Movement Disorders Vol. 6, No. 1, 1991, pp. 3 M 2 0 1991 Movement Disorder Society
Early-Onset Parkinson’s Disease P. Giovannini, I. Piccolo, S. Genitrini, P. Soliveri, F. Girotti, G. Geminiani, G. Scigliano, and T. Caraceni Department of Neurology, Center for Extrapyramidal Disorders, Neurological Institute “ C . Besta, ” Milan, Italy
Summary: The study was conducted on 120 patients (76 men and 44 women) affected by idiopathic Parkinson’s disease (IPD) responsive to L-dopa and observed for many years. Sixty had clinical onset between the ages of 2040, representing 10.2% of our PD population; in the others the symptoms began after the 40th birthday. The two groups were matched for sex and length of illness. In all patients a diagnosis of IPD depended on history and clinical and neuroradiological findings. Clinical, pharmacological, evolutive, and epidemiological data were collected on all patients. Thirty-six patients from each group performed motor dexterity tests (reaction time to expected and unexpected stimuli) and cognitive tests (Wechsler Adult Intelligence Scale, Benton, Short tale, and Zazzo’s speed and accuracy test). To assess the prevalence of dementia and the seventy of psychiatric side effects of L-dopa administration, the 60 patients with early-onset PD were compared with 134 consecutive unselected PD patients. Five percent of early-onset PD patients had a family history of the disorder. Our study showed that early-onset PD does not differ fundamentally from the late-onset form except that the former is characterized by a more rapid establishment of the full-blown parkinsonian clinical picture and deterioration of the therapeutic efficacy of L-dopa, with an earlier appearance of side effects. The results of our neuropsychological investigations suggest that early-onset PD may be a “pure” form of extrapyramidal compromise with exclusively motor manifestations. Key Words: IPD-Early-onset PD-Clinical and cognitive aspects-Dementia rate.
to patients whose disease onset was either before 20 or 40 years of age. The first case of juvenile (indeed, “infantile”) parkinsonism was described in 1875 (3). Later, several other patients were described (4-8) with different ages of onset and with signs different from those typical of IPD, and often with other relatives said to have parkinsonism. Patients with onset before age 20 often had peculiar clinical features. Exemplifying this problem is the case described by Kilroy and Paulsen (9) as juvenile PD that was subsequently reviewed by Plaitakis et al. (10) and diagnosed as type 4 OPCA. Pathological studies (11-16) have also brought contrasting results. Some very early-
The onset of idiopathic Parkinson’s disease (IPD) occurs in adult life and has a peak incidence between 50-69 years of age (1,2). It is therefore commonly believed that IPD is disease of the elderly. This concept is so widely ingrained that each time a physician sees a patient aged less than 30 or 40 years with parkinsonian features he asks himself, “Is this true Parkinson’s or a different disease?” The term juvenile PD has been variously applied Address correspondence and reprint requests to Dr. P. Giovannini, Dept. of Neurology, Centre for Extrapyramidal Disorders, Neurological Institute “C. Besta,” Via Celoria, 1 1 , 20133 Milano, Italy.
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EARL Y-ONSE T PARKINSON’S DlSEAS E
onset cases (at 15, 7, and 13 years, respectively) were correlated with pallidal atrophy (12-14), without evidence of the typical neuropathological features generally observed in IPD. On the basis of these considerations, it seems likely that at least some of the cases designated as juvenile PD with onset before the age of 20 have either clinical or pathological features not seen in IPD. Therefore, a firm diagnosis of juvenile PD should be supported by appropriate pathological findings. Attention has recently concentrated on cases defined as “early-onset PD” (17,18) or “young-onset PD” (19), where the disease manifests itself between the ages of 2040. Current opinion views a high prevalence of a family history of PD (20), rapidity and extent of disease progression (18), good initial response to therapy, early development of side effects to therapy (motor fluctuations and dyskinesias), and lack of mental deterioration as characteristic of this subtype of parkinsonism (18,19,21, 22). However, there is some divergence of views concerning the key characteristics of early-onset PD, so that further studies in this area are clearly necessary. PATIENTS AND METHODS One hundred and twenty patients (76 men and 44 women) affected by IPD, all observed for varying numbers of years, were studied. In 60 patients, disease onset was between the ages of 2040; in the others the disease manifested itself after the age of 40. The two groups were matched for sex and length of illness (Table 1). In all patients the diagnosis of IPD depended on the presence of bradykinesia, with rest tremor or muscular rigidity, without a known etiology or other diagnostic exclusion criteria. These exclusion
criteria suggestive of an alternative cause of parkinsonism were sustained remission of symptoms, history of definite encephalitis, repeated strokes or repeated head injury, oculogyric crises, neuroleptic treatment at onset of symptoms, supranuclear down-gaze palsy, cerebellar signs, pyramidal signs, and, last, cerebral tumor, communicating hydrocephalus, or white matter changes suggestive of subcortical ischemic encephalopathy on computed tomography scan. The following were determined for each patient: (a) symptom at onset (rigidity-akinesia, tremor, or mixed); (b) presence of minor signs of autonomic dysfunction (seborrhea, salivation, hyperhydrosis, orthostatic hypotension, or disturbances in sphincter control). (c) The rate of disease progression (estimated as the interval between the appearance of the first symptoms and development of the complete bilateral clinical picture) was characterized as rapid (if the interval was less than 12 months) and slow (if greater); and (d) the therapeutic efficacy of L-dopa medication was characterized as good, moderate, or poor depending on its ability to control parkinsonian symptoms after the 1st 6 months of treatment (good = an improvement of the Columbia University Rating Scale, CURS, total score 2 30%; moderate = improvement between 20-30%; poor = improvement < 20%). (e) The occurrence of long-term side effects of L-dopa therapy were motor effects (wearing off, involuntary movement, dystonia, and the “on-off” phenomenon), psychiatric effects (delusions, delirium, or hallucinations), and systemic effects (nausea, vomiting, orthostatic hypotension, etc.). Patients were labelled fluctuators if they had motor side effects and stable if these were absent. (f) The interval between initiation of L-dopa treatment and the appearance of motor side
TABLE 1. General synopsis of patients Parkinson’s disease patients
No. of cases Sex Age, mean yr (range) Age at onset, mean yr (range) Illness duration, mean yr (range) CURS, mean (range) H&Y S, mean (range)
Early onset
Late onset
Nonselected controls
60 38 M, 22 F 45.1 29-62 34.7 24-39 10.4 0.6-30 30.4 6-60 2.4 1 - 4
60 38 M, 22 F 62.9 52-80 53.6 42-68 9.3 0.8-28 26.9 7-58 2.5 1-5
134 73 M, 61 F 62.5 45-80 56.0 41-72 6.5 0.6-20 24.7 8-56 2.3 1-5
CURS, Columbia University Rating Scale score; H&Y S, Hoehn and Yahr stage.
