645
REVIEW ARTICL
Preventable
senility: a call for action against the vascular dementias
Introduction
By the age of 65-74 years, 3% of the population have cognitive impairment; by 85, nearly half may be
some
demented.1 Vascular dementia is claimed to be the leading cause of cognitive impairment among elderly people in Russia and Japan, and second to Alzheimer’s disease in the western world.2,3 In Alzheimer’s disease the cortical microvasculature is abnormal, making it also, in a sense, a vascular dementia ;4 whether the vascular changes contribute to the cognitive impairment remains unclear. The only major cause of dementia that is preventable is the syndrome of multi-infarct dementia. Although its precise incidence remains to be determined it is common. Yet little research is being done on the vascular dementias, whch is surprising and disappointing in view of the growing number of measures for preventing stroke.5,6
can be seen than understood. The most striking example is the identification of white-matter changes in elderly people, particularly those with dementia. Such changes have been uncritically attributed to ischaemia. Binswanger’s disease, which is neither Binswanger’s nor a disease,17 is invoked with unjustified frequency since the label is seldom supported by pathological data. Such white-matter changes occur in over 40% of Alzheimer patients’8 and in over 80% of individuals with multi-infarct dementia.,19 as determined by CT of the brain. The old idea of chronic ischaemia killing neurons (gray matter) resurfaced as ischaemic damage to their myelin-sheathed extensions (white matter), with no more evidence for this than for the original idea. However, white-matter changes are common, vascular risk factors are treatable, strokes are preventable, so the vascular dementias need to be addressed more
because the solutions matter.
Background Alzheimer gave the first convincing description of the pathological changes in a vascular dementia.’ Over the ensuing seven decades, the view that gradual narrowing of cerebral blood vessels starved the neurons and caused dementia has prevailed. This idea became pervasive; it was invoked by General George Marshall to justify retiring ineffectual colonels,8 and by a journalist to explain a Pope’s mental rigidity.9 The view that mental senility resulted from slow strangulation of the brain’s blood supply proved logical, compelling, and wrong. FisherlO pointed out that when mental impairment due to blood-vessel disease was responsible, it was the result of strokes, large or small. Tomlinson and colleagues showed a relation between the extent of cerebral infarction and the presence of dementia. 11l My colleagues and I crystallised the concept, introduced the term and proposed a standard method of diagnosing multi-infarct dementia, to emphasise that the vascular process is quantal and episodic rather than continuous and chronic.12,13 So far there has been no evidence of chronic ischaemic states of the brain, either in animals or in man. 14,15 The flagging credibility of a direct association between atherosclerosis and senility and the increasing recognition and interest in Alzheimer’s disease nurtured the perception that vascular dementias were rare.16 A resurgence of interest in vascular dementias arose from brain-imaging techniques, especially computed
tomography (CT) and magnetic resonance imaging (MRI), which depict changes in the brain so exquisitely that much
Problems Definition "Vascular dementia" is easy
to
define but difficult
to
apply. Problems arise from both the term "vascular" and the word "dementia". Most individuals would agree that "vascular" applies to any event leading to stroke, whereas they will disagree on whether chronic ischaemia exists and whether the white-matter changes seen on brain scans are ischaemic or the end-result of multiple processes.2o No agreement prevails as to whether "dementia" does or does not imply global intellectual involvement, progression, and irreversibility. The DSM-III criteria for dementia were developed largely to diagnose Alzheimer’s disease, and they are inappropriate for the vascular dementias, especially because of the heavy emphasis on memory impairment, which is not a universal finding in cognitive impairment due to vascular causes. Moreover, by the time a patient fulfills the criteria for dementia, it often is too late to do anything.
Incidence and prevalence Lack of agreement on a definition has resulted in widely different estimates of incidence and prevalence. "Multiinfarct dementia" has gained status as a specific disorder, Department of Clinical Neurological Sciences, University of Western Ontario, University Hospital, 339 Windermere Road, London, Ontario, Canada N6A 5A5 (Prof Vladimir Hachinski, MD)
ADDRESS
646
though it is a syndrome resulting from diverse causes multiple manifestations, depending on the number, nature, and location of the lesions. Attempts to develop criteria for vascular dementia have been modeled on those for Alzheimer’s disease.21 This approach does not
prognosis could be answered in therapeutic and preventive studies. The approach should be graded, ranging from simple prevention studies to complex longitudinal projects. The studies should be modular. Every study should include a minimum core of information that has been agreed
Alzheimer’s disease, whether one disease or predictable pattern of progression, whereas cognitive impairment due to vascular lesions varies greatly in clinical expression and course.
upon; validated scales should be
even
and with
make
sense.
more, has
a
an
used; and there should be
emphasis on quantification and standardisation.
Definition
be associated with dementia in the absence of the usual signs of Alzheimer’s disease. 23 Although these studies" 19,22 tend to relate multiple infarcts to mental impairment and draw conclusions regarding bilaterality and multiplicity of lesions, no systematic attempt has yet been made to correlate focal lesions with specific brain dysfunctions in multi-infarct dementia.
