1263
likewise
important to recognise progressive supranuclear palsy. In 1963, Steele, Richardson, and Olszewski in Toronto described patients with progressive palsy due to neurofibrillary degeneration
EDITORIALS
Parkinson’s disease: many
one
illness
or
syndromes?
was endowed with an unusual as well as remarkable powers of of commonsense store observation. He used the term shaking palsy or paralysis agitans for a mixed group of diseases with certain features in common, including tremor at rest, hurrying gait, flexed posture, dysarthria and dysphagia, insomnia, and severe constipation.1 Kinnier Wilson,in his encyclopaedic neurology textbook of 1940, listed three main types: postencephalitic, arteriosclerotic, and idiopathic. In 1991, Lang3 listed fifty possible varieties. We should not be surprised that so many clinical disorders result from abnormalities of the basal ganglia. This complex area of the brain, which includes the caudate, putamen, globus pallidus, subthalamic nucleus, and substantia nigra, contains the richest array of neurotransmitters and their receptors. A definite diagnosis of the cause of parkinsonism with neuropathological can be achieved only examination at necropsy. How good is clinical diagnosis in life? The disorder is readily diagnosed when a patient presents with slowness and poverty of movement, difficulty in doing two motor tasks simultaneously, gradual development of a flexed standing posture, muscular rigidity, and tremor. The most common error is to misdiagnose essential tremor.4 By contrast, it is surprisingly difficult to be sure of the pathological basis for this syndrome and to separate idiopathic Parkinson’s disease from the many other disorders that can cause identical symptoms.5 Thus it is sometimes hard to separate Parkinson’s disease in life from the group of multisystem atrophies (MSA) that include the Shy-Drager syndrome, olivopontocerebellar atrophy, and other rare and sometimes familial conditions.6Patients with MSA may present with the rapidly progressive parkinsonism without primary cerebellar or autonomic disturbance. Urodynamic studies often help to identify the autonomic component but can be abnormal in the idiopathic disease as well as in MSA. The dopamine agonist apomorphine will improve control of the perineal muscles in both conditions. It is
James Parkinson
in central nervous system nuclei.7 This condition is very similar to the amyotrophic lateral sclerosis/ parkinsonism/dementia complex that occurs among Chomorros of the Mariana islands.8 It is often mistaken for Parkinson’s disease despite nonparkinsonian features including a vertical gaze palsy, pseudobulbar palsy, dysarthria, and dystonic rigidity of the neck, and patients may respond to levodopa. Patients with both parkinsonism and dementia often pose considerable diagnostic difficulties.9 Estimates of the prevalence of dementia in Parkinson’s disease vary greatly: the overall figure is thought to be 20% or more The main cognitive defects are visuospatial deficits, language disorders, and memory
impairment. These behavioural changes may be fundamental to Parkinson’s disease, or alternatively may be due to Alzheimer lesions in the cortex or the presence of cortical Lewy bodies. If one looks hard enough, Lewy bodies, which are usually regarded as the pathological hallmark of idiopathic Parkinson’s disease, can be found in the cortex as well as the substantia nigra of most patients with Parkinson’s disease.l1 Diffuse Lewy body disease, involving the cortex as much as or more than the basal ganglia, is a common accompaniment of the parkinsonismdementia syndrome.12 The clinical features are fairly consistent: confusional episodes with pronounced impairment of attention appear early. Parkinsonian features are present in most cases but may be mild. Lewy bodies are present in the autonomic nervous system as well as the brain, being most frequent and numerous in Auerbach’s plexus of the lower oesophagus. 13 The combination of dystonia and parkinsonism in several conditions. Most commonly it is associated with long-term levodopa treatmentmobile or "on-period" dystonia or fixed, often painful, "off-period" dystonia. However, in a few patients with apparent Parkinson’s disease, dystonia is a presenting feature or an integral part of the illness,14 especially in juvenile parkinsonism. Dystonia can be troublesome in atypical patients with parkinsonism who have MSA.15 Several investigations may help to refine the clinical diagnosis of parkinsonism. In Parkinson’s disease the cerebrospinal fluid content of the major dopamine metabolite, homovanillic acid, and of the dopamine-synthesising enzyme, tyrosine hydroxylase, and the co-factor, tetrahydrobiopterin, is lower than normal. 16 High-field-strength magnetic resonance scans reveal wasting of the pars compacta of the substantia nigra in Parkinson’s disease whereas in MSA they show brainstem atrophy. 17 Positron and single photon emission tomography (PET and SPET) have made possible semi-quantitative localisation of striatal dopa uptake--eg, there are different uptake occurs