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effects and (g) the interval between disease onset and initiation of treatment were noted. (h) The history of disease in the family (first- and seconddegree relatives) and (i) cigarette smoking were noted. (i) Birthplace (as north, center, or south/ islands of Italy) and residence during the first 15 years of life (as rural, urban residential, or urban industrial), and (k) occupation (as land worker, industrial worker, tradesman/shopkeeper, office worker, managedself-employed professional, or housewife) were determined. Overall parkinsonian disability was assessed on the CURS and the Hoehn and Yahr scale. Thirty-six patients from each group also performed motor dexterity tests (tapping test, screw and nut test, and writing test) (23), their reaction times to expected and unexpected stimuli were measured electronically (24), intelligence was evaluated on the Wechsler Adult Intelligence Scale (WAIS) (verbal score, performance score, and total score), and their visuospatial attention abilities were quantified by Zazzo’s speed and accuracy test (25). To assess the prevalence of dementia and the severity of psychiatric side effects of L-dopa administration, the 60 patients with early-onset PD were compared with 134 consecutive unselected PD patients (73 men and 61 women) whose average age at the time of investigation was 62.5 (range, 45-80) years, with mean disease onset at age 56 (range, 41-72) years and mean illness duration of 6.5 (range, 0 . 6 2 0 ) years (Table 1). This group was also assessed clinically on the CURS and the Hoehn and Yahr scale, taking note of drug therapy, the presence or absence of dementia, and any psychotic side effects of treatment. The presence or absence of dementia was assessed according to DSM I11 criteria. The chi-squared test and the student’s t-test were employed in the statistical analysis.
RESULTS Frequency and Familial History Early-onset PD makes up 10.2% of the PD population observed in our center, and we have only three patients (5%) with one affected relative (two, first degree and one, second degree). The only patient with a disease onset earlier than at 25 had no relative affected.
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Clinical Characteristics and Pharmacological Aspects Comparing the clinical characteristics of the two groups (early-onset and late-onset PD, Table 2), no statistically significant differences were evident with respect to symptoms at onset except that more early-onset patients had tremor (35 versus 21.7%), with the inverse for the mixed clinical picture (20 versus 30%). Motor fluctuations were more prevalent in the early-onset group (78.4 versus 63.3%), but this difference was not statistically significant. A “slow” disease progression was significantly characteristic of late-onset patients (95 versus 40%, p < 0.01), whereas the “rapid” form characterized early-onset patients (60 versus 5%, p < 0.001). Sialorrhea, constipation, hyperhydrosis, or mild orthostatic hypotension was observed in 83.3% of early-onset PD patients but in only 58.3% of the other group (p < 0.01). Motor compromise (in the “on phase” for fluctuating patients) as determined by the CURS (30.4 versus 26.9, average score) and the method of Hoehn and Yahr (2.4 versus 2.5, average stage) was similar in both groups (Table 1). TABLE 2. Early- and late-onset Parkinson’s disease (PD)patients: clinical data
Symptom at onset, no. (%) rigid-akine tic mixed tremulous Clinical stage, no. (%) stable fluctuator Rate of disease progression, no. (%) slow rapid Autonomic symptoms, no. (%) Response to treatment,O after 6 mo, no. (%) good moderate poor Drug doses employed mean mg (range) L-dopa lisuride bromocriptine Years of L-dopa treatment, mean (range) ~
~~
Early-onset
Late-onset
PD
PD
27 (45.0) 12 (20.0) 21 (35.0)
29 (48.3) 18 (30.0) 13 (21.7)
13 (21.6) 47 (78.4)
22 (36.7) 38 (63.3)
24 (40.0) 36 (60.0) 50 (83.3)
57 (95.0) 3 (5.0) 35 (58.3)
5 (8.7) 23 (39.6) 30 (51.7)
45 (75.0) 13 (21.6) 2 (3.4)
570.8 (200-1,237.5) 3.7 (2.5-6) 24.6 (2.5-50)
667.1 (300-1,350) 2.6 (1-7) 22.7 (3.7-50)
8 (0.6-20) ~
~
8 (1-20) ~
Fifty-eight early-onset and 60 late-onset PD patients were treated. a
EARL Y-ONSET PARKINSON’S DISEASE
Fifty-eight of the 60 early-onset patients (96.7%) and all of the late-onset patients were treated with L-dopa. The dosages of dopaminergic compounds employed (L-dopa, lisuride, and bromocriptine) did not differ significantly between the two groups, although the L-dopa dosage was slightly larger in the late-onset group (Table 2). The efficacy of L-dopa therapy, which was good for all at the beginning, was still “good” in only 8.7% of early-onset patients (as against 75% of late-onset patients) after 6 months of treatment: this difference was significant (p < 0.001). Correspondingly, “poor” efficacy was more common in early-onset patients (5 1.7 versus 3.4%, p < 0.001), and less significant differences were observed between the two groups with respect to “moderate” efficacy (39.6 versus 21.6%, p < 0.05) (Table 2). Motor side effects of long-term L-dopa treatment were evident in 78% of early-onset patients and 62% of late-onset patients (difference not significant), with systemic side effects affecting 32 and lo%, respectively (a significant difference, p < 0.05). The mean interval between L-dopa therapy commencement and onset of side effects was 4.2 years (range, 0.1-12 years) in early-onset and 6 years (range, 1-10 years) in late-onset patients, a highly significant difference (p < O.OOOl), especially since average daily doses of L-dopa were closely similar in both groups. When one compares the clinical symptomatology at onset (tremulous, rigidakinetic, or mixed) with other indices in early-onset PD patients, it emerges that the mixed and tremulous onsets are overall more debilitating then the rigid-akinetic onset, but the latter group tends to have treatment side effects sooner. Side effects appeared on average 3 years after treatment initiation in rigid-akinetic patients, after 4 years in the tremulous patients, and after 5.6 years in the mixed cases; the differences between the latter and the two former were statistically significant (p < 0.001).