"Dementia" carries so many and contradictory implications that a new term has been suggested: "dysmentia", defined by specified criteria.29 It is doubtful that doctors would give up a term so entrenched in usage, and nothing would prevent use of the new term in the old way. A more practical solution may be for a definition of dementia to carry a description —eg, such as "multi-focal cognitive impairment"-preferably expressed in terms of a standardised set of neuropsychological tests. A range of increasingly more complex tests could be adopted so that several tests can be used according to the specific purpose. All studies should include at least one or two agreed measures of cognitive function. In retaining the term "dementia", it should be understood to be one extreme of a spectrum encompassing a symptomless "brain-at-risk" and a warning "pre-dementia" stage. The brain-at-risk stage represents individuals in whom symptoms or signs may or may not develop. Patients in the pre-dementia stage have some cognitive impairment that may be focal and may not add up to a conventional definition of dementia. The important point is to recognise the impairment and to do something about it.
Diagnosis
Incidence and prevalence
Pathogenesis and pathology Neuropathologists often do, but should not, have the last word on the diagnosis of "vascular dementia". When there is no clear evidence of Alzheimer’s disease, a pathologist can describe the cerebral infarcts and white-matter changes but is in no better position to determine to what extent the lesions account for the mental state than is a neurologist aware of the MRI findings. Nevertheless, only pathological examination can reveal micro-infarcts, grade of whitematter change, and nature of the vascular changes, including the unidentified deposits in the small blood vessels and the competence of the blood-brain barrier. Some of the leading clinicopathological studies’ 1,19,22 were done before the recognition of the frequency of Lewy body disease, which can
Difficulties
with
definition
and
misconstrued
pathogenesis unavoidably result in problems with diagnosis. An ischaemic score’-3 has been widely used to identify individuals with multi-infarct dementia. It discriminates well between Alzheimer’s disease and individuals with multi-infarct dementia and those with mixed dementias as verified by clinicopathologial studies. 1921 Although the score was originally used to identify two groups of demented patients for a comparative cerebral blood flow study, 13 definitions of the items used for the score2s were published only after the ischaemic score began to be used by others. A clinicopathological study confirmed the value of some of the items, 16 but it was too small for validating all the items and for providing weightings based on their predictive value. This needs to be done. Treatment and prevention
Imprecise diagnosis, uncertainty about pathogenesis, and the deteriorated state in which most patients come to medical attention contribute to the scarcity of therapeutic studies. Aspirin has been reported to produce improvement in patients with multi-infarct dementia;27 but although encouraging, the study needs to be validated by a larger series. Solutions The first step is to recognise -what we know and do not know. "The greatest obstacle to discovery is not ignorance-it is the illusion of knowledge".28 Studies of the vascular dementias should preferably be action oriented since we have the means of treating and preventing strokes. Many questions about diagnosis, pathophysiology, and
These rates will depend on the definition. A study should designed to identify individuals at all stages of the mental state. Individuals with an Alzheimer or related process and co-existent cerebral infarcts will form a "mixed" category.
be
Diagnosis The first step is the establishment of cognitive impairment. The diagnosis may be purely clinical and based of the individual’s behaviour and mental related to some previous time. The family or the patient’s attendants would have to be relied on for the history. "Dementia" is a relative term. A genius with cognitive impairment may still tower intellectually over most other people. At this stage a simple instrument such as the Mini Mental State can be helpful. 30 The ischaemic score13 distinguishes reliably Alzheimer’s disease from multi-infarct and mixed dementias.1924 After an Alzheimer’s group has been separated, and treatable causes of dementia have been ruled out, the doctor ought to indicate not only whether multi-infarct or mixed dementia exists, but also its likely cause and the evidence of supporting it. Since the ischaemic score recognises the effects of focal and cumulative brain damage it identifies a syndrome, and not a disease. Imaging of the brain, especially the depiction of whitematter changes, can complicate the diagnosis. In view of the likely heterogeneity of the white-matter changes,2O,31 it may be useful as a working hypothesis to divide individuals with dementia and white-matter changes into three categories according to whether white-matter changes are present without cognitive impairment (as occurs in some normal elderly individuals32); are associated with hypertension and on
the
assessment
status as
647
other evidence of cerebrovascular disease; with Alzheimer’s disease.
