COMM UNICATIONS
382
fortuitous coincidence: Population prevalence rates (per 100,000) of MS [110 cases; (lo)] and idiopathic Parkinson’s disease [164 cases; ( I l ) ] would in the Northern hemisphere render -1 individual per 500,000 likely to carry both conditions. Arguments against a mere coincidence and in favor of possible pathophysiological links between the two conditions may be as follows. (a) In case 1, the remission of parkinsonian features occurred in a time-locked fashion together with the remission of MS signs and symptoms subsequent to MS-directed drug therapy. (b) In both cases, MR imaging showed involvement of thalami and basal ganglia adjacent to the internal capsule. Overall, basal ganglia affection in MR imaging has been noted in 25% of MS patients (12). Size, distribution, and dynamics of plaque formation within a strategic area such as the internal capsule may contribute to different clinical expression, when the neighboring basal ganglia and thalamic structures are attached. (c) Because ventral and central parts of the thalamus are functionally involved in the basal ganglia-thalamo-cortical pathways, structural lesions such as demyelinating plaques affecting these circuitries at the thalamic or basal ganglia level may result clinically in hypokinetic (case 1) or full-blown parkinsonian states (case 2) (13). Longitudinal monitoring of MS cases with basal ganglia involvement on MR imaging may help to establish in-vivo the exact meaning of a clinicoradiological correlation between movement disorders and MS. P. Vieregge W. Klostermann Klinik fur Neurologie H. Briickmann Institut fiir Radiologie Medizinische Universitat zu Liibeck Liibeck, Germany
References 1 . Coleman RJ, Quinn NP, Marsden CD. Multiple sclerosis presenting as adult onset dystonia. Mov Disord 1988;3:329332. 2. Plant GT, Kermode AG, du Bouley EP, McDonald WI. Spasmodic torticollis due to a midbrain lesion in a case of multiple sclerosis. Mov Disord 1989;4:359-362. 3. Mao CC, Gancher ST, Herndon RM. Movement disorders in multiple sclerosis. Mov Disord 1988;3:109-1 16. 4. Riley D, Lang AE. Hemiballism in multiple sclerosis. Mov Disord 1988;3:88-94. 5. Reiber HO, Felgenhauer K. Protein transfer at the bloodCSF barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chem Acta 1987;163:319-328. 6. Tibbling G, Link H, Ohman S . Principles of albumin and IgG analysis in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385-390. 7. Schadlich H-J, Karbe H, Felgenhauer K. The prevalence of locally-synthesized virus antibodies in various forms of multiple sclerosis. J Neurol Sci 1987;80:343-349. 8. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231. 9. Barbeau A. Parkinson’s disease: clinical features and etiopathology. In: Vinken PJ, Bruyn GW, Klawans H, eds. Ex-
Movement Disorders, Vol. 7, No. 4, 1992
10. 11.
12.
13.
trapyramidal disorders. Amsterdam: Elsevier Science, 1986:87-152. [Handbook of clinical neurology; vol5 (49)l. Beer S , Kesselring J. Die Multiple Sklerose im Kanton Bern (CH). Fortschr Neurol Psychiatr 1988;56:390-397. Mutch WJ, Dingwall-Fordyce I, Downie AW, Paterson JG, Roy SK. Parkinson’s disease in a Scottish city. Br Med J 1986;292:534-536. Kesselring J, Ormerod IEC, Miller DH, du Bouley EPGH, McDonald WI. Magnetic resonance imaging in multiple sclerosis. Stuttgart and New York: Georg Thieme Verlag, 1989. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. TINS 1990;13:266271.