Risk Factors The prevalence of present cigarette smoking, place of birth, residence during the first 15 years of life, and profession did not differ significantly between the groups. Motor and Cognitive Performances The evaluation of motor dexterity (in the “on phase” in fluctuating patients) using writing, tapping, and screw and nut tests did not show any
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significant differences between the two groups, except for the tapping test: here, patients with earlyonset PD achieved better scores than late-onset PD patients (232.3 & 54.7 versus 175.6 ? 53.9; p < 0.01). The RT and MT in early-onset PD patients did not differ from those observed in late-onset PD patients (data not shown). Interestingly, the early-onset PD patients had worse performances with Zazzo’s test (speed: 31.3 2 18.4 versus 17.8 ? 12.7; accuracy: 0.18 +- 0.134 versus 0.24 f 0.227). No significant differences were observed on the WAIS (verbal, performance, and total scores) between our two groups of patients (data not shown). Psychotic Side Effects and Dementia Rate The current prevalence of psychotic side effects to dopaminergic medication was 5% in early-onset PD patients and 15% of 134 late-onset controls. The comparison between the 60 early-onset patients and these consecutive nonselected PD patients, which was performed in the same way as in an earlier study (24), showed that motor compromise (according to the CURS and Hoehn and Yahr stage) and the type and dosage of drugs received were closely similar, while the prevalence of dementia and psychotic side effects of dopaminomimetic therapy were significantly different (Table 3). No early-onset patient was in fact demented. In contrast, 21 (15.7%) of the nonselected patients were demented. Only three early-onset patients had psychotic symptoms secondary to treatment, while in the 113 nondemented patients in the nonselected group the prevalence was much greater (12 patients, ll%), and 19 (90%) of the 21 demented patients experienced psychotic side effects. TABLE 3 . Psychotic side-effects and dementia rate Parkinson’s disease (PD) patients Early onset
(60) Delirium Delusions Hallucinations Total (%) Dementia rate (%)
1 0
2 3/60 (5) 0/60(0)
Nonselected, nondemented (113)
Nonselected, demented (21)
3 2
17“
I
0 2 19/21‘ (90)
12/113 (11) 21/134 (15.7)
Chi-squared test, early-onset versus nonselected demented PD, p < 0.001; nonselected nondemented versus demented, p < 0.01. Chi-squared test, early-onset versus nonselected demented PD, p < 0.01; nonselected nondemented versus demented, p < 0.01. ‘Chi-squared test, early-onset versus nonselected PD, p < 0.05.
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DISCUSSION
The reported frequency of early-onset PD varies, from 4 (26) through 6.3 (2), 8.3 (l), and 12 (6), to 18.4%(27). Our percentage (10.2) falls in the middle of this range. Differences between these series could be due to variations in patient selection. The presence of affected relatives is often controversial for both PD in general and early-onset PD. Some authors have found a family history of parkinsonism in a high proportion of index cases with early-onset PD. Thus, Yokochi et al. (15) found that 42.5% of 40 cases of early-onset PD had an affected first- or second-degree relative, and Willige (4) found that 50% of patients with onset between 18-30 years of age had an affected relative. The figure of Barbeau and Pourcher (17) is 36%. Quinn et al. (19), on the other hand, separated their series of 60 early-onset PD patients into two groups: In 56 patients with onset between 25-39 years, 19.6% had an affected relative (1.3% of the total number of first- and second-degree relatives was affected). In the second group of four patients with onset ages between 20-25, three had one affected relative and one had three affected siblings. They concluded that patients with disease onset before the age of 21 had a different kind of parkinsonism, often genetically determined. The data of Quinn et al. (19) are substantially in agreement with ours. In our series, no statistically significant differences were evident with respect to symptoms at onset except that more early-onset patients had tremor. A different observation was made by Yokochi and Narabayashi (8): they reported that “juvenile parkinsonism” is distinguished by rigidity and that tremor, when present, is of slight intensity. The motor fluctuations and the “rapid” form were more prevalent in the early-onset group. This feature was also observed by Quinn et al. (19) and may represent an index of more rapid deterioration of the nigrostriatal dopaminergic system in patients in whom symptoms appear below the age of 40. Taken as a whole, the pharmacological findings observed in our series (deterioration of efficacy of dopaminergic therapy after only 6 months of treatment, earlier appearance of motor side effects with L-dopa therapy) suggest more malignant disease progression in early-onset parkinsonians, a conclusion very much in line with that of other workers (19-22). Recently, Diamond et al. (28) have published data
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suggesting a more favorable prognosis in patients with onset of PD under 50 years of age. This study analyzed 54 patients, but in only 13 was disease onset before 50 years (mean, 44.5 years in this subgroup). For this reason these results are not comparable with those of our study. According to Yokochi and Narabayashi (8), Narabayashi et al. (20), and Lima et al. (21), autonomic dysfunction is rare in patients with earlyonset PD. Our results differ from these observations. However, since criteria for autonomic dysfunction have not been universally agreed on, our findings cannot be regarded as definitive. Our data on risk factors (cigarette smoking, place of birth, residence during the first 15 years of life, and profession) do not support the recent suggestion (29,30) that agricultural chemicals similar to MPTP may have a parkinsonogenic effect. However, the relatively small