or are
associated
Pathogenesis No animal models of dementia exist but it is possible to the effect of specific lesions on animal’s learning and behaviour.33 Multiple cerebral embolisms provide a good human model for studying the effect of individual lesions on overall brain function. The study of patients after cardiac arrest or carbon monoxide poisoning can give insights into the effect of hypotension and hypoxia, respectively, on the white matter. A study of twins, especially of identical twins discordant for stroke, could provide clues to the effect of specific lesions on mental function. test
Treatment and prevention The vascular dementias should be viewed in the broadest terms, since only a tiny minority of those likely to have symptoms come to medical attention early. Patients suitable for prevention or treatment are those in the brain-at-risk stage (the elderly, hypertensives, smokers, diabetics, in atrial fibrillation, cardiac patients, subjects with asymptomatic extracranial arterial disease); those in the pre-dementia stage (patients with transient ischaemic attack, stroke, subtle cognitive impairment, silent cerebral infarctions, systemic lupus erythematosus, or other causes of stroke); and those in the dementia stage (patients with atherosclerosis of the extracranial arteries, cardiac embolism, intracranial small vessel disease, or other causes of stroke). One of the most promising lines of research is the conduct of trials of prevention in individuals with multiple risk factors. Therapeutic measures for individuals in the brain-at-risk stage include: smoking cessation, exercise (prevention and management of diabetes), diet (control of diabetes, hyperlipidemias, obesity), Ksupplementation (vascular effect), oestrogen (for protective replacement
postmenopausal women), antihypertensives (angiotensin converting enzyme inhibitors and Ca-channel blockers may be particularly suitable), lipid-lowering agents, anticoagulants (for atrial fibrillation), and aspirin (for selected patients at high risk). For those in the pre-dementia stage measures could include: carotid endarterectomy (patients with symptoms with carotid stenosis of 70-99%), anticoagulants, aspirin, ticlopidine, agents that interfere with amyloid deposition in vessels, or Ca2 channel blockers (pretreatment to attenuate the effect of infarcts). Measures for the dementia stage include: antidepressants, antihypertensives, cholinergics, nerve-growth factors, aspirin, and ticlopidine.
Implementation A conference to secure agreement about research opportunities in the prevention and treatment of the vascular dementias is a desirable prelude to the development of a plan of action. The conference should be attended by epidemiologists, investigators from major cardiovascular and cerebrovascular trials, leaders of Alzheimer study centres, sociologists, demographers, neurologists, psychiatrists, representatives from the pharmaceutical industry, and the government. Working groups on epidemiology, education, clinical trials, longitudinal clinicopathological studies, and standards should be set up, as should coordinating and training centres for exchange programmes, regular workshops and conferences, and modular research projects. Authors of
vascular dementia would submit a more detailed description of their patients than that published in their papers to a common database. This amplified database should provide material for computer modelling, metaanalysis, and generation of hypotheses. A close liaison with existing Alzheimer centres should be developed. In view of the overlap between Alzheimer’s disease and the vascular dementias, the two processes should be studied together. Few areas in medicine are as ripe for action as the vascular dementias. studies
on
The author Ontario.
is a career
investigator of the Head and Stroke Foundation of
REFERENCES 1. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higher than previously reported. JAMA 1989; 262: 2551-56. 2. Jorm AF, Korten AE, Henderson AS. The prevalence of dementia: a quantitative integration of the literature. Acta Psychiatr Scand 1987; 76: 465-79. 3. Kase CS. Epidemiology of multi-infarct dementia. Alzheimer Dis Assoc Disord 1991; 5: 71-76. 4. Munoz DG. The pathological basis of multi-infarct dementia. Alzheimer Dis Assoc Disord 1991; 5: 77-90. 5. Norris JW, Hachinski VC, eds. Prevention of stroke. New York: Springer-Verlag, 1991. 6. Barnett HJM, Hachinski VC, eds. Cerebral ischemia: advances in treatment and prevention. Neurologic Clinics of North America. Philadelphia: WB Saunders, 1992. 7. Alzheimer A. Beitrag zur Pathologischen Anatomie der Seelenstorungen des Griesenalters. Neurol Zentralbl 1899; 18: 95. 8. Pogue FC, Marshall GC. Ordeal and hope. New York: Viking Press, 1966. 9. The Economist, Aug 14, 1976, p 14. 10. Fisher CM. Dementia in cerebral vascular disease. In: Siekert R, Whisnant J, eds. Cerebral vascular disease, sixth conference. New York: Grune & Stratton, 1968: 232-36. 11. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970; 11: 205-42. 12. Hachinski VC, Lassen NA, Marshall J. Multi-infarct dementia: a cause of mental deterioration in the elderly. Lancet 1974; ii: 207-09. 13. Hachinski VC, Iliff LD, Zilkha E, et al. Cerebral blood flow in dementia. Arch Neurol 1975; 32: 632-37. 14. Frackowiak RSJ, Pozzilli C, Legg NJ, et al. Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen-15 and positron tomography. Brain 1981; 104: 753-78. 15. Brown WD, Frackowiak RSJ. Cerebral blood flow and metabolism studies in multi-infarct dementia. Alzheimer Dis Assoc Disord 1991; 5: 131-43. 16. Brust JCM. Vascular dementia is overdiagnosed. Arch Neurol 1988; 45: 799-801. 17. Hachinski VC, ed. Binswanger’s disease: neither Binswanger’s nor a disease.J Neurol Sci 1991; 103: 1. 18. Diaz F, Hachinski V, Merskey H, et al. Leuko-araiosis and cognitive impairment in Alzheimer’s disease. In: Iqbal K, McLachlan RC, Winblad B, Wisniewski, eds. Alzheimer’s disease: basic mechanisms, diagnosis and therapeutic strategies. Chichester: John Wiley, 1991: 9-11. 19. Erkinjuntti T, Haltia M, Palo J, Sulkava R, Paetau A. Accuracy of the clinical diagnosis of vascular dementia: a prospective clinical and
neuropathological study. J Neuro Neurosurg Psychiatry 1988; 51: 1037-44. 20. Hachinski VC, Potter P, Merskey H. Leuko-araiosis. Arch Neurol 1987; post-mortem
44: 42. 21. McKhann
22.