1264
patterns in young-onset Parkinson’s disease and dopa-responsive dystonia. 18 Striatal Dz receptor imaging will distinguish between Parkinson’s disease and progressive supranuclear palsy, and differences in striatal Dz receptor blockade by neuroleptics can be shown by both PET and SPET.19 Despite these technical advances, the hit rate for the clinical diagnosis of Parkinson’s disease remains poor. Hughes and colleaguesll lately described the
pathological findings in 100 patients diagnosed by consultant neurologists as having idiopathic Parkinson’s disease. 24 cases without Lewy bodies were misdiagnosed as shown by the necropsy findings of progressive supranuclear palsy, MSA, Alzheimer’s disease, or basal ganglia vascular disease. However poor the consultants’ score, does it matter? For the patient, perhaps not much. A trial of levodopa is indicated in almost all forms of parkinsonism, and most patients show at least a partial response to the drug. However, in the search for separate disease entities, the clinical diagnosis should be as accurate as possible, and we need to determine whether there is a
mechanism unique to Parkinson’s disease that results in dopamine cell loss. The finding of a selective increase in lipid peroxidation in the substantia nigra in Parkinson’s disease suggests that free radicals may cause chronic oxidative stress resulting in progressive dopamine neuron 10ss.2O,21 An excess of free radicals may be produced locally by oxidative degradation of dopamine, by neuromelanin synthesis, or by abnormal activity of the detoxifying enzymes superoxide dismutase and glutathione peroxidase. Other possible mechanisms include ineffective sulphur-conjugation mechanisms, impaired DNA repair, and deficient trophic factors. 22 One genetic factor that makes human beings susceptible to the illness is the cytochrome P450 genotype. Mammalian
specific
pathological
cytochrome P450-dependent oxygenases provide a central line of defence against many foreign compounds; the risk of Parkinson’s disease is more than twice as great for individuals with a P450 genetic polymorphism associated with deficient debrisoquine
2. Wilson SAK. Neurology, vol II. London: Edward Arnold, 1940: 787-805. 3.
Lang AE. Motor disorders symptomatology. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD. Neurology in clinical practice.
Boston: Butterworth-Heinemann, 1991: 315-36. Sjögren T. Essential tremor: a genetic and population study. Acta Neurol Scand 1960; 36 (suppl): 1-176. 5. Gibb WRG. Accuracy in the clinical diagnosis of parkinsonian syndromes. Postgrad Med J 1988; 64: 345-51. 6. Oppenheimer DR. Neuropathology of progressive autonomic failure. In: Bannister R, ed. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system. Oxford: Oxford University Press, 1983: 267-83. 7. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. Arch Neurol 1964; 10: 333-59. 8. Brody JA, Hirano A, Scott RM. Recent neuropathologic observations in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Neurology 1971; 21: 528-36. 9. Brown RG, Marsden CD. How common is dementia in Parkinson’s disease? Lancet 1984; ii: 1262-65. 10. Girotti F, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988; 51: 1498-1502. 11. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55: 181-84. 12. Gibb WRG. Cortical Lewy body dementia. Behav Neurol 1990; 3: 189-96. 13. Qualman SJ, Haupt HM, Yang P, Hamilton SR. Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Gastroenterology 1984; 87: 848-56. 14. Nygaard TG, Duvoisin RC. Hereditary dystonia-parkinsonism syndrome of juvenile onset. Neurology (NY) 1986; 36: 1424-28. 15. Berdano J. Olivopontocerebellar atrophy: a review of 117 cases. J Neurol Sci 1982; 53: 253-72. 16. Javoy-Agid F, Ruberg M, Taquet H, et al. Biochemical pathology of Parkinson’s disease. Adv Neurol 1984; 40: 189-218. 17. Morikawa F, Tashiro K, Itoh K, Hamada T, Miyasaka K. Magnetic resonance imaging in Parkinson’s disease—the evaluation of the width of the pars compacta on T2 weighted image. 10th International Symposium on Parkinson’s Disease, Oct 27-30 1991, Tokyo, Japan. P-03-39 (abstr): 267. 18. Snow BJ. Positron emission tomography in Parkinson’s disease. Can J Neurol Sci 1992; 19 (suppl): 138-41. 19. 123I-IBZM SPECT imaging of dopamine D2 receptors in Parkinson’s disease. 10th International Symposium on Parkinson’s disease, October 27-30, 1991, Tokyo, Japan. P-02-41: 223. 20. Dexter DT, Carter CJ, Wells RF, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 1989; 52: 381-89. 21. Olanow CW. Oxidation reactions in Parkinson’s disease. Neurology 1990; 40: 32-37. 22. Olanow CW. A rationale for dopamine agonists as primary therapy for Parkinson’s disease. Can J Neurol Sci 1992; 19 (suppl): 108-12. 23. Armstrong M, Daly AK, Cholerton S, Bateman N, Idle JR. Mutant debrisoquine hydroxylation genes in Parkinson’s disease. Lancet 1992; 339: 1017-18. 24. Johnson FN, Sandler M. The pharmacology of selegiline. Rev Contemp Pharmacother 1992; 3: 51-66. 4. Larsson T,
