. Men also appear to be vulnerable to bone adverse effects of epilepsy. Factors underlying such gender differences include genetic-ethnic factors, hormonal status, calcium intake physical activity, and weight. In twin study, heritability accounted for up to 80% of BMD accrual. Twins discordant for epilepsy demonstrated lowered BMD in the twin with epilepsy receiving AEDs for more than 2 years, particularly if an enzyme inducing AED was used. In menopause the decline in estrogen may be important factor in the pathogenesis of involutional osteoporosis. However, osteoporosis in adolescent patients may be related with application of AED, which are aromatase inhibitors, by disturbing skeleton maturation due to lowered oestrogen levels causing life long consequences if not properly treated (11,12). Hormonal influences on seizure frequency Experimental studies have shown that estrogen excites the brain cells and can make seizures more likely to happen (proconvulsive effect). In contrast, natural progesterone can inhibit or prevent seizures in some women and has anticonvulsive effect. The most important is the proportion of those two hormones, with occurrence of epileptic seizures with elevated estrogen concentration and normal progesterone concentration, as well as lowered progesterone concentrations with normal estrogen concentrations. Stable proportion of these hormones can have no influence on seizures (13–27). Hormonal changes in men are less obvious than in women because men do not have a monthly cycle. However, in men, hormones (testosterone and breakdown products) also influence brain function and may have an impact on seizures. Normally, women also have low concentration of androgens in serum whose influence on epileptic activity has not been well investigated. Until now it has been noticed that women tend to have less frequent seizures when the levels of serum androgens are higher (28–30). Some women with epilepsy experience changes in their seizure patterns at times of hormonal fluctuations. It is not unusual for certain kinds of seizures to disappear at puberty, while other seizure disorders may start at this time. Many women with epilepsy see changes in the number or the pattern of their seizures around the time of ovulation (mid-cycle), or just before and at the beginning of their menstrual periods. This is a condition called ‘‘catamenial epilepsy’’ and describes a tendency for increased seizures related to the menstrual cycle. In some women, seizures occur most frequently just before menstruation, during the first few days of menstruation and at mid-cycle, during ovulation. The balance between the two female sex hormones, estrogen and progesterone, may be disturbed, or you may not be producing enough progesterone during the second half of your menstrual cycle. It is also possible that the amount of antiepileptic drug (AED) circulating in your bloodstream may decrease before menstruation (31–34). For both women and men, identifying hormonal influences on seizure patterns may lead to a better understanding of treatment options for seizure control. Women should keep a calendar of their menstrual cycles and of days they have seizures. It is important to keep track of other factors that may affect the menstrual cycle or seizure patterns, such as missed medication, loss of sleep, unusual fatigue, intense physical training, stress or an illness.

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Most research on epilepsy in women has focused on the childbearing years, but as the population ages and older women take a more active role in the management of their health, more attention is being paid to the relationship between epilepsy and menopause (35). As a group, women with epilepsy who have gone through menopause have about the same frequency and severity of seizures as younger women, but this statistic hides a lot of individual differences. In one study, one-third of the women who had epilepsy before menopause reported no change in their seizures. A slightly larger proportion reported worsening of their seizures, and a slightly smaller number reported improvement. (There was even a group in which seizures occurred for the first time during or after menopause, with no known cause.) Another study similarly identified groups in which seizures were unchanged, increased, or decreased. This study found that women who had a pattern of catamenial epilepsy were more likely to have fewer seizures after menopause but they had more seizures during the period of changes just before menopause (called perimenopause). Women with catamenial epilepsy tend o have more frequent seizures during perimenopause when the level of progesterone is lower, and estrogen level is higher. In those cases progesterone therapy is recommended. Larger studies are needed to better identify which women are likely to have improved or worsening seizures. In menopause (low levels of estrogen and progesterone) there is reduced frequency of epileptic seizures due to stabilized proportion of the two hormones. In that period usage of hormone replacement therapy could lead to more frequent seizures. Low dosage of estrogen usually has no influence on seizure frequency. Estrogen therapy is important in prevention of osteoporosis, therefore hormone replacement therapy has to be given individually, depending on the risks and benefits. One small study suggested that seizure frequency increased in women who used hormone replacement therapy (HRT), but another study found that women who used the type of HRT that includes progestin (a form of progesterone) were much less likely to have worsening of their seizures than those who took only estrogen. The role of HRT in preventing osteoporosis can be especially important for women with epilepsy, since seizures can increase the risk of falling and breaking weakened bones. The problem is worsened by the fact that certain seizure medicines can cause bone loss. These medicines include phenytoin (Dilantin or Phenytek), carbamazepine (Tegretol or Carbatrol), and phenobarbital which all binds oestrogen or act as aromatase inhibitors. Women who take these medications should be especially careful to get enough calcium, vitamin D, and exercise, however the efficiency of such additional treatment may be limited due to lack of oestrogen as a key molecule in bone mass turnover (36). Antiepileptic drugs can contribute to the reproductive disfunction by lowering plasma steroid concentrations (carbamazepine, phenitoine, phenobarbital) or elevating gonadal androgen concentrations (valproate). In one third of women with epilepsy, during pregnancy more frequent epileptic seizure are noted mostly at the end of the first or at the beginning of third trimester, due to physiological changes during pregnancy as well as non compliance. Physiological changes are attributable to weight gain, increased liver metabolism, and lower binding of AET to plasma proteins. The greatest difference in plasma concentration during pregnancy is noticed during first trimester (phenobarbital) and third trimester (carbamazepine). Lamotrigine dosage should be also adjusted due to frequent lowering of plasma concentrations. All AET dosages usually should be brought back to the initial dosage after labor (37–41). Gestational epilepsy indicates idiopathic epilepsy which occurs for the first time during pregnancy. One study analysed gender differences in mesial temporal lobe patients with regard to clinical history, seizure semiology and EEG


data. Male patients experienced generalized seizures significantly more often and isolated auras significantly less often than female patients Analysing EEG data showed that seizure pattern lateralized to the side of hippocampal sclerosis occurred more often in female patients and they concluded that men had more often secondarily generalized tonic clonic seizures while women had isolated auras and lateralized EEG seizures pattern more often suggesting that seizure spread is more extended or occurs more frequently in men (42). Recent results of oncological, neurological, developmental and biochemical studies suggest that the reproductive dysfunction in men and women, as a side effect related with antiepileptic therapy, points that the estrogens and estrogens receptors have more important role in epilepsy that was thought before. It seems that contrary to the present definition of oestrogen as a compound affecting seizure susceptibility, based on causal chains: of increased estrogen levels (such as alcohol intake) and seizure, fact that all antiepileptic drugs are aromatase inhibitors or have estrogen binding properties, described cases of seizures in epileptic patients taking quinine (which increases oestrogen levels) as preventive therapy against malaria, impact of photic activation and sleep on estrogen level, it can be assumed that estrogen may plays the leading role in the mutual origin of different types of epilepsy (43– 58). Interdisciplinary and multiparameter approach in investigation of interaction between antiepileptic drugs and genetic polymorphisms of aromatase, canal membrane proteins, polymorphisms of metabolism and specific pattern of brain oestrogen receptors distribution of epilepsy patient in future may have impact on therapy improvement and possible application of gene therapy. References: 1. Brodie MJ. Epilepsy: randomized trials and genetic tribulations. Neurology the Lancet 2008;7:7–8. 2. Hauser WA, Annegers JF,Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia1993;34:453–468. 3. Kotsopoulos IA, van Merode T, Kessels FG, de Krom MC, Knottnerus JA. Systematic review and meta-analysis of incidence studies of epilepsy and unprovoked seizures. Epilepsia 2002;43:1402–1409. 4. McHugh JC, Dalanty N. Epidemiology and classification of epilepsy: gender comparison. Int Rev Neurobiol 2008;83:11–26. 5. Meisler JG. Toward Optimal Health: The Experts Discuss Epilepsy. Journal of Women’s Health & Gender-Based Medicine 2001;10(7):621–625. 6. AMA. Women and epilepsy: epilepsy presents unique problems for women, 2004 in: Christensen J, Kjeldsen MJ, Henning A, Friis ML, Sidenius P. Gender differences in epilepsy. Epilepsia 2005;46(6):956–960. 7. Crawford P, Lee P. Gender difference in management of epilepsy-what women are hearing? Seizure 1999;83(3):135–139. 8. Christensen J, Kjeldsen MJ, Henning A, Friis ML, Sidenius P. Gender differences in epilepsy. Epilepsia 2005;46(6):956–960. 9. Vagnerova K, Koernen IP, Hurn PD. Gender and the injured brain. Anesth Analg 2008;107(1):201–214. 10. Kimiskidis VK, Triantafyllou NI, Kararizou E, Gatzonis SS et al. Depression and anxiety in epilepsy: the association with demographic and seizure-related variables. Annals of General Psychiatry 2007;6:28. 11. Phabphal K, Limapichat K, Sathirapanya P, Setthawatcharawanich S, Leelawattana R, Thammakumpee N, Thamaprasit A, Geater A Bone mineral density following long-term use of antiepileptic drugs in a tropical Asian country. Epileptic Disord 2008;10(3):213–218. 12. Spencer JL, Waters EM, Romeo RD, Wood GE, Milner TA, McEwen BS. Uncovering the mechanisms of estrogen effects on hippocampal function. Front. Neuroendocrionol 2008;29:219–237.

13. Abizaid A, Mezei G, Thanarajasingam G, Horvath TL. Estrogen enhances light activation of dorsal raphe serotonergic neurons. Eur J Neurosci 2005;21(6):1536–1546. 14. Alkbrenner KA, Standley CA. Estrogen modulation of NMDA-induced seizures in ovariectomized and non-ovariectomized rats. Brain Res 2003. 15. Bao AM et al. Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression. Horm Behav 2004. 16. Epilepsy and Ovarian Hormones. In: Epilepsy and Female Reproductive Milestones. 2005. 17. Frve CA. Hormonal influences on seizures: basic neurobiology. Int Rev Neurobiol 2008;83:27–77. 18. Hart SA, Snyder MA, Smejkalova T, Woolley CS Estrogen mobilizes a subset of Estrogen receptor-alfa-immunoreactive vesicles in inhibitory presynaptic buttons in Hippocampal CA1. J Neuroscience 2007;27(8):2102–2111. 19. Ikeda T, Matsuki N, Yamada MK. Estrogen produced in cultured hippocampal neurons isa functional regulator of a GABAergic machinery. J Neurosci Res 2006;84(89):1771– 1777. 20. Ish H, Tsurugizawa T, Ogiue-Ikeda M. et al. Local production of sex hormones and their modulation of hippocampal synaptic plasticity. The Neuroscientist 2007;13(4):323–334. 21. Jacobsen NW. Halling -Sorensen B, Birkved FK. Inhibition of human aromatase Complex (CYP 19) by antiepileptic drugs. Toxicology in Vitro 2008;22:146–153. 22. Kimura N, Takamatsu N, Yaoita Y, Osamura RY, Kimura N. Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promotor and regions including estrogen response element half-site for estrogen activation. J Mol Endocrinology 2008;40(2):75–91. 23. Kow LM, Devidzem N, Patakym S, Shubuyam I, Pfaff DW. Acute estradiol application increases inward and decrease outward whole-cell currents of neurons in rat hypothalamic ventromedial nucleus. Brain Res 2006;1116(1):1–11. 24. McClean J, Nunez JL. 17 alpha estradiol is neuroprotective in male and female rats in a model early brain injury. Exp Neurol 2008;210(1):41–50. 25. McCarthy MM. Estradiol and the developing brain. Physiol Rev 2007;88:91–134. 26. Mize AL, Poisner AM, Alper RH. Estrogen act in rat hippocampus and frontal cortex to produce rapid, receptormediated decrease in serotonin 5-HT1A receptor function. Neuroendocrinol 2001;73(3):166–174. 27. Moss RL, Gu O, Wong M. Estrogen: nontranscriptional signaling pathway. Recent Prog Horm Res 1997;52:33–68. 28. Harden C, MacLusky NJ. Aromatase inhibition, testosterone, and seizures. Epilepsy Behav 2004. 29. Montouris G, Morris GL. Reproductive and sexual dysfunction in men with epilepsy. Epilepsy and Behaviour 2005;7:7–14. 30. Quian Y. Zeng F. Re-establishment of spermatogenesis by diethylstilbestrol after 2,5-hexanedione-induced irreversible testicular atrophy in rats. J Huazhong Univ Sci Technol Med Sci 2008;28(2):179–181. 31. Herzog et al. Three paterns of catamenial epilepsy. Epilepsia 1997;38:1082–1088. 32. Herzog et al. 2004. (Frequency of catamenial seizure exacerbation in woman with localisation related epilepsy. Ann Neurol 2004;56:431–434. 33. Foldvary-Schaefer N, Falcone T. Catamenial epilepsy: pathophysiology, diagnosis and management. Neurology, 2003. 34. Panovich PER, Helmers S. Catamenial epilepsy. Int Rev Neurobiol 2008;83:79–90. 35. Harden CL et al. The effect of menopause and perimenopause on the course of epilepsy. Epilepsia1999.


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36. Janszky J, Schulz R, Janszky I, Ebner A. Medial temporal lobe epilepsy: gender differences. J Neurol Neurosurg Psychiatry 2004;75:773–775. 37. Dolk H, J. Jentink, M. Loane, J. Morris, L.T.W. de Jong_van den Berg. Does lamotrigine use in pregnancy increase orofacial cleft risk relative to other malformations? Neurology 2008;71;714–722. 38. Harden CL, Sethi NK. Epileptic disorders in pregncy:an overwiew. Curr Opin Obstet Ginecol.2008;20(6):557–562. 39. Hovinga CA, Pennel PB. Antiepieltpic drug therapy in pregnancy II:fetal neonantal exposure. Int Rev Neurobiol 2008;83:241–258. 40. Vasudeva N, Pfaff DW. Non.genomic actions of estrogen and their interaction with genomic actions in the brain. Frontiers Neurol 2008;29:238–257. 41. Yeow W-S, Ziauddin MF, Maxhiemer JB. et al. Potentation of the anticancer effect of valproic, an antiepileptic agent with histone deacetylase inhibitory activity, by the kinase inhibitor staurosporine ot its clinically relevant analogue UCN-01. Brit J Cancer 2006;94:1436–1445. 42. Isojarvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms. Seizure 2008:111–119. 43. Klein P, van Passe-Clark LM, Pezzutllo JC. Onset of epilepsy at the time of menarche, Neurology 2003;60(3):495–497. 44. Ngoungou EB, Koko J, Druet-Cabanac M, et al. Cerebral malaria and squealer epilepsy: first matched case-control study in Gabon. Epilepsia 2006;47(12):2147–2153. 45. Rabinowicz AL, Starkstein SE, Leiguarda RC, Coleman AE. Transient epileptic amnesia in dementia: a treatable unrecognized cause of episodic amnestic wandering. Alzheimer Disease and Assoc Disorders 2000;14(4):231–233. 46. Rasgon N. The relationship between polycystic ovary syndrome and antiepileptic drugs:a review of the evidence. J Clin Psychopharmacol 2004.

