Does fluoxetine aggravate Parkinson\'s disease? A pilot prospective study

COMMUNICATIONS with ketosis or nonketosis. In nonketotic states gamma amino n-butyric acid (GABA) becomes depleted. GABA and L-glutamic acid are both amino acids and are present in high concentrations in nervous tissue. During the stress of nonketotic hyperglycemia the energy requirements change due to inhibition of the Krebs cycle thought to be the result of a direct influence from a hyperosmolar environment. Brain tissue then resorts to using ketone bodies and amino acids for metabolism, GABA is metabolized to succinic acid via the succinic semialdehyde pathway (GABA shunt) (12). This shunt can be used as an alternative pathway to the Krebs cycle and can generate as much as 40% of the total energy requirements in brain tissue. As a consequence to the greater utilization of the GABA shunt, GABA is depleted. In patients with Huntington’s disease with chorea type, neuronal subpopulations that utilize GABA as a neurotransmitter are preferentially lost in striatal neurons projecting to the globus pallidus externa (GPe) via the indirect pathway of the motor circuit of the basal gangliathalamocortical circuit (16,17). In primates, forty-seven percent of the GPe neurons are allocated to the active movement of the arm. In comparison, ten per cent are involved with active leg movements (18). Because of the relatively large number of GPe neurons functionally arranged in parallel circuits for both the execution and preparation of limb movement, these neurons are most SUSceptible to GABA depletion. As to why the dystonia involved the right arm, the patient could have either had lesions in the left basal ganglia not seen on MRI or the infarct in the left subcortical white matter could have interfered with t he circuitry of the basal gangliathalamocortical pathway. Hyperglycemia has been shown to decrease cerebral regional blood flow independent of changes in serum osmolality. Statistically significant (p < 0.01) blood flow decreases occurred in the globus pallidus and thalamus (19). Therefore, hyperglycemia induced regional blood flow pallidal and thalamic decreases could also contribute to the dysfunction of susceptible neurons. Again, due to the relatively high number of GPe neurons controlling active arm movements, these neurons would be rendered most susceptible to diminished regional blood flow. We describe a unique case of paroxysmal kinesigenic dystonic choreoathetosis as the presenting symptom of diabetes mellitus first appearing as non-ketotic hyperglycemia. John D. Clark Rajesh Pahwa William C. Koller Department of Neurology David Morales Department of Internal Medicine University of Kansas Medical Center Kansas C i o , Kansas, U.S.A.

References 1. Kertesz A. Kinesigenic choreoathetosis. Neurology 1967;17: 680-6!90.

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2. Plant G. Focal paroxysmal kinesigenic choreoathetosis. J Neurol Neurosurg Psychiatry 1983;46:345-348. 3. Camal A, Greene P, Khandj A. Paroxysmal kinesigenic dystonic choreoathetosis associated with a thalamic infarct. Mov Disord 1990;5:235-238. 4. Shibasaki H, Kuriowa Y,Fukuoka J. Painful tonic seizures in multiple sclerosis. Arch Neurol 1974;30:47-51. 5 . Adam A, Orinda D. Focal paroxysmal kinesigenic choreoathetosis preceding the development of SteeleRichardson-Olszewski syndrome. 3 Neurol Neurosurg Psychiatry 1986;49:957-959. 6. Michell F, Pardal M, Parera I, Giannaula R. Sporadic paroxysmal dystonic choreoathetosis associated with basal ganglia calcifications. Ann Neurol 1986;20:750. 7. Fishbeck K, Layzer R. Paroxysmal choreoathetosis associated with thyrotoxicosis. Ann Neurol 1979;6:453-454. 8. Newman RP, Kinkle WR. Paroxysmal choreoathetosis due to hypoglycemia. Arch Neurol 1984;41:341-342. 9. Maccario M. Neurologic dysfunction associated with nonketotic hyperglycemia. Arch Neurol 1968;19:525-534. 10. Rector WG, Jr., Herlong HF, Moses H, 111. Nonketotic hyperglycemia appearing as choreoathetosis or ballism. Arch Intern Med 1982;142:154-155. 11. Arieff AI, Carroll HJ. Nonketotic hyperosmolar coma with hyperglycemia: clinical features, pathophysiology, renal function, acid-base balance, plasma-csf equilibria and the effects of therapy in 37 cases. Medicine 1972;51:73-94. 12. Guisado R, Arieff AI. Neurologic manifestations of diabetic coma: correlation with biochemical alterations in the brain. Metabolism 1975;24:665-679. 13. Robin J . Paroxysmal choreoathetosis following head injury. Ann Neurol 1977;2:447448. 14. Tabaee-Zadeh M, Frame B, Kapphahn K. Kinesiogenic choreoathetosis and idiopathic hypoparathyroidism. N Engl J Med 1972;286:762-763. 15. Morres CA, Dire DJ. Movement disorders as a manifestation of nonketotic hyperglycemia. J Emerg Med 1989;7:359-364. 16. Albin RL, Reiner A, Anderson KD, Penney JB, Young AB. Striatal and nigral neuron subpopulations in rigid Huntington’s Disease: implications for the functional anatomy of chorea and rigidity-akinesia. Ann Neurol 1990;27:357-365. 17. Alexander GE, Crutcher MD, DeLong MR. Basal gangliathalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and ‘‘limbic’’ functions. Prog Brain Res 1990;85:119-146. 18. DeLong MR, Crutcher MD, Georgepoulos AP. Primate globus pallidus and subthalamic nucleus: function organization. 3 Neurophysiol 1985;53:530-543. 19. Duckrow RB, Beard DC, Brennan RW. Regional cerebral blood flow decreases during hyperglycemia. Ann Neurol 1985;17967-272.

