Pure akinesia due to lewy body Parkinson\'s disease: A case with pathology

Movement Disorders Vol. 4, No. 1, 1989, pp. 85-89 0 1989 Movement Disorder Society

Pure Akinesia Due to Lewy Body Parkinson’s Disease: A Case with Pathology N. P. Quinn, *P. Luthert, *M. Honavar, and tC. D. Marsden University Departments of Clinical Neurology and *Neuropathology, Institute of Psychiatry, London S B ;and tlnstitute of Neurology, Queen Square, London, England

Summary: The case of a patient with levodopa-responsive pure akinesia and freezing of gait for 17 years, whose brain showed the classical changes of Lewy body Parkinson’s disease at postmortem is presented. A short trial of DLthreo-DOPS was ineffective. Intellectual function was preserved despite the presence of Lewy bodies and mild cell loss in subcortical cholinergic nuclei. Pure akinesia is likely to be a heterogeneous condition, with most cases having little or no response to levodopa therapy. However, this case demonstrates that this clinical picture may be caused by Lewy body Parkinson’s disease. Key Words: Lewy body Parkinson’s-Akinesia-Freezing-DL-threo-DOPSLevodopa.

The diagnosis of parkinsonism traditionally depends on the presence of at least two of the three cardinal features of the disease, i.e., akinesia, rigidity, and tremor. Of these, the last usually takes the form of a resting tremor, although it may be combined with or replaced by a faster postural tremor, and a minority of subjects have no tremor at all. These latter cases are labelled akinetic-rigid Parkinson’s disease. Thus, although tremor is an inconstant finding, all subjects with Parkinson’s disease have akinesia, usually associated with rigidity. A small number of patients, however, may display pure akinesia without rigidity or tremor (1,2). In these cases, starting difficulties and festination or freezing of gait are the dominant features. Usually these patients do not respond well to levodopa therapy. In 1975 a group of four such patients with pure akinesia and freezing unaccompanied by either rigidity or tremor, and unresponsive to levodopa, was reported by Narabayashi et al. (1). Disease onset was between 53 and 63 (median 68.5) years. All patients had impaired postural reflexes, but flexed posture was not mentioned. Traditional manoeuvres such as

Address correspondence and reprint requests to C. D. Marsden at University Department of Neurology, Institute ofNeurology, The National Hospital for Nervous Diseases, Queen Square, London, England WCIN 3BG.

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stepping over objects or climbing stairs temporarily overcame the freezing of gait. Air encephalograms suggested vermal atrophy in three subjects, and dilated superior recess of the fourth ventricle, atrophic semilunar lobules, and dilation of the lateral ventricles in two subjects each. However, there were no clinical signs of cerebellar dysfunction. Levodopa given alone in doses of 1-3 g daily was ineffective. A more recent article by the same group (3) records that, to date, 20 cases of this disorder are known, some followed for as long as 10 years, but that no case has yet come to autopsy. Levodopa is stated to have mild-to-moderate effect. Horizontal gaze nystagmus and “apraxia of lid opening” have been noted in approximately one-thud of cases, and two have developed slowly progressive supranuclear ophthalmoplegia. None has had cerebellar signs. Three recent cases of the authors were described, two of whom had mildto-moderate resting tremor. Computed tomographic (CT) scans showed moderate cerebellar atrophy with relative preservation of the pons and midbrain in one case, and normal findings in the other two. We have been able to study at postmortem the brain in one of our own patients with pure akinesia.

CASE REPORT This man first developed akinesia affecting the left leg at age 53. His disability soon spread to the other side. Three years later, he began treatment with plain levodopa, and immediately developed drug-induced dyskinesias affecting his neck. Wearing-off and freezing became noticeable after 4 years of treatment and after a further 3 years he was placed on a combination of Sinemet, bromocriptine, and benzhexol. Despite the change in regime, “on-off’ fluctuations persisted. When “off,” he was severely troubled by akinesia and freezing, yet was able to walk backwards and climb stairs very well, and could consistently walk well in the sea if the water came up to his knees. When “on,” he had only occasional unpredictable freezing of gait and festinant speech. In May 1983 the patient was admitted to the hospital for a trial of DL-threo-DOPS. His other treatment of levodopa 1 ,OOO mg/day (taken with carbidopa in seven divided doses), benzhexol 2 mg b i d . , and bromocriptine 10 mg b.i.d. was continued unchanged. In the ‘‘off’ condition, there was no rigidity either axially, proximally, or distally (tone was somewhat reduced in the limbs, neck, and trunk), and there was a fine postural tremor in both hands graded at 0.5 (maximum score 3). Posture was mildly flexed (grade 1/3) in the lower limbs and right arm, and minimally so (grade 0 3 3 ) in the neck and trunk. There was mild hypomimia, complete absence of arm swing bilaterally, constant severe freezing of gait, impaired postural stability, and akinesia and fatigue of alternating movements of both hands and feet. Full KCH PD disability score was 30 (maximum disability on this scale is 117) (4). When “on,” disability score fell to 12.5. There was still minimal postural flexion, no tremor, and no rigidity. However, gait and arm swing were completely normal apart from very rare, unpredictable freezing episodes. Postural stability was still impaired, however, and though there was not a trace of akinesia in the arms, alternating movements of the feet still showed fatigue. A fixed walking task was repeatedly given and performance was timed both in the “on” and “off’ condition. Single doses of DL-threo-DOPS 1,200 mg per os, were then given on two separate study days: first, alone after complete overnight drug withdrawal, and second, after the morning dose on a day when the usual drug treatment was given. When the times for the walking task in “off’ and “on” periods on control days were compared with

