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Juvenile parkinsonism
Juvenile Parkinsonism Ergun Y. Uc and Robert L. Rodnitzky Juvenile parkinsonism (JP) is a clinically and etiologically heterogeneous entity. Unlike in the adult form, secondary causes, hereditary and metabolic conditions, are the predominant causes of JP. Idiopathic Parkinson's disease is very rare in this age group, in most cases of JP, parkinsonism is accompanied by other neurologic features, such as dystonia, cognitive impairment, seizures, oculomotor and visual dysfunction, and ataxia. Systemic findings, such as liver dysfunction or hepatosplenomegaly, may be present depending on the cause. This review article describes the clinical characteristics, classification, genetic basis, pathophysiology, biochemistry, pathology, and treatment of JP. © 2003 Elsevier Inc. All rights reserved.
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rileEs C A R D I N A L signs of parkinsonism are tremor, rigidity, bradykinesia (slowness of automatic and spontaneous movements), akinesia (impaired ability to initiate voluntary movements), and postural instability. 1 Shuffling gait, freezing, hypophonia, micrographia, postural and action tremor, and sialorrhea also may be seen. Parkinsonism is very rare in children. In adults, 75% to 80% of parkinsonism cases are due to idiopathic Parkinson's disease (PD). 2 PD is characterized by the progressive degeneration and presence of Lewy bodies in the dopaminergic neurons in the substantia nigra pars compacta, as well as variable involvement of selected aminergic brainstem nuclei (both catecholaminergic and serotoninergic), the cholinergic nucleus basalis of Meynert, hypothalamic neurons, small cortical neurons (particularly in the cingulate gyms and entorhinal cortex), the olfactory bulb, sympathetic ganglia, and parasympathetic neurons in the gut? Depending on the degree of involvement of systems aside from the dopaminergic nigrostriatal pathway, cognitive impairment (executive dysfunction, attention disorders, dementia), psychiatric manifestations (depression, anxiety, psychosis), dysautonomia (orthostasis, gastrointestinal dysmotility), and sleep disorders (REM sleep behavior syndrome, excessive daytime sleepiness) can be observed. 3 PD is rare before age 50, and incidence increases with advancing age thereafter.4'5 The prevalence of PD increases exponentially with age between 65
From the Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA. Address reprint requests to Dr. Ergun Y. Uc, Department of Neurology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive-2100 RCP, Iowa City, IA 52246. © 2003 Elsevier Inc. All rights reserved. 1071-9091/03/1001-0009530.00/0 doi:l O.lO53/spen.2003.0000 62
and 90; approximately 0.3% of the general population and 3% of people over age 65 have PD? Between 5% and 10% of patients have symptoms before age 40. Arbitrarily, PD with onset between age 21 and 39 is termed young-onset Parkinson's disease (YOPD), and that with onset before age 21 is termed juvenile parkinsonism (jp).6-9 In the past, JP was used to designate onset before age 40] o YOPD frequently presents with dystonia and tends to have more gradual progression, but with earlier appearance of levodoparelated dyskinesias and levodopa-dose-related motor fluctuations. 6 A review of 139 patients with YOPD revealed that mortality rate is increased in comparison with the normal population and is similar to that in the general PD population. ~ Intellectual function and postural reflexes are usually well preserved for many years despite a long history of parkinsonism and the early and frequent occurrence of treatment complications. JP, although described almost a century ago, 11 continues to be a confusing and heterogeneous entity that is clinically and pathologically distinct from YOPD. 6'7'12'13 JP constituted 0.6% of 918 patients with parkinsonism seen at a large Movement Disorders Clinic over 6 years] 2 Of the six JP patients in this series, five were male, and one was female. The mean age at onset of parkinsonism was 12.5 years (range, 7 to 19) and the mean follow-up time was 49.3 months (range, 40 to 57). Bradykinesia, rigidity, and postural instability were observed in all patients, and tremor was observed in five. Dystonia was present in four subjects. Illustrating the clinical heterogeneity of JP, other clinical features included dementia (five subjects), supranuclear ophthalmoparesis (five subjects), seizures (three subjects), multifocal myoclonus (one subject), decreased muscle stretch reflexes (one subject), and pyramidal signs (one subject). Family history of PD was positive in one Seminars in Pediatric Neurology, Vo[ 10, No 1 (March), 2003: pp 62-67
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subject. Neuroimaging studies showed cortical atrophy in two subjects and mild brainstem atrophy in two others. Sea-blue histiocytes were found in one subject, but in most patients, no underlying cause was identified. However, no genetic testing was done, L-dopa improved parkinsonism symptoms in all subjects, but four rapidly developed fluctuations and dyskinesias that in one necessitated stereotaxic surgery. After a mean disease duration of 6.5 years, five subjects required assistance in performing activities of daily living, indicating a more aggressive and rapidly progressive course than PD. Many patients with JP have one or more atypical features, including opthalmoparesis, seizures, and dementia, leading to a diagnosis of one of the childhood encephalopathies, a2 Some have identifiable causes, such as drug toxicity, encephalitis, or tumors, leading to the diagnosis of secondary parkinsonism. 