Parkinson’s Disease in a Patient with Mitochondria1 Myopathy: Is There a Causative Relationship? To the Editor: The cause of the progressive nigral degeneration in Parkinson’s disease (PD) is unknown. It was recently suggested that the mitochondrial respiratory enzyme complex-1 (NADH: ubiquinone oxidoreductase) activity is deficient in the CNS and platelets of patients with PD (1-3). Interestingly, 1-methyl-4-phenyl-pyridinium ion (MPP ), the toxic metabolite of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), kills nigral neurons by poisoning their mitochondrial respiration (4). After its entry into dopaminergic neurons, MPP is taken-up and concentrated by the mitochondria where it inhibits the NADH-linked fraction of complex-I activity (5). These observations suggest that nigral neurons may die in PD because of impaired mitochondrial energy metabolism due to hereditary, neurotoxic, or other factors (6,7). The mitochondrial myopathies are a heterogenous group of diseases that share the common features of structural changes in skeletal muscle mitochondria and may cause muscular as well as nervous system dysfunction. We now report a patient with longstanding mitochondrial myopathy who developed PD. The intriguing question is whether the two disorders are causatively related or purely coincidental. A 60-year-old man was under long-term follow-up because of a syndrome consisting of slowly progressive muscle weakness, peripheral neuropathy and external ophthalmoplegia. He was readmitted because during the last year he developed symptoms of PD. There was no family history of myopathy, PD, or other neurological disorders. He was never exposed to neuroleptic drugs. On examination, his older signs included complete external ophthalmoplegia, bilateral facial weakness, reduced proximal muscle strength symmetrically affecting both upper and lower limbs, generally absent tendon jerks, and distal hypoesthesia to pain and touch. Plantar responses were bilaterally flexor. There were no signs of dementia. The new neurological findings included marked reduced facial mimicry with monotonous and slow speech. He was generally bradykinetic and rigid, with slow and shuffling gait. He had coarse resting tremor af-
+
+
COMMUNICA TIONS fecting his right hand. Electromyographic work-up showed typical myopathic and neuropathic changes. The CSF was normal except for mildly elevated protein content of 60 mg%. Muscle biopsy was taken from his right deltoid. With the modified Gomori trichrome method, 25% of the fibers showed dense subsarcolemmal deposits of red staining granular material, which gave an intense reaction for succinic dehydrogenase, compatible with red-ragged fibers, confirming the diagnosis of mitochondrial myopathy . Treatment with levodopa and carbidopa was started with partial improvement. The patient became less bradykinetic and rigid, and his tremor was partly reduced. This patient developed PD on the background of histologically verified mitochondrial myopathy. Defective mitochondrial function has been reported in patients with PD and it has been hypothesized that nigral neurons may degenerate because of an underlying mitochondrial encephalopathy (8). It would therefore be tempting to use the concurrent association of PD and mitochondrial myopathy in our patient to support that theory and suggest that his dopaminergic cell loss developed or became accelerated because the mitochondrial dysfunction spread from the skeletal muscles to his substantia nigra. However, impaired mitochondrial respiration as the cause of PD is not solidly established. The observation by Parker et al. (1) that complex-1 activity is reduced in platelets of parkinsonians has not been confirmed. Decreased mitochondrial complex- 1 activity was found in PD only in the substantia nigra and not elsewhere in the brain (9). Presence of a defective gene encoding for abnormal proteins is not supported by mitochondrial DNA analysis that disclosed no deletions (10,ll). There is yet no proof that an environmental or endogenous MPTP-like substance that might act to suppress nigral mitochondrial complex-1 activity, has any role in the etiology of PD. Thus, mitochondrial enzymatic abnormalities may represent a secondary phenomenon and not a primary cause for nigral cell death in PD. Furthermore, in addition to the muscle weakness, mitochondrial myopathies may cause a variety of CNS clinical abnormalities including dementia, ataxia, seizures, stroke-like episodes, and quite infrequently, movement disorders (12,13). Among the latter, parkinsonism is extremely rare (14). It is feasible that if PD is indeed due to a primary nigral mitochondrial dysfunction, this illness might have been more common and emerge more frequently and even at an earlier age in patients with mitochondrial myopathy. The rarity of this association does not support this theory. Parkinson’s disease is a common neurological disorder and it is more than likely that its emergence at the age of about 59 in our patient is purely coincidental and not etiologically related to his preexisting mitochondrial myopathy . R. Djaldetti I. Ziv A. Achiron E. Melamed Department of Neurology Bellinson Medical Center Petah-Tikva, Israel
383 References
1. Parker WD, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989;26:719-723. 2. Schapira AHV, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex-1 deficiency in Parkinson’s disease. Lancet 1989;1:1269. 3. Mizuno Y, Ohta S, Tanaka M, et al. Deficiencies in complex-1 subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun 1989;163:1450-1455. 4. Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine analog synthesis. Science 1983;219:979-980. 5. Ramsay RR, Singer TP. Energy dependent uptake of N-methyl-4-phenylpyndinium,the neurotoxic metabolite of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine by mitochondria. J Biol Chem 1986;261:7585-7587. 6. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to MPTP. Neurology 1985;35:949-956. 7. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-l,2,3,6tetrahydropyridine. Uptake of the metabolite N-methyl-4phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 1985;82:2173-2177. 8. Jenner P. Clues to the mechanism underlying dopamine cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1989;52(suppl):22-28. 9. Schapira AHV, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH CoQ reductase (complex-1) deficiency in Parkinson’s disease. J Neurochem 1990;55:21422145. 10. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:7 17-719. 11. Schapira AHV, Holt IJ, Sweeney M, Harding AE, Jenner P, Marsden CD. Mitochondrial DNA analysis in Parkinson’s disease. M o v Disord 1990;5:294-297. 12. DiMauro S, Bonilla E, Zeviani M, Masanori N, DeVivo CD. Mitochondria1 myopathies. Ann Neurol 1985;17:521-538. 13. Morgan-Hughes JA, Hayes DJ, Clark JB. Mitochondrial encephalomyopathies: biochemical studies in two patients revealing defects in the respiratory chain. Brain 1982;105:553582. 14. Truong DD, Harding AE, Scaravilli F. Movement disorders in mitochondrial myopathies: a study of nine cases with two autopsy studies. Mov Disord 1990;5:109-1 17.
