Dopa-responsive dystonia with depigmentation of the substantia nigra and formation of Lewy bodies

Dopa-responsive dystonia with depigmentation of the substantia nigra and formation of Lewy bodies

Journal of the Neurological Sciences, 112 (1992) 90-95 © 1992 Elsevier Science Publishers B.V. All rights reserved 0022-510X/92/$05.00 90 JNS 03847 ...

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Journal of the Neurological Sciences, 112 (1992) 90-95 © 1992 Elsevier Science Publishers B.V. All rights reserved 0022-510X/92/$05.00


JNS 03847

Dopa-responsive dystonia with depigmentation of the substantia nigra and formation of Lewy bodies Jan E. Olsson


Ulf Brunk b, Bjfrn Lindvall


and Orvar Eeg-Olofsson c

Departments of a Neurology, b Pathology and c Pediatrics, Faculty of Health Sciences, Universityof [email protected], S-58I 85 Linkb'ping, Sweden' (Received 23 October, 1991) (Revised, received 21 April, 1992) (Accepted 26 April, 1992)

Key words: Dystonia; Juvenile parkinsonism; Dopa responsiveness; Monoamine deficiency; Lewy bodies

Summary The patient, who died at 23 years of age, was first diagnosed when she was 12 year old as having a dopa-responsive dystonia with decreased concentrations of monoamine metabolites in the cerebrospinal fluid. Also the concentrations of other neurotransmitters including somatostatin, substance P and metenkefalin were lowered indicating a more widespread damage of the cerebral neurotransmittor systems. At autopsy the brain was essentially intact except for pronounced gliosis and extreme loss of melanotic nerve cells in the substantia nigra. Several remaining nerve cells showed the presence of Lewy bodies.


Case report

Basal ganglia disorders in children are rare if adverse reactions to drugs and hereditary diseases such as Huntington's chorea, spino-cerebellar ataxia and Wilson's disease are excluded. Cases of juvenile onset Parkinson disease (JOPD) which have been described are sometimes familial and occasionally sporadic (Martin et al. 1971; Quinn et al. 1987). These patients usually respond to levodopa treatment as do the doparesponsive dystonia (DRD) cases described by Segawa et al. (1971, 1986). In addition, the term "juvenile Parkinson" is commonly used in patients with motor symptoms and dystonia and onset before 21 years of age whereas the term "young-onset Parkinson's disease" (YOPD) is given to the patients where symptoms start between 21 and 39 years of age (Golbe 1991). The etiology and linkage between these conditions are still controversial and unclear. We describe a young girl in whom the clinical picture was dominated by dystonia but where autopsy showed typical Parkinsonian neuropathological findings including Lewy bodies. Repeated analyses of the cerebrospinal fluid (CSF) indicated a widespread disturbance of several neurotransmitter systems.

This white female was born in 1966 to essentially healthy parents without any hereditary neurological disorders. Her father had polioencephalitis as a child with some residual symptoms. The patient had 3 healthy siblings, 2 older and I younger. Pregnancy and delivery were normal. At the age of 4 she had parotitis, probably with slight meningoencephalitis. She was treated at home without complications. At about the same age, she also had chicken pox and measles. At the age of 7 she had rubella, and in the same year, she sustained head trauma with brief unconsciousness. At the age of 8 years she suffered another head trauma when ~he fell off her bike. At the age of 9 she had scarlet fever and some years later, tonsillitis. Both illnesses were treated with penicillin. Thereafter she was completely healthy with normal schooling up to the age of 12. At that age she experienced daily attacks of oculogyric crises. The eyes were drawn upwards against the patient's will for many minutes, even hours. Later, during the fall in 1978, she experienced tonic cramping attacks in her feet that usually started on the left side and spread to her right foot. Her speech was sometimes slurred and stumbling, especially in connection with stress and fatigue. She also noticed a slight tremor in her hands. In school she became more passive with difficulties in concentration and in maintaining contacts with her school friends.

Correspondence to: Prof. Jan E. Olsson, Department of Neurology, University Hospital, S-581 85 Link6ping, Sweden. Tel.: (+ 46 13) 22 14 04; Fax: (+ 46 13) 22 44 38.