14 A positive family history for parkinsonism is not uncommon. Langston and Tan, 13 in a recent editorial, explained the continuing use of the term "juvenile parkinsonism" despite the fact that many patients display atypical accompanying features. In their view, the rarity of any form of parkinsonism during childhood or adolescence tends to place it center stage, even if it is a minor part of the total clinical picture. There is scant evidence that typical Lewy body parkinsonism (idiopathic PD) ever occurs in childhood or adolescence. 13 There are only two possible cases of pathologically proven juvenile PD. 15'16 Without the requirement for pathological verification, the number of patients in the literature with pure parkinsonism in juveniles increases. However, more than 50% of these patients have positive family histories, s'9'172° raising the question as to whether they may harbor a parkin mutation. Even in those individuals without a family history (a total of about 20 such cases have been reported), 7"8'21-23 a parkin disorder cannot be ruled out because this is an autosomal-recessive disorder that may not have yet affected any other family members. In this article, JP is considered a syndrome rather than a distinct nosological entity. The secondary and hereditary/metabolic causes of JP show great overlap with childhood dystonias. Hence the reader is directed to the article titled "Childhood Dystonias" in this issue of Seminars in Pediatric Neurology for the differential diagnosis, laboratory evaluation, and broader discussion of some of the
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conditions mentioned later herein, including doparesponsive dystonia, Wilson's disease, mitochondrial disorders, and others. The following section discusses disorders with parkinsonism as the major clinical manifestation. PARKIN-RELATED PARKINSONISM
Mutations on chromosome 6q25-27 were identified as the cause of autosomal-recessive JP, initially in Japan 15'24 but later also in European and North African familiesY -27 The causative gene, PARK2, 28 spans more than 500 kilobases and encodes a ubiquitin ligase called parkin. 29-31 The absence of ubiquitin ligases like parkin that target proteins for degradation by the ubiquitin-proteasome pathway may lead to accumulation of those proteins and disruption of cellular function. Symptoms of autosomal-recessive JP usually begin before age 20, but can also begin in adulthood (age range, 7 to 58). 27 Double-staining of Parkinson's disease brains shows that parkin and alpha synuclein colocalize to both Lewy bodies and axonal spheroids. 32 Parkin interacts with and ubiquitinates a 22-kilodalton glycosylated form of alpha synuclein (alpha Sp22) 33 and the alpha synuclein-interacting protein synphilin. 34 Mutations in parkin result in an accumulation of these proteins. Although families with parkin mutations and Lewy body pathology have been described, 35 Lewy bodies are generally absent in this disorder, suggesting that parkin might be required for the formation of these cellular inclusions. Although somewhat variable, the disease phenotype of autosomal-recessive JP usually comprises classic parkinsonism accompanied by foot dystonia, hyperreftexia, good response to levodopa, and the early appearance of levodopa-induced dyskinesiasY A remarkable sleep benefit is seen in some patients, resulting in diurnal fluctuations in symptoms. The large number of missense and nonsense mutations, deletions, duplications, and exon rearrangements 36 make streamlined genetic testing for this condition difficult. Treatment strategies similar to those used for idiopathic PD are used to treat this condition. DRUG-INDUCED PARKINSONISM
Drug-induced parkinsonism (DIP), possibly the most common secondary etiology in children] 4 produces a symptom complex very similar to that of idiopathic PD. Yet some clues can help the clinician distinguish between the two syndromes.
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A symmetrical presentation is more common in DIP than in idiopathic PD, and the incidence of resting tremor is only 50%. One sign that is highly characteristic, although not pathognomonic, of DIP is a low-frequency, perioral, high-amplitude tremor known as the "rabbit syndrome." The coexistence of typical signs of tardive dyskinesia in a patient with parkinsonism should raise the possibility of DIP. 37 DIP symptoms often appear in the first month after initiation of therapy with a dopamine-receptor blocking agent. Underlying brain pathology or combination with other drugs may increase vulnerability. All of the typical neuroleptics and the antiemetic dopamine-receptor blocking agents, including metoclopramide, can cause DIP. Of the atypical neuroleptics, clozapine and quetiapine have the lowest risk of causing DIP. Reserpine and tetrabenazine cause DIP by depleting presynaptic dopaminergic vesicles. Other medications with the potential to cause DIP include valproic acid, fluoxetine and other selective serotonin reuptake inhibitors, lithium, phenytoin, captopril, cytosine arabinoside, 38 amphothericin-B, 14"39 adriamycine, vinca alkaloids, 4° cyclosporine,41 and some calcium channel blockers. 14 Two calcium channel blockers that are relatively potent dopamine blockers, flunarizine and cinnarizine, are not marketed in the United States. The most effective therapy for DIP is discontinuing the offending drug. Most patients exhibit resolution of symptoms within 1 to 2 months of discontinuation, but on rare occasions complete resolution may take up to a year. If discontinuing the offending drug does not produce improvement, or if the offending drug must be continued, then medical therapy should begin with administration of an anticholinergic agent. Amantadine can also be used successfully. Finally, levodopa can be used, with care taken to avoid exacerbating the underlying psychiatric disorder. 4z STRUCTURAL CAUSES