23. 24. 25.
G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task force on Alzheimer’s Disease. Neurology 1984; 34: 939-44. del Ser T, Bermejo F, Portera A, Arredondo JM, Bouras C, Constantinidis J. Vascular dementia: a clinicopathological study. J Neurol Sci 1990; 96: 1-17. Forstl H, Levy RFH. Lew on Lewy bodies, parkinsonism and dementia. Int J Geriat Psychiatry 1991; 6: 757-66. Wade JPH, Mirsen TR, et al. The clinical diagnosis of Alzheimer’s disease. Arch Neurol 1987; 44: 24-29. Hachinski VC. Differential diagnosis of Alzheimer’s dementia: multiinfarct dementia. In: Riseberg B, ed. Alzheimer’s disease. New York: Free Press (MacMillan), 1983: 188-92.
648
26. Rosen WG, Terry RD, Fuld PA, et al. Pathological verification of ischemic score in differentiation of dementia. Ann Neurol 1980; 7: 486-88. 27. Meyer JS, Rogers RL, McClintick K, et al. Randomized clinical trial of daily aspirin therapy in multi-infarct dementia. A pilot study. J Am Geriatr Soc 1989; 37: 549-55. 28. Boorstin DJ. Cited in: Roger J, McWilliams P, Zachery C, et al, eds. Do it! Let’s get off our buts. Los Angeles: Prelude Press, 1991: 404. 29. Hachinski V. Cerebral blood flow: differentiation of Alzheimer’s disease from multi-infarct dementia. In: Katzman R, Terry RD, Bick KL, eds. Alzheimer’s disease: senile dementia and related disorders. New York: Raven Press, 1978: 97-103.
30. Fcher
EP, Mahurin RK, Doody RS, Cooke N, Sim J, Pirozzolo FJ.
the limits of the Mini-Mental State. Examination of "subtests". Arch Neurol 1992; 49: 87-92. 31. Valentine AR, Moseley IF, Kendall BE. White matter abnormality in cerebral atrophy: clinicoradiological correlations. J Neurol Neurosurg Psychiatr 1980; 43: 139-42. 32. Fein G, Van Dyke C, Davenport L, et al. Preservation of normal cognitive functioning in elderly subjects with extensive white-matter lesions of long duration. Arch Gen Psychiatry 1990; 47: 220-23. 33. Naritomi H. Experimental basis of multi-infarct dementia: memory impairments in rodent models of ischemia. Alzheimer Dis Assoc Disord 1991; 5: 103-11.
Establishing
Antifungal chemotherapy in patients with acquired immunodeficiency syndrome
Fungi are prominent among the many microorganisms responsible for opportunistic infection in patients with the acquired immunodeficiency syndrome (AIDS). World wide, Candida albicans and Cryptococcus neoformans cause most fungal infections in AIDS patients, but the dimorphic fungi Histoplasma capsulatum and Coccidioides immitis, amongst others, can also cause life-threatening systemic infection in patients who have lived in or travelled to endemic areas. Pneumocystis carinii has features similar to those of fungi, as well as protozoa;’ however, it is not susceptible to currently licensed antifungal drugs and will be discussed here. The underlying immunodeficiency in AIDS accounts for the particular clinical and laboratory features associated with fungal infections, and these features have an important
not
bearing on the approach to antifungal therapy. For example, with existing therapy mycoses cannot be completely eradicated because of the sustained immune depression that follows onset of AIDS ; thus, the aim of antifungal therapy is to treat the initial infection as effectively as possible and to prevent relapse if necessary by giving indefinite suppressive chemotherapy. Candidosis
Oropharyngeal candidosis (OPC) is the most frequent fungal infection in patients with AIDS and AIDS-related complex (ARC). As human immunodeficiency virus (HIV) infection progresses, oral colonisation by candida becomes more
common,
and
clinical
infection
heralds
the
development of ARC or full-blown AIDS.’ OPC has a natural history of recurrence and, in many cases, failure to respond to normally effective treatment. Oral amphotericin B, nystatin, or clotrimazole may be effective in ARC and early AIDS, but are often inadequate in advanced disease, in which orally absorbed azoles are suitable. Oral tablets of ketoconazole are not well absorbed in AIDS patients because of reduced gastric-acid production associated with gastric atrophy. Other potential complications of ketoconazole use are hepatotoxicity (albeit rare) and interference with adrenal hormone metabolism when given in high doses. A trial of ketoconazole suspension in 33 patients’ achieved a 72% response rate with the disappearance of clinical symptoms and reduction in candida counts. However, in this study therapy was stopped because of poor compliance due to the taste of the medication (9 treatment courses), the emergence of persistent Candida glabrata infection (2), or concurrent therapy with rifampicin (2). There has been less experience more