Hitler’s Parkinson’s Disease: A Videotape Illustration To the Editor: It is a well known fact that Adolf Hitler had Parkinson’s disease. Typical symptoms had been noted by Hitler’s own physician, Dr. Theodore Morel1 (I). Comparing Hitler’s signature through the years 1932 to 1945 demonstrates the development of micrographia (1-3). Parkinsonian motor symptomatology is also evident from German world war newsreels, as has been thoroughly analyzed by professor Ellen Gibbels (4). From 1941 to 1945, the films show the successive appearance of left-sided hypokinesia, abnormal posture, pathological walking, hypomimia, and finally, tremor. The characteristic left-sided tremor was not seen until March 1945, when censorship began to fail. A discussion of possible differential diagnosis has
Movement Disorders, Vol. 7, No. 4, 1992
382
fortuitous coincidence: Population prevalence rates (per 100,000) of MS [110 cases; (lo)] and idiopathic Parkinson’s disease [164 cases; ( I l ) ] would in the Northern hemisphere render -1 individual per 500,000 likely to carry both conditions. Arguments against a mere coincidence and in favor of possible pathophysiological links between the two conditions may be as follows. (a) In case 1, the remission of parkinsonian features occurred in a time-locked fashion together with the remission of MS signs and symptoms subsequent to MS-directed drug therapy. (b) In both cases, MR imaging showed involvement of thalami and basal ganglia adjacent to the internal capsule. Overall, basal ganglia affection in MR imaging has been noted in 25% of MS patients (12). Size, distribution, and dynamics of plaque formation within a strategic area such as the internal capsule may contribute to different clinical expression, when the neighboring basal ganglia and thalamic structures are attached. (c) Because ventral and central parts of the thalamus are functionally involved in the basal ganglia-thalamo-cortical pathways, structural lesions such as demyelinating plaques affecting these circuitries at the thalamic or basal ganglia level may result clinically in hypokinetic (case 1) or full-blown parkinsonian states (case 2) (13). Longitudinal monitoring of MS cases with basal ganglia involvement on MR imaging may help to establish in-vivo the exact meaning of a clinicoradiological correlation between movement disorders and MS. P. Vieregge W. Klostermann Klinik fur Neurologie H. Briickmann Institut fiir Radiologie Medizinische Universitat zu Liibeck Liibeck, Germany
References 1 . Coleman RJ, Quinn NP, Marsden CD. Multiple sclerosis presenting as adult onset dystonia. Mov Disord 1988;3:329332. 2. Plant GT, Kermode AG, du Bouley EP, McDonald WI. Spasmodic torticollis due to a midbrain lesion in a case of multiple sclerosis. Mov Disord 1989;4:359-362. 3. Mao CC, Gancher ST, Herndon RM. Movement disorders in multiple sclerosis. Mov Disord 1988;3:109-1 16. 4. Riley D, Lang AE. Hemiballism in multiple sclerosis. Mov Disord 1988;3:88-94. 5. Reiber HO, Felgenhauer K. Protein transfer at the bloodCSF barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chem Acta 1987;163:319-328. 6. Tibbling G, Link H, Ohman S . Principles of albumin and IgG analysis in neurological disorders. I. Establishment of reference values. Scand J Clin Lab Invest 1977;37:385-390. 7. Schadlich H-J, Karbe H, Felgenhauer K. The prevalence of locally-synthesized virus antibodies in various forms of multiple sclerosis. J Neurol Sci 1987;80:343-349. 8. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;13:227-231. 9. Barbeau A. Parkinson’s disease: clinical features and etiopathology. In: Vinken PJ, Bruyn GW, Klawans H, eds. Ex-
Movement Disorders, Vol. 7, No. 4, 1992
10. 11.