Although parkinsonism is a rare symptom of central nervous system neoplasms, such tumors as craniopharyngiomas, gliomas, ependymomas, and meningiomas may cause parkinsonism by infiltrating the basal ganglia or compressing the brainstem. 43 Hydrocephalus from tumor compression or aqueductal stenosis may also lead to parkinsonism. 44-46 Removal of the tumor or shunting may
alleviate parkinsonism. Temporary treatment with antiparkinsonian medications may be needed. 44 INFECTIOUS/IMMUNE-RELATED CAUSES
Encephalitis lethargica (EL), or Von Economo's encephalitis, temporally associated with the 1918 Spanish influenza pandemic, is of great historical interest. Besides being an acute akinetic form, EL may possibly lead to postencephalitic parkinsonism that can emerge years after the original infection, often without signs of prodromal "~flO. ''47 However, recent genetic analysis of histopathologically confirmed repository cases with acute EL and postencephalitic parkinsonism indicates that the 1918 influenza virus was unlikely to be neurotropic and directly responsible for the outbreak of Encephalitis lethargica. 48 Viral encephalitic illnesses (Japanese B, 49 varicella, measles, mumps, coxsackievirus, Western equine, St. Louis encephalitis), 14 and subacute sclerosing panencephalitis 5° have been associated with parkinsonism. Postinfectious encephalomyelitis after a mycoplasma infection may involve the striatum. 51 The associated parkinsonism and striatal radiologic abnormalities gradually resolve, but symptomatic antiparkinsonian treatment may be needed for a short time. HEREDITARY/METABOLIC CAUSES
Huntington's disease (HD) deserves special mention as a cause of YOPD. This autosomaldominant disorder, due to expansion and instability of a specific CAG repeat sequence in a gene (IT15) on chromosome 4, can present in childhood. These cases are associated with large CAG expansions, often as a result of paternal inheritance, and represent 1% of all HID patients. In juvenile HD there is often a preponderance of an akinetic-rigid syndrome(Westphal's variant). Other clinical hallmarks of presentation in this age group include seizures, learning disabilities, and a rapid course. 52'53 There are several rare disorders that may cause parkinsonism (Table 1); see the article on "Childhood Dystonias" in this issue for discussions of some of the conditions mentioned. TREATMENT
The underlying disease should be treated when a secondary or metabolic cause is identified. Additionally, symptomatic treatment of parkinsonism may be needed infinitely (neurodegenerative con-
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Table 1. Hereditary/Metabolic Causes of Juvenile Parkinsonism
Huntington's disease Wilson's disease Dopa-responsive dystonia Aromatic aminoacid decarboxylase deficiency Tyrosine hydroxylase deficiency Hallervorden-Spatz disease Calcification of the basal ganglia (Fahr's disease) Spinocerebellar ataxia type 3 (Machado-Joseph disease) Neuronal ceroid lipofuscinosis Rapid-onset dystonia-parkinsonism syndrome Lubag's syndrome (Filipino X-linked dystonia-parkinsonism). Leber's disease Leigh's syndrome Glutaric aciduria type 1 Methylmalonic acidemia c~-ketoglutaric aciduria Neuroacanthocystosis GM1 gangliosidosis Biotin-dependent encephalopathy Biotinidase deficiency Lesch-Nyhan disease Familial glucocorticoid deficiency Metachromatic leukodystrophy Gaucher's disease Phenylketonuria
ditions) or temporarily (drug-induced parkinsonism). Physical therapy and assistive device for ambulation can be used as needed. There are no specific guidelines for symptomatic pharmaceutical or surgical treatment of parkinsonism in childhood. Medications similar to those used to treat PD in adults are used. 3"54Dosages for children are adjusted on an empirical basis. Treatment is aimed at enhancing dopaminergic transmission in the nigrostriatal pathway. Because dopamine does not cross the blood-brain barrier, its immediate precursor levodopa is used. Levodopa is combined with a dopa decarboxylase blocker, such as carbidopa (the formulation available in the United States) or benserazide, to block peripheral
conversion to dopamine. Dopaminergic agonists (eg, pramipexole, ropinirole, bromocriptine, pergolide) act predominantly by stimulating D2-type dopamine receptors. Anticholinergics (eg, trihexyphenidyl, benztropine), amantadine, or selegiline (a monoamine oxidase B inhibitor) may be tried before a dopamine agonist or levodopa is given. Catechol-O-methyl transferase (COMT) inhibitors (eg, entacapone, tolcapone) prolong the response to levodopa. Tolcapone has been associated with several deaths due to liver failure, and thus careful monitoring of liver function is required. In PD and other similar degenerative conditions, patients typically develop a "wearing off" of response to levodopa, with the subsequent emergence of various types of dyskinesias, after several years of therapy. In adults, initial monotherapy with the dopamine agonists ropinirole and pramipexole has been shown to postpone the onset of dyskinesias, but usually at the cost of less marked improvement in motor function.55'56 Side effects of antiparkinsonian medications include nausea/vomiting, dizziness and orthostatic hypotension, cognitive impairment, sedation, hallucinations, and psychosis. These side effects can be addressed by decreasing the dose or withdrawing the offending agent and/or by adding medications to address the particular side effect symptomatically. Additional carbidopa or domperidone (not available in the United States) can be used for nausea; salt supplementation, fludrocortisone, or midodrine, for orthostatic hypotension; and modafinil, for sleepiness. In adults, the atypical antipsychotics quetiapine and clozapine (which requires weekly white blood cell count monitoring for agranulocytosis) are used to combat such side effects. There are no established guidelines for surgical treatment of parkinsonism in children; it should be approached be great caution.