metabolism than in those without.23 All these considerations may be relevant to or disease prevention. There is increasing monoamine oxidase inhibitors,24 radical that hope scavengers, iron chelators, calcium antagonists, and antioxidants will improve parkinsonism. However, to establish the value of these treatments in the different forms of parkinsonism will depend as much on exact clinical diagnosis as on molecular science. We have now come to the time that James Parkinson anticipated, when he wrote "until we are better informed respecting the nature of this disease, the employment of internal medicines is scarcely treatment
warrantable". 1. Parkinson J. An essay on the and Jones, 1817: 66
shaking palsy. London: Sherwood, Neely
Ascariasis: indiscriminate or selective mass
chemotherapy?
The nematode Ascaris lumbricoides infects about a quarter of the world’s population and is responsible for 1 million cases of disease each year.1,2 Although prevalence does not, in itself, represent a useful quantitative marker of the health impact of ascariasis, it mirrors the level of environmental contamination by Ascaris eggs and, as such, is sometimes regarded as a valuable indicator of the level of socioeconomic development and the quality of sanitation.3In most infected individuals, the infection is either symptomless or symptoms are mild, but this is not so in the poorer populations of the developing world,
likewise
important to recognise progressive supranuclear palsy. In 1963, Steele, Richardson, and Olszewski in Toronto described patients with progressive palsy due to neurofibrillary degeneration
EDITORIALS
Parkinson’s disease: many
one
illness
or
syndromes?
was endowed with an unusual as well as remarkable powers of of commonsense store observation. He used the term shaking palsy or paralysis agitans for a mixed group of diseases with certain features in common, including tremor at rest, hurrying gait, flexed posture, dysarthria and dysphagia, insomnia, and severe constipation.1 Kinnier Wilson,in his encyclopaedic neurology textbook of 1940, listed three main types: postencephalitic, arteriosclerotic, and idiopathic. In 1991, Lang3 listed fifty possible varieties. We should not be surprised that so many clinical disorders result from abnormalities of the basal ganglia. This complex area of the brain, which includes the caudate, putamen, globus pallidus, subthalamic nucleus, and substantia nigra, contains the richest array of neurotransmitters and their receptors. A definite diagnosis of the cause of parkinsonism with neuropathological can be achieved only examination at necropsy. How good is clinical diagnosis in life? The disorder is readily diagnosed when a patient presents with slowness and poverty of movement, difficulty in doing two motor tasks simultaneously, gradual development of a flexed standing posture, muscular rigidity, and tremor. The most common error is to misdiagnose essential tremor.4 By contrast, it is surprisingly difficult to be sure of the pathological basis for this syndrome and to separate idiopathic Parkinson’s disease from the many other disorders that can cause identical symptoms.5 Thus it is sometimes hard to separate Parkinson’s disease in life from the group of multisystem atrophies (MSA) that include the Shy-Drager syndrome, olivopontocerebellar atrophy, and other rare and sometimes familial conditions.6Patients with MSA may present with the rapidly progressive parkinsonism without primary cerebellar or autonomic disturbance. Urodynamic studies often help to identify the autonomic component but can be abnormal in the idiopathic disease as well as in MSA. The dopamine agonist apomorphine will improve control of the perineal muscles in both conditions. It is
James Parkinson
in central nervous system nuclei.7 This condition is very similar to the amyotrophic lateral sclerosis/ parkinsonism/dementia complex that occurs among Chomorros of the Mariana islands.8 It is often mistaken for Parkinson’s disease despite nonparkinsonian features including a vertical gaze palsy, pseudobulbar palsy, dysarthria, and dystonic rigidity of the neck, and patients may respond to levodopa. Patients with both parkinsonism and dementia often pose considerable diagnostic difficulties.9 Estimates of the prevalence of dementia in Parkinson’s disease vary greatly: the overall figure is thought to be 20% or more The main cognitive defects are visuospatial deficits, language disorders, and memory