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those for the task in equivalent states on DL-threo-DOPS study days, there was no significant difference. On this admission, unenhanced CT scan (EM1 1010) showed only some slight widening of the superficial cortical sulci. Psychometric testing on the WAIS revealed a full-scale IQ of 128 (verbal 125, performance 127), with adequate performance on tests of memory (Wechsler logical memory 9, associate learning 6) i.e., superior intelligence with no evidence of deterioration of intellect or memory functions other than those expected for his age The patient was discharged home on his usual treatment, but died suddenly 6 months later at age 70, after 17 years of disease.

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POSTMORTEM FINDINGS The cause of death was a large pulmonary abscess with empyema. The fixed weight of the brain was 1,679 g (brainstem and cerebellum weighed 228 g). Apart from bilateral pallor of substantia nigra and locus coeruleus, the brain appeared macroscopically normal. Microscopic examination revealed mild-to-moderate cell loss, with the presence of extraneuronal pigment, in substantia nigra. A few of the surviving neurons showed Lewy bodies, which were also present in the locus coeruleus, nucleus tegmentalis pedunculopontinis, nucleus of Meynert, nucleus of the diagonal band of Broca, and septal nuclei (Fig. 1). Cell loss was moderate in locus coeruleus, and mild at the other sites. No Lewy bodies were present in the neocortex, and no plaques or tangles were seen. The striatum, globus pallidus, cerebellum, the other pontine nuclei, and the olives were normal.

DISCUSSION To our knowledge, this is the first pathological report of a subject who displayed pure akinesia during life. In this patient, who had the condition for 17 years before death, the akinesia and freezing were clearly levodopa responsive, and postmortem examination of the brain revealed the classical changes of idiopathic Parkinson’s disease. Therefore this picture, though rare, is part of the clinical spectrum of idiopathic Parkinson’s disease. The pathological substrate of non-levodopa-responsive cases of pure akinesia remains to be determined. In this patient (and in eight other patients-seven with probable idiopathic and one with postencephalitic Parkinson’s disease seen by us [ 5 ] ) the administration of DL-threo-DOPS in single or repeated doses did not improve freezing of gait, provided “off’ periods were compared with “off’ periods, and “on” with “on.” This contrasts with the favorable Japanese results with this treatment reported by Narabayashi et al. (6.7). Finally, this case demonstrates (in common with other reported cases) that normal intellectual function may be retained in some patients with Parkinson’s disease despite long disease duration and proven Lewy body pathology in subcortical cholinergic nuclei.

REFERENCES 1. Narabayashi H, Imai H, Yokochi M, Hirayama K, Nakamura R. Cases of pure akinesia without rigidity and tremor and with no effect by L-DOPAtherapy. In: Birkmayer W, Hornykiewicz 0, eds. Advances in parkinsonism. Basle: Editiones Roche, 197633542. 2. Narabayashi H. Clinical analysis of akinesia. J Neural Transm, 198qsuppl 16):12%36. 3. Imai H, Narabayashi H, Sakata E. “Pure akinesia” and the later added supranuclear ophthalmoplegia. Adv Neurol 1986;45:207-12.

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4. Quinn N, Marsden CD, Parkes JD. Complicated response fluctuations in Parkinson's disease: response to continuous intravenous infusion of levodopa. Lancet 1982;2:412-5. 5 . Quinn N, Perlmutter JS, Marsden CD. Acute administration of DL-threo-DOPS does not s e c t the freezing phenomenon of parkinsonian patients. Neurology 1984;34(suppl 1): 149. 6. Narabayashi H, Kondo T, Nagatsu T, Hayashi A, Suzuki T. DL-threo-3,4-dihydroxyphenylserine for freezing symptom in parkinsonism. Adv Neurol 1984;40:497-502. 7. Narabayashi H, Kondo T, Yokochi F, Nagatsu T. Clinical effect of ~-threo-3,4-dihydroxyphenylserine in cases of parkinsonism and pure akinesia. Adv Neurol 1986;45:593-602.

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