REFERENCES 1. Gelb DJ, Oliver E, Gilman S: Diagnostic criteria for Parkinson disease. Arch Neurol 56:33-39, 1999 2. Rodnitzky RL, Uc EY: Approach to the hypokinetic patient, in Biller J (ed): Practical Neurology. Philadelphia, Lippincott Williams & Wilkins, 2002, pp 343-357 3. Lang AE, Lozano AM: Parkinson's disease (part 1). N Engl J Med 339:1044-1053, 1998 4. Tanner CM, Goldman SM: Epidemiology of Parkinson's disease. Neurol Clin 14:317-335, 1996 5. Zhang ZX, Roman GC: Worldwide occurrence of Parkin-
son's disease: An updated review. Neuroepidemiology 12:195208, 1993 6. Golbe LI: Young-onset Parkinson's disease: A clinical review. Neurology 41(pt 1):168-173, 1991 7. Muthane UB, Swamy HS, Satishchandra P, et al: Earlyonset Parkinson's disease: Are juvenile and young-onset different? Mov Disord 9:539-544, 1994 8. Schrag A, Ben Shlomo Y, Brown R, et al: Young-onset Parkinson's disease revisited: Clinical features, natural history, and mortality. Mov Disord 13:885-894, 1998
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9. Quinn N, Critchley P, Marsden CD: Young-onset Parkinson's disease. Mov Disord 2:73-91, 1987 10. Lima B, Neves G, Nora M: Juvenile parkinsonism: Clinical and metabolic characteristics. J Neurol Neurosurg Psychiatry 50:345-348, 1987 11. Willage R: Uber paralysis agitans in jugendlichem. Neurol Psychiatrie 4:520-587, 1911 (in German) 12. Cardoso F, Camargos S: Juvenile parkinsonism: A heterogeneous entity. Eur J Neurol 7:467-471, 2000 13. Langston JW, Tan LC: Juvenile parkinsonism: A term in search of an identity. Eur J Neurol 7:465-466, 2000 14. Pranzatelli MR, Mott SH, Pavlakis SG, et al: Clinical spectrum of secondary parkinsonism in childhood: A reversible disorder. Pediatr Neurol 10:131-140, 1994 15. Yokochi M, Narabayashi H, Iizuka R, et al: Juvenile parkinsonism: Some clinical, pharmacological, and neuropathological aspects. Adv Neurot 40:407-413, 1984 16. Bernheimer H, Birkmayer W, Hornykiewicz O, et al: Brain dopamine and the syndromes of Parkirlson and Huntington: Clinical, morphological and neurochemical correlations. J Neurol Sci 20:415-455, 1973 17. Curlier G, Dubru JM: Familial juvenile Parkinsonism. Acta Paediatr Belgica 32:123-127, t 979 18. Sachdev KK, Singh N, Krishnamoorthy MS: Juvenile parkinsonism treated with levodopa. Arch Neurol 34:244-245, 1977 19. Martin WE, Resch JA, Baker AB: Juvenile parkinsonism. Arch Neurol 25:494-500, 1971 20. Ishikawa A, Miyatake T: A family with hereditary juvenile dystonia-parkinsonism. Mov Disord 10:482-488, 1995 21. Naidu S, Wolfson LI, Sharpless NS: Juvenile parkinsonism: A patient with possible primary striatal dysfunction. Ann Neurol 3:453-455, 1978 22. Clough CG, Mendoza M, Yahr MD: A case of sporadic juvenile Parkinson's disease. Arch Neurol 38:730-731, 1981 23. Gershanik OS, Leist A: Juvenile-onset Parkinson's disease. Adv Neurol 45:213-216, 1987 24. Yamamura Y, Sobue I, Ando K, et al: Paralysis agitans of early onset with marked diurnal fluctuation of symptoms. Neurology 23:239-244, 1973 25. Hattori N, Matsumine H, Asakawa S, et al: Point mutations (Thr240Arg and Gln311Stop) in the parkin gene. Biochem Biophys Res Commun 249:754-758, 1998 26. Lucking CB, Abbas N, Durr A, et al: Homozygous deletions in the parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinson's Disease and the French Parkinson's Disease Genetics Study Group. Lancet 352:1355-1356, 1998 27. Lucking CB, Durr A, Bonifati V, et ah Association between early-onset Parkinson's disease and mutations in the parkin gene. French Parkinson's Disease Genetics Study Group. N Engl J Med 342:1560-1567, 2000 28. Kitada T, Asakawa S, Hattori N, et al: Mutations in the parldn gene cause autosomal recessive juvenile parkinsonism. Nature 392:605-608, 1998 29. Imai Y, Soda M, Takahashi R: Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. J Biol Chem 275:35661-35664, 2000 30. Shimura H, Hattori N, Kubo S, et ah Familial Parkinson
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disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302-305, 2000 31. Zhang Y, Gao J, Chung KK, et al: Parkin functions as an E2-dependent ubiquitin-protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proc Nat Acad Sci U S A 97:13354-13359, 2000 32. Choi P, Golts N, Snyder H, et al: Co-association of parkin and alpha-synuclein. Neuroreport 12:2839-2843, 2001 33. Shimura H, Schlossmacher MG, Hattori N, et ah Ubiquitination of a new form of alpha-synuclein by parkin from human brain: Implications for Parkinson's disease. Science 293:263-269, 2001 34. Chung KK, Zhang Y, Lim KL, et al: Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1 : hnplications for Lewy-body formation in Parkinson disease. Nat Med 7:1144-1150, 2001 35. Farrer M, Chan P, Chen R, et al: Lewy bodies and parkinsonism in families with parkin mutations. Ann Neurol 50:293-300, 2001 36. Hattori N, Kitada T, Matsumine H, et al: Molecular genetic analysis of a novel Parkin gene in Japanese families with