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47. Reviere JH, Back DJ. Inhibition of ethinyloestradiol and tolbutamide metabolism by quinoline derivates in vitro. Chem Biol Interact 1986;59(3):301–308. 48. Roepke TA, Malayala A, Bosch MA, Kelly M, Ronnekliev OK. Estrogen regulation of genes important for K+ channel signaling in the arcute nucleus. Endocrinology 2007;148(10): 4937–4951. 49. Rhodes ME et al. Gonadal, adrenal and neuroactive steroidsÕ role in ictal activity. Brain Res 2004. 50. Rhodes ME, Talluri J, Harney J, Frye CA. Ketogenic diet decreases circulating concentrations of neuroactive steroids of female rats. Epilepsy Behav 2005;7(2):231–239. 51. Sakuma S, Tokuhara D, Hattori H, Matsuoka O, Yamaro T. Expression of estrogenreceptor alpha and beta in reactive astrocytes at the male rat hippocampus after status epilepticus, Neuropathology 2008 doi:10.1111/j.1440-1789.2008.00946x. 52. Sheth RD, Binkley N, Hermann BP. Gender differences in bone mineral density in epilepsy. Epilepsia 2008;49(1):125–131. 53. Steinhoff BJ. Pregnancy, epilepsy,and anticonulsant. Dialoues Clin Neurosci 2008;10:63–75. 54. Tatum WO IV. Updates on the treatment of epilepsy in women. Arch Int.Med 2004. 55. Velisek L, Veliskova J. New avenue of research: antiepileptic drug and estradiol neuroprotection in epilepsy. Recent Patents CNS Drug Discov 2008;3(2):128–137. 56. Veliskova J et al. Neuroprotective affects of estrogens on hippocampal cells in adult female rats after status epilepticus. Epilepsia 2000. 57. Wooley CS. Acute effects of estrogen on neuronal physiology. Ann Rev Pharamcol Toxicol 2007;47:657–680. 58. Fucic A., Misˇ kov S., Zˇeljezˇic´ D, Bogdanovic N, Katic´ J, Gjergja R, Karelson E., Gamulin M, Is the role of estrogens and estrogen receptors in epilepsy still underestimated?, Medical hypothesis, in press.


PSYCHOIMMUNOLOGY SYMPOSIUM: THE IMPACT OF DYSFUNCTIONAL ENDOCRINE AND IMMUNE SYSTEMS ON PSYCHIATRIC DISORDERS Immune dysfunction, depression and neurodegeneration B. E. Leonard1,2 & A. M. Myint1 1 Department of Psychiatry and Psychotherapy, Laboratory of Psychoneuroimmunology, University Psychiatric Hospital, Ludwig Maximilians University, Munich, Germany, 2Department of Pharmacology, National University of Ireland, Galway The possible link between a dysfunctional immune system, depression and physical ill health has been known since antiquity. However, it is only recently that the possible mechanisms whereby chronic inflammation can initiate changes in the endocrine and cardiovascular system leading to type 2 diabetes, cardiovascular disease, cancers and psoriasis, have begun to be elucidated. Furthermore, evidence that inflammatory changes can initiate depression has arisen from observations of non-depressed patients who are undergoing interferon alpha or interleukin (IL)2 treatment for melanoma or chronic hepatitis. A substantial majority (approximately 40%) of these patients develop severe depression that abates when the inflammatory cytokine treatment is stopped (1). It is now known that in patients with major depression the peripheral macrophages and monocytes, and in the brain the microglia and astrocytes, are activated leading to an increase in pro-inflammatory mediators such as the pro-inflammatory cytokines (interleukins-1 and -6, interferon (IFN)gamma, tumour necrosis factor(TNF)-alpha) in addition to prostaglandin (PG)E2 and nitric oxide (2). The changes in these immune parameters are largely reversed following effective antidepressant treatment.. Important advances in our understanding of the relationship between different types of stressor and changes in immune and endocrine function have been obtained from experimental studies mainly in rodents. These studies have indicated that there is an increase inIL-1 messenger RNA expression and IL-1 concentration in the hypothalamus (3,4), increased IL-1 beta and TNF –alpha in isolated alveolar macrophages (5) and an increase in IL-6 in the plasma (6,7)following different types of stress. In the olfactory bulbectomised rat model of depression, the blood and brain concentrations of the pro-inflammatory cytokines are also increased, changes that are associated with depressive-like behaviour and which are normalised following effective, but chronic, antidepressant treatments(8). The inflammatory changes are known the impact upon the hypothalamic-pituitary-adrenal axis. The proinflammatory cytokines enhance the release of corticotrophin releasing factor(CRF) thereby resulting in an elevation in plasma corticosterone;such changes frequently occur in patients with major depression (9). The chronic increase in the corticosteroids results in glucocorticoid receptor tolerance as a consequence of the receptor desensitisation thereby impairing the negative feed-back mechanism whereby the rise in the plasma concentration of corticosteroids would normally inhibit the further activation of the CRF-ACTH pathway. In addition to the increase in CRF caused by the proinflammatory

cytokines, IL-1 beta is known to increase the release of arginine vasopressin (AVP) from the anterior pituitary. AVP is usually released in response to chronic stress and maintains the activation of the adrenal glands, and therefore the secretion of corticosteroids.(10) Thus chronic, low grade inflammation that occurs in depression, and following chronic stress, is associated with hypercortisolaemia in experimental models of depression and in depressed patients. The chronic increase in plasma and brain corticosteoids may contribute to the neurodegenerative changes that occur in elderly depressed patients that have suffered from chronic major depression (11,12) One of the key factors that contribute to neurodegeneration is the increase in corticosteroids that are known to impair the synthesis of neurotrophic factors (such as brain derived neurotrophic factor) that are responsible for the repair of damaged dendrites and axons(13) Thus the increase in corticosteroids, combined with the neuronal damage caused by the actions of the proinflammatory cytokines, probably contribute to the increase in apoptosis and therefore the neurodegenerative changes that frequently occur in patients with chronic major depression (14). For over 40 years there has been widespread acceptance of the hypothesis that a dysfunctional serotonergic system plays a fundamental role in the aetiology of depression. It now seems possible to link the deficit in serotonergic function with the increase in proinflammatory cytokines in depression. It is now known that IFN-gamma, and other proinflammatory cytokines, induce the widely distributed enzyme indoleamine 2,3 dioxygenase (IDO) thereby enhancing the metabolism of tryptophan through the kynurenine pathway, and away from serotonin synthesis. Kynurenine is then metabolised either to kynurenic acid (an N-methyl-Daspartate glutamate (NMDA) receptor antagonist) or to 3hydroxykynurenine (3OHK) and quinolinic acid (a NMDA receptor agonist). This neurodegenerative quinolinic acid pathway is induced by IFN-gamma and by TNF-alpha (15,16). Of these neurotoxins that are produced by proinflammatory cytokines, quinolinic acid is excitotoxic and 3OHK induces apoptosis. In the brain, the astrocytes have been shown to metabolise tryptophan to kynurenic acid whereas the microglia, and peripheral macrophages that produce the proinflammatory cytokines in the blood, produce mainly 3OHK and quinolinic acid( 17,18). Furthermore the astrocytes metabolise quinolinic acid produced by the neighbouring microglia. In addition, kynurenic acid has been shown to antagonise the excitotoxic action quinolinic acid. In the plasma of depressed patients, tryptophan breakdown has been reported to be increased but the neuroprotective, kynurenic acid pathway is decreased (19). This suggests that the neurodegenerative arm of the tryptophan-kynurenine pathway is increased in depression, a view that is supported by the recent finding that the plasma 3OHK concentration is increased in the plasma of depressed patients. Preliminary in vitro studies have also shown that in a human cell culture the astrocytes are particularly


45

vulnerable to the toxic effects of IL-1 beta. Thus a combination of raised proinflammatory cytokines, an increase in the neurotoxins 3OHK and quinolinic acid and a decreased protection against quinolinic acid by the astrocytes contribute to the neurodegenerative changes that predispose the elderly depressed patient to dementia. Chronic IFN-gamma treatment of rats results in depressive-like behaviour (20) together with a loss of astrocytes in the dentate gyrus of the hippocampus, changes that are not reversed by the chronic administration of antidepressants. This may have some clinical relevance where it has been shown that aspects of cognitive dysfunction remain even after the mood of the patients has improved. Furthermore, the interval between the episodes of depression tends to become shorter as the chronicity of the disorder increases. Such factors lead to the hypothesis that in chronic depression changes occur that not only lead to neuronal loss in selected regions of the mesocortical and mesolimbic systems but also enhance the synthesis of neurotoxic factors (such as beta amyloid) that contribute to dementia (21) Thus the interaction between the increase in proinflammatory mediators, corticosteroids and the resulting dysfunction in neurotrans mitter systems play a fundamental role in major depression that not only contributes to profound mood and cognitive changes but also predisposes the patient to dementia in later life. References: 1. Wichers MC, Kenis G, Koch GH, Robaegs G, Nicolson NA, Maes M. Interferon apha induced depressive symptoms are related to changes in the cytokine network but not to cortisol. J Psychosom Res 2007;62:207–214. 2. Myint A-M, Leonard BE, Steinbusch H, Kim Y-K. Th1,Th2 and Th3 cytokine alterations in major depression. J Affect Dis 2005;88:169–173. 3. Minami M, Kuraishi Y, Yamaguchi T, Nalai S, Hirai Y, Satoh M. Immobilisation stress induces IL-1 beta nRNA in the rat hypothalamus. Neurosci Lett 1991;123:254–256. 4. Shintani F, Nakaki T, Kanba S, Asai M. Role of IL-1 in stress responses.A putative neurotransmitter. Mol Neurobiol 1995;10:47–71. 5. Persoons JH, Schormagel K, Breve J, Berlkenbosch F, Kraal G. Acute stress affects cytokines and nitric oxide production by alveolar macrophages differently. Am J Respir Crit Care Med 1995;152:619–624. 6. Zhou D, Kusnecov AW, Shurin MR, De Paoli M, Rabin BS. Exposure to physical and psychological stressors elevates plasma IL-6: relationship to the activation of HPA axis. Endocrinol 1993;133:2523–2530. 7. Shizuya K, Komori T, Fujiwara R, Miyahara S, Ohmori M, Nomura J. Influence of restraint stress on the expression of mRNA for IL6 and IL-6 receptor in the hypothalamus and mid brain. Life Sci 1997;61:135–140. 8. Song C, Leonard BE. The olfactory bulbectomised rat model of depression.Neurosci Biobehav Rev 2005;29:627–647. 9. Maes M. Major depression and activation of the inflammatory response. Adv Exp Biol Med 1999;461:25–46. 10. Holsboer F. The rationale for CRH receptor antagonists to treat depression and anxiety. J Psychiat Res 1999;33:181– 214. 11. Leonard BE, Myint A-M. Inflkammation and depression: is there a causal connection with dementia?. Neurotox Res 2006;10:149–160. 12. Geerlings MI, Schoevers RA, Beckman AT. Depression and rik of cognitive decline and Alzheimer’s disease. Results of two prospective community based studies in the Netherlands. Br J Psychiat 2000;176:568–575. 13. Chen P, Ganguli M, Mulsant BH, DeKosky ST. The temporal relationship between depressive symptoms and dementia.Arch Gen Psychiat 1999;56:261–266.

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14. Nibuya M, Takahashi M, Russell DS, Duman RS. Repeated stress increases catalytic TrkB mRNA in rat hippocampus. Neurosci Lett 1999;267:81–84. 15. Myint A-M, Kim Y-K. Cytokine-serotonin interaction through indoleamine dioxygenase: a neurodegenerative hypothesis of depression. Med Hypoth 2003;61:81–84. 16. Chiarrugi A, Calvani M, Meli E, Traggiai F. Synthesis and release of neurotoxic kynurenine metabolites by human monocyte derived macrophages. J Neuroimmunol 2001;120:190–198. 17. Guillemin GJ, Smith DG, Kerr SJ, Smythe GA, Kapoor V, Armati PJ. Characterisation of the kymurenine pathway metaboilism in human astrocytes and implications in neuropathogenesis. Redox Rep 2000;5:108–111. 18. Guillemin GJ, Kerr SJ, Smythe GA, Smith DG, Kapoor V, Armali PJ.Kynurenine pathway metabolism in human astrocytes: a paradox for neuronal protection. J Neurochem 2001;78:842–853. 19. Myint A-M,Kim Y-K,Verkerk R, Scharpe S, Steinbusch H, Leonard BE. Kynurenine pathway in major depression: evidence of impaired neuroprotection. J Affect Dis 2007;98:143–151. 20. De La Garga R. Endotoxin or proinflammatory cytokine induced sickness behaviour as an animal model of depression: focus on anhedonia. Neurosci Biobehav Rev 2005;29:761– 770. 21. Leonard BE. Inflammation.depression and dementia:are they connected? Neurochem Res 2007;32:1749–1756.

Changes in immune and endocrine systems in posttraumatic stress disorder – prospective study An delko Vidovic´1, Maja Vilibic´2, Ante Sabioncello3, Katja Gotovac3, Sabina Rabatic´3, Vera Folnegovic´-malc2 & Dragan Dekaris3 1 University Hospital Dubrava, Department of Psychiatry, Referral Centre for the Stress-Related Disorders, Zagreb, Croatia, 2University Department of Psychiatry, Psychiatric Hospital Vrapcˇe, Zagreb, Croatia, 3Department for Cellular Immunology, Institute of Immunology, Zagreb, Croatia Abstract: Introduction and aim: Posttraumatic stress disorder (PTSD) is associated with increased medical morbidity, particularly from the autoimmune and cardiovascular diseases. Changes in the endocrine and immune system are key mediators in this process. The aim of our study was to investigate weather hormones (cortisol and prolactin), proinflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)), components of HPA-axis (lymphocyte expression of glucocorticoid receptor (GR)), immune function (natural killer cell cytotoxicity) and peripheral blood percentages of various lymphocyte subpopulations (T cells, helper T cells, cytotoxic T cells, B cells and natural killer cells) change in patients with posttraumatic stress disorder over time. Subjects and methods: We assessed 39 patients with PTSD and 37 sex and age matched healthy volunteers in two time points separated by 5.6 years (median; interquartile range: 5.4–6.3). Hormones were measured by radioimmunoassay and cytokines were determined by immunoenzyme assays. Immune function was assessed with the in vitro natural killer cell cytotoxicity (NKCC) toward 51Cr-labeled K562 target cells. Lymphocyte counts, immunophenotye and intracellular glucocorticoid receptor expression were determined by three-color flow cytometry. Results: In the first time point cortisol, prolactin, NKCC, lymphocyte count, total T cells and helper T cells were increased, while glucocorticoid receptor expression was decreased in all lymphocyte subpopulations in PTSD patients compared to controls. In the second time point only prolactin levels and