with itraconazole, but in a preliminary reports the agent was effective at a dose of 200 mg daily given for 4 weeks. As with ketoconazole, serum concentrations of itraconazole are reduced when gastric-acid production is impaired-hence the dose of 200 mg used in AIDS-and also during concomitant therapy with rifampicin or phenytoin. In a randomised double-blind study of treatment of OPC,6 ketoconazole (200 mg per day) was compared with the new triazole fluconazole (50 mg per day); each drug was prescribed for 28 days. Clinical cure was achieved in all fluconazole recipients compared with 75% of ketoconazole recipients, and fluconazole was also better at eradicating yeasts as determined by negative cultures at the end of treatment. Further studies7.8 have confirmed this good response rate with fluconazole at 50 mg per day given for 14-28 days, with cure being achieved in 4-5 days. Negligible side effects have been reported with this regimen. De Wit and colleagues9 have done a follow-up study with fluconazole, comparing a single dose of 150 mg with 50 mg daily for 7 days and found similar rates of clinical cure and fungal eradication. However, further follow-up of such treated cases may reveal a high rate of relapse. Oesophageal candidosis occurs as a progression of OPC, and is characterised clinically by dysphagia and burning retrosternal pain. The diagnosis is established by oesophagoscopy and histology of biopsy specimens taken from mucosal lesions. Orally administered ketoconazole,io itraconazole,s and fluconazole8 are effective therapies. In studies of oral or oesophageal candidosis in which drug therapy has been stopped once the acute infection has resolved, the incidence of relapse by 1 month has been as high as 50%. Reinfection may also occur, but in the absence of a readily available candida biotyping system the frequency of this event is unknown. Indefinite suppressive antifungal therapy has, therefore, been used in some centres, although intermittent dosing (depending on symptoms) has been advocated to prevent the emergence of drug resistance." Fluconazole has gained wide acceptance as an effective continuous-suppression drug. Leen et al8 found a regular weekly dose of 150 mg to be satisfactory. However, these researchers have since reported12 4 patients in whom weekly therapy failed because of fluconazole-resistant strains of C albicans; 3 of 4 strains were sensitive to ketoconazole. Conversely, in AIDS patients with Correspondence to Dr T. R. Rogers, Department of Medical Microbiology, Charing Cross and Westminster Medical School, 17 Horseferry Road, London SW1 P 2AR, UK
REVIEW ARTICL
Preventable
senility: a call for action against the vascular dementias
Introduction
By the age of 65-74 years, 3% of the population have cognitive impairment; by 85, nearly half may be
some
demented.1 Vascular dementia is claimed to be the leading cause of cognitive impairment among elderly people in Russia and Japan, and second to Alzheimer’s disease in the western world.2,3 In Alzheimer’s disease the cortical microvasculature is abnormal, making it also, in a sense, a vascular dementia ;4 whether the vascular changes contribute to the cognitive impairment remains unclear. The only major cause of dementia that is preventable is the syndrome of multi-infarct dementia. Although its precise incidence remains to be determined it is common. Yet little research is being done on the vascular dementias, whch is surprising and disappointing in view of the growing number of measures for preventing stroke.5,6
can be seen than understood. The most striking example is the identification of white-matter changes in elderly people, particularly those with dementia. Such changes have been uncritically attributed to ischaemia. Binswanger’s disease, which is neither Binswanger’s nor a disease,17 is invoked with unjustified frequency since the label is seldom supported by pathological data. Such white-matter changes occur in over 40% of Alzheimer patients’8 and in over 80% of individuals with multi-infarct dementia.,19 as determined by CT of the brain. The old idea of chronic ischaemia killing neurons (gray matter) resurfaced as ischaemic damage to their myelin-sheathed extensions (white matter), with no more evidence for this than for the original idea. However, white-matter changes are common, vascular risk factors are treatable, strokes are preventable, so the vascular dementias need to be addressed more
because the solutions matter.