autosomaI recessive juvenile parkinsonism: Evidence for variable homozygous deletions in the parkin gene in affected individuals. Ann Neurol 44:935-941, 1998 37. Hardie RJ, Lees AJ: Neuroleptic-induced Parkinson's syndrome: Clinical features and results of treatment with levodopa. J Neurol Neurosurg Psychiatry 51:850-854, 1998 38. Luque FA, Selhorst JB, Petruska P: Parkinsonism induced by high-dose cytosine arabinoside. Mov Disord 2:219222, 1987 39. Devinsky O, Lemann W, Evans AC, et al: Akinetic mutism in a bone marrow transplant recipient following totalbody irradiation and amphotericin B chemoprophylaxis: A positron emission tomographic and neuropatbologic study. Arch Neurol 44:414-417, 1987 40. Boranic M, Raci F: A Parkinson-like syndrome as side effect of chemotherapy with vincristine and adriamycin in a child with acute leukaemia. Biomedicine 31:124-125, 1979 41. Wasserstein PH, Honig LS: Parkinsonism during cyclosporine treatment. Bone Marrow Transplant 18:649-650, 1996 42. Rodnitzky RL: Drug-induced movement disorders. Clin Neuropharmacol 25:142-152, 2002 43. Scott M: Parkinsonian-like and cogwheel rigidity in a child secondary to massive ependymoma of the frontal lobe and the caudate nucleus: Prefrontal lobectomy, with cessation of tremor and rigidity. Arch Neurol Psychiatry 57:649-651, 1947 44. Shahar E, Lambert R, Hwang PA, et al: Obstructive hydrocephalus-induced parkinsonism. I: Decreased basal ganglia regional blood flow. Pediatr Neurol 4:117-119, 1988 45. Braziu ME, Epstein LG: Reversible parkinsonism from shunt failure. Pediatr Neurol 1:306-307, 1985 46. Lung AE, Meadows JC, Parkes JD, et al: Early onset of the "on-off' phenomenon in children with symptomatic parkinsonism. J Neurol Neurosurg Psychiatry 45:823-825, 1982 47. Dickman MS: von Economo encephalitis. Arch NeuroI 58:1696-1698, 2001 48. McCall S, Henry JM, Reid AH, et al: Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases. J Neuropathol Exp Neurol 60:696-704, 2001 49. Misra UK, Kalita J: Prognosis of Japanese encephalitis
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patients with dystonia compared to those with parkinsonian features only. Postgrad Med J 78:238-241, 2002 50. Sawaishi Y, Yano T, Watanabe Y, et al: Migratory basal ganglia lesions in subacute sclerosing panencephalitis (SSPE): Clinical implications of axonal spread. J Neurol Sci 168:137140, 1999 51. Kim JS, Choi IS, Lee MC: Reversible parkinsonism and dystonia following probable mycoplasma pneumoniae infection. Mov Disord 10:510-512, 1995 52. Rasmussen A, Macias R, Yescas P, et al: Huntington disease in children: Genotype-phenotype correlation. Neuropediatrics 31:190-194, 2000
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53. Siesling S, Vegter-van der Vlis M, Roos RA: Juvenile Huntington disease in the Netherlands. Pediatr Neurol 17:3743, 1997 54. Lang AE, Lozano AM: Parkinson's disease (part 2). N Engl J Med 339:1130-1143, 1998 55. Parkinson Study Group: Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 284:1931-1938, 2000 56. Rascol O, Brooks DJ, Korczyn AD, et al: A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa: 056 study group. N Engl J Med 342:1484-1491, 2000
T
rileEs C A R D I N A L signs of parkinsonism are tremor, rigidity, bradykinesia (slowness of automatic and spontaneous movements), akinesia (impaired ability to initiate voluntary movements), and postural instability. 1 Shuffling gait, freezing, hypophonia, micrographia, postural and action tremor, and sialorrhea also may be seen. Parkinsonism is very rare in children. In adults, 75% to 80% of parkinsonism cases are due to idiopathic Parkinson's disease (PD). 2 PD is characterized by the progressive degeneration and presence of Lewy bodies in the dopaminergic neurons in the substantia nigra pars compacta, as well as variable involvement of selected aminergic brainstem nuclei (both catecholaminergic and serotoninergic), the cholinergic nucleus basalis of Meynert, hypothalamic neurons, small cortical neurons (particularly in the cingulate gyms and entorhinal cortex), the olfactory bulb, sympathetic ganglia, and parasympathetic neurons in the gut? Depending on the degree of involvement of systems aside from the dopaminergic nigrostriatal pathway, cognitive impairment (executive dysfunction, attention disorders, dementia), psychiatric manifestations (depression, anxiety, psychosis), dysautonomia (orthostasis, gastrointestinal dysmotility), and sleep disorders (REM sleep behavior syndrome, excessive daytime sleepiness) can be observed. 3 PD is rare before age 50, and incidence increases with advancing age thereafter.4'5 The prevalence of PD increases exponentially with age between 65
From the Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA. Address reprint requests to Dr. Ergun Y. Uc, Department of Neurology, Carver College of Medicine, University of Iowa, 200 Hawkins Drive-2100 RCP, Iowa City, IA 52246. © 2003 Elsevier Inc. All rights reserved. 1071-9091/03/1001-0009530.00/0 doi:l O.lO53/spen.2003.0000 62