impairment. These behavioural changes may be fundamental to Parkinson’s disease, or alternatively may be due to Alzheimer lesions in the cortex or the presence of cortical Lewy bodies. If one looks hard enough, Lewy bodies, which are usually regarded as the pathological hallmark of idiopathic Parkinson’s disease, can be found in the cortex as well as the substantia nigra of most patients with Parkinson’s disease.l1 Diffuse Lewy body disease, involving the cortex as much as or more than the basal ganglia, is a common accompaniment of the parkinsonismdementia syndrome.12 The clinical features are fairly consistent: confusional episodes with pronounced impairment of attention appear early. Parkinsonian features are present in most cases but may be mild. Lewy bodies are present in the autonomic nervous system as well as the brain, being most frequent and numerous in Auerbach’s plexus of the lower oesophagus. 13 The combination of dystonia and parkinsonism in several conditions. Most commonly it is associated with long-term levodopa treatmentmobile or "on-period" dystonia or fixed, often painful, "off-period" dystonia. However, in a few patients with apparent Parkinson’s disease, dystonia is a presenting feature or an integral part of the illness,14 especially in juvenile parkinsonism. Dystonia can be troublesome in atypical patients with parkinsonism who have MSA.15 Several investigations may help to refine the clinical diagnosis of parkinsonism. In Parkinson’s disease the cerebrospinal fluid content of the major dopamine metabolite, homovanillic acid, and of the dopamine-synthesising enzyme, tyrosine hydroxylase, and the co-factor, tetrahydrobiopterin, is lower than normal. 16 High-field-strength magnetic resonance scans reveal wasting of the pars compacta of the substantia nigra in Parkinson’s disease whereas in MSA they show brainstem atrophy. 17 Positron and single photon emission tomography (PET and SPET) have made possible semi-quantitative localisation of striatal dopa uptake--eg, there are different uptake occurs
1264
patterns in young-onset Parkinson’s disease and dopa-responsive dystonia. 18 Striatal Dz receptor imaging will distinguish between Parkinson’s disease and progressive supranuclear palsy, and differences in striatal Dz receptor blockade by neuroleptics can be shown by both PET and SPET.19 Despite these technical advances, the hit rate for the clinical diagnosis of Parkinson’s disease remains poor. Hughes and colleaguesll lately described the
pathological findings in 100 patients diagnosed by consultant neurologists as having idiopathic Parkinson’s disease. 24 cases without Lewy bodies were misdiagnosed as shown by the necropsy findings of progressive supranuclear palsy, MSA, Alzheimer’s disease, or basal ganglia vascular disease. However poor the consultants’ score, does it matter? For the patient, perhaps not much. A trial of levodopa is indicated in almost all forms of parkinsonism, and most patients show at least a partial response to the drug. However, in the search for separate disease entities, the clinical diagnosis should be as accurate as possible, and we need to determine whether there is a
mechanism unique to Parkinson’s disease that results in dopamine cell loss. The finding of a selective increase in lipid peroxidation in the substantia nigra in Parkinson’s disease suggests that free radicals may cause chronic oxidative stress resulting in progressive dopamine neuron 10ss.2O,21 An excess of free radicals may be produced locally by oxidative degradation of dopamine, by neuromelanin synthesis, or by abnormal activity of the detoxifying enzymes superoxide dismutase and glutathione peroxidase. Other possible mechanisms include ineffective sulphur-conjugation mechanisms, impaired DNA repair, and deficient trophic factors. 22 One genetic factor that makes human beings susceptible to the illness is the cytochrome P450 genotype. Mammalian
specific
pathological
cytochrome P450-dependent oxygenases provide a central line of defence against many foreign compounds; the risk of Parkinson’s disease is more than twice as great for individuals with a P450 genetic polymorphism associated with deficient debrisoquine
2. Wilson SAK. Neurology, vol II. London: Edward Arnold, 1940: 787-805. 3.
Lang AE. Motor disorders symptomatology. In: Bradley WG, Daroff RB, Fenichel GM, Marsden CD. Neurology in clinical practice.