12.
13.
trapyramidal disorders. Amsterdam: Elsevier Science, 1986:87-152. [Handbook of clinical neurology; vol5 (49)l. Beer S , Kesselring J. Die Multiple Sklerose im Kanton Bern (CH). Fortschr Neurol Psychiatr 1988;56:390-397. Mutch WJ, Dingwall-Fordyce I, Downie AW, Paterson JG, Roy SK. Parkinson’s disease in a Scottish city. Br Med J 1986;292:534-536. Kesselring J, Ormerod IEC, Miller DH, du Bouley EPGH, McDonald WI. Magnetic resonance imaging in multiple sclerosis. Stuttgart and New York: Georg Thieme Verlag, 1989. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. TINS 1990;13:266271.
Parkinson’s Disease in a Patient with Mitochondria1 Myopathy: Is There a Causative Relationship? To the Editor: The cause of the progressive nigral degeneration in Parkinson’s disease (PD) is unknown. It was recently suggested that the mitochondrial respiratory enzyme complex-1 (NADH: ubiquinone oxidoreductase) activity is deficient in the CNS and platelets of patients with PD (1-3). Interestingly, 1-methyl-4-phenyl-pyridinium ion (MPP ), the toxic metabolite of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), kills nigral neurons by poisoning their mitochondrial respiration (4). After its entry into dopaminergic neurons, MPP is taken-up and concentrated by the mitochondria where it inhibits the NADH-linked fraction of complex-I activity (5). These observations suggest that nigral neurons may die in PD because of impaired mitochondrial energy metabolism due to hereditary, neurotoxic, or other factors (6,7). The mitochondrial myopathies are a heterogenous group of diseases that share the common features of structural changes in skeletal muscle mitochondria and may cause muscular as well as nervous system dysfunction. We now report a patient with longstanding mitochondrial myopathy who developed PD. The intriguing question is whether the two disorders are causatively related or purely coincidental. A 60-year-old man was under long-term follow-up because of a syndrome consisting of slowly progressive muscle weakness, peripheral neuropathy and external ophthalmoplegia. He was readmitted because during the last year he developed symptoms of PD. There was no family history of myopathy, PD, or other neurological disorders. He was never exposed to neuroleptic drugs. On examination, his older signs included complete external ophthalmoplegia, bilateral facial weakness, reduced proximal muscle strength symmetrically affecting both upper and lower limbs, generally absent tendon jerks, and distal hypoesthesia to pain and touch. Plantar responses were bilaterally flexor. There were no signs of dementia. The new neurological findings included marked reduced facial mimicry with monotonous and slow speech. He was generally bradykinetic and rigid, with slow and shuffling gait. He had coarse resting tremor af-
+
+
COMMUNICA TIONS fecting his right hand. Electromyographic work-up showed typical myopathic and neuropathic changes. The CSF was normal except for mildly elevated protein content of 60 mg%. Muscle biopsy was taken from his right deltoid. With the modified Gomori trichrome method, 25% of the fibers showed dense subsarcolemmal deposits of red staining granular material, which gave an intense reaction for succinic dehydrogenase, compatible with red-ragged fibers, confirming the diagnosis of mitochondrial myopathy . Treatment with levodopa and carbidopa was started with partial improvement. The patient became less bradykinetic and rigid, and his tremor was partly reduced. This patient developed PD on the background of histologically verified mitochondrial myopathy. Defective mitochondrial function has been reported in patients with PD and it has been hypothesized that nigral neurons may degenerate because of an underlying mitochondrial encephalopathy (8). It would therefore be tempting to use the concurrent association of PD and mitochondrial myopathy in our patient to support that theory and suggest that his dopaminergic cell loss developed or became accelerated because the mitochondrial dysfunction spread from the skeletal muscles to his substantia nigra. However, impaired mitochondrial respiration as the cause of PD is not solidly established. The observation by Parker et al. (1) that complex-1 activity is reduced in platelets of parkinsonians has not been confirmed. Decreased mitochondrial complex- 