Background Alzheimer gave the first convincing description of the pathological changes in a vascular dementia.’ Over the ensuing seven decades, the view that gradual narrowing of cerebral blood vessels starved the neurons and caused dementia has prevailed. This idea became pervasive; it was invoked by General George Marshall to justify retiring ineffectual colonels,8 and by a journalist to explain a Pope’s mental rigidity.9 The view that mental senility resulted from slow strangulation of the brain’s blood supply proved logical, compelling, and wrong. FisherlO pointed out that when mental impairment due to blood-vessel disease was responsible, it was the result of strokes, large or small. Tomlinson and colleagues showed a relation between the extent of cerebral infarction and the presence of dementia. 11l My colleagues and I crystallised the concept, introduced the term and proposed a standard method of diagnosing multi-infarct dementia, to emphasise that the vascular process is quantal and episodic rather than continuous and chronic.12,13 So far there has been no evidence of chronic ischaemic states of the brain, either in animals or in man. 14,15 The flagging credibility of a direct association between atherosclerosis and senility and the increasing recognition and interest in Alzheimer’s disease nurtured the perception that vascular dementias were rare.16 A resurgence of interest in vascular dementias arose from brain-imaging techniques, especially computed
tomography (CT) and magnetic resonance imaging (MRI), which depict changes in the brain so exquisitely that much
Problems Definition "Vascular dementia" is easy
to
define but difficult
to
apply. Problems arise from both the term "vascular" and the word "dementia". Most individuals would agree that "vascular" applies to any event leading to stroke, whereas they will disagree on whether chronic ischaemia exists and whether the white-matter changes seen on brain scans are ischaemic or the end-result of multiple processes.2o No agreement prevails as to whether "dementia" does or does not imply global intellectual involvement, progression, and irreversibility. The DSM-III criteria for dementia were developed largely to diagnose Alzheimer’s disease, and they are inappropriate for the vascular dementias, especially because of the heavy emphasis on memory impairment, which is not a universal finding in cognitive impairment due to vascular causes. Moreover, by the time a patient fulfills the criteria for dementia, it often is too late to do anything.
Incidence and prevalence Lack of agreement on a definition has resulted in widely different estimates of incidence and prevalence. "Multiinfarct dementia" has gained status as a specific disorder, Department of Clinical Neurological Sciences, University of Western Ontario, University Hospital, 339 Windermere Road, London, Ontario, Canada N6A 5A5 (Prof Vladimir Hachinski, MD)
ADDRESS
646
though it is a syndrome resulting from diverse causes multiple manifestations, depending on the number, nature, and location of the lesions. Attempts to develop criteria for vascular dementia have been modeled on those for Alzheimer’s disease.21 This approach does not
prognosis could be answered in therapeutic and preventive studies. The approach should be graded, ranging from simple prevention studies to complex longitudinal projects. The studies should be modular. Every study should include a minimum core of information that has been agreed
Alzheimer’s disease, whether one disease or predictable pattern of progression, whereas cognitive impairment due to vascular lesions varies greatly in clinical expression and course.
upon; validated scales should be
even
and with
make
sense.
more, has
a
an
used; and there should be
emphasis on quantification and standardisation.
Definition
be associated with dementia in the absence of the usual signs of Alzheimer’s disease. 23 Although these studies" 19,22 tend to relate multiple infarcts to mental impairment and draw conclusions regarding bilaterality and multiplicity of lesions, no systematic attempt has yet been made to correlate focal lesions with specific brain dysfunctions in multi-infarct dementia.
"Dementia" carries so many and contradictory implications that a new term has been suggested: "dysmentia", defined by specified criteria.29 It is doubtful that doctors would give up a term so entrenched in usage, and nothing would prevent use of the new term in the old way. A more practical solution may be for a definition of dementia to carry a description —eg, such as "multi-focal cognitive impairment"-preferably expressed in terms of a standardised set of neuropsychological tests. A range of increasingly more complex tests could be adopted so that several tests can be used according to the specific purpose. All studies should include at least one or two agreed measures of cognitive function. In retaining the term "dementia", it should be understood to be one extreme of a spectrum encompassing a symptomless "brain-at-risk" and a warning "pre-dementia" stage. The brain-at-risk stage represents individuals in whom symptoms or signs may or may not develop. Patients in the pre-dementia stage have some cognitive impairment that may be focal and may not add up to a conventional definition of dementia. The important point is to recognise the impairment and to do something about it.
Diagnosis
Incidence and prevalence
Pathogenesis and pathology Neuropathologists often do, but should not, have the last word on the diagnosis of "vascular dementia". When there is no clear evidence of Alzheimer’s disease, a pathologist can describe the cerebral infarcts and white-matter changes but is in no better position to determine to what extent the lesions account for the mental state than is a neurologist aware of the MRI findings. Nevertheless, only pathological examination can reveal micro-infarcts, grade of whitematter change, and nature of the vascular changes, including the unidentified deposits in the small blood vessels and the competence of the blood-brain barrier. Some of the leading clinicopathological studies’ 1,19,22 were done before the recognition of the frequency of Lewy body disease, which can
Difficulties
with
definition
and
misconstrued
pathogenesis unavoidably result in problems with diagnosis. An ischaemic score’-3 has been widely used to identify individuals with multi-infarct dementia. It discriminates well between Alzheimer’s disease and individuals with multi-infarct dementia and those with mixed dementias as verified by clinicopathologial studies. 1921 Although the score was originally used to identify two groups of demented patients for a comparative cerebral blood flow study, 13 definitions of the items used for the score2s were published only after the ischaemic score began to be used by others. A clinicopathological study confirmed the value of some of the items, 16 but it was too small for validating all the items and for providing weightings based on their predictive value. This needs to be done. Treatment and prevention
Imprecise diagnosis, uncertainty about pathogenesis, and the deteriorated state in which most patients come to medical attention contribute to the scarcity of therapeutic studies. Aspirin has been reported to produce improvement in patients with multi-infarct dementia;27 but although encouraging, the study needs to be validated by a larger series. Solutions The first step is to recognise -what we know and do not know. "The greatest obstacle to discovery is not ignorance-it is the illusion of knowledge".28 Studies of the vascular dementias should preferably be action oriented since we have the means of treating and preventing strokes. Many questions about diagnosis, pathophysiology, and
These rates will depend on the definition. A study should designed to identify individuals at all stages of the mental state. Individuals with an Alzheimer or related process and co-existent cerebral infarcts will form a "mixed" category.