Does Fluoxetine Aggravate Parkinson’s Disease? A Pilot Prospective Study To the Editor: The number of drugs able to induce parkinsonism or aggravate Parkinson’s disease is now rapidly growing. Besides reserpine, tetrabenazine, and classical neurolep-

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tics (phenothiazines, butyrophenones, thioxanthenes), several reports have described drug-inducing parkinsonism in patients treated with benzamides (sulpiride, metoclopramide, clebopride, tiapride) or other drugs like methyldopa, flunarizine, cinnarizine, or cisapride (for reviews, see 1,2). Fluoxetine is a selective inhibitor of serotonin uptake widely used as an antidepressant. Recent papers have described extrapyramidal side effects of fluoxetine in psychiatric patients (3-8). More recently, several cases of exacerbation of Parkinson’s disease disability have been reported (9,lO). However, these studies were only case reports and, as far as we know, no prospective trial of fluoxetine in patients with Parkinson’s disease was performed. We therefore investigated the effects of an addon therapy with fluoxetine in patients with Parkinson’s disease. Fourteen nondemented patients with idiopathic Parkinson’s disease [mean age, 68 (SEM 2) years; disease duration 6 (1) years; Hoehn and Yahr staging 2.4 (0.2); daily dose of levodopa 583 (85) mg; duration of levodopa therapy 5 (1) years] were included in the study. They were given full information about the protocol and gave oral informed consent. They suffered from a global decline in treatment’s efficacy and required an increase in levodopa daily dose. They did not suffer from motor fluctuations. Fluoxetine (20 mgldaily) was added, and parkinsonian and depressive symptoms evaluated in the morning (10 a.m.) according to the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Montgomery-Asburg Depression Rating Scale (MADRS) (11) before and after 1 month of treatment. Each new assessment was made blind (i.e., without the previous scale in front of the physician). Usual antiparkinsonian treatment remained unchanged during the study. Results are presented as mean values SEM. Statistical evaluation was made using Student’s t test for paired comparison. Thirteen patients completed the study. One dropped out because of untolerable asthenia. Add-on therapy with 20 mg fluoxetine did not modify the global [parts I to 111: 29 (4) versus 27 (4)] or motor [part 111: 16 (3) versus 15 (2)] UPDRS scores. The UPDRS subscores for rigidity and bradykinesia did not change: 1.7 (0.4) versus 2.1 (0.5) and 9.1 (1.2) versus 9.5 (I.@, respectively. In contrast, tremor subscore significantly (p < 0.05) decreased: 2.1 (0.5) versus 1.5 (0.5). MADRS depression scale, which was within the normal range at the entry into the study [ l l (3)], also significantly (p < 0.05) decreased after a 1 month treatment with fluoxetine [5 (2)]. No major side effect was observed, except in one patient, who has reported a subjective feeling of increased tremor. This prospective pilot open trial shows that a 1-month treatment with fluoxetine did not change the motor UPDRS score. We failed to find any change in rigidity and bradykinesia subscores, suggesting that fluoxetine does not aggravate akineto-rigid symptoms in Parkinson’s disease. As far we know, no large prospective trial was previously performed. In a retrospective study performed in 23 patients with idiopathic Parkinson’s disease, Caley and Friedman (12) reported three patients with worsening of parkinsonism, probably due to fluoxetine. They concluded that, at doses up to 40 mglday, fluoxetine does not