lymphocyte counts remained elevated and no significant differences in other variables have been observed. Conclusion: Changes in the endocrine and immune systems are not static in persons with PTSD but rather depend on duration of alostatic load posed by the disorder and its impact on interactions involved in response to stress. There is growing evidence that posttraumatic stress disorder (PTSD) is associated with increased medical morbidity, particularly from the autoimmune and cardiovascular diseases (1). It has been implicated that the hypothalamic-pituitary-adrenal (HPA) axis disturbances and changes in the immune system are the key mediators in this process (2). Studies of the HPA axis activity (3) in PTSD yielded controversial results. It is believed that PTSD is linked with low plasma cortisol levels and higher glucocorticoid receptor (GR) expression, suggesting enhanced feedback sensitivity to cortisol (3). In contrast to these findings, we have found that Croatian combat veterans with PTSD had lower expression of the GCR in peripheral blood lymphocytes with higher serum cortisol concentration than healthy subjects (4). Shorter duration of allostatic load caused by adaptive response to stress in Croatian combat veterans compared to Vietnam veterans or Holocaust survivors could be the reason for this discrepancy. The immune system interacts with the hypothalamic-pituitaryadrenal axis in a bidirectional fashion to maintain homeostasis. Studies of the leukocyte recirculation (5,6) and immune cells function (7) in PTSD have also yielded various, often opposite, results. Overall findings support the hypothesis that immune activation in PTSD may be associated with Th2 cytokine shift and alterations in the proinflammatory cytokine system (2). Considering the above mentioned discrepancies, we assumed that changes in endocrine and immune systems in PTSD are not static during the course of illness. To test this hypothesis we have measured hormones (cortisol and prolactin), proinflammatory cytokines (interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-a)), components of HPA-axis (lymphocyte expression of glucocorticoid receptor (GR)), immune function (natural killer cell cytotoxicity) and peripheral blood percentages of various lymphocyte subpopulations (T cells, helper T cells, cytotoxic T cells, B cells and natural killer cells) in patients with posttraumatic stress disorder and healthy controls on two occasions separated by 5.6 years (median; interquartile range: 5.4–6.3). Subjects and methods: Subjects Patients were 39 Croatian combat veterans (age: 38.46 ± 9.1 in the first and 44.10 ± 9.3 in the second time point), all men, recruited from the outpatient PTSD program at Vrapcˇe Psychiatric Hospital, and control subjects were 37 sex matched healthy civilians (age: 34.2 ± 10.6 in the first time point), hospital and laboratory personnel with no combat experience. While all PTSD subjects were assessed on two occasions, we managed to follow only 25 healthy controls (age: 38.7 ± 8.3). The participants were tested in two time points separated by 5.6 years (median; interquartile range: 5.4–6.3) using exactly the same methods. The study was approved by the Ethic Committee of the Vrapcˇe Hospital. All patients met the International Classification of Disorders (ICD)-10 PTSD criteria cit_bfcit_af ref_bf(World Health Organization, 1992 ref_num778)ref_af, the official classification in Croatian psychiatric practice. For purposes of this study, the diagnosis of PTSD, as well as the specificities of clinical picture was determined by using Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV based ClinicianAdministered PTSD Scale (CAPS) and all 39 patients met criteria for chronic PTSD. Related to DSM-IV A (traumatic event) criterion, each patient witnessed another person(s) death and experienced threat to individual’s physical integrity and/or wounding. On the basis of intrusive thoughts content, the focal traumatic experience was identified and the time passed until

assessment was recorded. The PTSD-group was relatively homogenous related to the severity of the illness. Patients with psychiatric premorbidity or comorbidity, including major depression, were excluded from this study. Prior to blood drawing, healthy civilians were examined by experienced physician and relevant data for purposes of this study were recorded on the basis of patientsÕ histories. They had negative history of any psychiatric disorder and no symptoms or signs of acute or chronic physical illness. All participants were free of any psychotropic medication, drug or alcohol abuse for at least 1 month, and did not suffer from any infectious, allergic or endocrine disorder. Samples Heparinized and unheparinized blood samples (10 mL each) were collected by venipuncture between 8 and 9 AM in Vacutainer tubes (Becton Dickinson Vacutainer System Europe, Grenoble, France). The sera for determination of cortisol concentration were stored at -80C. Serum cortisol and prolactin determination Serum cortisol and prolactin concentrations were determined by the radioimmunoassay kits (CORT-CT2 for cortisol and RIA-gnost PROL for prolactin, Schering S.A. Cis bio international, Gif-surYvette, France). All samples were analyzed in duplicates following manufacturer’s protocol. The sensitivity of the CORT-CT2 assay was 0.17 lg/100mL, and the intra-assay and inter-assay coefficients of variation were less than 6% and 8%, respectively. The sensitivity of the RIA-gnost PROL assay was 0.1 lg/mL, and the intra-assay and inter-assay coefficients of variation were 5.5–8.3% and 7.5– 10.8%, respectively. Cytokines Serum concentrations of IL-6 i TNF-a were determined by ELISA (Enzyme-Linked Immunosorbent Assay) commercially available kits. In the first time point the concentrations were assessed with Milenia kits (Diagnostic Products Corporation, Los Angeles, USA) in duplicates following manufacturer’s protocol. The sensitivity of IL-6 assay was 4 pg/mL, and for the TNF-a assay 6 pg/mL. In the second time point the concentrations were assessed with Quntikine kits (R&D Systems, Minneapolis, USA). The sensitivity of IL-6 assay was 1 pg/mL, and for the TNF-a assay 2 pg/mL. Natural killer cell cytotoxicity Peripheral blood mononuclear cells (PBMC) were separated by centrifugation on Ficoll-Hypaque (Pharmacia AB, Uppsala, Sweden) density gradient. The in vitro natural killer cell cytotoxicity (NKCC) toward 51Cr-labeled K562 target cells (185 MBq/mL, Amersham, UK) was performed according to previously described technique (8) ccit_af ref_bf(Timonen, 1979 ref_num1078)ref_af. Immunophenotyping and intracellular glucocorticoid receptor determination Lymphocyte counts were determined by flow cytometry, using Flow-CountTM Fluorospheres (Coulter Corporation, Miami, USA) according to the manufacturer’s protocol. Flow cytometric, three-color staining method was used for the simultaneous labeling of surface lymphocyte markers and intracellular lymphocyte glucocorticoid receptor expression. The method was previously described in detail 4. Briefly, surface staining was achieved by phycoerytrin (PE) conjugated anti-CD3, anti-CD16,56, anti-IgG2a, and peridinin chlorophyll protein (PerCP) conjugated anti-CD4, anti-CD8, anti-CD20, anti-IgG1 monoclonal antibodies (MoAb) (Becton Dickinson, Heidelberg, Germany), 5 lL per 50 lL of whole blood each. After incubation in the dark for 15 minutes, cells were washed and fixed, followed by erythrocytes lysis. The cells were then washed in the permeabilization buffer, containing predetermined optimal concentration of fluorescein isothiocyanate (FITC) conjugated anti-glucocorticoid receptor MoAb (9) or 5 lL of isotype control, left for 20 minutes in the dark, washed with permeabilization buffer again, and resuspended in 500 lL of fixation buffer. Prepared samples were run on FACSCalibur flow cytometer and analyzed by CELLQuest software (Becton Dickinson, Heidelberg,


47

75 CAPS B CAPS C CAPS D CAPS total

70 CAPS total

65

CAPS scor e

60

55 30 CAPS C

25

20

CAPS B CAPS D

15

10 1

2 Time

Fig. 8. Changes in Clinician-Administered posttraumatic stress Disorder scale (CAPS) scores.

Germany). At least 5000 events in the light-scatter lymphocyte gate were acquired and the percentages of surface marker positive cells were determined in PE vs. PerCP dot plots. The relative quantity of lymphocyte glucocorticoid receptor (mean glucocorticoid receptor fluorescence), expressed as mean fluorescence intensity, was calculated as the difference between mean values of glucocorticoid receptor and isotype control. The instrument calibration was performed on a daily basis. Statistics Variables that did not follow Gaussian distribution were normalized using Box-Cox transformations. Since TNF-a could not be normalized we did not include it in overall model but tested the group difference in each time point using Mann-Whitney’s U test. Because of the presence of missing data, all other analyses were performed on 5 imputed datasets after multiple imputations. To assess group differences in measured variables in each time point, multivariate general linear model with age and smoking as covariates was performed. To test equality of covariance matrices Box’s M-test was used followed by multivariate tests (Pillai’s Trace, WilksÕ Lambda, Hotelling’s Trace, Roy’s Largest Root) to test overall significance of the model. If the model was significant multiple univariate general linear model tests were performed to test the effect of group on single variable. To minimize possibility of type I error because of the multiple comparisons we used the false discovery rate method (10). Statistical analyses were done with Statistica v6 (StatSoft, Inc., Tulsa, OK, USA). Results: The total CAPS score, as well as all scores referring to all three clusters of symptoms have significantly declined over years in PTSD patients (Figure 1). The differences in biological variables between PTSD patients and controls in both time points are summarized in Tables 1 and 2. PTSD patients had higher cortisol and prolactin levels in the first assessment. Prolactin levels remained elevated in the second assessment. We did not observe the difference in IL-6 concentration between groups in both assessments while TNF-a was higher in the patients during first assessment (U = 309.0, P = 0.008). NKCC was elevated in PTSD patients and GR levels in lymphocytes, as well as all lymphocyte

48

subpopulations were lower in PTSD patients in the first time point. These differences disappeared in the second time point. Lymphocyte count was higher in PTSD patients in both assessments. Percentages of circulating total T cells (CD3+) and helper T cells (CD3+CD4+) in particular, were higher in PTSD patients only in the first time point. Discussion: Our results indicate that changes in the endocrine and immune systems in PTSD are not static but change during the course of the illness in parallel with clinical symptoms of the disorder. To our knowledge this is the first prospective study of its kind. Findings of low cortisol level with enhanced negative feedback sensitivity to cortisol, i.e. lower number of GR, are considered to be a distinctive biological feature of PTSD that separates this disorder from other psychiatric conditions such as depression (11). Simultaneous determination of the cortisol and its receptor enables better characterization of the HPA axis than cortisol alone (11). Using this approach, we have previously reported that Croatian combat veterans had higher cortisol concentration with lower lymphocyte GCR expression (4). This finding was confirmed in this study as well, but we also managed to show that over the course of about 6 years lymphocyte GR expression tends to be higher in all lymphocyte subpopulations assessed while cortisol levels decline. Although we didn’t observe group differences in GR expression in the second time point, we assume that distinct profile of HPA axis shown in the other studies is probably achieved later in the course of PTSD, more than 10 years following trauma. This hypothesis is further supported by finding of positive correlation between lymphocyte GR expression and number of years passed since trauma (data not shown). Along with cortisol, prolactin is another stress hormone that we have assessed in this study. Opposite to cortisol, prolactin is considered to be mainly immunostimulatory hormone (12). Prolactin has shown to be increased in civilians displaced by war (13), decreased in civilian PTSD (14), or unchanged in earthquake survivors with PTSD (15). Serum levels of prolactin were elevated in PTSD patients in both time points in our study. We have also observed week-positive correlation (r = 0.452; P = 0.012) between NKCC (25:1) and prolactin level in PTSD patients in the first time point. Since NKCC was elevated in PTSD patients in the first time point, there is a possibility that prolactin contributed to this effect. This is further supported by in vitro findings of the effect of prolactin on human NK cells function (16). Since PTSD patients were taking medications (not systematically assessed) in the years between assessments there is also potential long term effect of drugs, especially commonly prescribed serotonin reuptake inhibitors (SSRI), on prolactin levels. Further studies are needed to elucidate this finding. Elevated proinflammatory cytokines support the hypothesis for low-grade systemic proinflammatory activity in patients with PTSD (17). Consistent with previous findings (17,18) we found TNF-a to be higher in PTSD patients compared to controls, but only in the first time point. IL-6 was found both higher and unchanged in PTSD patients compared to controls (19,20,21). We did not observe any differences in IL-6 between patients and controls in our study. The finding of higher cortisol levels in the first time point suggests active suppressive action of endogenous cortisol on proinflammatory cytokine production (22). Since this may be the case for IL-6, elevated TNF-a in the first time point does not support this notion. More likely, severity of symptoms which indicates activation of stress response systems could be associated with TNF-a elevation. The symptoms of the PTSD were more pronounced in the first time point in our study and others showed that TNF-a correlated with most of the PTSD symptoms determined by CAPS (17). Research on the immune function in PTSD showed generally an increased delayed-type hypersensitivity (23), higher percentage of


Table 1. Group differences in biological variables in the second time point1 95% CI Mean Hormones Cortisol (lg/100 mL) Prolactin (lg/L) Cytokine IL-6 (pg/mL) NKCC (%) 25:15 50:1 100:1 GR expression (mfi) Lymphocytes

2

Lower

Upper

b3

SE

t

FDR (d)4

P

PTSD Controls PTSD Controls

13.46 11.81 11.82 5.64

11.27 9.26 9.31 4.26

15.85 14.68 15.00 7.48

0.232

0.257

0.902

0.027

0.371

0.740

0.198

3.731

0.002

5 cells/lL) Protein CSF(mg/dL) 3 12.49 6 (normal 20–50 mg/dL) IgG CSF (mg/mL) 5 20.8 5 (Normal (10–40) IgA CSF (mg/mL) 3 12.49 1 (Normal 0.5–6) IgM CSF (mg/mL) 1 4.1 4 (normal 0.05–0.8) Neopterin CSF (n = 23) 26 (n = 38) (normal < 6.9 nmol/L) 6 7 Specific antibody index 1 4.1 0 Borna disease virus (>2) Specific antibody 1 4.1 1 index for ANA or APA (>2) Inthrathecal IgG and/or 1 4.1 2 IgA and/or IgM production Q albumin increased 10 41.6 11 (age adjusted) OCB in the CSF 1 4.1 3 OCB in serum and CSF 5 20.8 0

All patients

%

n (63)

%

7.69

5

7.93

15.38

9

14.28

12.82

10

15.87

2.56

4

6.34

10.25

5

7.93

18.4

21.3

0

(n = 61) 13 1

2.56

2

3.16

5.12

3

4.76

28.20

21

33.33

7.69 0

4 5

6.34 7.93

1.58

Table 3. Display of defined signs of inflammatory processes in CSF or peripheral blood by psychiatric diagnosis

Systemic inflammation: oligoclonal bands in Serum und CSF simultaneously Category I: Inflammatory signs in imaging without CSF or systemic signs of inflammation Category I = Strong evidence: CSF inflammation (one or more of the following: AI ANA, AI APA,AI BVD; intrathecal production of IgG, and/or IgG and/or IgM; oligoclonal bands only in CSF) Category II BCB impairment as measured by Q albumin increased age adjusted Systemic signs for inflammation and/or one or more of category one and/or II and/or increased CSF IgG and/or IgA and/or IgM No signs of inflammation Total

Affective spectrum

Schizophrenic spectrum

%

n

%

n

%

n

20.8

5

0

0

7.9

5

4.16

1

5.12

2

4.76

3

16.7

4

12.8

5

14.2

9

41.66

10

28.2

11

33.33

21

66.6

16

56.4

22

60.31

38

33.33 100

8 24

51.28 100

20 39

44.44 100

28 63

Total

CD45+subset: The leukocyte common antigen CD45 is a tyrosine phosphatase expressed in various isoformes. The isoforms are linked to autoimmune diseases, pointing to an immunomodulatory function of the enzyme. CD45RO, in opposite to CD45RA, is expressed on the memory T cell type (68,82).