1 activity was found in PD only in the substantia nigra and not elsewhere in the brain (9). Presence of a defective gene encoding for abnormal proteins is not supported by mitochondrial DNA analysis that disclosed no deletions (10,ll). There is yet no proof that an environmental or endogenous MPTP-like substance that might act to suppress nigral mitochondrial complex-1 activity, has any role in the etiology of PD. Thus, mitochondrial enzymatic abnormalities may represent a secondary phenomenon and not a primary cause for nigral cell death in PD. Furthermore, in addition to the muscle weakness, mitochondrial myopathies may cause a variety of CNS clinical abnormalities including dementia, ataxia, seizures, stroke-like episodes, and quite infrequently, movement disorders (12,13). Among the latter, parkinsonism is extremely rare (14). It is feasible that if PD is indeed due to a primary nigral mitochondrial dysfunction, this illness might have been more common and emerge more frequently and even at an earlier age in patients with mitochondrial myopathy. The rarity of this association does not support this theory. Parkinson’s disease is a common neurological disorder and it is more than likely that its emergence at the age of about 59 in our patient is purely coincidental and not etiologically related to his preexisting mitochondrial myopathy . R. Djaldetti I. Ziv A. Achiron E. Melamed Department of Neurology Bellinson Medical Center Petah-Tikva, Israel
383 References
1. Parker WD, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson’s disease. Ann Neurol 1989;26:719-723. 2. Schapira AHV, Cooper JM, Dexter D, Jenner P, Clark JB, Marsden CD. Mitochondrial complex-1 deficiency in Parkinson’s disease. Lancet 1989;1:1269. 3. Mizuno Y, Ohta S, Tanaka M, et al. Deficiencies in complex-1 subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun 1989;163:1450-1455. 4. Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine analog synthesis. Science 1983;219:979-980. 5. Ramsay RR, Singer TP. Energy dependent uptake of N-methyl-4-phenylpyndinium,the neurotoxic metabolite of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine by mitochondria. J Biol Chem 1986;261:7585-7587. 6. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to MPTP. Neurology 1985;35:949-956. 7. Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH. Parkinsonism-inducing neurotoxin, N-methyl-4-phenyl-l,2,3,6tetrahydropyridine. Uptake of the metabolite N-methyl-4phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 1985;82:2173-2177. 8. Jenner P. Clues to the mechanism underlying dopamine cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1989;52(suppl):22-28. 9. Schapira AHV, Mann VM, Cooper JM, et al. Anatomic and disease specificity of NADH CoQ reductase (complex-1) deficiency in Parkinson’s disease. J Neurochem 1990;55:21422145. 10. Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988;331:7 17-719. 11. Schapira AHV, Holt IJ, Sweeney M, Harding AE, Jenner P, Marsden CD. Mitochondrial DNA analysis in Parkinson’s disease. M o v Disord 1990;5:294-297. 12. DiMauro S, Bonilla E, Zeviani M, Masanori N, DeVivo CD. Mitochondria1 myopathies. Ann Neurol 1985;17:521-538. 13. Morgan-Hughes JA, Hayes DJ, Clark JB. Mitochondrial encephalomyopathies: biochemical studies in two patients revealing defects in the respiratory chain. Brain 1982;105:553582. 14. Truong DD, Harding AE, Scaravilli F. Movement disorders in mitochondrial myopathies: a study of nine cases with two autopsy studies. Mov Disord 1990;5:109-1 17.
Hitler’s Parkinson’s Disease: A Videotape Illustration To the Editor: It is a well known fact that Adolf Hitler had Parkinson’s disease. Typical symptoms had been noted by Hitler’s own physician, Dr. Theodore Morel1 (I). Comparing Hitler’s signature through the years 1932 to 1945 demonstrates the development of micrographia (1-3). Parkinsonian motor symptomatology is also evident from German world war newsreels, as has been thoroughly analyzed by professor Ellen Gibbels (4). From 1941 to 1945, the films show the successive appearance of left-sided hypokinesia, abnormal posture, pathological walking, hypomimia, and finally, tremor. The characteristic left-sided tremor was not seen until March 1945, when censorship began to fail. A discussion of possible differential diagnosis has
Movement Disorders, Vol. 7, No. 4, 1992