Results At neurological examination the patient had slight dysarthria with tremor of her tongue. She had slight endside nystagmus and difficulties to open her eyelids with repeated twitchings. She had no palsies but coordination tests were abnormal and were performed

91 slowly. Her gait was hypokinetic without ordinary arm movements. The sensory tests and refexes were normal and there was no Babinski sign. Laboratory investigations including analyses of the CSF proteins, EEG, CT scan of the brain and evoked potentials were normal. The initial diagnosis was postencephalitic Parkinsonism with oculogyric crises and leg and foot dystonia. A therapeutic test with 200 mg levodopa was judged positive and she was prescribed 50 mg levodopa q.i.d. She responded well and during the following years she was almost completely free of signs and symptoms. However, the dose of levodopa had to be gradually increased up to 800 mg daily, and she was very sensitive to any delay of the medication time. If one dose was forgotten she often had oculogyric crises, tremor and dystonic movements. Repeated neurological examinations at the age of 15 showed episodic dystonic cramps in her legs lasting 20-120 min, upwards tonic deviation of her eyes and eyelids and forced retroflexion of her head. A new CT scan was normal. A 5-10-fold increased excretion of urine copper was found but the serum values of copper and ceruloplasmin were normal. A liver biopsy was normal with a normal copper content of 6.9/.tg/g liver. She did not have Kayser-Fleischer rings. The dopamine agonist bromocriptine was added at the dose of 10 mg t.i.d to the levodopa therapy. A copper-free diet was recommended.

The combination therapy decreased some of the symptoms, especially the tremor and the dysarthria. After 1 year the levodopa dose was diminished to 450 mg daily, the bromocriptine dose to 12.5 rag, and orphenadine 100 mg t.i.d, was added. During the next years her dysarthria progressed, whereas the general hypokinesia was almost unchanged and she could walk, ride a bicycle and ski without major problems. The dystonic attacks occurred with fatigue, often in the evenings and during nights and could be relieved by 5-10 mg diazepam. The dosage of levodopa was increased to 550 mg daily, bromocriptine to 15 mg, whereas orphenadine was maintained at 300 mg daily. The disorder progressed. A therapeutic attempt with carbamazepine up to 800 mg daily had no effect on the dystonic cramps. At the age of 17 years, the orphenadine treatment was withdrawn. Without levodopa treatment in January, 1986, lumbar puncture with examination of the CSF monoamine metabolites showed markedly decreased concentrations of the dopamine metabolite homovanillic acid (HVA) and hydroxymethoxyphenylglycol (HMPG) down to 32 and 23 nmol/l, respectively, whereas the concentration of 5-hydroxyindoleacetic acid (5-HIAA) was normal (95 nmol/l). Repeated CSF analyses were performed over several years (Table 1). The HVA values correlated more with the dosage of levodopa than the neurological

TABLE 1 VALUES OF ALBUMIN, IgG, HVA, 5-HIAA, HMPG, SOMATOSTATIN, SUBSTANCE P, Met-ENKEPHALIN IN THE CEREBROSPINAL FLUID DURING 1979-1988 All lumbar punctures w e r e performed in the morning with the patient in bed and fasting overnight. The preceding doses of L-dopa and bromocriptine are given below. Time of CSF analyses (month/year)

Proteins albumin (rag/l) (80-260) albumin ratio ( < 5.7) IgG (mg/l) (7-26) IgG index ( < 0.70)










170 3.9 27 0.66

230 4.9 22 0.43

185 4.3 21 0.47

155 3.9 14 0.47

200 22 -

208 5.1 21 0.45

177 4.8 22 0.41

221 5.5 32 0.49

226 5.4 37 0.52

64 67 -

114 108 -

111 74 -

14 4 92

17 9 -

9 157

350 7.5

400 2.5

300 -

Dopamine metabolites (nmol/I) HVA (140-440) 5-HIAA (70-170) HMPG (40-80)


96 110 24

32 95 23

Neuropeptides somatostatin (pg/ml) (30-90) substance P (pmol/l) ( < 10) metenkephalin (pmol/I) (30-150) Treatment with levodopa mg/day bromocriptine mg/day a 24 h after withdrawal of treatment.


300 -

400 30.0

500 17.5

500 17.5



Fig. 1. Severe nerve cell degeneration within the nucleus niger with loss of most melanotic nerve cells and pronounced reactive gliosis and spongiosis. HE, x390.

symptoms, which progressed further with increasing speech problems to complete anarthria. Her walking was affected either by severe dystonia or hyperkinetic

movements with impaired balance. The reflexes in her legs were increased and she showed a bilateral Babinski sign. At the age of 21 years she required a Witzel

Fig. 2. Neurons within the substantia nigra, some of which contain Lewy bodies. HE, x 380.