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Together with other T cell markers, determination of CD45RO on CSF-cells has been used to monitor MS patients (69,83). In PB of psychiatric patients, CD45RO+ on CD4+ or CD8+ cells were reported to be non-significant lower in schizophrenic patients than in matched normal controls (84). Patients in this study with CIND displayed the lowest frequency of CD4+CD45RO+ cells in PB and CSF as compared to all other groups. In psychiatric patients we observed the highest frequency, indicating a post-acute downregulation in a chronic state (CIND) and a persistent high (non-significant) CD4 activation status in psychiatric patients in the CSF but not in the PB. CD69+ subset: CD69 is considered a surrogate marker for T cell activation by mitogen or antigen stimulation (85,86) . Changes in frequency were reported in neuropsychiatric diseases (65,87,88,89). In our patient the non-significant lower frequency of CD4+CD69+ lymphocytes in the CSF in chronic inflammatory neurological diseases as compared to other patients groups may indicate that the activation markers CD69 is transiently elevated in the initial phase on CSF cells only, since defined as a very early marker, and later in the course of the disease the downregulation of this marker is higher in CIND patients then in the other patient groups. Consequences for diagnostic procedures: We now tried to use the information on T cell frequencies in the compartments CSF and peripheral blood to approach a classification of neuropsychiatric disorders by immunological guidance. As an example the distribution of T regulatory cells as characterized by CD4+CD127dim surface markers is shown in Figure 1 . To apply other surface markers to peripheral blood and CSF derived cells will likely reveal clusters when applying to a larger and less heterogeneous patient study group. Another accumulation analysis of cell distribution only in the peripheral blood revealed 6 out of 17 MPD displaying a ratio of CD4+/CD8+ cells in PB > 3.2, but only 2 NIND patients.. Overall summary: The consequences of CSF analysis of these psychiatric patients are as follows: 1) In combination with an interdisciplinary clinical approach CSF analysis validated in neurology provides an underestimated tool for differential diagnosis in psychiatric diseases. 2) We were able to demonstrate in a small number of patients suffering from chronic psychiatric disorders a substantial and lasting improvement by enhancing the diagnostic sensitivity by CSF analysis. 3) Similarities in CSF analysis and lack of significant differences may be due to moderate specificity of psychiatric symptoms for affective and schizophrenic spectrum disorders, although the observation of systemic inflammation in affective spectrum disorders only may be supported by a study detecting autoantibodies in bipolar but not in schizophrenic patients (90). 4) The subgroup of psychiatric patients with abnormal CSF and serum data or with intrathecal pathologies are candidates for further investigation for immunofunctions with regards to LLCI or ME pathology. 5) To validate immuno-and inflammatory markers (91–94) for the diagnostic procedure in psychiatric disorders (95), it is necessary to combine the investigation with well established CSF and serum markers of known pathophysiological function. The class of histochemical markers is proposed to be supplemented by T-and B-cell typing as outlined in the presentation. Proposal for further investigation: 6) Identical OCBs in blood and CSF were found. The observation remains in psychiatric disorders without an explanatory model. 7) The impact of substance class and dose of medication on the CSF flow rate needs to be investigated.

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8) Astroglia may play a role in patients with an isolated BCB-D without signs of a humoral or cellular immune response but with increased CSF neopterin. 9) Detailed work has to be done on the term neuroinflammation and neurodegeneration (96) and on the difference from acute inflammation (97). LLCI respectively ME in psychiatric spectrum disorders share similarities with unrecognized encephalitis. The proposed new term para-inflammation may only partially cover the pathophysiological and nosological entities. Acknowledgement: We thank Dagmar Vogel, CSF Laboratory and Dr. R. Kilian, Clinic for Psychiatry and Psychotherapy II, Ulm University for help, the Margarete Ammon Stiftung for major and the Stiftung Propter Homines, Vaduz -Fu¨rstentum Liechtenstein for financial support. There are no conflicts of interest between the authors. There are no financial interests, personal relationships or affiliations which could have influenced the work. References: 1. Davis KL, Stewert DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR et al. White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 2003;60:443–456. 2. Sperner-Unterweger B. Immunological aetiology of major psychiatric disorders: evidence and therapeutic implications. Drugs 2005;65:1493–1520. 3. Irwin MR, Miller AH. Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav Immun 2007;21:374–383. 4. Yolken RH, Torrey EF. Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry 2008;13:470–479 5. Licinio J, Wong ML. The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999;4:317–327 6. Meyer U, Nyffeler M, Schwendener S, Knuesel I, Yee BK, Feldon J. Relative prenatal and postnatal maternal contributions to schizophrenia-related neurochemical dysfunction after In Utero immune challenge. Neuropsychopharmacology 2008;33:441–456. 7. Buka SL, Cannon TD, Torrey EF, Yolken RH ; Collaborative Study Group on the Perinatal Origins of Severe Psychiatric Disorders. Maternal exposure to herpes simplex virus and risk of psychosis among adult offspring. Biol Psychiatry 2008;63:809–815. 8. Dalman C, Allebeck P, Gunnell D, Harrison G, Kristensson K, Lewis G et al. Infections in the CNS during childhood and the risk of subsequent psychotic illness: a cohort study of more than one million Swedish subjects. Am J Psychiatry 2008;165:59–65. 9. Bechter K, Bogerts B. Abstracts of the 9th Psychoimmunology Expert Meeting: Neuropsychoimmunology of Psychoses. Immune and inflammatory aspects of psychoses. In Vivo 2007,21:917–953. 10. Rioux JD, Abbas AK. Paths to understanding the genetic basis of autoimmune disease. Nature 2005;435:584–589. 11. Dickerson FB, Boronow JJ, Stallings CR, Origoni AE, Yolken RH. Reduction of symptoms by valacyclovir in cytomegalovirus-seropositive individuals with schizophrenia. Am J Psychiatry 2003;160:2234–2236. 12. Torrey EF, Leweke MF, Schwarz MJ, Mueller N, Bachmann S, Schroeder J, Dickerson F, Yolken RH. Cytomegalovirus and schizophrenia. CNS Drugs 2006;20(11):879–85. 13. Bechter K. Infektionen und Depression – Allgemeine Aspekte und spezifische Auslo¨ser. Neurotransmitter 2008;1:46–50.


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CRASH COURSE: CEREBROSPINAL FLUID DIAGNOSTICS FOR PSYCHIATRISTS AND NEUROLOGISTS Cerebrospinal fluid analysis for diagnosis of noninflammatory, dementive and psychiatric diseases H. Reiber1, M. Otto2 & K. Bechter3 1 CSF and Complexity Studies, University Goettingen, Germany, 2 Department of Neurology, Ulm University, Germany 3Clinic for Psychiatry and Psychotherapy II, Ulm University, Germany Abstract: CSF analysis contributes to differential diagnosis of noninflammatory diseases by: 1) exclusion of a chronic or acute inflammation. 2) detection of particular brain-derived proteins, surrogate markers, corresponding to the suggested diagnosis (tumor, dementia, brain hypoxia, hemorrhage, autoimmune disease, psychiatric disease, metabolic disorder, rhinorhea, Table 1) and 3. differential cell count in CSF. Interpretation of brain-derived proteins in CSF uses absolute concentrations (in contrast to CSF/serum quotients for bloodderived proteins) and must discriminate between different sources: Neuronal or glial proteins like NSE, or tau protein are evaluated using their absolute concentrations in CSF for maximal sensitivity without reference to QAlb. The leptomeningeal proteins like beta trace or cystatin C are evaluated as absolute concentrations with reference to QAlb. As application examples we review the group of dementive and psychiatric diseases. Alzheimer’s disease, Parkinson¢s disease dementia, Lewy-body disease and frontotemporal dementia are the major causes of neurodegenerative memory impairment and dementia. Combined analysis of Tau-Protein and Beta Amyloid 1–42 in CSF represent the classic approach, meanwhile extended with further surrogate markers. In 15% of psychiatric patients with schizophrenic or affective disorders an inflammatory process could be detected which points to a brain-organic involvement. In 24% of these patients with a psychiatric disease a moderately increased albumin quotient was observed as the only unexplained pathological sign. In psychiatric diseases it has to be regarded as a serious deficit not to make at least once a CSF analysis in the patients which could modify the diagnosis (in 6%). Introduction: The different traditions in different countries and the different judgements about the relevance of CSF analysis in the context of other clinical or imaging methods led to a wide spectrum of acknowledgement for CSF analysis. In case of infectious, acute neurological diseases (1,2) or in case of multiple sclerosis (3,4) with a chronic inflammatory process there is no controversy about the relevance of CSF analysis in Neurology (including analysis of CSF/ serum quotients QAlb, QIgG, QIgA, QIgM, cell count, oligoclonal IgG and specific antibodies). But what about psychiatric diseases or dementive processes in brain, brain trauma, autoimmune diseases with involvement of the brain? The chance for rehabilitation after neurodegenerative processes is primarily based on an early and correct diagnosis. A recent investigation (5) shows that in psychiatric diseases it has to be regarded as a serious deficit not to make at least once a CSF analysis in the patients: In 15% of psychiatric patients with schizophrenic or affective disorders an inflammatory process could be detected and in 30% an increased albumin quotient (i.e. a blood-CSF barrier

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dysfunction) which points to a brain-organic involvement and could modify the possibly wrong diagnosis in 6% of the patients. So CSF analysis must be the base for diagnostic approaches in all neurological and psychiatric diseases as CSF data pattern (1,2) can contribute to differential diagnosis of brain diseases by 1) Supporting suggested diagnosis by disease-related typical data patterns 2) Pointing to unexpected diagnosis by disease-related typical data patterns 3) Exclusion of inflammatory processes 4) Discrimination of chronic from acute diseases 5) Leading to further more specific analytical efforts. The relevance of cerebrospinal fluid and blood analysis offers a most specific and sensitive approach, but needs for reliability sophisticated, knowledge-based data interpretation. In general CSF analysis takes advantage of the intrathecal synthesis of immunoglobulins, increased release or production of marker proteins for tumor metastasis (CEA) or increased release of neuronal or glial proteins in degenerative diseases (Tau, beta amyloid, NSE, S100). In some rare cases the increased release of brain proteins (NSE) can be detected in blood. The basic issue is the difference for a source related interpretation of the proteins in CSF. After an earlier report in this journal (2) on basics in CSF analysis, focusing on blood derived proteins in CSF we focus now on the different approach for the brain-derived proteins (6,7), serving as surrogate markers for differential diagnosis of noninflammatory processes in the brain (Table 1). After reviewing the knowledge base for interpretation of brain-derived proteins we focus on two examples, the dementive and psychiatric diseases. Interpretation of blood- vs. brain-derived proteins in CSF: The understanding of the source-related dynamics of molecules in CSF with their subsequently different variability allows the rational choice between the different evaluation concepts for blood- and brain-derived proteins. Blood-derived proteins: For the primarily blood-derived proteins the discrimination of a brain-derived fraction from a bloodderived fraction in CSF is done with highest sensitivity and specificity by evaluation of CSF /serum quotients with reference to the albumin quotient in a nonlinear hyperbolic function (Fig. 1). This allows to take into account the positive rostro-caudal concentration gradients in CSF and the decreasing CSF flow rate in case of a blood CSF barrier dysfunction (8). The graphical interpretation is done with nonlinear reference ranges in quotient diagrams (Fig. 3) or by the numerical interpretation which also refers to the hyperbolic relation of proteins in CSF (1). Brain-derived proteins: A brain-derived protein in CSF is recognized by one of the following properties (Table 2) including the different source related biological coefficient of variation (CV): 1) CSF concentration > Blood concentration 2) Blood derived fraction CV in CSF) Physiology of brain-derived proteins: Proteins from neurons or glial cells like tau protein, neuron-specific enolase, S-100 protein, all enter CSF primarily in the ventricular and cisternal space. Their


concentration between normal ventricular and lumbar CSF is decreasing (in contrast to blood-derived proteins), and in the case of pathologically decreasing CSF flow rate, the concentration in lumbar CSF remains invariantly constant (Fig. 2). Concentrations of the primarily leptomeningeal proteins, ß-trace protein and cystatin C, increase between normal ventricular and lumbar CSF. In the case of pathologically decreased CSF flow rate they increase linearly(Fig. 2) in lumbar CSF (concentrations of blood-derived proteins increase nonlinearly, Fig. 1). The predominantly brain-derived proteins in CSF of neuronal or glial origin are evaluated using their absolute concentrations in CSF for maximal sensitivity without reference to QAlb. The leptomeningeal proteins like beta trace or cystatin C are evaluated as absolute concentrations with reference to QAlb. Interpretation of Brain-derived proteins in blood In case of brain hypoxia with a very strong release of Neuronspecific enolase (NSE) into brain tissue the protein reaches high concentrations in blood by direct diffusion from brain tissue into blood capillaries. In contrast Beta trace protein reaches the blood by CSF bulk flow into venous blood. So the pathological increase of NSE and S100 is detectable in blood, e.g. in cases of brain hypoxia or infarction. In particular NSE has a high predictive value for clinical outcome of the patient after brain trauma or hypoxia (9). Relevance of CSF analysis for diagnosis of dementive processes: Alzheimer’s disease (AD), Parkinson¢s disease dementia (PDD)/Lewy-body disease (DLB) and frontotemporal

Fig. 1. CSF/serum quotients as a function of QA1b, a measure of CSF flow rate (7,8).

Fig. 3. CSF data of patients with schizophrenic or affective spectrum disorders in Reibergrams (1). These patients represent a subgroup with inflammatory signs in CSF (9/63) involving 3 cases with intrathecal IgG, 1 case with intrathecal IgA and 3 cases with intrathecal IgM synthesis or other signs of inflammation, like intrathecal antibodies or increased cell count in CSF (5). The graph is created with the CSF statistics tool of COMED (14). Fig. 2. CSF protein concentration as a function of QA1b.


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dementia (FTD) are the major causes of neurodegenerative memory impairment and dementia. As new therapeutic agents are visible for the different diseases there is an ultimate need for an early differential diagnosis. Until recently the diagnosis of AD was made according to the McKhann criteria (10) in which cerebrospinal fluid findings were used to exclude other diseases. A recent update of the criteria originates from an international consensus group (11). In the last 10 years it was shown that a combined determination of just these few markers (tau-proteins, and abeta-peptides) is already sufficient to achieve a high degree of diagnostic certainty in the diagnosis of AD(12,13). According to the new research criteria low abeta 1–42 and high total–tau protein in CSF are suggested as additional criteria for the diagnosis for AD. As result of this there is a rising need for quality control of CSF samples and determination methods and on the knowledge of typical CSF findings in the various neurodegenerative diseases. Depending on the differential diagnostic question e.g. MCI vs. AD, depressive syndrome vs. AD or AD vs. FTD or AD vs. PDD, the used cut-off values will vary. The typical low abeta 1-42 and high tau-protein finding is especially helpful in the differential diagnosis of a depressive syndrome vs. AD, however for other differential diagnostic questions e.g. AD vs. PDD this profile will not be sufficient to differentiate between the two diseases especially not in the single patient approach (12,13). Typical findings of markers in neurodegenerative diseases are shown in Table 3. New research approaches from direct measurement of oligomers in specific diseases to proteomic expression profiles might come into clinical use (12,13). CSF analysis in psychiatric patients: In a recent study(5) the authors analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in CSF and serum from hospitalised affective and schizophrenic spectrum disorder patients. Numerical and graphical interpretation of CSF protein data was performed in Reibergrams (1) with a new CSF statistics tool for nonlinear group analysis with reference to a large control group (14). As much as 41% of the psychiatric patients investigated (n = 63) had pathological parameters in CSF: 14% intrathecal humoral immune responses, 10% slightly increased CSF cell counts. 24% had moderate increase of the Albuminquotient QAlb (blood-CSF barrier dysfunction) as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF. CSF analysis and interdisciplinary clinical approach helped to rediagnose 6% of psychiatric patients as likely representing a specific virus, streptococcus or autoimmune associated disorder with CNS involvement. Conclusions: CSF analysis is an underestimated diagnostic tool for differential diagnosis in psychiatric and noninflammatory diseases. Table 1. Disease-related relevance of marker proteins Disease

Marker proteins

Tumors

Carcino embryonic antigen, CSF IgM, tumor cells Tau-Protein, Beta Amyloid 1-42, Protein 14.3.3, NSE, S-100b Neuronspecic enolase (NSE), S100b (serial analysis in blood) Neuronspecic enolase (NSE) (serial analysis in blood) Polyspecific intrathecal antibodies (M,R,Z-antibody reaction) Erythrophages, Siderophages, Ferritin, Hemoglobin Beta trace Protein

Dementia Brain Hypoxia (9) Head brain trauma Autoimmune disease in brain (16) Hemorrhage Rhinorhea (15)

›increase; fl, decrease; M, not changed; -, negative immunoblot;+, positive immunoblot; AD, Alzheimer¢s disease, DLB, Lewy-body disease; FTD, fronto-temporal dementia; MSA, multiple system atrophy; CJD, Creutzfeldt-Jakob disease. 95% confidence interval. à Mann–Whitney U test with Exact statistical significance (P).