and 90; approximately 0.3% of the general population and 3% of people over age 65 have PD? Between 5% and 10% of patients have symptoms before age 40. Arbitrarily, PD with onset between age 21 and 39 is termed young-onset Parkinson's disease (YOPD), and that with onset before age 21 is termed juvenile parkinsonism (jp).6-9 In the past, JP was used to designate onset before age 40] o YOPD frequently presents with dystonia and tends to have more gradual progression, but with earlier appearance of levodoparelated dyskinesias and levodopa-dose-related motor fluctuations. 6 A review of 139 patients with YOPD revealed that mortality rate is increased in comparison with the normal population and is similar to that in the general PD population. ~ Intellectual function and postural reflexes are usually well preserved for many years despite a long history of parkinsonism and the early and frequent occurrence of treatment complications. JP, although described almost a century ago, 11 continues to be a confusing and heterogeneous entity that is clinically and pathologically distinct from YOPD. 6'7'12'13 JP constituted 0.6% of 918 patients with parkinsonism seen at a large Movement Disorders Clinic over 6 years] 2 Of the six JP patients in this series, five were male, and one was female. The mean age at onset of parkinsonism was 12.5 years (range, 7 to 19) and the mean follow-up time was 49.3 months (range, 40 to 57). Bradykinesia, rigidity, and postural instability were observed in all patients, and tremor was observed in five. Dystonia was present in four subjects. Illustrating the clinical heterogeneity of JP, other clinical features included dementia (five subjects), supranuclear ophthalmoparesis (five subjects), seizures (three subjects), multifocal myoclonus (one subject), decreased muscle stretch reflexes (one subject), and pyramidal signs (one subject). Family history of PD was positive in one Seminars in Pediatric Neurology, Vo[ 10, No 1 (March), 2003: pp 62-67
JUVENILE PARKINSONISM
subject. Neuroimaging studies showed cortical atrophy in two subjects and mild brainstem atrophy in two others. Sea-blue histiocytes were found in one subject, but in most patients, no underlying cause was identified. However, no genetic testing was done, L-dopa improved parkinsonism symptoms in all subjects, but four rapidly developed fluctuations and dyskinesias that in one necessitated stereotaxic surgery. After a mean disease duration of 6.5 years, five subjects required assistance in performing activities of daily living, indicating a more aggressive and rapidly progressive course than PD. Many patients with JP have one or more atypical features, including opthalmoparesis, seizures, and dementia, leading to a diagnosis of one of the childhood encephalopathies, a2 Some have identifiable causes, such as drug toxicity, encephalitis, or tumors, leading to the diagnosis of secondary parkinsonism. 14 A positive family history for parkinsonism is not uncommon. Langston and Tan, 13 in a recent editorial, explained the continuing use of the term "juvenile parkinsonism" despite the fact that many patients display atypical accompanying features. In their view, the rarity of any form of parkinsonism during childhood or adolescence tends to place it center stage, even if it is a minor part of the total clinical picture. There is scant evidence that typical Lewy body parkinsonism (idiopathic PD) ever occurs in childhood or adolescence. 13 There are only two possible cases of pathologically proven juvenile PD. 15'16 Without the requirement for pathological verification, the number of patients in the literature with pure parkinsonism in juveniles increases. However, more than 50% of these patients have positive family histories, s'9'172° raising the question as to whether they may harbor a parkin mutation. Even in those individuals without a family history (a total of about 20 such cases have been reported), 7"8'21-23 a parkin disorder cannot be ruled out because this is an autosomal-recessive disorder that may not have yet affected any other family members. In this article, JP is considered a syndrome rather than a distinct nosological entity. The secondary and hereditary/metabolic causes of JP show great overlap with childhood dystonias. Hence the reader is directed to the article titled "Childhood Dystonias" in this issue of Seminars in Pediatric Neurology for the differential diagnosis, laboratory evaluation, and broader discussion of some of the
63
conditions mentioned later herein, including doparesponsive dystonia, Wilson's disease, mitochondrial disorders, and others. The following section discusses disorders with parkinsonism as the major clinical manifestation. PARKIN-RELATED PARKINSONISM