be
Diagnosis The first step is the establishment of cognitive impairment. The diagnosis may be purely clinical and based of the individual’s behaviour and mental related to some previous time. The family or the patient’s attendants would have to be relied on for the history. "Dementia" is a relative term. A genius with cognitive impairment may still tower intellectually over most other people. At this stage a simple instrument such as the Mini Mental State can be helpful. 30 The ischaemic score13 distinguishes reliably Alzheimer’s disease from multi-infarct and mixed dementias.1924 After an Alzheimer’s group has been separated, and treatable causes of dementia have been ruled out, the doctor ought to indicate not only whether multi-infarct or mixed dementia exists, but also its likely cause and the evidence of supporting it. Since the ischaemic score recognises the effects of focal and cumulative brain damage it identifies a syndrome, and not a disease. Imaging of the brain, especially the depiction of whitematter changes, can complicate the diagnosis. In view of the likely heterogeneity of the white-matter changes,2O,31 it may be useful as a working hypothesis to divide individuals with dementia and white-matter changes into three categories according to whether white-matter changes are present without cognitive impairment (as occurs in some normal elderly individuals32); are associated with hypertension and on
the
assessment
status as
647
other evidence of cerebrovascular disease; with Alzheimer’s disease.
or are
associated
Pathogenesis No animal models of dementia exist but it is possible to the effect of specific lesions on animal’s learning and behaviour.33 Multiple cerebral embolisms provide a good human model for studying the effect of individual lesions on overall brain function. The study of patients after cardiac arrest or carbon monoxide poisoning can give insights into the effect of hypotension and hypoxia, respectively, on the white matter. A study of twins, especially of identical twins discordant for stroke, could provide clues to the effect of specific lesions on mental function. test
Treatment and prevention The vascular dementias should be viewed in the broadest terms, since only a tiny minority of those likely to have symptoms come to medical attention early. Patients suitable for prevention or treatment are those in the brain-at-risk stage (the elderly, hypertensives, smokers, diabetics, in atrial fibrillation, cardiac patients, subjects with asymptomatic extracranial arterial disease); those in the pre-dementia stage (patients with transient ischaemic attack, stroke, subtle cognitive impairment, silent cerebral infarctions, systemic lupus erythematosus, or other causes of stroke); and those in the dementia stage (patients with atherosclerosis of the extracranial arteries, cardiac embolism, intracranial small vessel disease, or other causes of stroke). One of the most promising lines of research is the conduct of trials of prevention in individuals with multiple risk factors. Therapeutic measures for individuals in the brain-at-risk stage include: smoking cessation, exercise (prevention and management of diabetes), diet (control of diabetes, hyperlipidemias, obesity), Ksupplementation (vascular effect), oestrogen (for protective replacement
postmenopausal women), antihypertensives (angiotensin converting enzyme inhibitors and Ca-channel blockers may be particularly suitable), lipid-lowering agents, anticoagulants (for atrial fibrillation), and aspirin (for selected patients at high risk). For those in the pre-dementia stage measures could include: carotid endarterectomy (patients with symptoms with carotid stenosis of 70-99%), anticoagulants, aspirin, ticlopidine, agents that interfere with amyloid deposition in vessels, or Ca2 channel blockers (pretreatment to attenuate the effect of infarcts). Measures for the dementia stage include: antidepressants, antihypertensives, cholinergics, nerve-growth factors, aspirin, and ticlopidine.