*

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exacerbate parkinsonian symptoms. Jansen and Kolling (13) found that, in a group of 20 patients with Parkinson’s disease, aggravation of the symptoms occurred in only four. The observation that fluoxetine reduces tremor subscore is more surprising. The explanation remains unclear. Early studies have suggested that serotonin precursors might be effective in improving tremor (14). However, further studies failed to confirm these results (15,16). Future controlled studies are necessary to confirm this putative action of fluoxetine in patients with Parkinson’s disease. In conclusion, this pilot study did not find any significant increase of parkinsonian symptoms after a 1-month treatment with fluoxetine. It suggests that fluoxetineinduced parkinsonism could be due to an individual susceptibility. *Jean-Louis Montastruc tNelly Fabre SOlivier Blin *Jean-Michel Senard *Olivier Rascol BAndrk Rascol *Department of Medical and Clinical Pharmacology, Inserm U317, and Centre Midi-Pyre‘nkes de Pharmacovigilance et &Informations sur le Mtdicament, Centre Hospitalier Universitaire, Faculte‘ de Me‘decine, Toulouse; fDepartment of Neurology, Centre Hospitalier Universitaire, H6pital Rangueil, Toulouse; $Department of Medical and Clinical Pharmacology, Faculte‘ de Mtdecine, Marseille; $Department of Neurology, Centre Hospitalier Universitaire, H6pital Purpan, Toulouse, France

References 1 . Montastruc JL, Llau ME, Rascol 0, Senard JM. Druginduced parkinsonism: a review. Fund Clin Pharmacoll994; 8 :293-306. 2. Llau ME, Nguyen L, Senard JM, Rascol 0, Montastruc JL. Syndromes parkinsoniens d’origine mtdicamenteuse: expkrience d‘un centre rtgional de pharmacovigilance sur dix ans. Rev Neurol (Paris) 1994;150:757-762. 3. Brod TM. Fluoxetine and extrapyramidal side effects. Am J Psychiatry 1989;146:1353. 4. Bouchard RH, Pourcher E, Vincent P. Fluoxetine and extrapyramidal side effects. Am J Psychiatry 1989;146:13521353. 5 . Meltzer HJ, Young M, Metz J. Extrapyramidal side effects and increased serum prolactin following fluoxetine, a new antidepressant. J Neural Transm 1979;45:165-175. 6. Tate JL. Extrapyramidal symptoms in a patient taking haloperidol and fluoxetine. Am J Psychiatry 1989;146:399400. 7. Austin LS, Arana GW, Melvin JA. Toxicity resulting from lithium augmentation of antidepressant treatment in elderly patients. J Clin Psychiatry 1990;51:344345.

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COMM UNICATIONS 8. Daric C, Dollfus S, Mihout B, Omnient Y, Petit M. Fluoxetine et syndromes extrapyramidaux. A propos de deux observations. Encephale 1993;19:61-62. 9. Chouinard G,Sultan S. A case of Parkinson’s disease exacerbated by fluoxetine. Hum Psychopharmacol1992;7:6366. 10. Jansen Steue ENH. Increase of Parkinson disability after fluoxetine medication. Neurology 1993;43:211-213. 11. Asberg M,Montgomery SA, Perris C, Schalling D, Sedvall G. A comprehensive psychopathological rating scale. Acta Psychiatr Scand 1978;(suppl 271):5-27. 12. Caley CF, Friedman JH. Does fluoxetine exacerbate Parkinson’s disease. J CIin Psychiatry 1992;53:278-282. 13. Jansen ENH, Kolling P. Parkinsonism and fluoxetine. Ned Tijdschr Geneeskd 1992;136:755-756. 14, Barbeau A. The pathogenis of Parkinson’s disease: a new hypothesis. Can Med Assoc J 1962;87:802-807. 15. Lang AE. Treatment of Parkinson’s disease with agents other than levodopa and dopamine agonists: controversies and new approaches. Can J Neurol Sci 1984;11:21&220. 16. Pinder RM. Drug-induced tremor. In: Findley LJ, Capildeo R, eds. Movement disorders: tremor. New York: Macmillan, 1984:445461.