Mutations on chromosome 6q25-27 were identified as the cause of autosomal-recessive JP, initially in Japan 15'24 but later also in European and North African familiesY -27 The causative gene, PARK2, 28 spans more than 500 kilobases and encodes a ubiquitin ligase called parkin. 29-31 The absence of ubiquitin ligases like parkin that target proteins for degradation by the ubiquitin-proteasome pathway may lead to accumulation of those proteins and disruption of cellular function. Symptoms of autosomal-recessive JP usually begin before age 20, but can also begin in adulthood (age range, 7 to 58). 27 Double-staining of Parkinson's disease brains shows that parkin and alpha synuclein colocalize to both Lewy bodies and axonal spheroids. 32 Parkin interacts with and ubiquitinates a 22-kilodalton glycosylated form of alpha synuclein (alpha Sp22) 33 and the alpha synuclein-interacting protein synphilin. 34 Mutations in parkin result in an accumulation of these proteins. Although families with parkin mutations and Lewy body pathology have been described, 35 Lewy bodies are generally absent in this disorder, suggesting that parkin might be required for the formation of these cellular inclusions. Although somewhat variable, the disease phenotype of autosomal-recessive JP usually comprises classic parkinsonism accompanied by foot dystonia, hyperreftexia, good response to levodopa, and the early appearance of levodopa-induced dyskinesiasY A remarkable sleep benefit is seen in some patients, resulting in diurnal fluctuations in symptoms. The large number of missense and nonsense mutations, deletions, duplications, and exon rearrangements 36 make streamlined genetic testing for this condition difficult. Treatment strategies similar to those used for idiopathic PD are used to treat this condition. DRUG-INDUCED PARKINSONISM
Drug-induced parkinsonism (DIP), possibly the most common secondary etiology in children] 4 produces a symptom complex very similar to that of idiopathic PD. Yet some clues can help the clinician distinguish between the two syndromes.
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A symmetrical presentation is more common in DIP than in idiopathic PD, and the incidence of resting tremor is only 50%. One sign that is highly characteristic, although not pathognomonic, of DIP is a low-frequency, perioral, high-amplitude tremor known as the "rabbit syndrome." The coexistence of typical signs of tardive dyskinesia in a patient with parkinsonism should raise the possibility of DIP. 37 DIP symptoms often appear in the first month after initiation of therapy with a dopamine-receptor blocking agent. Underlying brain pathology or combination with other drugs may increase vulnerability. All of the typical neuroleptics and the antiemetic dopamine-receptor blocking agents, including metoclopramide, can cause DIP. Of the atypical neuroleptics, clozapine and quetiapine have the lowest risk of causing DIP. Reserpine and tetrabenazine cause DIP by depleting presynaptic dopaminergic vesicles. Other medications with the potential to cause DIP include valproic acid, fluoxetine and other selective serotonin reuptake inhibitors, lithium, phenytoin, captopril, cytosine arabinoside, 38 amphothericin-B, 14"39 adriamycine, vinca alkaloids, 4° cyclosporine,41 and some calcium channel blockers. 14 Two calcium channel blockers that are relatively potent dopamine blockers, flunarizine and cinnarizine, are not marketed in the United States. The most effective therapy for DIP is discontinuing the offending drug. Most patients exhibit resolution of symptoms within 1 to 2 months of discontinuation, but on rare occasions complete resolution may take up to a year. If discontinuing the offending drug does not produce improvement, or if the offending drug must be continued, then medical therapy should begin with administration of an anticholinergic agent. Amantadine can also be used successfully. Finally, levodopa can be used, with care taken to avoid exacerbating the underlying psychiatric disorder. 4z STRUCTURAL CAUSES
Although parkinsonism is a rare symptom of central nervous system neoplasms, such tumors as craniopharyngiomas, gliomas, ependymomas, and meningiomas may cause parkinsonism by infiltrating the basal ganglia or compressing the brainstem. 43 Hydrocephalus from tumor compression or aqueductal stenosis may also lead to parkinsonism. 44-46 Removal of the tumor or shunting may
alleviate parkinsonism. Temporary treatment with antiparkinsonian medications may be needed. 44 INFECTIOUS/IMMUNE-RELATED CAUSES
Encephalitis lethargica (EL), or Von Economo's encephalitis, temporally associated with the 1918 Spanish influenza pandemic, is of great historical interest. Besides being an acute akinetic form, EL may possibly lead to postencephalitic parkinsonism that can emerge years after the original infection, often without signs of prodromal "~flO. ''47 However, recent genetic analysis of histopathologically confirmed repository cases with acute EL and postencephalitic parkinsonism indicates that the 1918 influenza virus was unlikely to be neurotropic and directly responsible for the outbreak of Encephalitis lethargica. 48 Viral encephalitic illnesses (Japanese B, 49 varicella, measles, mumps, coxsackievirus, Western equine, St. Louis encephalitis), 14 and subacute sclerosing panencephalitis 5° have been associated with parkinsonism. Postinfectious encephalomyelitis after a mycoplasma infection may involve the striatum. 51 The associated parkinsonism and striatal radiologic abnormalities gradually resolve, but symptomatic antiparkinsonian treatment may be needed for a short time. HEREDITARY/METABOLIC CAUSES
