- Email: [email protected]
TIMING OF LEVODOPA THERAPY: EVIDENCE FROM MPTP-TREATED PRIMATES
625 occurs only in the context of pathological features of AD is not necessarily correct.5-7 However, the cases recorded in these studies do not show Lewy bodies within cortical structures. Lewy bodies are not age-related and, although found in 7-10% of brains of normal subjects aged over 60, may be a preclinical stage of Parkinson’s disease,8 as has been suggested for senile plaques and neurofibrillary tangles in non-demented patients who die between the ages of 55 and 64.9 In addition, dementia can occur in the absence of any specific lesion or inclusion bodies.5,10 There may simply be a fortuitous overlap ofsubclinical AD and Lewy bodies in some patients. If so, the relative frequency of the
various combinations of Parkinson’s disease with and without dementia, and with and without Alzheimer changes may be predicted theoretically." Conversely, the correlations in Alzheimer patients between the density of senile plaques and neurofibrillary tangles and the severity of clinical or neurochemical changes are significant but not conclusive,12 and these pathological features may not be important.13 Section of Old Age Psychiatry, Institute of Psychiatry, London SE5 8AF
M. PHILPOT R. LEVY
1. Kosaka K, Yoshimura M, Ikeda K, Budka H. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree: A new disease. Clin Neuropathol 1984; 3: 185-92. 2. Philpot M, Colgan J, Janota I, Levy R. Dementia without Alzheimer pathology. Neurology 1986; 36: 133. 3. Hakim AM, Mathieson G. Dementia in Parkinson disease: a neuropathologic study. Neurology 1979; 29: 1209-14. 4. Boiler F, Mizutani T, Roessman U, Gambetti P. Parkinson disease, dementia and Alzheimer disease: Clinicopathological correlations. Ann Neurol 1980; 7: 329-35. 5. Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical diagnosis in primary degenerative dementia: Correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 1983; 46: 9-13. 6. Heilig CW, Knopman DS, N astri AR, Frey W. Dementia without Alzheimer pathology. Neurology 1985; 35: 762-65. 7. Perry EK, Curtis M, Dick DJ, et al. Cholinergic correlates of cognitive impairment in Parkinson’s disease: Comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1985; 48: 413. 8. Ulrich J. Alzheimer changes in nondemented patients younger than sixty-five: Possible early stages of Alzheimer’s disease and senile dementia of Alzheimer type. Ann Neurol 1985; 17: 273-77. 9. Gibb WRG. Idiopathic Parkinson’s disease and the Lewy body disorders. Neuropath Appl Neurobiol 1986; 12: 223-34. 10. Kim RC, Collins GH, Parisi JE, Wright AW, Chu YB. Familial dementia of adult onset with pathological findings of a ’non-specific’ nature. Brain 1981; 104: 61-78. 11. Quinn NP, Rossor MN, Marsden CD. Dementia and Parkinson’s disease: Pathological and neurochemical considerations. Br Med Bull 1986; 42: 86-90. 12. Mountjoy CJ, Rossor MN, Iversen LL, Roth M. Correlation of cortical cholinergic and GABA deficits with quantitative neuropathological findings in senile dementia. Brain 1984; 107: 507-18. 13. Calne DB, Eisen A, McGeer E, Spencer P. Alzheimer’s disease, Parkinson’s disease, and motoneurone disease: Abiotropic interaction between ageing and environment? Lancet 1986; ii: 1067-70.