number of patients observed in our study does not provide definitive answers to this question. In agreement with our previous data (24) and those reported by others (31-33), RT and MT were significantly longer in PD patients than in normal subjects matched for age, sex, and educational level. However, the RT and MT in early-onset PD patients did not differ from those observed in lateonset PD patients. In our study, the early-onset PD patients had worse performances with Zazzo’s test. This attention test requires protracted vigilance, the capacity to perform visual discrimination, and the ability to register motor responses. It discriminates very well between PD patients and normal subjects. The marked impairment shown by our patients with Zazzo’s test confirms, as previously observed (24), that in PD, no matter what the age of onset, attention processes are selectively impaired. This finding is in accordance with the hypothesis that the basal ganglia play an important role in selective attention and preparation of motor responses (34-36). No significant differences were observed on the WAIS between our two groups of patients. The close linkage between motor and cognitive performances for both groups suggests that motor and cognitive functions are either impaired to the same degree or normal in these two different groups of parkinsonians. Although both groups had comparable disease duration and disease severity (as rated on the CURS and Hoehn and Yahr scale), since the early-onset PD patients were much younger than
EARL Y-ONSET PARKINSON’S DISEASE the late-onset PD patients when examined, it is likely that ultimate disease progression may be worse in early-onset PD patients. The greater prevalence of psychotic side effects in the late-onset group can be attributed neither to duration of illness nor to duration of treatment and correlates only with current age. None of our early-onset patients was demented; this was also the finding of other workers (19,20, 22). In contrast, 21 (15.7%) of the nonselected patients were demented. This supports a conclusion of other studies (37,38), including one of our own (39), that the prevalence of dementia in PD increases with age much as it does in the general population, but probably at a higher rate. A low incidence of psychotic side effects in early-onset patients has been reported before (37), and the phenomenon has been correlated with advanced age rather than duration or severity of the illness. In conclusion, the term juvenile PD could be reserved for patients with age at onset before 20, and early-onset PD only for patients with age at onset from 20 to 40 years. Our study has shown that early-onset PD does not differ fundamentally from the late-onset form except that the former is characterized by a more rapid establishment of the full-blown parkinsonian clinical picture, deterioration of the therapeutic efficacy of L-dopa, and earlier appearance of side effects. On the basis of the differences in neuropsychological and cognitive measures and in dementia rate, it is proposed that early-onset PD may be a “pure” form of extrapyramidal compromise with exclusively motor manifestations. REFERENCES 1. Hoehn M, Yahr M. Parkinsonism: onset, progression and mortality. Neurology 1967 ;17 :427442.
2. Zetusky W, Jankovic J, Pirozzolo F. The heterogeneity of Parkinson’s disease: clinical and prognostic implications. Neurology 1985;35:522-526. 3. Huchard H. Observation de paralysie agitante datante de I’age de trois ans. Union Medicale 1875;19:7-76. 4. Willige H. Uber paralysis agitans in jugendlicten alter. Z Gesamte Neurol Psychiatr 1910;4:52&587. 5. Krabbe KH. Nogle Undersogelser over paralysis agitans. Bibl Laeger 1923;115:355-364. 6. Mjones H. Paralysis agitans: a clinical and genetic study. Acta Psychiatr Neurol 1949;suppl 54:1-195. 7. Scott M, Brody J. Benign early onset of Parkinson’s disease. A syndrome distinct from classic post-encephalitic parkinsonism. Neurology 1971;21:366-368. 8. Yokochi M, Narabayashi H. Clinical characteristics of juvenile parkinsonism. In: Rose FC, Capildeo R, eds. Research
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progress in Parkinson’s disease. London: Pitman Medical, 1981:35-39. 9. Kilroy A, Paulsen W. Juvenile Parkinsonism treated with levodopa. Arch Neurol 1972;27:350. 10. Plaitakis A, Nicklas W, Desmick R. Glutamate dehydrogenase deficiency in three patients with spinocerebellar syndrome. Ann Neurol 1980;7:297-303. 1 1 . Horowitz G, Greenberg J. Pallido-pyramidal syndrome treated with levodopa. J Neurof Neurosurg Psychiatry 1975;38:238-240. 12. Hunt J. Progressive atrophy of the globus pallidus (primary atrophy of the pallidal system). A system disease of the paralysis agitans type, characterised by atrophy of the motor cells of the corpus striatum. A contribution to the functions of the corpus striatum. Brain 1917;40:5%148. 13. Van Bogaert L. Contribution clinique et anatomique a I’ttude de la paralysie agitante, juvenile primitive. Rev Neurol 1930;37:315-326. 14. Davison C. Pallido-pyramidal disease. J Neuropaihol Exp Neurol 1947 ;1 3 :50-59. 15. Yokochi M, Narabayashi H, Iizuka R. Juvenile parkinsonism-some clinical, pharmacological and neuropathological aspects. In: Hassler RG, Christ JF, eds. Advances in neurology. Vol. 40. New York: Raven Press, 1984:407413. 16. Gibb W, Narabayashi H, Yokochi M, Iizuka R. Additional pathological observations in juvenile onset parkinsonism with dystonia. Neurology 1989;39(suppl 1):139. 17. Barbeau A, Pourcher E. New data on the genetics of Parkinson’s disease. Can J Neurol Sci 1982;9:5360. 18. Caraceni T, Giovannini P, Girotti F, Grassi MP, Piccolo I, Soliveri P. Juvenile parkinsonism: a different clinical expression of Parkinson’s disease. J Neurol 1985;suppl 232:66. 19. Quinn N, Critchley P, Marsden CD. Young onset Parkinson’s disease. Movement Dis 1987;2:73-91. 20. Narabayashi H, Yokochi M, Iizuka R, Nagatsu T. Juvenile parkinsonism. In: Vinken PJ,Bruyn GW, Klawans HL, eds. Handbook of clinical neurology. Vol. 5(49): Extrapyramidal disorders. New York: Elsevier Science Publishers BV, 1986:153-165. 