Botulinum Toxin Treatment Is Not Effective for Epilepsy Partialis Continua To the Editor: Epilepsia partialis continua (EPC), sometimes referred to as cortical myoclonus, is defined as spontaneous regular or irregular clonic muscle twitching of cerebral cortical origin, sometimes aggravated by action or sensory stimuli, confined to one part of the body, and continuing for a period of hours, days, or weeks ( I ) . EPC has been reported following a variety of focal cortical and subcortical brain abnormalities (2,3). Childhood-onset EPC of prolonged duration has been attributed by Rasmussen to a focal encephalitis of unknown cause (4). Involuntary movements are typically myoclonic but are sometimes more irregular and may resemble extrapyramidal involuntary movements (3). Variable degrees of weakness and clumsiness of the affected limb are usually present. We attempted to treat two young adults with long-standing, medication-resistant EPC due to presumed chronic encephalitis of Rasmussen with intramuscular botulinum toxin (BTX-A).

Case 1 A 27-year-old, right-handed man had a generalized tonic-clonic seizure at 13 years of age followed by increasingly frequent partial motor seizures involving the right arm, face, and leg. Continuous myoclonus of the right arm, face, and leg with mild hemiparesis and inability to use the right arm followed and have persisted to the present time despite treatment with phenytoin, phenobarbital, valproic acid, and carbamazepine. Electroencephalography (EEG) showed left parietal-occipital-posterior temporal discharges some of which occurred simultaneous with right-sided myoclonus. In some cases left occipital electrical events spread to parietal-central regions before right-sided body jerks. Large-amplitude visual and somatosensory evoked potentials were recorded from the same location. Electrocorticography-guided left subtotal

occipital lobectomy at 17 years of age showed cortical and subcortical gliosis but produced only slight improvement. Continuous right-sided myoclonus and episodic right-sided motor seizures with occasional generalization persisted. A recent examination showed dystonic posturing, mild weakness, and impaired dexterity of the right hand, right homonomous hemianopia, right hyperreflexia, right hand cortical sensory loss, and continuous myoclonus of the right hand, arm, shoulder, pectoral region, and face, which increases in amplitude with passive muscle stretch and voluntary movements. Visual inspection, muscle palpation, and needle electromyography at rest and during voluntary activity were used to identify the most severely involved muscles. BTX-A was injected (three to four injection sites per muscle) into right biceps (70 U), triceps (70 U), flexor carpi radialis (230 U), flexor digitorum profundus (80 U), and extensor digitorum (120 U) for a total of 570 U administered in five treatment sessions over 8 weeks. Clinical examination, electromyography, videotape recordings, and functional assessment showed no reduction in myoclonus or improved functional use of the arm and hand after treatment. Mild clinical weakness was produced in extensor and flexor forearm muscles but not in biceps and triceps muscles.

Case 2 A 20-year-old, right-handed man experienced a generalized seizure at 5 years of age that was followed by recurrent left-sided partial motor seizures. Within 2 years he began to have nearly continuous myoclonus of the left arm and leg associated with increased hemiparesis, which has persisted to the present time. EEG showed diffuse right hemisphere abnormality with independent foci in right frontal, parietal, and temporal regions. Computed tomography showed right hemisphere atrophy. Treatment with phenytoin, phenobarbital, carbamazepine, valproic acid, clonazepam, and primidone were not effective. At 12 years of age electrocorticography-guided right temporal lobectomy was performed and showed subpial, deep cortical, and superficial white matter gliosis with perivascular mononuclear infiltration in the white matter felt to be consistent with chronic encephalitis of the Rasmussen type. After surgery continuous left-sided myoclonus persisted and seizure frequency increased, including generalized tonic-clonic seizures, complex partial seizures, akinetic seizures, and left-sided partial motor seizures. At 16 years of age he underwent further resection of the right posterior temporal cortex and multiple subpial transections of postcentral and precentral gyri without improvement. EEG at 18 years of age showed evidence of cortical myoclonus with closely related right central epileptiform discharges and left deltoid myoclonus, which increased with voluntary flexion of the left hand. A recent examination at 20 years of age showed cognitive impairment, dysarthria, impaired dexterity and functional use of the left hand and arm, left hyperreflexia and spasticity, and continuous myoclonus in proximal muscles of the left arm and leg that increases with passive muscle stretch and voluntary movements. Visual inspection, muscle palpation, and needle elec-

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