93 fistula due to increased dysphagia and anorexia. Thereafter a certain improvement was noticed but mental disturbances with psychotic hallucinations and episodes of aggressivity made hospitalization necessary. The levodopa treatment was maintained whereas bromocriptine was withdrawn. Low doses of haloperidol were given. An orthostatic blood pressure reaction was treated with etilefrine. However, the disease progressed and one morning in December 1989, she was found dead in her bed at the nursing home. Autopsy showed that death was related to respiratory insufficiency with stagnation of tracheal and bronchial secretion. The brain weight was 1330 g with macroscopically normal configuration. In the mesencephalon the substantia nigra (SN) was strikingly and symmetrically depigmentated. Microscopically almost all of the neuromelanin containing nerve cells of the substantia nigra and locus ceruleus were lost and replaced by sponginess and pronounced reactive gliosis. Only few remaini~ag nerve cells containing neuromelanin were found, and several of these showed Lewy bodies (Figs. 1-3). In these regions macrophages containing iron and phagocytosed neuromelanin from desintegrated melanotic nerve cells were plentiful. Neuromelanin was also found frequently in the neurophil. Other organs were normal.


Parkinsonism in children is rare. In 1917, Hunt reported 4 sporadic cases with onset between the ages of 13 and 30 years. The pathological examination of one case who died at the age of 38 showed disappearance of the large neurons in the globus pallidus, caudate nucleus and putamen with glial proliferation. Later on, Van Bogaert (1930) and Davison (1954) reported 2 additional cases. The first familial cases of juvenile parkinsonism were reported by Ota et al. in 1958. There were 3 siblings, 2 females and 1 male, who developed parkinsonism at the ages of 12, 13 and 20 years, respectively. Lange and Poppe in 1963 described 6 affected siblings in a family of 12. Autopsy in 1 case showed atrophy of the globus pallidus. Martin et al. in 1971 described 2 brothers with onset of juvenile parkinsonism at 10 and 19 years. Both these patients could successfully be treated with levodopa. Considering only the neurological symptoms our case is most similar to the DRD syndrome first described by Segawa et al. (1971) in 2 patients with dystonic posture and movement abnormalities. 14 patients have been reported, all with onset of the disease before 9 years of age and improvement on levodopa therapy whereas



Fig. 3. Substantia nigra with one of the very few remaining melanin-containing neurons within an area of severe degeneration. Masson stall,, x 380.

94 anticonvtilsants and anticholinergic treatment aggravated the symptoms (Segawa et al. 1986). The monoamine metabolites were disturbed with increased urinary excretion of DOPA and HVA. There was no change in 5-HIAA. CSF analyses have been performed in a few cases, with marked reduction of the HVA levels (Ouvrier 1978; Kumamoto et al. 1984). The etiology of this syndrome is unknown although disappearance and desensitization of postsynaptic dopamine receptors in the striatum with preservation of dopaminergic neurons has been suggested (Nygaard et al. 1991). Recent studies with positron emission tomography using [ZSF]fluorodopa have shown a reduction of tracer uptake in both putamen and the caudate nucleus indicating a more complex defect of the dopaminergic system (Sawle et al. 1991). This is in accordance with the CSF changes of the monoamine metabolism found in our patient. The increase of the HVA values in CSF after levodopa treatment can also be seen in patients with Parkinson's disease (Lindvall and Olsson 1990) whereas the serotonergic system is usually unaffected with normal values of 5-HIAA in the CSF. The neuropeptide somatostatin is normal in patients with Parkinson's disease who are not demented (Dupont et al. 1982; Epelbaum et al. 1983; Volicer et al. 1986). Our patient had extremely low values of HVA, HMPG, somatostatin, substance P and Met-enkephalin in repeated analyses. These findings probably reflect a more widespread degeneration of several transmitter systems in addition to the dopaminergic neurons (Pezzoli et al. 1984). The presence of cytoplasmic Lewy bodies in pigmented neurons of degenerated parts of the basal ganglia is generally considered to be characteristic of idiopathic parkinsonism. However, they can also be found in some other neurological disorders, e.g. Hallervorden.Spatz disease and some forms of hereditary spinocerebellar ataxia as well as in elderly asymptomatic individuals. Two cases of JOPD with reduced pigmentation of the SN containing Lewy bodies have been described (Yokochi et al. 1984; Gibb et al. 1991). Recently, Mizutani et al. (1991) described findings of Lewy bodies in a 39-year-old female suffering from juvenile parkinsonism. However, o neuronal degenerations seen in typical cases of PD were found so they concluded that Lew~ bodies could also be a direct result of abnormal dopamine metabolism due to the hypoplasia and dysgenesis as a defect in cellular devel. opment and not a result of degenerative processes. Age may be less important in the formation of Lewy bodies (Fearnley and Lees 1991). Therefore, regarding both the neurological symp. toms, and the CSF analyses, the final classification on the spectrum between DRD, JOPD and juvenile PD of our case is more like the DRD syndrome, due to the

early onset with generalized motor symptoms without marked diurnal fluctuations and without heritance, but with a steady progress in spite of a certain answer on levodopa treatment. The neuropathological findings connect this syndrome with any of those described as juvenile parkinsonism.

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