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Table 2. Predominantly brain-derived proteins in CSF regarding the intrathecal fraction (IF) calculated from theoretical molecular size (MW = molecular weight) dependent transfer of the blood derived fraction into CSF Proteins ß-trace protein Cystatin C Tau Protein S-100 B NSE Transthyretin

MW (kDa)

CSF Concentration

CSF:Serum Ratio

IF (%)

25 13.3 55–74 21 78 55(+21)

16.6 mg/L 3.1 mg/L 0.2 lg/L 1.5 lg/L 8 mg/L 17 mg/L

34:1 5:1 10:1 18:1 1:1 1:18

>99 >99 >99 >99 >99 ~90

Table 3. Marker proteins for differential diagnosis of dementive diseases (12). Typical constellation of laboratory findings in neurodegenerative diseases markers diagnosis

First priority totaltau

AD DLB FTD MSA CJD

›› › › › ›››

Ab

1-42

fl Mfl M Mfl Mfl

Second priority phosphotau ›› › › › M›

Ab

1-40

Third priority S-100 CSF

Mfl › Mfl Mfl

›››

Neuro filaments

14-3-3 WB

M

(+) rare +

› ›

References: 1. Reiber H & Peter JB. Cerebrospinal fluid analysis – diseaserelated data patterns and evaluation programs. J Neurol Sci 2001;184:101–122. 2. Reiber H. Basic CSF diagnostic in neuroimmunological diseases. Acta Neuropsychiatrica 2008;20(S1): 9–10. 3. Reiber H, Ungefehr St, Jacobi Chr. The intrathecal, polyspecific and oligoclonal immune response in multiple sclerosis. Multiple Sclerosis 1998;4:111–117. 4. Rostasy K, Reiber H. Clinical and neurochemical characteristics of pediatric Multiple sclerosis – CSF analysis as knowledge base for differential diagnosis and pathopysiology. Acta Neuropsychiatrica, 2009; this issue. 5. Bechter K, Reiber H, Herzog S, Fuchs D, Tumani H, Maxeiner HG. Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders. Recognition of subgroups with immune responses and blood-CSF barrier dysfunction. J Psych Res 2009; submitted. 6. Reiber H: Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 2001;310:173–186 7. Reiber H. Proteins in cerebrospinal fluid and blood: Barriers, CSF flow rate and source-related dynamics. Restorative Neurology and Neuroscience 2003;21:79–96. 8. Reiber H. Flow rate of cerebrospinal fluid (CSF)- a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci 1994;122:189–203. 9. Schaarschmidt H, Prange H, Reiber H. Neuron-specific enolase concentrations in blood as a prognostic parameter in cerebrovascular diseases. Stroke 1994;24:558–565. 10. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34:939–944. 11. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDSADRDA criteria. Lancet Neurol. 2007;6(8):734–746.


12. Otto M, Lewczuk P, Wiltfang J. Neurochemical approaches of cerebrospinal fluid diagnostics in neurodegenerative diseases.Methods. 2008;44:289–298. 13. Jesse S, Steinacker P, Lehnert S, Gillardon F, Hengerer B, Otto M. Neurochemical approaches in the laboratory diagnosis of Parkinson’s and Parkinson’s dementia syndromes: A review. CNS Neuroscience and therapeutics 2009;1–26 (online available). 14. Reiber H, Albaum,W. Statistical evaluation of intrathecal protein synthesis in CSF/Serum quotient diagrams. Acta

Neuropsychiatrica 2008;20(S1):48–49. Free download of the CSF Statistics Tool from www.COMED-com.de. 15. Reiber H, Walther K, Althaus H. Betra-trace protein as sensitive marker for CSF Rhinorhea and CSF Otorhea. Acta Neurol Scandinavica 2003;108:359–362. 16. Graef IT, Henze T und Reiber H. Polyspezifische Immunreaktion im ZNS bei Auto-Immunerkrankungen mit ZNS-Beteiligung. Zeitschrift fu¨r a¨rztliche Fortbildung 1994;88: 587–591.


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INPC YOUNG PSYCHIATRISTS PROGRAMME History of personality disorders Gerd Huber & Gisela Gross Bonn, Germany Personality disorders (PD) were explained as states of volitional failure or loss of coherence between cognitive-emotional and conative functions or of automatism, i.e. the manifestation of lower (primitive) forms of behaviour, escaping the control of higher (human) ones. By DSM-III-R PD are defined ’’as clusters of personality traits that are inflexible and maladaptive and cause either significant functional impairment or subjective distress’’. ’’Personality traits’’ thus remain the conceptual unit of analysis, and are defined as ’’enduring patterns of perceiving, relating and thinking about the environment and oneself exhibited in a wide range of important social and personal contexts’’ (1]. In the history PD were first considered as forms of attenuated insanity (’’Geisteskrankheit’’). ICD-10 in turn suggests ’’conditions and patterns of behaviour that emerge early in the course of individual development, as a resultant of both constitutional factors and social experience, while others are acquired later in life’’. DSM-III-R and ICD-10 accounts of PD can be described as palimpsests, whose earlier text has been hidden by recent layers of ’’empirical’’ varnish. The clinician must be mindful of the rich German and French conceptual tradition of thinking on personality and PD from which recent scripts have emerged. It must be considered that during the last 150 years terms as personality, PD, character, temperament, constitution, self, type, trait or psychopathic inferiority have changed and exchanged meanings. We notice that by conflating the history of PD as a term, as a behavioural form and as a concept, confusion has been caused. Words are the concern of historical semantics. Patterns of behaviour, similar to those currently named PD (or personality types), albeit called differently, have been known for millennia. Concepts, models and theories have been created to explain such behaviour patterns. The historian must locate the moment in which name, behaviour and concept converged; in the case of PD these seem to have taken place in the beginning of the 20th century. Numerous questions have to be answered e.g. regarding the relationship between psychoses and PD or are the terms currently favoured really better than older ones, e.g. psychopathy or ’’moral insanity’’? In the 19th century there were two predominant psychological theories: Faculty psychology conceived the mind as a set of cognitive (intellectual), emotional and volitional (conative) functions; the second theory, associationism, starting with LOCKE, conceived the mind as an empty slate, i.e. knowledge originated from ideas, obtained from the external world or from their combination by means of rules of association. Thomas REID and KANT had expressed a preference for faculty psychology; their main argument was that experience alone could not explain all knowledge, i.e. innate structures were necessary. Faculty psychology inspired phrenology, a theory, leading to new ideas on personality profiling and brain localisation; associatonism, in turn, was instrumental in the development of psychophysics and quantification in psychology. Both contributed to the creation of the new descriptive psychopathology, of psychiatric taxonomy and of the concepts of trait, type and character.

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The view that human character was innate was challenged by the view that behaviour was also shaped by environmental factors. The notion of habitude (habit) became popular and in the 2nd half of the 19th century the term (ÔhabitudeÕ) was incorporated into medical parlance. Terms derived from the same Latin stem, were later used by KRETSCHMER (21) and SHELDON, who referred to specific types of human physique. Mind and behaviour were divided into recognizable traits (parts); first monolithic descriptions of human character were broken up into their ingredients, thereby transforming ÔmolarÕ descriptions into molecular ones. Traits became the unit of analysis for human behaviour, measurement scales developed and as cerebral localization theories gained acceptance, correlations between traits and brain sites were sought. By the beginning of the 19th century psychological typologies were well known and constituted the theoretical framework within which the new concept of character (personality) has to be analyzed. As the measurement of psychological data had reached a high level, it has been also tried to measure personality traits. This was helped by the work of GALTON and the expansion of statistics and probability theory. The notion of correlation, discovered by GALTON (3), provided a new form of evidence for the view that some personality traits went together. GALTON believed that intellectual differences had a hereditary origin. Relevant terms, imported into the 19th century, as self, temperament, constitution, character and personality, had to be refurbished with new meanings. The notion constitution, equivalent to diathesis or habit (e.g. pyknic habit) was until the 20th century used in a bodycentered view, unlike to Hippocratic usage, emphasizing environmental variables. The analysis of personality, consciousness and introspection, revolving around the concept of ’’self’’, achieved clarity in the work of DESCARTES, and later in the systems of LOCKE, LEIBNIZ and KANT. JANET (16) pleaded that personality should become a topic for experimental psychology and suggested that a scientific period was about to begin in which personality would be defined in objective terms and on the basis of material obtained from new sources such as the study of the mentally ill. During the late 19th century aggressive acts, committed by the insane were characterized as ’’involuntary’’, dealt with under the notion of impulsion and explained as unmotivated motor explosions or as disorders of the will, i.e. as irresistible feelings, difficult to control. Impulsion and impulsive insanity provided one of the kernels around which the notion of psychopathic personality was to be organized. The volitional explanation had then disappeared, as the psychological aspects of the concept of ’’will’’ (20) came under scrutiny. During the 1920s the observation of the major behavioural sequelae of Encephalitis Economo spoke in favour of an organic explanation. Encephalitis in childhood gave rise to severely antisocial behaviour. Degeneration theory and personality disorder Degeneration theory was developed by MOREL (23) according to which noxious behaviour (alcoholism, masturbation) caused alterations in the human seed, which in later generations expressed themselves as mental illnesses (melancholia, mania or dementia) and physical stigmata. MAGNAN emphasized its neurobiological aspects. Without the framework of degeneration theory the concept of


psychopathic inferiority would have made little sense. Degeneration theory was relevant to the development of later typologies, such as those of KRETSCHMER, SCHNEIDER, KAHN and HENDERSON (7,18,21,8,6). Psychopathic Disorders The terms Ôpsychopathic personalityÕ (and psychopathic disorder) have disappeared from current classifications. In ICD-10 they have been incorporated into dissocial PD (F60.2), in DSM-III-R into cluster B (antisocial personality disorder, 301.70). However, the behaviours to which these terms referred, remain diagnostically relevant (24). E.g., KOCH (19) grouped under ’’psychopathic inferiority’’ abnormal behavioural states that were not to be considered as diseases. Severe such inferiorities, seen as the result of degeneration, included antisocial behaviours. According to SCHNEIDER KOCH’s main classificatory criterion had been moral rather than scientific (30). Here we must, also in order to understand SCHNEIDER’s view, realize, how ideas and concepts about PD have developed since the beginning of the 19th century. In this connection belong the descriptions of ’’Manie sans de´lire’’ by PINEL, of the ’’moral insanity’’ by PRICHARD (25) and of Henry MAUDSLEY (22), who continued the concept of moral insanity and the introduction of the term ’’psychopathic inferiority’’ (1891) with marked abnormalities of behaviour in the absence of mental illness or intellectual impairment. Later the word inferiority was replaced by (psychopathic) personality, to avoid judgemental overtones. KRAEPELIN, sharing the general doubt about the best way to classify such people, only in the 8th edition of his textbook finally adopted the term ’’psychopathic personality’’, devoted a long chapter to it and described seven separate types: Excitable, unstable, eccentric, liars, swindlers, antisocial and quarrelsome. A further and, at that time, thoroughly new step was taken by Kurt SCHNEIDER. Whereas KRAEPELIN’s seven types of psychopathic personality included only those causing inconvenience, annoyance or suffering to other people, SCHNEIDER extended the concept by including those causing suffering to themselves and not necessarily to others. Thus, he included people with markedly depressive, sensitive and insecure personality. For SCHNEIDER psychopathic personality covered the whole range of abnormal and not just antisocial personalities. In this way the term came to have two meanings: The wider meaning of abnormal personality of all kinds and the narrower meaning of antisocial personality (26, 30). Further variations in the meaning of the term ÔpsychopathicÕ were introduced by HENDERSON (7) and by the Mental Health Act for England and Wales, for which psychopathic disorder was defined as ’’persistent disorder or disability of mind, which results in abnormally aggressive or seriously irresponsible conduct’’, a definition, returning to the idea of aggressive or irresponsible acts, causing suffering to other people. HENDERSON has extended his definition by referring also to a group of passive and inadequate personalities including also those prone to suicide, drug addiction and alcohol abuse. Classifications of abnormal personalities as given in ICD-10 and DSM may also seem necessary for the purpose of collecting statistics. In everyday clinical work it may be sometimes better, to give a brief description of the main features of the personality than the names of the ICD-10- or the DSM-IV-classification. This was also the view of the authors of the 2nd edition of the Oxford Textbook of Psychiatry (4). Above all we should avoid the error which JASPERS (17) called ’’pseudo-insight through terminology’’ and classify types of personality disorders according to the medical model of diseases. One merit of SCHNEIDER’s understanding lies in the clear conceptual demarcation of the types of personality disorders from the psychotic illnesses, i.e. the organic psychosyndromes and the affective and schizophrenic psychoses. Another advantage is in our view, to avoid as far as possible value judgements. SCHNEIDER set out to replace KRAEPELIN’s socially valuating descriptions of such patients with an unsys-

tematic typology which was non-evaluating, psychological and clinically relevant (s.32,33). For each type SCHNEIDER provided a description and a background review, including genetic studies and social impact. There is a high degree of internal consistency in his accounts (33). ’’The psychopath simply is such a person’’, he said: We should not speak of a ’’disorder’’, unless we see in suffering, sensitivity or depressivity on .principle a disorder and not the expression of the ’’condition humana’’. SCHNEIDER published the 1st edition of the ’’Psychopathic personalities’’ in 1923. The 9th edition (English translation 1958) includes a preface and reply to critics, finding its strength in the simplicity of its criteria and the empirical approach. SCHNEIDER defined abnormal personality as a state of divergence from the average. Psychopathic personalities are a subclass of the abnormal personality and referred to those, who suffer under themselves or make society suffer on account of their abnormality. Abnormal personalities are not pathological in a medical sense and fall outside the disease model. SCHNEIDER described ten psychopathic types, i.e. hyperthymic, depressive, insecure-self-distrusting psychopaths with the subtypes sensitives and anancastics; then fanatic, attentionseeking, labile, explosive, affectionless, weakwilled and asthenic psychopathic personalities. He conceived these types not as diagnostic entities; they are not always permanent, they could, as e.g. also KAHN suggested, be ’’reactive’’ and ’’episodic’’. SCHNEIDER did not see any relationship between his types and the psychoses, but, that personality whether normal or abnormal, might modulate the appearance, the themes (the ’’Sosein’’) of the psychosis. SCHNEIDER’s book was often subject to criticism. Authors as HUMBERT (1947) denied the existence of a separate clinical category for psychopathic disorders, believing that they either were attenuated forms of psychotic illness, i.e. in the sense of KRETSCHMER schizothymic and schizoid or cyclothymic and cycloid personalities, or acquired states, e.g. childhood neurosis of character, susceptible to psychodynamic treatment. According to Schneider it is a selfdeception to believe that abnormal personalities are but developmental syndromes. Eugen KAHN, publishing his ’’Psychopathic personalities’’ in 1928 and PETRILOWITSCH in his book ’’Abnormal personalities’’ (3rd edition 1966), supported SCHNEIDERs definition of psychopathic personalities as states that make their bearer and/ or the society suffer. The predominant explanatory hypothesis of PD is neurobiological (2). Nevertheless, it is not unnecessary to explore the impact of psychodynamic models. Pierre JANET (16) used the model of ’’psychological automatism’’, based on the hierarchical levels of Hughlings JACKSON, to explain both mental symptoms and the ’’alterations of personality’’. He spoke of psychological automatism, when a part or all of the mental apparatus escaped the control of the will or of consciousness and continued functioning in an independent manner. He used the model of psychological automatism, to explain hysterical and dissociative states with their disconnection between the conscious and unconscious aspects of the personality. The mechanism of psychological automatism has remained popular in psychiatry, e.g. in the work of CLERAMBAULT. KRETSCHMER, following KRAEPELIN’s division of the psychoses, published his book ’’Physique and character’’ first in 1921, suggesting cycloid and schizoid temperaments. According to KRETSCHMER there are four types of physique, i.e. asthenic or leptosomatic, athletic, pyknic and dysplastic and there exist correlations between manic-depressive illness and the pyknic type and between schizophrenia and the leptosomatic-asthenic and dysplastic type. KRETSCHMER suggested not only a relationship between personality and body build, but also an association between personality and schizophrenic and manic-depressive psychoses. Schizoid and cycloid personalities are conceived as part way to schizophrenic and manic-depressive psychoses respectively. Although this theory remained without convincing support, it lingers on in the names cycloid and schizoid. According to GELDER


