Movrmenr Disorders Vol. 13, No. 2, 1998, pp. 369-370 0 1998 Movzment Disorder Societ)

Letter to the Editor Is Levodopa Toxic to Human

Substantia Nigra?

To the Editor: I was delighted to read the article by Rajput and colleagues’

detailing five cases of prolonged exposure to levodopa in pa- tients with diagnoses other than Parkinson’s disease (PD). My experience parallels theirs. In the past 10 years, I have seen 13 patients treated with levodopa for 5-26 years for conditions other than PD (Table 1). None of the patients had a history or showed any signs of levodopa-induced dyskinesias. All except one patient discontinued the medication with no deterioration in their clinical status. Patient 8 was previously and correctly diagnosed as having progressive supranuclear palsy, but he stated that levodopa had helped on initiation, and he refused to stop it until his death. At that time, an autopsy confirmed the diagnosis. The eight patients without parkinsonism were exam- ined after withdrawal of levodopa. None had any degree of rigidity or akinesia.

The patients reported here demonstrate that treatment with levodopa alone, even at high doses for many years, is insuffi- cient to produce parkinsonism or dyskinesias. The findings of the present study may be added to the large weight of clinical evidence which suggests that drug-induced dyskinesias in PD are related to levodopa only in terms of the current dose, and that the major determinants of the presence and seventy of dyskinesias are the duration and severity of the PD. This evi- dence can be summarized as follows:

1. Dyskinesias are typically worse on the side where the dis-

2. If treatment with levodopa is delayed, dyskinesias develop

3. Synthetic dopamine agonists may cause dyskinesias. 4. The time of onset of dyskinesias vanes with different un-

derlying diseases. Dyskinesias actually occur sooner in

ease started and which is most affected.2.3

sooner after initiati~n.~.’

MPTP-induced parkinsonism,6 postencephalitic parkinson- ism? and dopa-responsive dystonia’ than in PD.

5. Even within the PD population, younger patients develop dyskinesias sooner.’

None of these points prove that dyskinesias are not related to cumulative levodopa toxicity, but together they indicate that patient- and disease-related factors play a dominant role in the genesis of dyskinesias.

David Riley Movement Disorders Center

Mt. Sinai Medical Center Department of Neurology

Case Western Reserve University Cleveland, Ohio, U.S.A.

References 1.

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6.

7.

Rajput AH, Fenton ME, Birdi S, Macauley R. Is levodopa toxic to humrui substantia nigra? Mov Disord 1997; 12:634-638. Horstink MW, Zijlmans JC, Paswan JW, et al. Severity of Parkin- son’s disease is a risk factor for peak-dose dyskinesia. J Neurol Neurosurg Psychiatry 199053:224-226. Marconi R, Lefehvre-Caparros D, Bonnet AM, Vidailhet M, Dubois B, Agid Y. Levodopa-induced dyskinesias in Parkinson’s disease: phenomenology and pathophysiology. Mov Disord 1994;9:2-12. Bergmann KJ, Mendoza MR, Yahr MD. Parkinson’s disease and long-term levodopa therapy. Adv Neurol 1987;45:463467. Cedarbaum JM, Gandy SE, McDowell FH. ‘Early’ initiation of levodopa treatment does not promote the development of motor response fluctuations, dyskinesias, or dementia in Parkinson’s dis- ease. Neurology 1991;41:622-629. Ballard PA, Tetrud JW, Langston JW. Permanent human parkin- sonism due to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MFTP): seven cases. Neurology 1985;35:949-956. Friedman JH. Postencephalitic parkinsonism. In: Stern MB, Koller WC, eds. Pnrkinsonian Syndromes. New York, NY: Dekker; 1993: 203-226.

TABLE 1. Medication regimen of 13 patients treated with levodopa for 5-26 years for conditions other than Parkinson’s disease

No. Age Diagnosis Years of treatment Maintenance dose

1 92 Essential tremor 26 150 mg/day 2 62 Essential tremor 22 3 g/day* 3 79 Essential tremor 15 1.5 g/day 4 82 Essential tremor 14 400 mg/day 5 82 Essential tremor 8 400 mg/day 6 73 Progressive supranuclear palsy 14 1.75 g/day 7 72 Progressive supranuclear palsy 8 1.5 glday 8 85 Progressive supranuclear palsy 5 800 mg/day 9 89 Tardive dyskinesia 16 300 mg/day 10 83 Tardive dyskinesia 7 300 mg/day 1 I 87 Multi-infarct parkinsonism 15 1 glday 12 6.5 Post-anoxic parkinsonism 9 1.1 glday 13 79 Idiopathic generalized dystonia 6 750 mg/day

*Without carbidopa. All other doses were given with variable amounts of carhidopa. All ages are given as the age at cessation of levodopa (or death in the case of patient 8).

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8. Nygaard TG, Marsden CD, Fahn S. Dopa-responsive dystonia: long-term treatment response and prognosis. Neurology 199 1;41: 174-1 81.

9. Quinn NP. A case against early levodopa treatment of Parkinson’s disease. Clin Neuropharnzacol 1994; 17(suppl 3):S43-S49.

We are pleased to see that Dr. Riley’s observations confirm our report’ that prolonged levodopa (LD) administration is not toxic to human substantia nigra.

In general, we agree with Dr. Riley’s analysis that levodopa- induced dyskinesias are related to the current LD dose and the major determinants are the duration and severity of Parkinson’s disease (PD). In most patients, the seventy of PD correlates with the duration of illness; thus, the duration of disease is the critical indicator.

Blanchet et al.’ compared clinical parameters in patients who developed dyskinesias with those who did not. The daily dose of LD at the emergence of dyskinesias was higher in the dys- kinesia group compared with the non-dyskinesia group. How- ever, neither the duration of PD nor the severity of illness at LD initiation were different in the two groups.’ In several of our long-term-followed, autopsy-verified PD cases, dyskinesias were never observed.

It is a common clinical experience that some individuals are sensitive whereas others are relatively resistant to dyskinesias. Case 3 in our report’ developed dyskinesias on a modest dose

of LD (without decarboxylase inhibitor); however, on a lower dose, he has no dyskinesias, even after 26 years of follow up. Thus, the duration of disease was not the major determinant of dyskinesias. This patient also shows dissociation between the severity and duration of illness because by all criteria, he has a mild disability but a long duration of disease.

We agree with Dr. Riley that dyskinesias occur on the back- ground of nigrostriatal dysfunction and some of the factors predisposing to dyskinesias have been identified. There are many patients with LD-induced dyskinesias who do not have those features as would presumably predispose to dyskinesias, whereas others who one expects to have dyskinesias do not. These observations indicate that all issues related to patho- physiology of dyskinesias have not been identified thus far.

1.

2.

A. H. Rajput M. E. Fenton

S. Birdi R. Macaulay

Division of Neurology University of Saskatchewan

Saskutoon, SK Canada

References Rajput AH, Fenton ME, Birdi S, Macaulay R. Is levodopa toxic to human substantia nigra? Mov Disord 1997;12:634-638. Blanchet PJ, Allard P, Gregoire L, Tardif F, Bedard PJ. Risk fac- tors for peak dose dyskinesia in 100 levodopa-treated parkinsonian patients. Can J Neurol Sci 1996;23:189-193.

Movement Disorders, Vol. 13, No. 2, 1998