Implementation A conference to secure agreement about research opportunities in the prevention and treatment of the vascular dementias is a desirable prelude to the development of a plan of action. The conference should be attended by epidemiologists, investigators from major cardiovascular and cerebrovascular trials, leaders of Alzheimer study centres, sociologists, demographers, neurologists, psychiatrists, representatives from the pharmaceutical industry, and the government. Working groups on epidemiology, education, clinical trials, longitudinal clinicopathological studies, and standards should be set up, as should coordinating and training centres for exchange programmes, regular workshops and conferences, and modular research projects. Authors of
vascular dementia would submit a more detailed description of their patients than that published in their papers to a common database. This amplified database should provide material for computer modelling, metaanalysis, and generation of hypotheses. A close liaison with existing Alzheimer centres should be developed. In view of the overlap between Alzheimer’s disease and the vascular dementias, the two processes should be studied together. Few areas in medicine are as ripe for action as the vascular dementias. studies
on
The author Ontario.
is a career
investigator of the Head and Stroke Foundation of
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Establishing
Antifungal chemotherapy in patients with acquired immunodeficiency syndrome
Fungi are prominent among the many microorganisms responsible for opportunistic infection in patients with the acquired immunodeficiency syndrome (AIDS). World wide, Candida albicans and Cryptococcus neoformans cause most fungal infections in AIDS patients, but the dimorphic fungi Histoplasma capsulatum and Coccidioides immitis, amongst others, can also cause life-threatening systemic infection in patients who have lived in or travelled to endemic areas. Pneumocystis carinii has features similar to those of fungi, as well as protozoa;’ however, it is not susceptible to currently licensed antifungal drugs and will be discussed here. The underlying immunodeficiency in AIDS accounts for the particular clinical and laboratory features associated with fungal infections, and these features have an important
not
bearing on the approach to antifungal therapy. For example, with existing therapy mycoses cannot be completely eradicated because of the sustained immune depression that follows onset of AIDS ; thus, the aim of antifungal therapy is to treat the initial infection as effectively as possible and to prevent relapse if necessary by giving indefinite suppressive chemotherapy. Candidosis
Oropharyngeal candidosis (OPC) is the most frequent fungal infection in patients with AIDS and AIDS-related complex (ARC). As human immunodeficiency virus (HIV) infection progresses, oral colonisation by candida becomes more
common,
and
clinical
infection
heralds
the
development of ARC or full-blown AIDS.’ OPC has a natural history of recurrence and, in many cases, failure to respond to normally effective treatment. Oral amphotericin B, nystatin, or clotrimazole may be effective in ARC and early AIDS, but are often inadequate in advanced disease, in which orally absorbed azoles are suitable. Oral tablets of ketoconazole are not well absorbed in AIDS patients because of reduced gastric-acid production associated with gastric atrophy. Other potential complications of ketoconazole use are hepatotoxicity (albeit rare) and interference with adrenal hormone metabolism when given in high doses. A trial of ketoconazole suspension in 33 patients’ achieved a 72% response rate with the disappearance of clinical symptoms and reduction in candida counts. However, in this study therapy was stopped because of poor compliance due to the taste of the medication (9 treatment courses), the emergence of persistent Candida glabrata infection (2), or concurrent therapy with rifampicin (2). There has been less experience more
with itraconazole, but in a preliminary reports the agent was effective at a dose of 200 mg daily given for 4 weeks. As with ketoconazole, serum concentrations of itraconazole are reduced when gastric-acid production is impaired-hence the dose of 200 mg used in AIDS-and also during concomitant therapy with rifampicin or phenytoin. In a randomised double-blind study of treatment of OPC,6 ketoconazole (200 mg per day) was compared with the new triazole fluconazole (50 mg per day); each drug was prescribed for 28 days. Clinical cure was achieved in all fluconazole recipients compared with 75% of ketoconazole recipients, and fluconazole was also better at eradicating yeasts as determined by negative cultures at the end of treatment. Further studies7.8 have confirmed this good response rate with fluconazole at 50 mg per day given for 14-28 days, with cure being achieved in 4-5 days. Negligible side effects have been reported with this regimen. De Wit and colleagues9 have done a follow-up study with fluconazole, comparing a single dose of 150 mg with 50 mg daily for 7 days and found similar rates of clinical cure and fungal eradication. However, further follow-up of such treated cases may reveal a high rate of relapse. Oesophageal candidosis occurs as a progression of OPC, and is characterised clinically by dysphagia and burning retrosternal pain. The diagnosis is established by oesophagoscopy and histology of biopsy specimens taken from mucosal lesions. Orally administered ketoconazole,io itraconazole,s and fluconazole8 are effective therapies. In studies of oral or oesophageal candidosis in which drug therapy has been stopped once the acute infection has resolved, the incidence of relapse by 1 month has been as high as 50%. Reinfection may also occur, but in the absence of a readily available candida biotyping system the frequency of this event is unknown. Indefinite suppressive antifungal therapy has, therefore, been used in some centres, although intermittent dosing (depending on symptoms) has been advocated to prevent the emergence of drug resistance." Fluconazole has gained wide acceptance as an effective continuous-suppression drug. Leen et al8 found a regular weekly dose of 150 mg to be satisfactory. However, these researchers have since reported12 4 patients in whom weekly therapy failed because of fluconazole-resistant strains of C albicans; 3 of 4 strains were sensitive to ketoconazole. Conversely, in AIDS patients with Correspondence to Dr T. R. Rogers, Department of Medical Microbiology, Charing Cross and Westminster Medical School, 17 Horseferry Road, London SW1 P 2AR, UK