dyskinesia in the face, arms and legs on a scale: (0) (1) intermittent, (2) continuous/mild, or (3) continuous/ severe (interfering with normal activity). Activity and dyskinesia totals were produced for 90 min. Dose-response curves to apomorphine (0-0-2 mg/kg) were produced before and after 3 used
to assess
none,
months of levodopa treatment. All trials were in duplicate. MPTP produced severe parkinsonism in all primates, consisting of hypokinesia, bradykinesia, rigidity, and resting and postural tremor. The 1-2 week dose intervals produced a predictable stepwise decline in activity, with little of the aphagia and adipsia encountered with other regimens. There was some recovery for 3-4 weeks after the end of the MPTP course but in the monkeys not given levodopa, both clinical status and activity counts in response to apomorphine remained stable over the ensuing 3 months. Levodopa abolished parkinsonian features and did not immediately cause dyskinetic movements. However, after 4-8 weeks of regular levodopa all three monkeys manifest peak-dose choreoathetoid movements of the legs which gradually progressed to affect the face and arms. Trials with apomorphine produced similar involuntary movements in the levodopa-treated animals only and revealed that the severity of dyskinesia was directly related to the administered dose. Exposure to MPTP in man has also been rapidly followed by drug-induced dyskinesias:8 of seven such patients treated with levodopa five developed dyskinesia within the first year of therapy and three have required drug-free "holidays"9 because of side-effects. The absence of changes in non-treated animals strongly suggests that the pathological change induced by MPTP had remained stable so that the appearance, and subsequent progression, of dyskinesia in animals treated with levodopa for only 4-8 weeks must be related to exposure to the drug rather than to worsening disease. This experience with MPTP-induced parkinsonism in macaques, when combined with the results of clinical trials,1,2 implicates levodopa therapy in the genesis of involuntary movements in these conditions and points to the need for levodopa to be used more cautiously in the management of idiopathic Parkinson’s disease. The animal model described here should prove useful in studies of the neural mechanisms underlying abnormal involuntary movements in parkinsonism. Departments of Neurology and Cell and Structural Biology, University of Manchester, Manchester M13 9PT
C. E. CLARKE S. BOYCE M. A. SAMBROOK A. R. CROSSMAN
1. Lesser
2.
TIMING OF LEVODOPA THERAPY: EVIDENCE FROM MPTP-TREATED PRIMATES
3. 4.
SIR,--Clinical studies1,2 of dyskinesia and response fluctuations have led to the view that levodopa treatment in idiopathic Parkinson’s disease should be delayed for as long as possible and be given at the lowest therapeutic dose. This policy, however, has been challenged.3-6 The difficulty lies in distinguishing the effects of long-term levodopa therapy from those of pathological deterioration in the disease itself. We have studied l-methyl-4phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treated primates, a pathologically stable model of parkinsonism suitable for long-term pharmacological experiments, to assess the effect of long-term levodopa on the speed of development of dyskinesia. Six Macaca fascicularis monkeys were given intravenous injections of MPTP 0-4-0-57 mg/kg every 1-2 weeks until parkinsonism reached stage IV.7 This happened after a mean total dose of 7(range 2-6-27-0) mg/kg. 15-7-0 months was allowed to elapse between the last MPTP injection and the start of regular oral levodopa therapy in three primates in the form of 75 mg powdered ’Sinemet’ three times daily (ie, about 70 mg levodopa plus 7 mg carbidopa). The progress of two treated and two untreated animals was monitored every 2 weeks by assessing their response to intramuscular apomorphine 0-1mg/kg in an observation cage equipped with photoelectric sensors and counters. Videotapes were
5.
6. 7.
8.
9.
RP, Fahn S, Snider S, et al. Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 1979; 29: 1253-60. Rajput AH, Stem W, Laverty WH. Chronic low-dose levodopa therapy in Parkinson’s disease: an argument for delaying levodopa therapy. Neurology 1984; 34: 991-96. Pincus JN. Rationale for early use of levodopa in parkinsonism. Lancet 1986; i: 612-13. Quinn N, Critchley P, Parkes D, Marsden CD. When should levodopa be started? Lancet 1986; ii: 985-86. Markham CH, Diamond S. Evidence to support early levodopa therapy in Parkinson’s disease. Neurology 1981; 31: 125-31. Markham CH, Diamond S. Long-term follow-up of early dopa treatment in Parkinson’s disease. Ann Neurol 1986; 19: 365-72. Hoehn MM, Yahr MD. Parkinsonism: Onset, progression, and mortality. Neurology 1967; 17: 427-42. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurology 1985; 35: 949-56. Hotson JR, Langston EB, Langston JW. Saccade responses to dopamine in human MPTP-induced parkinsonism. Ann Neurol 1986; 20: 456-63.