Huntington's disease (HD) deserves special mention as a cause of YOPD. This autosomaldominant disorder, due to expansion and instability of a specific CAG repeat sequence in a gene (IT15) on chromosome 4, can present in childhood. These cases are associated with large CAG expansions, often as a result of paternal inheritance, and represent 1% of all HID patients. In juvenile HD there is often a preponderance of an akinetic-rigid syndrome(Westphal's variant). Other clinical hallmarks of presentation in this age group include seizures, learning disabilities, and a rapid course. 52'53 There are several rare disorders that may cause parkinsonism (Table 1); see the article on "Childhood Dystonias" in this issue for discussions of some of the conditions mentioned. TREATMENT
The underlying disease should be treated when a secondary or metabolic cause is identified. Additionally, symptomatic treatment of parkinsonism may be needed infinitely (neurodegenerative con-
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Table 1. Hereditary/Metabolic Causes of Juvenile Parkinsonism
Huntington's disease Wilson's disease Dopa-responsive dystonia Aromatic aminoacid decarboxylase deficiency Tyrosine hydroxylase deficiency Hallervorden-Spatz disease Calcification of the basal ganglia (Fahr's disease) Spinocerebellar ataxia type 3 (Machado-Joseph disease) Neuronal ceroid lipofuscinosis Rapid-onset dystonia-parkinsonism syndrome Lubag's syndrome (Filipino X-linked dystonia-parkinsonism). Leber's disease Leigh's syndrome Glutaric aciduria type 1 Methylmalonic acidemia c~-ketoglutaric aciduria Neuroacanthocystosis GM1 gangliosidosis Biotin-dependent encephalopathy Biotinidase deficiency Lesch-Nyhan disease Familial glucocorticoid deficiency Metachromatic leukodystrophy Gaucher's disease Phenylketonuria
ditions) or temporarily (drug-induced parkinsonism). Physical therapy and assistive device for ambulation can be used as needed. There are no specific guidelines for symptomatic pharmaceutical or surgical treatment of parkinsonism in childhood. Medications similar to those used to treat PD in adults are used. 3"54Dosages for children are adjusted on an empirical basis. Treatment is aimed at enhancing dopaminergic transmission in the nigrostriatal pathway. Because dopamine does not cross the blood-brain barrier, its immediate precursor levodopa is used. Levodopa is combined with a dopa decarboxylase blocker, such as carbidopa (the formulation available in the United States) or benserazide, to block peripheral
conversion to dopamine. Dopaminergic agonists (eg, pramipexole, ropinirole, bromocriptine, pergolide) act predominantly by stimulating D2-type dopamine receptors. Anticholinergics (eg, trihexyphenidyl, benztropine), amantadine, or selegiline (a monoamine oxidase B inhibitor) may be tried before a dopamine agonist or levodopa is given. Catechol-O-methyl transferase (COMT) inhibitors (eg, entacapone, tolcapone) prolong the response to levodopa. Tolcapone has been associated with several deaths due to liver failure, and thus careful monitoring of liver function is required. In PD and other similar degenerative conditions, patients typically develop a "wearing off" of response to levodopa, with the subsequent emergence of various types of dyskinesias, after several years of therapy. In adults, initial monotherapy with the dopamine agonists ropinirole and pramipexole has been shown to postpone the onset of dyskinesias, but usually at the cost of less marked improvement in motor function.55'56 Side effects of antiparkinsonian medications include nausea/vomiting, dizziness and orthostatic hypotension, cognitive impairment, sedation, hallucinations, and psychosis. These side effects can be addressed by decreasing the dose or withdrawing the offending agent and/or by adding medications to address the particular side effect symptomatically. Additional carbidopa or domperidone (not available in the United States) can be used for nausea; salt supplementation, fludrocortisone, or midodrine, for orthostatic hypotension; and modafinil, for sleepiness. In adults, the atypical antipsychotics quetiapine and clozapine (which requires weekly white blood cell count monitoring for agranulocytosis) are used to combat such side effects. There are no established guidelines for surgical treatment of parkinsonism in children; it should be approached be great caution.
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