Boston: Butterworth-Heinemann, 1991: 315-36. Sjögren T. Essential tremor: a genetic and population study. Acta Neurol Scand 1960; 36 (suppl): 1-176. 5. Gibb WRG. Accuracy in the clinical diagnosis of parkinsonian syndromes. Postgrad Med J 1988; 64: 345-51. 6. Oppenheimer DR. Neuropathology of progressive autonomic failure. In: Bannister R, ed. Autonomic failure: a textbook of clinical disorders of the autonomic nervous system. Oxford: Oxford University Press, 1983: 267-83. 7. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. Arch Neurol 1964; 10: 333-59. 8. Brody JA, Hirano A, Scott RM. Recent neuropathologic observations in amyotrophic lateral sclerosis and parkinsonism-dementia of Guam. Neurology 1971; 21: 528-36. 9. Brown RG, Marsden CD. How common is dementia in Parkinson’s disease? Lancet 1984; ii: 1262-65. 10. Girotti F, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988; 51: 1498-1502. 11. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992; 55: 181-84. 12. Gibb WRG. Cortical Lewy body dementia. Behav Neurol 1990; 3: 189-96. 13. Qualman SJ, Haupt HM, Yang P, Hamilton SR. Esophageal Lewy bodies associated with ganglion cell loss in achalasia. Gastroenterology 1984; 87: 848-56. 14. Nygaard TG, Duvoisin RC. Hereditary dystonia-parkinsonism syndrome of juvenile onset. Neurology (NY) 1986; 36: 1424-28. 15. Berdano J. Olivopontocerebellar atrophy: a review of 117 cases. J Neurol Sci 1982; 53: 253-72. 16. Javoy-Agid F, Ruberg M, Taquet H, et al. Biochemical pathology of Parkinson’s disease. Adv Neurol 1984; 40: 189-218. 17. Morikawa F, Tashiro K, Itoh K, Hamada T, Miyasaka K. Magnetic resonance imaging in Parkinson’s disease—the evaluation of the width of the pars compacta on T2 weighted image. 10th International Symposium on Parkinson’s Disease, Oct 27-30 1991, Tokyo, Japan. P-03-39 (abstr): 267. 18. Snow BJ. Positron emission tomography in Parkinson’s disease. Can J Neurol Sci 1992; 19 (suppl): 138-41. 19. 123I-IBZM SPECT imaging of dopamine D2 receptors in Parkinson’s disease. 10th International Symposium on Parkinson’s disease, October 27-30, 1991, Tokyo, Japan. P-02-41: 223. 20. Dexter DT, Carter CJ, Wells RF, et al. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 1989; 52: 381-89. 21. Olanow CW. Oxidation reactions in Parkinson’s disease. Neurology 1990; 40: 32-37. 22. Olanow CW. A rationale for dopamine agonists as primary therapy for Parkinson’s disease. Can J Neurol Sci 1992; 19 (suppl): 108-12. 23. Armstrong M, Daly AK, Cholerton S, Bateman N, Idle JR. Mutant debrisoquine hydroxylation genes in Parkinson’s disease. Lancet 1992; 339: 1017-18. 24. Johnson FN, Sandler M. The pharmacology of selegiline. Rev Contemp Pharmacother 1992; 3: 51-66. 4. Larsson T,
metabolism than in those without.23 All these considerations may be relevant to or disease prevention. There is increasing monoamine oxidase inhibitors,24 radical that hope scavengers, iron chelators, calcium antagonists, and antioxidants will improve parkinsonism. However, to establish the value of these treatments in the different forms of parkinsonism will depend as much on exact clinical diagnosis as on molecular science. We have now come to the time that James Parkinson anticipated, when he wrote "until we are better informed respecting the nature of this disease, the employment of internal medicines is scarcely treatment
warrantable". 1. Parkinson J. An essay on the and Jones, 1817: 66
shaking palsy. London: Sherwood, Neely
Ascariasis: indiscriminate or selective mass
chemotherapy?
The nematode Ascaris lumbricoides infects about a quarter of the world’s population and is responsible for 1 million cases of disease each year.1,2 Although prevalence does not, in itself, represent a useful quantitative marker of the health impact of ascariasis, it mirrors the level of environmental contamination by Ascaris eggs and, as such, is sometimes regarded as a valuable indicator of the level of socioeconomic development and the quality of sanitation.3In most infected individuals, the infection is either symptomless or symptoms are mild, but this is not so in the poorer populations of the developing world,