24-HOUR MONITORING OF OESOPHAGEAL pH IN OUTPATIENTS
SIR,-Dr Donald and colleagues (Jan 10, p 89) demonstrate the value of ambulatory 24 h pH recordings in the environment of a district general hospital. The value of that study should not be diminished by concerns about the exact positioning of the pH electrode (Feb 7, p 332). We submit that the exact position is of minor importance. The currently accepted distance above the lower oesophageal sphincter (LOS) at which the electrode should ideally be situated (5 cm) was derived empirically.! Walker et al2 have demonstrated that, in both control subjects and those with
diagnostic
various combinations of Parkinson’s disease with and without dementia, and with and without Alzheimer changes may be predicted theoretically." Conversely, the correlations in Alzheimer patients between the density of senile plaques and neurofibrillary tangles and the severity of clinical or neurochemical changes are significant but not conclusive,12 and these pathological features may not be important.13 Section of Old Age Psychiatry, Institute of Psychiatry, London SE5 8AF
M. PHILPOT R. LEVY
1. Kosaka K, Yoshimura M, Ikeda K, Budka H. Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree: A new disease. Clin Neuropathol 1984; 3: 185-92. 2. Philpot M, Colgan J, Janota I, Levy R. Dementia without Alzheimer pathology. Neurology 1986; 36: 133. 3. Hakim AM, Mathieson G. Dementia in Parkinson disease: a neuropathologic study. Neurology 1979; 29: 1209-14. 4. Boiler F, Mizutani T, Roessman U, Gambetti P. Parkinson disease, dementia and Alzheimer disease: Clinicopathological correlations. Ann Neurol 1980; 7: 329-35. 5. Sulkava R, Haltia M, Paetau A, Wikstrom J, Palo J. Accuracy of clinical diagnosis in primary degenerative dementia: Correlation with neuropathological findings. J Neurol Neurosurg Psychiatry 1983; 46: 9-13. 6. Heilig CW, Knopman DS, N astri AR, Frey W. Dementia without Alzheimer pathology. Neurology 1985; 35: 762-65. 7. Perry EK, Curtis M, Dick DJ, et al. Cholinergic correlates of cognitive impairment in Parkinson’s disease: Comparisons with Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1985; 48: 413. 8. Ulrich J. Alzheimer changes in nondemented patients younger than sixty-five: Possible early stages of Alzheimer’s disease and senile dementia of Alzheimer type. Ann Neurol 1985; 17: 273-77. 9. Gibb WRG. Idiopathic Parkinson’s disease and the Lewy body disorders. Neuropath Appl Neurobiol 1986; 12: 223-34. 10. Kim RC, Collins GH, Parisi JE, Wright AW, Chu YB. Familial dementia of adult onset with pathological findings of a ’non-specific’ nature. Brain 1981; 104: 61-78. 11. Quinn NP, Rossor MN, Marsden CD. Dementia and Parkinson’s disease: Pathological and neurochemical considerations. Br Med Bull 1986; 42: 86-90. 12. Mountjoy CJ, Rossor MN, Iversen LL, Roth M. Correlation of cortical cholinergic and GABA deficits with quantitative neuropathological findings in senile dementia. Brain 1984; 107: 507-18. 13. Calne DB, Eisen A, McGeer E, Spencer P. Alzheimer’s disease, Parkinson’s disease, and motoneurone disease: Abiotropic interaction between ageing and environment? Lancet 1986; ii: 1067-70.
dyskinesia in the face, arms and legs on a scale: (0) (1) intermittent, (2) continuous/mild, or (3) continuous/ severe (interfering with normal activity). Activity and dyskinesia totals were produced for 90 min. Dose-response curves to apomorphine (0-0-2 mg/kg) were produced before and after 3 used
to assess
none,
months of levodopa treatment. All trials were in duplicate. MPTP produced severe parkinsonism in all primates, consisting of hypokinesia, bradykinesia, rigidity, and resting and postural tremor. The 1-2 week dose intervals produced a predictable stepwise decline in activity, with little of the aphagia and adipsia encountered with other regimens. There was some recovery for 3-4 weeks after the end of the MPTP course but in the monkeys not given levodopa, both clinical status and activity counts in response to apomorphine remained stable over the ensuing 3 months. Levodopa abolished parkinsonian features and did not immediately cause dyskinetic movements. However, after 4-8 weeks of regular levodopa all three monkeys manifest peak-dose choreoathetoid movements of the legs which gradually progressed to affect the face and arms. Trials with apomorphine produced similar involuntary movements in the levodopa-treated animals only and revealed that the severity of dyskinesia was directly related to the administered dose. Exposure to MPTP in man has also been rapidly followed by drug-induced dyskinesias:8 of seven such patients treated with levodopa five developed dyskinesia within the first year of therapy and three have required drug-free "holidays"9 because of side-effects. The absence of changes in non-treated animals strongly suggests that the pathological change induced by MPTP had remained stable so that the appearance, and subsequent progression, of dyskinesia in animals treated with levodopa for only 4-8 weeks must be related to exposure to the drug rather than to worsening disease. This experience with MPTP-induced parkinsonism in macaques, when combined with the results of clinical trials,1,2 implicates levodopa therapy in the genesis of involuntary movements in these conditions and points to the need for levodopa to be used more cautiously in the management of idiopathic Parkinson’s disease. The animal model described here should prove useful in studies of the neural mechanisms underlying abnormal involuntary movements in parkinsonism. Departments of Neurology and Cell and Structural Biology, University of Manchester, Manchester M13 9PT
C. E. CLARKE S. BOYCE M. A. SAMBROOK A. R. CROSSMAN
1. Lesser
2.