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and co-workers could be some less specific genetic connection between mental disorder and personality disorder, as suggested by reports of an increased frequency of various kinds of personality abnormality among relatives of schizophrenic patients and of patients with manic-depressive disorder (4). To this question and to the controversial discussion on the psychopathic personality and the possibility of its psychotherapy (27,29,31) we refer to our comment in the 15th edition of SCHNEIDER’s ’’Clinical Psychopathology’’ (31, pp 89–94), and, regarding the fascinating debate on the questions of ’’free will’’, ’’free will and brain’’ (20) and ’’Neurobiology of Psychotherapy’’, we refer to the comprehensive new literature and here also on the academic lecture of KORNHUBER at this congress. References: 1. Berrios GE. European views on personality disorders: A conceptual history. Compr Psychiatry 1993;34:14–30. 2. Cloninger CR. A systematic method for clinical description and classification of personality variants. Arch Gen Psychiatry 1987;44:573–588. 3. Galton F. Personality. Nature 1894;62:517–518. 4. Gelder M, Gath D, Mayou R. Oxford Textbook of Psychiatry. 2nd edn. Oxford Univ Press, Oxford New York Melbourne, 1989. 5. Gross G, Huber G, Morgner J (eds.) Perso¨nlichkeit – Perso¨nlichkeitssto¨rung – Psychose. Schattauer, Stuttgart New York, 1996. 6. Gross G, Huber G. Somatically based psychoses and the problem of symptomatic schizophrenia. Neurol Psychiatry Brain Res 2007;14:131–142. 7. Henderson DK. Psychopathic states. Norton, New York, 1939. 8. Hoenig J. Kurt Schneider and anglophone psychiatry. Compr Psychiatry 1982;23:391–400. 9. Huber G. Personality and schizophrenia. In: Sarteschi P. Maggini C (eds.) Personalita` e Psicopatologia. Vol I. ETS Editrice, Pisa, 1990:pp 365–379. 10. Huber G. Psychopathologie – eine versiegende Quelle? Fortschr Neurol Psychiat 2002;70:393–402. 11. Huber G (2002) The psychopathology of K. Jaspers and K. Schneider as a fundamental method for psychiatry. World J Biol Psychiatry 2002;3:50–57. 12. Huber G. Psychiatrie. Lehrbuch fu¨r Studium und Weiterbildung. 7th edition. Schattauer, Stuttgart New York, 2005. 13. Huber G 50 years of schizophrenia research in a personal view. Neurol Psychiatry Brain Res 2006;13:41–54. 14. Huber G, Gross G. Bridges between Neurology and Psychiatry. Neurol Croat 2003;52(S2):65–77. 15. Huber G, Gross G. History of exogenous reaction types. Neurol Croat 2007;56(S2):34–45. 16. Janet P. LÕautomatisme psychologique. Alcan, Paris, 1889. 17. Jaspers K. Allgemeine Psychopathologie. 4th edn. Springer, Berlin, 1946. 18. Kahn E. Psychopathic personalities. CT Yale Univ Press, New Haven, 1931. 19. Koch JA. Die psychopathischen Minderwertigkeiten. Maier, Ravensburg, 1891. 20. Kornhuber HH, Deecke L. Wille und Gehirn. Edn Sirius, Bielefeld Locarno, 2007. 21. Kretschmer E. Physique and character. Transl. by Sprott WJ. Kegal Paul Trench Trubner & Co, London UK, 1936. 22. Maudsley H. Responsibility in mental disease. Kegan Paul & Trench, London, 1885. 23. Morel BA. Traite´ des de´geńe´rescences physiques, intellectuelles et morales de lÕespe`ce humaine. Baillie`re, Paris, 1957. 24. Pichot P. Psychopathic behaviour. A historical overview. In: Hare RD, Schalling D (eds.) Psychopathic behaviour: Approaches to research. Wiley, New York, 1978:pp 55–70. 25. Prichard JC Treatise of insanity. Sherwood Gilbert & Piper, London, 1835.

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26. Schneider K. Die psychopathischen Perso¨nlichkeiten. Deuticke, Wien (9th edn. 1950), 1923. 27. Schneider K. Zur Frage der Psychotherapie endogener Psychosen. Dtsch Med Woschr 1954;79:873–875. 28. Schneider K. Kraepelin und die gegenwa¨rtige Psychiatrie. Fortschr Neurol Psychiat 1956;24:1–7. 29. Schneider K. ’’Der Psychopath’’ in heutiger Sicht. Fortschr Neurol Psychiat 1958;26:1–6. 30. Schneider K. Psychopathic Personalities. Cassell, London, 1958. 31. Schneider K. Klinische Psychopathologie. 15th edn. With a commentary by Huber G and Gross G. Thieme, Stuttgart New York, 2007. 32. Standage K. A clinical and psychometric investigation comparing Schneider’s and the DSM-III typologies of personality disorders. Compr Psychiatry 1986;27:35–46. 33. Standage K 1989. Psychopathic personalities: Kurt Schneider. Books reconsidered. Br J Psychiatry 1986;155:271–273.

Treatment choice in psychiatry? Would trainees choose similar treatments to those prescribed, and what influences decision-making? A survey of the European Federation of TraineesÕ (EFPT) Research Group Sameer Jauhar, on behalf of the EFPT Research Group* General Adult Psychiatry, Gartnavel Royal Hospital, Glasgow.*The Members of EFPT are S. Gerber, O. Andlauer, J. G. Marques, L. Mendonca, I. Dumitrescu, C. Roventa, G. Lydall, S. Guloksuz, E. Dobrzynska, N. De Vriendt, A. Mufic, J. Van Zanten F Riese, G. Favre, A. Nazaralieva, M. Bendix, I. Nwachukwu, S. Soriano & A. Nawka. Keywords: Survey, rainees, decision-making, efficacy, antipsychotics, antidepressants, mood stabilisers Introduction: Recent evidence has questioned modern psychiatric clinical practice, specifically the prescribing of ’’atypical’’ antipsychotics (1–4). Our Pan-European Research Group asked Psychiatry trainees for their own treatment preferences and factors influencing decision-making. We questioned if traineesÕ own choices differed to those for patients, what their actual choices were, and what factors influenced decision-making. Material and methods: A semi-structured survey was constructed from prior literature (5–7), piloted, and a homogenous sample size of 50 was agreed upon from each country, with 50% minimum response rate. It was distributed in English, via web-link, with questions on guidelines, preference of antipsychotic/mood stabiliser/ antidepressant for patients in given scenarios, and factors influencing choice. Physicians were asked for their own preference. Results: As the survey is ongoing, data are preliminary, that pertaining to antipsychotics presented below. i) Treatment choice of antipsychotic 95% (n = 208) chose to receive ’’atypical’’ antipsychotics (excluding Clozapine), 5% (n = 10) choosing ’’typical’’ antipsychotics, one choosing Clozapine as first-line therapy. ii) Factors influencing choice These mapped onto three domains: efficacy, side-effect profile and cost (less than 5% other reasons). Strikingly, for antipsychotics, 81% (n = 177) felt efficacy most important, 48% (n = 105) felt side-effect profile most important and 3% (n = 7) considered cost of paramount importance. Discussion: Though data are preliminary, it appears Psychiatry trainees would choose to receive some treatments based on perceived benefits, as opposed to evidence base and recent literature. It will be interesting to analyse factors influencing decision-making in clinical practice. Word count 240 words Acknowledgements: We would like to thank all those who contributed to the survey and Drs Malik and Rojnic (EFPT President and President-Elect) for their continued support and guidance.


References: 1. Jones PB, Barnes TRE, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized Controlled Trial of the Effect on Quality of Life of Second- vs. First-Generation Antipsychotic Drugs in Schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006 ;63(10):1079–1087. 2. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. N Engl J Med 2005;353(12):1209–1223. 3. Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, et al. Double-Blind Comparison of First- and SecondGeneration Antipsychotics in Early-Onset Schizophrenia and Schizo-affective Disorder: Findings From the Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS) Study. Am J Psychiatry 2008 ;appi.ajp.2008.08050756. 4. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation vs. first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 2009 ;373(9657):31– 41. 5. Steinert T. Which neuroleptic would psychiatrists take for themselves or their relatives? Eur Psychiatry 2003;18(1):40–41. 6. Bleakley S, Olofinjana O, Taylor D. Which antipsychotics would mental health professionals take themselves? Psychiatr Bull 2007;31(3):94–96. 7. Taylor M, Brown T. ’’Do unto others as…’’-Which Treatments do Psychiatrists Prefer?. Scottish Medical Journal. 2007;52(1);17–19.

2. Fleischhacker WW, Oehl MA et al. Factors influencing compliance in schizophrenia patients. J Clin Psychiatry 2003;64(Suppl. 16):10–13. 3. Hogan TP, Awad AG et al. A self-report scale predictive of drug compliance in schizophrenics: reliability and discriminative validity. Psychol Med 1983;13:177–183. 4. Hogan TP, Awad AG. Subjective response to neuroleptics and outcome in schizophrenia: a re-examination comparing two measures. Psychol Med 1992;22:347–352. 5. Libiger J. Neurolepticka´ dysforie v e´rˇ e antipsychotik: nove´ ota´zky. Psychiatrie 2004;8(Suppl. 1):25. 6. Naber D, Karow A et al. Subjective well-being under neuroleptic treatment and its relevance for compliance. Acta Psychiatricac Scand Suppl 2005;427:29–34. 7. Naber D. A self-rating to measure subjective effects of neuroleptic drugs, relationships to objective psychopathology, quality of life, compliance and other clinical variables. Int Clin Psychopharmacol 1995;10(Suppl. 3):133–138. 8. Sˇvestka J, Bitter I. Nonadherence to antipsychotic treatment in patients with schizophrenic disorders. Neuroendocrinol Lett 2007;28(Suppl. 1):95–116. 9. Van Putten T, May PRA et al. Subjective response to antipsychotic drugs. Arch Gen Psychiatry 1981;38:187–190. 10. Van Putten T, May PRA et al. Akathisia with haloperidol and thiothixene. Arch gen Psychiatry 1984;41:1036–1039.

Subjective well-being with antipsychotic treatment

Abstract: Electroencephalography has probably represented the first modern and scientifically sound attempt to functionally explore the in vivo activity of the human brain and it has, since ever, attracted attention of psychiatrists, from both the clinical and the research viewpoint. Probably due to the limitations implied by their traditional low spatial resolution, the use of psychophysiological techniques in psychiatry has been not continuous over the last century; however, the availability of newer EEG-based brain imaging techniques has recently renovated some interest (1). Furthermore, recent theories proposed that psychopathology may result from the failure to integrate the activity of different areas involved in cognitive processes, rather than from the impairment of one or more brain areas (2); within this view, a reliable brain imaging tool should be able to explore the dynamics of complex interactions among brain regions, with high sensitivity to the subtle deviation in complex processes that last fractions of seconds; psychophysiological techniques, indeed, offer the possibility to explore the functional correlates of major psychiatric illnesses, as well as to understand of the effects of psychotropic drugs on the central nervous system, with incomparable time resolution. Finally, the recent technical possibility to combine different brain imaging approaches has further fostered a renovated enthusiasm to ward the use of EEG-based techniques in psychiatry. This contribution will provide an historical overview of the EEGbased brain imaging techniques and an update on some recent advances concerning the use of such techniques within the psychiatric field. Finally, some examples of psychophysiological and ’’multimodal’’ imaging investigations in subjects with different psychiatric conditions will be provided. References: 1. Boutros NN, Arfken C, Galderisi S, Warrick J, Pratt G, Iacono W. The status of spectral EEG abnormality as a diagnostic test for schizophrenia. Schizophr Res 2008;99:225–237.

R. Kçhler, Jiri Masopust & Jan Libiger Charles University in Prague, Faculty of Medicine in Hradec Krlov, and University Hospital Hradec Krlov, Department of Psychiatry, Hradec Krlov, Czech Republic Objectives: The factors that influence compliance with antipsychotic treatment in schizophrenia are related to the patient, the patient’s environment, the attending physician, and the treatment itself (2). Important causes of nonadherence are adverse effects (AEs) of antipsychotics. Initial dysphoric reaction, extrapyramidal symptoms, akathisia, sexual dysfunction and obesity belong to the most frequent AEs (1,2,5,8,9). The patient’s subjective well-being and attitude toward antipsychotic medication are considered important for compliance (8,10). Methods: Severity of symptoms was estimated using the PANSS (Positive and Negative Symptoms of Schizophrenia) and CGI (Clinical Global Impression) scales. Self-rating Subjective Wellbeing under Neuroleptic scale (SWN) was applied to evaluate the patients¢ subjective well-being (6,7). We also administered the Drug Attitude Inventory (DAI) scale to evaluate the attitude of the study subjects toward antipsychotic medication (3,4). Results: Seventy-five outpatients (women n = 25) at the mean age of 34.6 years (median 32 years) with the diagnosis of schizophrenia were included into the study. The patients with the most pronounced subjective well-being were in remission, treated with monotherapy, and low doses of antipsychotic drugs. Conclusion: Subjective well-being is increasingly being accepted as a valid and important measure of antipsychotic treatment outcomes and tolerability. Meaningful way of antipsychotic treatment with minimal AEs can increase the patient’s subjective well-being and compliance. References: 1. Awad AG, Voruganti LN. Neuroleptic dysphoria: revisiting the concept 50 years later. Acta Psychiatr Scand Suppl 2005;427:6–13.

EEG-based brain imaging techniques in psychiatry Umberto Volpe Department of Psychiatry, University of Naples Sun, Naples, Italy


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2. Galderisi S, Mucci A. Psychophysiology in psychiatry: new perspectives in the study of mental disorders. World Psychiatry. 2002;1(3):166–168. 3. Mulert C, Pogarell O, Hegerl U. Simultaneous EEG-fMRI: perspectives in psychiatry. Clin EEG Neurosci. 2008;39:61–64.