21. Lima B, Neves G, Nora M. Juvenile parkinsonism: clinical and metabolic characteristics. J Neurol Neurosurg Psychiatry 1987;50:345-348. 22. Gibb WRG, Lees AJ. A comparison of clinical and pathological features of young- and old-onset Parkinson’s disease. Neurology 1988;38:1402-1406. 23. Caraceni T, Giovannini P, Girotti F, Avanzini G. Pharmacology of Huntington’s chorea: personal experience. Eur Neurol 1977;16:42-50. 24. Girotti F, Grassi MP, Carella F, et al. Possible involvement of attention processes in Parkinson’s disease. In: Yahr MD, Bergmann KJ, eds. Advances in neurology. Vol. 45. New York: Raven Press, 1986:425429. 25. Zazzo R. Manuel pour I’examen psychologique de l’enfant. Neuchstel, Switzerland: Delachaux et Niestk, 1969. 26. Broman T. Parkinson syndrome, prevalence and incidence in Goteborg. Acfa Neurol Scand 1963;39(suppl4):95-101. 27. Izumi K, Kuroiwa Y. Naika. Intern Med 1971;27:311. 28. Diamond SG, Markham CH, Hoehn MM, McDowell FH, Muenter MD. Effect of age at onset on progression and mortality in Parkinson’s disease. Neurology 1989;39:1187-1 190. 29. Bocchetta A, Corsini GU.Aetiology of Parkinson’s disease. Lancet 1985;i;112-113. 30. Barbeau A, Roy M, Cloutier T, Plasse L, Paris S. Environmental and genetic factors in the etiology of Parkinson’s disease. In: Yahr MD, Bergmann KJ, eds. Advances in neurology. Vol. 45. New York: Raven Press, 1986:299-306. 31. Heilman KM, Bowers D, Watson RT, Greer M. Reaction
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times in Parkinson’s disease. Arch Neurol 1976;33:139-140. 32. Evarts EV, Teravainen H, Beuchert DE, Calne DB. Pathophysiology of motor performance in Parkinson’s disease. In: Fuxe K, Calne DB, eds. Dopaminergic ergot derivatives and motor functions. London: Pergamon Press, 1979:45-59. 33. Evarts EV, Teravainen H, Calne DB. Reaction time in Parkinson’s disease. Brain 1981;104:167-186. 34. Hassler R. Striatal control of locomotion, intentional actions and of integrating and perceptive activity. J Neurol Sci 1978;36:187-224. 35. Damasio AR, Damasio H, Chang Chui H. Neglect following damage to frontal lobe or basal ganglia. Neuropsychologia 1980;18 :123-1 32.
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36. Heilman KM, Watson RT, Valenstein E. Neglect and related disorders. In: Heilman KM, Valente E, eds. Clinical neuropsychology. Oxford, England: Oxford University Press, 1985~243-293. 37. Brown RG, Marsden CD. Neuropsychology and cognitive function in Parkinson’s disease: an overview. In: Marsden CD, Fahn S , eds. Movement disorders 2 . London: Butterworths, 1987:99-123. 38. Marttila RJ, R i m e UK. Dementia in Parkinson’s disease. Acta Neurol Scand 1976;54:531-541. 39. Girotti F, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1988;51:1498-1502.
Early-Onset Parkinson’s Disease P. Giovannini, I. Piccolo, S. Genitrini, P. Soliveri, F. Girotti, G. Geminiani, G. Scigliano, and T. Caraceni Department of Neurology, Center for Extrapyramidal Disorders, Neurological Institute “ C . Besta, ” Milan, Italy
Summary: The study was conducted on 120 patients (76 men and 44 women) affected by idiopathic Parkinson’s disease (IPD) responsive to L-dopa and observed for many years. Sixty had clinical onset between the ages of 2040, representing 10.2% of our PD population; in the others the symptoms began after the 40th birthday. The two groups were matched for sex and length of illness. In all patients a diagnosis of IPD depended on history and clinical and neuroradiological findings. Clinical, pharmacological, evolutive, and epidemiological data were collected on all patients. Thirty-six patients from each group performed motor dexterity tests (reaction time to expected and unexpected stimuli) and cognitive tests (Wechsler Adult Intelligence Scale, Benton, Short tale, and Zazzo’s speed and accuracy test). To assess the prevalence of dementia and the seventy of psychiatric side effects of L-dopa administration, the 60 patients with early-onset PD were compared with 134 consecutive unselected PD patients. Five percent of early-onset PD patients had a family history of the disorder. Our study showed that early-onset PD does not differ fundamentally from the late-onset form except that the former is characterized by a more rapid establishment of the full-blown parkinsonian clinical picture and deterioration of the therapeutic efficacy of L-dopa, with an earlier appearance of side effects. The results of our neuropsychological investigations suggest that early-onset PD may be a “pure” form of extrapyramidal compromise with exclusively motor manifestations. Key Words: IPD-Early-onset PD-Clinical and cognitive aspects-Dementia rate.
to patients whose disease onset was either before 20 or 40 years of age. The first case of juvenile (indeed, “infantile”) parkinsonism was described in 1875 (3). Later, several other patients were described (4-8) with different ages of onset and with signs different from those typical of IPD, and often with other relatives said to have parkinsonism. Patients with onset before age 20 often had peculiar clinical features. Exemplifying this problem is the case described by Kilroy and Paulsen (9) as juvenile PD that was subsequently reviewed by Plaitakis et al. (10) and diagnosed as type 4 OPCA. Pathological studies (11-16) have also brought contrasting results. Some very early-
The onset of idiopathic Parkinson’s disease (IPD) occurs in adult life and has a peak incidence between 50-69 years of age (1,2). It is therefore commonly believed that IPD is disease of the elderly. This concept is so widely ingrained that each time a physician sees a patient aged less than 30 or 40 years with parkinsonian features he asks himself, “Is this true Parkinson’s or a different disease?” The term juvenile PD has been variously applied Address correspondence and reprint requests to Dr. P. Giovannini, Dept. of Neurology, Centre for Extrapyramidal Disorders, Neurological Institute “C. Besta,” Via Celoria, 1 1 , 20133 Milano, Italy.