TIMING OF LEVODOPA THERAPY: EVIDENCE FROM MPTP-TREATED PRIMATES
3. 4.
SIR,--Clinical studies1,2 of dyskinesia and response fluctuations have led to the view that levodopa treatment in idiopathic Parkinson’s disease should be delayed for as long as possible and be given at the lowest therapeutic dose. This policy, however, has been challenged.3-6 The difficulty lies in distinguishing the effects of long-term levodopa therapy from those of pathological deterioration in the disease itself. We have studied l-methyl-4phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) treated primates, a pathologically stable model of parkinsonism suitable for long-term pharmacological experiments, to assess the effect of long-term levodopa on the speed of development of dyskinesia. Six Macaca fascicularis monkeys were given intravenous injections of MPTP 0-4-0-57 mg/kg every 1-2 weeks until parkinsonism reached stage IV.7 This happened after a mean total dose of 7(range 2-6-27-0) mg/kg. 15-7-0 months was allowed to elapse between the last MPTP injection and the start of regular oral levodopa therapy in three primates in the form of 75 mg powdered ’Sinemet’ three times daily (ie, about 70 mg levodopa plus 7 mg carbidopa). The progress of two treated and two untreated animals was monitored every 2 weeks by assessing their response to intramuscular apomorphine 0-1mg/kg in an observation cage equipped with photoelectric sensors and counters. Videotapes were
5.
6. 7.
8.
9.
RP, Fahn S, Snider S, et al. Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology 1979; 29: 1253-60. Rajput AH, Stem W, Laverty WH. Chronic low-dose levodopa therapy in Parkinson’s disease: an argument for delaying levodopa therapy. Neurology 1984; 34: 991-96. Pincus JN. Rationale for early use of levodopa in parkinsonism. Lancet 1986; i: 612-13. Quinn N, Critchley P, Parkes D, Marsden CD. When should levodopa be started? Lancet 1986; ii: 985-86. Markham CH, Diamond S. Evidence to support early levodopa therapy in Parkinson’s disease. Neurology 1981; 31: 125-31. Markham CH, Diamond S. Long-term follow-up of early dopa treatment in Parkinson’s disease. Ann Neurol 1986; 19: 365-72. Hoehn MM, Yahr MD. Parkinsonism: Onset, progression, and mortality. Neurology 1967; 17: 427-42. Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neurology 1985; 35: 949-56. Hotson JR, Langston EB, Langston JW. Saccade responses to dopamine in human MPTP-induced parkinsonism. Ann Neurol 1986; 20: 456-63.
24-HOUR MONITORING OF OESOPHAGEAL pH IN OUTPATIENTS
SIR,-Dr Donald and colleagues (Jan 10, p 89) demonstrate the value of ambulatory 24 h pH recordings in the environment of a district general hospital. The value of that study should not be diminished by concerns about the exact positioning of the pH electrode (Feb 7, p 332). We submit that the exact position is of minor importance. The currently accepted distance above the lower oesophageal sphincter (LOS) at which the electrode should ideally be situated (5 cm) was derived empirically.! Walker et al2 have demonstrated that, in both control subjects and those with
diagnostic