Differences in cholesterol and metabolic syndrome between bipolar disorder men with and without suicide attempts Bjanka Vuksan-Cúsa1, Darko Marcˇinko2, Sanea Na d2, Miro Jakovljevic´2 1 Department of Psychiatry, University Hospital Centre, Zagreb, 2 Department of Psychiatry, General Hospital Virovitica, Virovitica, Croatia Abstract: Patient with mental illnesses such as schizophrenia and bipolar disorder have an increased prevalence of metabolic syndrome (MetS) and its components compared to general population. Among psychiatric disorders, bipolar disorder ranks highest in suicidality with a relative risk ratio of completed suicide of about 25 compared to the general population. Regarding the biological hypotheses of suicidality, low blood cholesterol level has been extensively explored, although results are still conflicting. The aim of this study was to investigate whether there were differences in the serum cholesterol levels in hospitalized bipolar disorder men patients with history of suicide attempts (n = 20) and without suicide attempts (n = 20). Additionally, we investigated if there were differences in the prevalence of MetS according to NCEP ATP-III criteria in these two groups of patients. Results of the study indicated significantly lower serum cholesterol levels (P = 0.013) and triglyceride levels (P = 0.047), in the bipolar disorder men with suicide attempts in comparison to bipolar disorder men without suicide attempts. The overall prevalence of MetS was 11/40 (27.5%). On this particular sample it was higher in the non–attempters 8/20 (40.0%) than in attempters 3/20 (15.0%) bipolar men group, but without statistical significance. Lower concentrations of serum cholesterol might be useful biological markers of suicidality in men with bipolar disorder. Introduction: Patient with mental illnesses such as schizophrenia and bipolar disorder have an increased prevalence of metabolic syndrome (MetS) and its components, risk factors for cardiovascular disease and type 2 diabetes (Ryan and Thakore, 2002; Newcomer, 2007) compared to general population in which incidence of MetS is also rising at an alarming rate (Nuggent, 2004). Although in the past years more attention has been devoted to the medical burden suffered by patients with schizophrenia, very recently similar concern have arisen for bipolar disorder patients. Previous studies on the prevalence of MetS in bipolar patients found 30% and 49% prevalence of MetS in US bipolar patients (Fagiolini et al., 2005; Cardenas et al., 2008), 32% prevalence of MetS in Turkish bipolar patients (Yumru et al., 2007) and 22.4% in Spanish bipolar patients (Garcia-Portilla et al., 2008). The etiology associated with this increased risk of MetS in bipolar disorder is unknown. In addition to psychosocial factors such as poverty, poor diet, lack of physical activities, increasing concern has focused on the association between second generation antipsychotics, weight gain and subsequent risk of hyperlipidaemia and diabetes. Among psychiatric disorders, bipolar disorder ranks highest in suicidality with a relative risk ratio of completed suicide of about 25 compared to the general population (Baldessarini and Tondo, 2003). During their lifetime 80% of patients with bipolar disorder exhibit suicidal behaviour and 51% attempt suicide (Valtonen et al., 2005). Suicidal behavior varied markedly between different phases of bipolar disorder and it is predominantly associated with depressive

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and mixed phases of the illness, rarely with pure manic phase. (Goldberg et al., 1999; Oquendo et al., 2000; Valtonen et al., 2007). Numerous studies showed lower cholesterol levels in patients hospitalized after suicide attempt as compared to non attempters hospitalized patients (Sarchiapone et al., 2001; Guillem et al., 2002; Kim et al., 2002) .On the other hand, there are some other studies showing no relationship between low cholesterol levels and suicide attempt (Roy et al., 2001; Tsai et al., 2002; Deisenhammer et al., 2004; Fiedorowizc et al., 2007) . The current study was created to investigate if serum cholesterol level is decreased in male bipolar disorder patients with suicide attempts compared to non-attempters. Additionally, the aim of this study was to estimate if there were differences in the prevalence of metabolic syndrome between bipolar disorder male patients with and without lifetime suicide attempts. Methods: Sample Subjects were male patients (n = 40) with bipolar disorder treated at the Department of Psychiatry, University Hospital Centre Zagreb during the period of 36 months. Within patients, 20 patients were consecutively admitted men with bipolar disorder with history of suicide attempt, and 20 patients were consecutively admitted men with bipolar disorder without history of suicide attempt. Needed sample size was calculated respected the following parameters: alpha error level of 95% (P < 0.05), large effect size (Cohens d ‡ 0.8), infinite population, t-tests for two independent samples with homogenous variances) . The diagnosis of bipolar disorder was made according to diagnostic criteria of the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10), (WHO, 1996). According to ICD-10 criteria in suicide attempter group 7 patients were in depressive, 5 in manic and 8 in mixed episode. In non attempter group 6 patients were in depressive, 12 in manic and 2 in mixed episode. Intensity of depressive symptoms was assessed by Hamilton Depression Rating Scale, HDRS-17 (Hamilton, 1960), while manic symptoms were assessed by Young Mania Rating Scale, YMRS (Young et al., 1978). Brief Psychiatric Rating Scale (BPRS18) was used to estimate a broad range of psychopathology (Overall and Gorham, 1962). Clinical Global Impression severity, CGI sev (Guy, 1976) was performed to asses the severity of illness, and Suicide Assessment Scale, SUAS for symptoms of suicidality (Stanley et al., 1986). Suicide attempt, by definition, included intent to die, self –harm did not count. The trained psychiatrist performed clinical evaluation. All participants were free of all psychotropic medication for the previous 3 months. Two groups of patients were closely matched for age. All subjects gave written consent for participation in the study after detailed information about the procedures. This study was approved by Clinical Hospital Center Medical Ethics Committee. Venous blood samples were collected within 24 h of admission. The exclusion criteria were: hypertension, diabetes mellitus, inherited disorders of lipoprotein metabolism, diagnosis of substance abuse, including alcoholism, eating disorder and organic brain syndrome. Assessment Venipuncture was performed for all subjects between 8 and 9 a.m. after 12 hours overnight fast. Immediately after collecting blood samples, serum concentration of total cholesterol, High density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides and serum glucose were determined using enzyme methods and commercial kits (Olympus Diagnostic, GmbH, Hamburg, Germany) on Olympus AU 600 automated analyzer. Inter- assay laboratory coefficients of variation were 3.2% for cholesterol, 2.5 for triglycerides and 3.0% for HDL- cholesterol. Reference intervals for the measured parameters were as follows: cholesterol 1.0 mmol/L, triglycerides 6.1 mmol/L.


Table 1. Differences in demographic, biological and clinical parameters between bipolar disorder men with suicide attempts (n = 20) and bipolar disorder men without suicide attempts (n = 20) Characteristics

Age(years) Duration of illness /year/ BMI (kg/m2) Waist circumference (cm) Cholesterol (mmol/L) Triglycerides (mmol/L) LDL-c (mmol/L) HDL-c (mmol/L) GUK(mmol/L) CGI severity BPRS (score) HDRS-17 (score) YMRS (score) SUAS (score)

Suicide attempters Mean€SD 36.4 € 9.95 10.6 € 7.01 26.9 € 4.88 94.1 € 12.14 4.0 € 0.83 1.4 € 0.52 2.7 € 1.50 2.3 € 2.98 6.4 € 3.99 4.5 € 1.00 62.0 € 9.93 24.6 € 10.29 17.7 € 15.67 54.9 € 6.83

95% CI for mean 31.69–41.01 7.27–13.83 24.64–29.21 88.42–99.78 3.6349–4.42 1.1749–1.66 1.9982–3.40 0.9498–3.74 4.482–8.22 4.03–4.97 57.35–66.65 19.78–29.42 10.32–24.98 51.65–58.05

Non attempters Median 32.0 9.5 25.7 92.5 3.9 1.3 2.3 1.2 4.8 5.0 64.5 26.5 14.0 55.5

Mean € SD 36.714.43 8.8 € 7.05 27.3 € 3.83 97.3 € 9.22 5.1 € 1.58 2.3 € 1.74 3.1 € 1.32 2.1 € 2.67 6.2 € 2.53 4.6 € 0.76 63.3 € 10.58 19.4 € 10.5 26.8 € 17.25 47.7 € 9.96

In addition to biochemical parameters, height, weight, waist circumference and blood pressure were measured. Height, weight and waist circumference of each patient were measured. Sitting blood pressure was measured in subjects after they were interviewed in the sitting position for about 5 min while discussing neutral topics. MetS was defined according to NCEP ATP III criteria (Expert panel JAMA, 2001). The presence of 3 or more of the following criteria was required to meet criteria for MetS: 1). abdominal obesity: waist circumference >102 cm in men and >88 in woman 2). hypertrigliceridemia: ‡1.7 mmol/L 3). low HDL-cholesterol: 0.05). The BPRS scores did not differ significantly between bipolar suicide attempters and non attempters (M-W = 186.5; P = 0.718), as well as CGI severity scores (M-W = 198.5; P = 0.968).

95% CI for mean 29.94–43.46 5.45–12.05 25.48–29.06 92.94–101.56 4.33–5.8 1.44–3.06 2.46–3.7 0.83–3.33 4.97–7.34 4.19–4.91 58.35–68.25 14.49–24.31 18.73–34.87 42.99–52.31

Median 29.5 5.5 26.4 96.5 4.8 1.6 3.0 1.2 5.5 4.5 64.0 15.5 33.0 50.5

Uà

P

Effect size (for significant results only)

176.5 154.0 178.0 155.5 109.0 119.5 157.5 197.0 148.0 198.5 186.5 144.0 139.5 116.0

0.529 0.221 0.565 0.231 0.013 0.028 0.253 0.947 0.165 0.968 0.718 0.134 0.102 0.023

0.15 0.10 0.16

HDRS scores were higher (M-W = 144.0; P = 0.134) and YMRS scores were lower (M-W = 139.5; P = 0.102) in suicide attempters group than in non attempters group, but without statistical significance. SUAS scores were significantly higher (M-W = 116.0; P = 0.023) in attempters than in non attempters group. Average total cholesterol was statistical significantly lower (MW = 109.0, P = 0.013) among suicide attempters (4.0 ± 0.83) than among suicide non-attempters (5.1 ± 1.58). The same was true in the case of triglycerides. Suicide attempters had statistically significantly lower (M-W = 119.5, P = 0.028) triglycerides levels (1.4 ± 0.52) than non-attempters (2.3 ± 1.74). Analysis showed that there are no statistically significant differences between bipolar patients with history of lifetime suicide attempts and bipolar patients without history of suicide attempts in HDL – cholesterol, LDL – cholesterol, blood pressure parameters and blood glucose levels (P > 0.05). The overall prevalence of MetS in our sample was 27.5%. Among attempters group only 3 patients met the criteria for MetS and in the group of non-attempters 8 patients met the criteria for MetS. Although without statistical significance, the prevalence of MetS is higher in the group of patients who never made a suicide attempt (P = 0.155). Suicidality measured by SUAS was significantly positively correlated with HDRS score (Spearman R = 0.735, P < 0.001), and significantly negatively correlated with YMRS score (Spearman R=-0.681, P < 0.001). Significant positive correlation was found for SUAS score and age (Spearman R = 0.358, P = 0.023), but no correlation was found for SUAS and duration of illness (P > 0.05). We searched further for a possible correlation between SUAS score and anthropometric measures (BMI and waist) and did not find any significant correlation (P > 0.05). Discussion: Principal findings Results of the study showed differences between bipolar disorder male patients with and without suicide attempts both on biological and clinical level. Bipolar suicide attempters had statistically significantly lower levels of cholesterol and triglycerides compared to non attempters. LDL-C values were lower and HDL-C values were higher in attempters group, but without significance. These findings are in agreement with previous study results regarding low cholesterol and suicidal behavior in different psychiatric diagnostic categories (Sarchiapone et al., 2001; Bocchetta et al., 2001; Atmaca et al., 2002, 2007; Marcˇinko et al., 2004, 2005, 2007a, 2007b, 2008). Several different mechanisms have been suggested to explain the


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potential effect of low cholesterol levels on suicidality. Low cholesterol and suicidality might be related to decreased 5-HT transmission (Hawton et al., 1993) and reduced lipid micro– viscosity in the brain cell membrane surface, resulting in decreased 5-HT receptor function (Engelberg, 1992), inhibited 5HT transmission, which may lead to a poorer suppression of impulsive behavior or to a depressive state. In accordance with previous studies investigating depressive symptoms and suicidality in mood and/or psychotic disorders (Strakovski et al., 1996; Marcˇinko et al., 2008), our study also confirmed that suicidal patients had more pronounced depressive symptoms compared to non –suicidal patients, which was evident in higher HDRS scores in suicidal patients and positive correlation between SUAS and HDRS scores. The overall prevalence of MetS was 27.5% which is similar to the results of the previous studies investigating MetS in bipolar patients (Fagiollini et al., 2005; Yumru et al., 2007; Cardenas et al., 2008; Garcia –Portilla et al., 2008). The relatively high prevalence of Met S (27.5%) is reason for concern because syndrome has very highly significant health implications, including a three to five fold increased risk of mortality due to coronary heart disease (Alexander and al., 2003; Bonora et al., 2004) and sixfold risk of developing type 2 diabetes (Laaksonen et al., 2002). On the other hand, results of our study showed that the prevalence of MetS was higher(on this particular sample, that is without reaching statistical significance) in non attempters bipolar disorder group compared to attempters group. We hypothesized that the serum lipid levels were responsible for the differences in the prevalence of MetS, since there were no significant differences in other modal subcomponents of MetS between bipolar attempters and non–attempters group. Contrasting results were shown in previous study (Fagiollini et al., 2005) demonstrating positive correlation between the presence of MetS, and obesity in particular, and a history of suicide attempts. The possible explanation for these differences may lie in different age and gender structure of the patient’s sample. The metabolic syndrome (or at least some of its components, especially obesity) can contribute to a worse prognosis of bipolar disorder through its negative impact on general physical well-being and functioning, quality of life, self esteem and psychological well-beeing (Fagiollini et al., 2003). However, some other components of MetS regarding hyperlipidemia may possibly have positive impact on the course and outcome of the disease since low lipid levels are associated with increased suicidality. To our knowledge, results of this study are the first to show relationship between reduced cholesterol, metabolic syndrome and suicidality in bipolar disorder. Since suicidality is complex behavior and influenced by biological markers and different psychological factors, recognizing the patients with biological predisposition to lack of behavioral control could be of help in prevention and treatment activities in routine clinical practice. Unanswered question and future research Limitations of this study are small patient sample, patients in different phases of bipolar disorder and cross sectional design which reflects only a specific moment in time. Also, there was no information on patient’s nutritive habits, lifestyle characteristics and daily physical activities, as well as genetic factors, which may all contribute to the alterations in serum cholesterol and the presence of MetS in bipolar suicidal male patients. Conclusions: Our results suggest that bipolar disorder male patients with suicide attempt in history have lower levels of serum cholesterol and triglyceride as compared to those patients without suicide attempt. The overall prevalence of MetS in our bipolar patient population was 27.5%. The presence of MetS was associated with lower frequency of suicide attempts in history of male patient with bipolar disorder. These results implicates that serum lipid levels may have important role in the neurobiology of