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EARL Y-ONSE T PARKINSON’S DlSEAS E
onset cases (at 15, 7, and 13 years, respectively) were correlated with pallidal atrophy (12-14), without evidence of the typical neuropathological features generally observed in IPD. On the basis of these considerations, it seems likely that at least some of the cases designated as juvenile PD with onset before the age of 20 have either clinical or pathological features not seen in IPD. Therefore, a firm diagnosis of juvenile PD should be supported by appropriate pathological findings. Attention has recently concentrated on cases defined as “early-onset PD” (17,18) or “young-onset PD” (19), where the disease manifests itself between the ages of 2040. Current opinion views a high prevalence of a family history of PD (20), rapidity and extent of disease progression (18), good initial response to therapy, early development of side effects to therapy (motor fluctuations and dyskinesias), and lack of mental deterioration as characteristic of this subtype of parkinsonism (18,19,21, 22). However, there is some divergence of views concerning the key characteristics of early-onset PD, so that further studies in this area are clearly necessary. PATIENTS AND METHODS One hundred and twenty patients (76 men and 44 women) affected by IPD, all observed for varying numbers of years, were studied. In 60 patients, disease onset was between the ages of 2040; in the others the disease manifested itself after the age of 40. The two groups were matched for sex and length of illness (Table 1). In all patients the diagnosis of IPD depended on the presence of bradykinesia, with rest tremor or muscular rigidity, without a known etiology or other diagnostic exclusion criteria. These exclusion
criteria suggestive of an alternative cause of parkinsonism were sustained remission of symptoms, history of definite encephalitis, repeated strokes or repeated head injury, oculogyric crises, neuroleptic treatment at onset of symptoms, supranuclear down-gaze palsy, cerebellar signs, pyramidal signs, and, last, cerebral tumor, communicating hydrocephalus, or white matter changes suggestive of subcortical ischemic encephalopathy on computed tomography scan. The following were determined for each patient: (a) symptom at onset (rigidity-akinesia, tremor, or mixed); (b) presence of minor signs of autonomic dysfunction (seborrhea, salivation, hyperhydrosis, orthostatic hypotension, or disturbances in sphincter control). (c) The rate of disease progression (estimated as the interval between the appearance of the first symptoms and development of the complete bilateral clinical picture) was characterized as rapid (if the interval was less than 12 months) and slow (if greater); and (d) the therapeutic efficacy of L-dopa medication was characterized as good, moderate, or poor depending on its ability to control parkinsonian symptoms after the 1st 6 months of treatment (good = an improvement of the Columbia University Rating Scale, CURS, total score 2 30%; moderate = improvement between 20-30%; poor = improvement < 20%). (e) The occurrence of long-term side effects of L-dopa therapy were motor effects (wearing off, involuntary movement, dystonia, and the “on-off” phenomenon), psychiatric effects (delusions, delirium, or hallucinations), and systemic effects (nausea, vomiting, orthostatic hypotension, etc.). Patients were labelled fluctuators if they had motor side effects and stable if these were absent. (f) The interval between initiation of L-dopa treatment and the appearance of motor side
TABLE 1. General synopsis of patients Parkinson’s disease patients
No. of cases Sex Age, mean yr (range) Age at onset, mean yr (range) Illness duration, mean yr (range) CURS, mean (range) H&Y S, mean (range)
Early onset
Late onset
Nonselected controls
60 38 M, 22 F 45.1 29-62 34.7 24-39 10.4 0.6-30 30.4 6-60 2.4 1 - 4
60 38 M, 22 F 62.9 52-80 53.6 42-68 9.3 0.8-28 26.9 7-58 2.5 1-5
134 73 M, 61 F 62.5 45-80 56.0 41-72 6.5 0.6-20 24.7 8-56 2.3 1-5
CURS, Columbia University Rating Scale score; H&Y S, Hoehn and Yahr stage.
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effects and (g) the interval between disease onset and initiation of treatment were noted. (h) The history of disease in the family (first- and seconddegree relatives) and (i) cigarette smoking were noted. (i) Birthplace (as north, center, or south/ islands of Italy) and residence during the first 15 years of life (as rural, urban residential, or urban industrial), and (k) occupation (as land worker, industrial worker, tradesman/shopkeeper, office worker, managedself-employed professional, or housewife) were determined. Overall parkinsonian disability was assessed on the CURS and the Hoehn and Yahr scale. Thirty-six patients from each group also performed motor dexterity tests (tapping test, screw and nut test, and writing test) (23), their reaction times to expected and unexpected stimuli were measured electronically (24), intelligence was evaluated on the Wechsler Adult Intelligence Scale (WAIS) (verbal score, performance score, and total score), and their visuospatial attention abilities were quantified by Zazzo’s speed and accuracy test (25). To assess the prevalence of dementia and the severity of psychiatric side effects of L-dopa administration, the 60 patients with early-onset PD were compared with 134 consecutive unselected PD patients (73 men and 61 women) whose average age at the time of investigation was 62.5 (range, 45-80) years, with mean disease onset at age 56 (range, 41-72) years and mean illness duration of 6.5 (range, 0 . 6 2 0 ) years (Table 1). This group was also assessed clinically on the CURS and the Hoehn and Yahr scale, taking note of drug therapy, the presence or absence of dementia, and any psychotic side effects of treatment. The presence or absence of dementia was assessed according to DSM I11 criteria. The chi-squared test and the student’s t-test were employed in the statistical analysis.
RESULTS Frequency and Familial History Early-onset PD makes up 10.2% of the PD population observed in our center, and we have only three patients (5%) with one affected relative (two, first degree and one, second degree). The only patient with a disease onset earlier than at 25 had no relative affected.