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suicide. Suicidality is a complex behavior influenced by many different biological and psychological parameters, so a better understanding of mutual relationship of these factors can facilitate more successful screening and treatment for suicidal patients. Acknowledgements: This work was supported by the Ministry of Science, Education and Sport of the Republic of Croatia, Grant No.0108106 References: Alexander C, Landsman P, Teutsch S, Haffner S. NCEP –defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;52:1210–1214. Atmaca M, Kuloglu M, Tezcan E, Ustundag B, Gecici O, Firidin B. Serum leptin and cholesterol values in suicide attempters. Neuropsychobiology 2002;45:124–127. Atmaca M, Kuloglu M, Tezcan E, Ustundag B. Serum leptin and cholesterol values in violent and non-violent suicide attempters. Psychiatry Res 2008;158(1):87–91. Baldessarini RJ, Tondo L 2003. Suicide risk and treatments for patients with bipolar disorder. JAMA;290:1517–1519. Baldessarini RJ, Pompili M, Tondo L. Suicide in bipolar disorder: Risks and management. CNS Spectr 2006;11(6):465–471. Bocchetta A, Chillotti C, Carboni G, Oi A, Ponti M, Del Zompo M. Association of personal and familial suicide risk with low serum cholesterol concentration in male lithium patients. Acta Psychiatr Scand 2001;104(1)37–41. Bonora E, Targher G, Fomentini G, Calcaterra F, Lombardi S, Marini F et al.The metabolic syndrome is an independent predictor of the cardiovascular disease in type 2 diabetic subjects. Prospective data from Verona Diabetes Complications Study. Diabet Med 2004;21:52–58. Cardenas J, Frye MA, Marusak SL, Levander ME, Chirichigno WJ, Lewis S et al. Modal subcomponents of metabolic syndrome in patients with bipolar disorder. J Affect Disord 2008;106:91–97. Deisenhammer EA, Kramer-Reinstadler K, Liensberger D, Kemmler G, Hinterhuber H, Fleischhacker WW. No evidence for an association between serum cholesterol and the course of depression and suicidality. Psychiatry Research 2004;121:253– 261. Executive Summary: The Third Report of the National Cholesterol Education Program (NCEP). Expert Panel on detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497. Fagiollini A, Kupfer DJ, Houck PR, Novick DM, Frank E. Obesity as a correlate of outcome in patient. The prevalence of metabolic syndrome in patients with bipolar disorder. J Affect Disord 2003;106:197–201. Fiedorowicz JG, Coryell WH. Cholesterol and suicide attempts: A prospective study of depressed patients. Psychiatry Res 2007;152(1):11–20. Garcia –Portilla MP, Saiz PA, Benabarre A, Sierra P, Perez J, Rodriguez A et al. The prevalence of metabolic syndrome in patients with bipolar disorder. J Affect Disord 2008;197–201. Goldberg et al. Correlates of suicidal ideation in dysporic mania. J Affect Disord 1999;56;75–81. Guillem E, Pelissolo A, Notides C, Lepine JP. Relationship between attempted suicide, serum cholesterol level and novelty seeking in psychiatric in-patients. Psychiatry Res 2002;112:83–88. Guy W. ECDEU assessment manual for psychopharmacology, revised. Bethesda MD: US Department of Health, Education and Welfare, 1976. Kim YK, Lee HJ, Kim JY, Yoon DK, Choi SH, Lee MS. Low serum cholesterol is correlated to suicidality in a Korean sample. Acta Psychiatr Scand 2002;105:141–148. Laaksonen DE, Laaka HM, Niskanen L, Kaplan G, Salonen J, Laaka T. Metabolic syndrome and development of diabetes


mellitus :application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol 2002;156:1070–1077. Lee HJ, Kim YK. Serum lipid levels and suicide attempts. Acta Psychiatr Scand 2003;108:215–221. Marcˇinko D, Martinac M, Karlovic´ D, Loncˇar Cˇ. Cholesterol serum levels in violent and non-violent young male schizophrenic suicide attempters. Psych Danubina 2004;16: 161–164. Marcˇinko D, Martinac M, Karlovic´ D, Filipcˇic´ I, Loncˇar Cˇ, Pivac N, Jakovljevic´ M. Are There Differences in Serum Cholesterol and Cortisol Concentrations Between Violent and Non-Violent Schizophrenic Male Suicide Attempters? Coll Antropol 2005;30:153–157. Marcˇinko D, Pivac N., Martinac M., Jakovljevic´ M., Mihaljevic´Pelesˇ A, Muck-Sˇeler D. Platelet serotonin and serum cholesterol concentrations in suicidal and non-suicidal male patients with first episode of psychosis. Psychiatry Res 2007;150:105– 108. Marcˇinko D, Marcˇinko A, Jakovljevic´ M, or d evic´ V, Gregurek R, Henigsberg N et al. Serum cholesterol concentrations in suicidal and non-suicidal male patients suffering from persistent delusional disorder. Coll Antropol 2007;31(3):113–117. Marcˇinko D, Marcˇinko V, Karlovic´ D, Marcˇinko A, Martinac M, Begic´ D, Jakovljevic´ M. Serum lipid levels and suicidality among male patients with schizoaffective disorder. Prog Neuropsychopharmacol Biol Psychiatry 2008;32(1):193–196. Newcomer JW. Metabolic syndrome and mental illness. Am J Manag Care 2007;13(11):170–177. Nuggent AP. The metabolic syndrome. Food Nutr Bull 2004;29:36. Oquendo MA, Waternaux C, Brodsky, Parsons B, Haas GL, Malone KM et al. Suicidal behavior in bipolar mood disorder: clinical characteristics of attempters and non-attempters. J Affect Disord 2000;59:107–117. Overall JE, Gorham DR. The Brief Psychiatric rating Scale. Psychol Res 1962;10:799–812.

Roy A, Gonzalez B, Marcus A, Berman J. Serum cholesterol, suicidal behavior and impulsivity in cocaine-dependent patients. Psychiatry Res 2001;101:243–247. Ryan MCM, Thakore JH. Physical consequences of schizophrenia and its treatment; the metabolic syndrome (mini review). Life Sci 2002;71:239–257. Sarchiapone M, Camardese G, Roy A, Della Casa S, Satta MA, Gonzales B et al. Cholesterol and serotonin indices in depressed and suicidal patients. J Affect Disord 2001;62:217–219. Stanley B, Traskman Bendz L,Stanley M. The Suicide Assesment Scale: a scale evaluating change in suicidal behaviour. Psychopharm Bull 1986;1:200–205. Strakowski SM, McElroy SL, Keck PE, West SA. Suicidality among patients with mixed and manic bipolar disorder. Am J Psychiatry 1996;153:674–676. Tsai SY, Kuo CJ, Chen CC, Lee HC. Risk factors for completed suicide in bipolar disorder. J Clin Psychiatry 2002;63:469–476. Valtonen H, Suominen K, Mantere O, Leppamaki S, Arvilommi P, Isometsa E. Suicide ideation and attempts in bipolar I and II disorders. J Clin Psychiatry 2005;66:1456–1462. Valtonen H, Suominen K, Mantere O, Leppamaki S, Arvilommi P, Isometsa E. Suicidal behaviour during different phases of bipolar disorder. J Affect Disord 2007;97:101–107. Yumru M, Savas HA, Kurt E, Kaya MC, Selek S, Savas E et al.. Atypical antipsychotic related metabolic syndrome in bipolar patients. J Affect Disord 2007;98:247–252. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;133:149–435. World Health Organization. World Health Organization International Statistical Classification of Diseases and related health Problems, Tenth Revision. Switzerland, Geneva, 1996. Zalsman G, Braun M, Arendt M, Grunebaum MF, Sher L, Burke et al. A comparison of the medical lethality of suicide attempts in bipolar and major depressive disorders. Bipolar Disor 2006;8:558–565.


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JOINT MEETING OF THE PULA CONGRESS WITH CENTRAL AND EAST EUROPEAN STROKE SOCIETY Management of stroke in central and east Europe Vida Demarin, Vlasta Vukovic´ & Drazˇen Azˇman University Department of Neurology, Sestre Milosrdnice University Hospital, Reference Center for Neurovascular Disorders and Reference Center for Headache of the Ministry of Health and Social Welfare of the Republic of Croatia, Vinogradska 29, Zagreb, Croatia Objectives: Stroke has been the third most common cause of death in the majority of the developed countries. Therefore, prevention and treatment of stroke have become recognized health priorities in most European countries. Most epidemiologic data show an eastwest difference in terms of stroke risk factors, diagnostics and treatment. In eastern countries, stroke incidence is higher, stroke is the leading cause of death and 30-day case fatality; hospitalization rates for stroke are lower. Data show that eastern countries are very close to standardized quality indicators established in western countries, except for availability of certain technological possibilities (such as CT scaning) in some eastern countries. Over the past few decades, the burden of stroke in developing countries has grown to epidemic proportions. In low- and middle income countries 2/3 of global stroke occurs. Hospital-based studies suggest that the patterns of stroke types and causes of stroke differ between developing and developed countries, resulting in differing needs for acute and long-term care. Eastern countries have a higher 30-day case fatality (mostly above 20%) compared with western countries (mostly below 20%). This is probably due to the higher prevalence of common risk factors for stroke in eastern countries which may result in more severe strokes and worse outcome. Stroke units have been established as a standard care for stroke and proved their usefulness and cost-benefit; in some European countries a nationwide network of acute stroke units was set in accordance to evidence-based recommendations and prespecified criteria. However, stroke units have not been widely established in developing countries mostly due to limited resources. The Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST) demonstrated that intraveneous alteplase is well tolerated when used in routine clinical practice within 3 hours of ischemic stroke onset; the analysis showed that the proportion of symptomatic intracerebral hemorrhage is 8.5% and mortality 15.5%. Older age, high blood glucose, high NIH Stroke Scale score and current infarction on imaging scanes are related to poor outcome. Disability before current stroke, diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers and male sex are related to high mortality at 3 months. Several developing countries introduced thrombolysis for acute stroke treatment, however, the number of such countries is still small. The two main barriers for implementation of thrombolytic therapy in developing countries are high costs and lack of proper infrastructure. Thrombolytic therapy can be applied in a small number of stroke patients; the two main barriers for implementation of thrombolytic therapy in developing countries are high costs and lack of proper infrastructure.

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Aims: We have conducted this study in order to analyze current management of acute stroke in 17 European countries: Austria, Belarus, Bosnia and Hercegovina, Bulgaria, Croatia, Czech Republic, Estonia, Georgia, Hungary, Italy, Kosovo, Lithuania, Montenegro, Romania, Russian Federation, Serbia and Slovenia. Methods: A questionnaire has been sent to collaborating stroke centers. Results: Stroke incidence is within the range of 183–623/100 000 inhabitants. All countries have stroke units, except Georgia, Montenegro and Kosovo. The majority of stroke patients are treated in Stroke units, followed by traditional neurological ward, and a small percentage of stroke patients are treated on other wards than neurological. Availability of diagnostic procedures in stroke management largely depends on urban/rural setting and is as follows: computerized tomography (CT) scan is performed in 93–100% of all stroke cases; however CT is performed in 30–70% within the first 24 hours after stroke admission. Duplex sonography is performed in 25–100% of all stroke patients. Thrombolysis is being performed in most countries, it is still not available in Romania, Georgia, Montenegro and Kosovo. The number of patients treated with thrombolysis is increasing every year. After demission, 20–100% (on average 20–40%) of patients is sent to a rehabilitation center. Conclusions: The results of our study showed that most eastern European countries have a well developed neurological care system for acute stroke and most apply thrombolysis for stroke treatment. However, some countries still have technological and socioeconomical needs. Developing countries should focus on primary and secondary stroke prevention strategies and establish stroke units; such approach would be more cost-effective in long-term. References: 1. Demarin V, Lovrencˇic´-Huzjan A, Trkanjec Z, Vukovic´ V,, Vargek-Solter V, Sˇeric´ V, Lusˇ ic´ I, Kadojic´ D, Bielen I, Tusˇ kanMohar L, Aleksic´-Shihabi A, Dikanovic´ M, Hat J, DeSyo D, Lupret V, Berosˇ V. Recommendations for stroke management 2006 update. Acta Clin Croat 2006;45:219–285. 2. Vukovic´ V, Molin CA, Ribo M, Lovrencˇic´ Huzjan A, Budisˇ ic´ M, Demarin V. Neuroimaging techniques-improving diagnostic and therapeutic options in acute stroke. Acta Clin Croat 2006;45:331–341. 3. Lovrencˇic´ Huzjan A, Vukovic´ V, Demarin V. Neurosonology in stroke. Acta Clin Croat 2006;45:385–401. 4. Wahlgren N, Ahmed N, Eriksson N et al. Multivariable Analysis of Outcome Predictors and Adjustment of Main Outcome Results to Baseline Data Profile in Randomized Controlled Trials. Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST). Stroke. 2008 Oct 16 [ahead of print]. 5. Wardlaw JM, Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2003;(3):CD000213. 6. Durai Pandian J, Padma V, Vijaya P, Sylaja PN, Murthy JM. Stroke and thrombolysis in developing countries. Int J Stroke. 2007;2(1):17–26.


7. Brainin M, Teuschl Y, Kalra L. Acute treatment and longterm management of stroke in developing countries. Lancet Neurol 2007;6(6):553–561. 8. Steiner MM, Brainin M. Austrian Stroke Registry for Acute Stroke Units. The quality of acute stroke units on a nationwide level: the Austrian Stroke Registry for acute stroke units. Eur J Neurol. 2003;10(4):353–360.

9. Brainin M, Bornstein N, Boysen G, Demarin V. Acute neurological stroke care in Europe: results of the European Stroke Care Inventory. Eur J Neurol 2008;7:5– 10. 10. Czlonkowska A, Skowron˜ska M, Niewada M. Stroke service in Central and Eastern Europe. Int J Stroke 2007;2(4): 276–278.


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SYMPOSIUM ON FORENSIC PSYCHIATRY Psychopathy, dissocial personality disorder, evil: forensic psychiatric aspects Ljubicˇic´ 1, Folnegovic´-malc V2 & Letica-Crepulja M3 1 Department for Psychiatry, University Hospital Centre Rijeka, Cambierieva, Rijeka, Croatia, 2University Department of Psychiatry, Psychiatric Hospital Vrapcˇe, Zagreb, Croatia, 3Prison in Rijeka, Imprisonment System Administration, Ministry of Justice, Rijeka, Croatia Psychopathy has traditionally been characterised as a disorder primarily of personality (particularly affective deficits) and, to a lesser extent, behaviour. Although often used interchangeably, the diagnostic constructs of psychopathy, antisocial personality disorder, and dissocial personality disorder are distinct. There are defferences in diagnostic criteria for psychopathy, antisocial personality disorder, and dissocial personality. Also, consideration should be given to the assessment, prevalence, and implications of psychopathy for violence risk and treatment efficacy. Patients with personality disorder are generally regarded as irritating, attention-

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seeking, difficult to menage and unlikely to comply with advice or treatment. Suicide attempts and other behaviours by patients previously diagnosed as having personality disorder were comonly regarded as manipulative and under voluntary control rather than the result of illness. Personality disorders are risk and complicating factor for a wide range of mental disorders with great forensic imlications. Forensic psychiatrists have more opportunities than most to contemplate the nature of evil and depravity. They are asked to evaluate individuals accused of committing some of the most horrific acts imaginable. People often assume that serial killers and genocidal leaders are ‘‘crazy.’’ If this were true, psychiatrists might have some expertise to offer in the evaluation of such evil. However, such individuals are rarely psychotic. Some perpetrators of the worst atrocities do not have a diagnosable psychiatric disorder. Part of our fascination with these individuals is their appearance of normality. The Gordian knot of evil cannot be untied by forensic psychiatry.


Nursing and human freedom.

The psychoanalytic understanding of human freedom: freedom from and freedom for.

Six Degree-of-Freedom Measurements of Human Mild Traumatic Brain Injury.

Operation Iraqi Freedom Veterans.

Operation Iraqi Freedom Veterans with a history of mild traumatic brain injury.

OIF) Veterans with and without Blast Exposure, Mild Traumatic Brain Injury, and Posttraumatic Stress Symptoms.

Balancing responsibility and freedom.

The freedom of choice.

The freedom of choice.

Freedom and moral enhancement.

Freedom in Research: The Situation.

Laetrile: quacks and freedom.

Freedom and responsibility.

The Beagle Freedom Deception Project.

Freedom and authority in the Clinical Diary.

The Ethics of Human Freedom and Healthcare Policy: A Nursing Theoretical Perspective.

Functional Freedom: A Psychological Model of Freedom in Decision-Making.

Wisdom, prudence and academic freedom.

Freedom of and from religion.

Set menus and clinical freedom.

Alcoholism, freedom, and moral responsibility.

Moral bioenhancement, freedom and reasoning.

OIF) Hispanic Veterans-A Review Using the PRISMA Method.

Operation Iraqi Freedom veterans.