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Clinical Characteristics and Pharmacological Aspects Comparing the clinical characteristics of the two groups (early-onset and late-onset PD, Table 2), no statistically significant differences were evident with respect to symptoms at onset except that more early-onset patients had tremor (35 versus 21.7%), with the inverse for the mixed clinical picture (20 versus 30%). Motor fluctuations were more prevalent in the early-onset group (78.4 versus 63.3%), but this difference was not statistically significant. A “slow” disease progression was significantly characteristic of late-onset patients (95 versus 40%, p < 0.01), whereas the “rapid” form characterized early-onset patients (60 versus 5%, p < 0.001). Sialorrhea, constipation, hyperhydrosis, or mild orthostatic hypotension was observed in 83.3% of early-onset PD patients but in only 58.3% of the other group (p < 0.01). Motor compromise (in the “on phase” for fluctuating patients) as determined by the CURS (30.4 versus 26.9, average score) and the method of Hoehn and Yahr (2.4 versus 2.5, average stage) was similar in both groups (Table 1). TABLE 2. Early- and late-onset Parkinson’s disease (PD)patients: clinical data
Symptom at onset, no. (%) rigid-akine tic mixed tremulous Clinical stage, no. (%) stable fluctuator Rate of disease progression, no. (%) slow rapid Autonomic symptoms, no. (%) Response to treatment,O after 6 mo, no. (%) good moderate poor Drug doses employed mean mg (range) L-dopa lisuride bromocriptine Years of L-dopa treatment, mean (range) ~
~~
Early-onset
Late-onset
PD
PD
27 (45.0) 12 (20.0) 21 (35.0)
29 (48.3) 18 (30.0) 13 (21.7)
13 (21.6) 47 (78.4)
22 (36.7) 38 (63.3)
24 (40.0) 36 (60.0) 50 (83.3)
57 (95.0) 3 (5.0) 35 (58.3)
5 (8.7) 23 (39.6) 30 (51.7)
45 (75.0) 13 (21.6) 2 (3.4)
570.8 (200-1,237.5) 3.7 (2.5-6) 24.6 (2.5-50)
667.1 (300-1,350) 2.6 (1-7) 22.7 (3.7-50)
8 (0.6-20) ~
~
8 (1-20) ~
Fifty-eight early-onset and 60 late-onset PD patients were treated. a
EARL Y-ONSET PARKINSON’S DISEASE
Fifty-eight of the 60 early-onset patients (96.7%) and all of the late-onset patients were treated with L-dopa. The dosages of dopaminergic compounds employed (L-dopa, lisuride, and bromocriptine) did not differ significantly between the two groups, although the L-dopa dosage was slightly larger in the late-onset group (Table 2). The efficacy of L-dopa therapy, which was good for all at the beginning, was still “good” in only 8.7% of early-onset patients (as against 75% of late-onset patients) after 6 months of treatment: this difference was significant (p < 0.001). Correspondingly, “poor” efficacy was more common in early-onset patients (5 1.7 versus 3.4%, p < 0.001), and less significant differences were observed between the two groups with respect to “moderate” efficacy (39.6 versus 21.6%, p < 0.05) (Table 2). Motor side effects of long-term L-dopa treatment were evident in 78% of early-onset patients and 62% of late-onset patients (difference not significant), with systemic side effects affecting 32 and lo%, respectively (a significant difference, p < 0.05). The mean interval between L-dopa therapy commencement and onset of side effects was 4.2 years (range, 0.1-12 years) in early-onset and 6 years (range, 1-10 years) in late-onset patients, a highly significant difference (p < O.OOOl), especially since average daily doses of L-dopa were closely similar in both groups. When one compares the clinical symptomatology at onset (tremulous, rigidakinetic, or mixed) with other indices in early-onset PD patients, it emerges that the mixed and tremulous onsets are overall more debilitating then the rigid-akinetic onset, but the latter group tends to have treatment side effects sooner. Side effects appeared on average 3 years after treatment initiation in rigid-akinetic patients, after 4 years in the tremulous patients, and after 5.6 years in the mixed cases; the differences between the latter and the two former were statistically significant (p < 0.001).
Risk Factors The prevalence of present cigarette smoking, place of birth, residence during the first 15 years of life, and profession did not differ significantly between the groups. Motor and Cognitive Performances The evaluation of motor dexterity (in the “on phase” in fluctuating patients) using writing, tapping, and screw and nut tests did not show any
39
significant differences between the two groups, except for the tapping test: here, patients with earlyonset PD achieved better scores than late-onset PD patients (232.3 & 54.7 versus 175.6 ? 53.9; p < 0.01). The RT and MT in early-onset PD patients did not differ from those observed in late-onset PD patients (data not shown). Interestingly, the early-onset PD patients had worse performances with Zazzo’s test (speed: 31.3 2 18.4 versus 17.8 ? 12.7; accuracy: 0.18 +- 0.134 versus 0.24 f 0.227). No significant differences were observed on the WAIS (verbal, performance, and total scores) between our two groups of patients (data not shown). Psychotic Side Effects and Dementia Rate The current prevalence of psychotic side effects to dopaminergic medication was 5% in early-onset PD patients and 15% of 134 late-onset controls. The comparison between the 60 early-onset patients and these consecutive nonselected PD patients, which was performed in the same way as in an earlier study (24), showed that motor compromise (according to the CURS and Hoehn and Yahr stage) and the type and dosage of drugs received were closely similar, while the prevalence of dementia and psychotic side effects of dopaminomimetic therapy were significantly different (Table 3). No early-onset patient was in fact demented. In contrast, 21 (15.7%) of the nonselected patients were demented. Only three early-onset patients had psychotic symptoms secondary to treatment, while in the 113 nondemented patients in the nonselected group the prevalence was much greater (12 patients, ll%), and 19 (90%) of the 21 demented patients experienced psychotic side effects. TABLE 3 . Psychotic side-effects and dementia rate Parkinson’s disease (PD) patients Early onset
(60) Delirium Delusions Hallucinations Total (%) Dementia rate (%)
1 0
2 3/60 (5) 0/60(0)
Nonselected, nondemented (113)
Nonselected, demented (21)
3 2
17“
I
0 2 19/21‘ (90)
12/113 (11) 21/134 (15.7)
Chi-squared test, early-onset versus nonselected demented PD, p < 0.001; nonselected nondemented versus demented, p < 0.01. Chi-squared test, early-onset versus nonselected demented PD, p < 0.01; nonselected nondemented versus demented, p < 0.01. ‘Chi-squared test, early-onset versus nonselected PD, p < 0.05.
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DISCUSSION
The reported frequency of early-onset PD varies, from 4 (26) through 6.3 (2), 8.3 (l), and 12 (6), to 18.4%(27). Our percentage (10.2) falls in the middle of this range. Differences between these series could be due to variations in patient selection. The presence of affected relatives is often controversial for both PD in general and early-onset PD. Some authors have found a family history of parkinsonism in a high proportion of index cases with early-onset PD. Thus, Yokochi et al. (15) found that 42.5% of 40 cases of early-onset PD had an affected first- or second-degree relative, and Willige (4) found that 50% of patients with onset between 18-30 years of age had an affected relative. The figure of Barbeau and Pourcher (17) is 36%. Quinn et al. (19), on the other hand, separated their series of 60 early-onset PD patients into two groups: In 56 patients with onset between 25-39 years, 19.6% had an affected relative (1.3% of the total number of first- and second-degree relatives was affected). In the second group of four patients with onset ages between 20-25, three had one affected relative and one had three affected siblings. They concluded that patients with disease onset before the age of 21 had a different kind of parkinsonism, often genetically determined. The data of Quinn et al. (19) are substantially in agreement with ours. In our series, no statistically significant differences were evident with respect to symptoms at onset except that more early-onset patients had tremor. A different observation was made by Yokochi and Narabayashi (8): they reported that “juvenile parkinsonism” is distinguished by rigidity and that tremor, when present, is of slight intensity. The motor fluctuations and the “rapid” form were more prevalent in the early-onset group. This feature was also observed by Quinn et al. (19) and may represent an index of more rapid deterioration of the nigrostriatal dopaminergic system in patients in whom symptoms appear below the age of 40. Taken as a whole, the pharmacological findings observed in our series (deterioration of efficacy of dopaminergic therapy after only 6 months of treatment, earlier appearance of motor side effects with L-dopa therapy) suggest more malignant disease progression in early-onset parkinsonians, a conclusion very much in line with that of other workers (19-22). Recently, Diamond et al. (28) have published data
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suggesting a more favorable prognosis in patients with onset of PD under 50 years of age. This study analyzed 54 patients, but in only 13 was disease onset before 50 years (mean, 44.5 years in this subgroup). For this reason these results are not comparable with those of our study. According to Yokochi and Narabayashi (8), Narabayashi et al. (20), and Lima et al. (21), autonomic dysfunction is rare in patients with earlyonset PD. Our results differ from these observations. However, since criteria for autonomic dysfunction have not been universally agreed on, our findings cannot be regarded as definitive. Our data on risk factors (cigarette smoking, place of birth, residence during the first 15 years of life, and profession) do not support the recent suggestion (29,30) that agricultural chemicals similar to MPTP may have a parkinsonogenic effect. However, the relatively small number of patients observed in our study does not provide definitive answers to this question. In agreement with our previous data (24) and those reported by others (31-33), RT and MT were significantly longer in PD patients than in normal subjects matched for age, sex, and educational level. However, the RT and MT in early-onset PD patients did not differ from those observed in lateonset PD patients. In our study, the early-onset PD patients had worse performances with Zazzo’s test. This attention test requires protracted vigilance, the capacity to perform visual discrimination, and the ability to register motor responses. It discriminates very well between PD patients and normal subjects. The marked impairment shown by our patients with Zazzo’s test confirms, as previously observed (24), that in PD, no matter what the age of onset, attention processes are selectively impaired. This finding is in accordance with the hypothesis that the basal ganglia play an important role in selective attention and preparation of motor responses (34-36). No significant differences were observed on the WAIS between our two groups of patients. The close linkage between motor and cognitive performances for both groups suggests that motor and cognitive functions are either impaired to the same degree or normal in these two different groups of parkinsonians. Although both groups had comparable disease duration and disease severity (as rated on the CURS and Hoehn and Yahr scale), since the early-onset PD patients were much younger than
EARL Y-ONSET PARKINSON’S DISEASE the late-onset PD patients when examined, it is likely that ultimate disease progression may be worse in early-onset PD patients. The greater prevalence of psychotic side effects in the late-onset group can be attributed neither to duration of illness nor to duration of treatment and correlates only with current age. None of our early-onset patients was demented; this was also the finding of other workers (19,20, 22). In contrast, 21 (15.7%) of the nonselected patients were demented. This supports a conclusion of other studies (37,38), including one of our own (39), that the prevalence of dementia in PD increases with age much as it does in the general population, but probably at a higher rate. A low incidence of psychotic side effects in early-onset patients has been reported before (37), and the phenomenon has been correlated with advanced age rather than duration or severity of the illness. In conclusion, the term juvenile PD could be reserved for patients with age at onset before 20, and early-onset PD only for patients with age at onset from 20 to 40 years. Our study has shown that early-onset PD does not differ fundamentally from the late-onset form except that the former is characterized by a more rapid establishment of the full-blown parkinsonian clinical picture, deterioration of the therapeutic efficacy of L-dopa, and earlier appearance of side effects. On the basis of the differences in neuropsychological and cognitive measures and in dementia rate, it is proposed that early-onset PD may be a “pure” form of extrapyramidal compromise with exclusively motor manifestations. REFERENCES 1. Hoehn M, Yahr M. Parkinsonism: onset, progression and mortality. Neurology 1967 ;17 :427442.
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