114 Letters to the Editor

conduction studies revealed no abnormalities 5 Streib EW. Distal ulnar neuropathy as a cause of Patients were enrolled in an off label uncon- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.1.114 on 1 January 1993. Downloaded from in the face, upper or lower extremities. finger : a case report. Neurology trolled dose-ranging trial of buspirone using 1990;40: 153-4. Supramaximal stimulation of the tibial nerve anxiolytic dose guidelines. The starting dose elicited unusual late components in addition was 5 mg orally three times a day. The dose to F waves. Normal electrophysiological was increased every 3 days by 5 mg to a studies included blink reflex, median nerve Buspirone in progressive maximum of 60 mg/d. Two of the patients somatosensory evoked potentials, brain stem epilepsy were videotaped performing a standardised auditory evoked potentials, visual evoked battery of clinical tests including Archime- potentials and EEG. des's spirals. Repetitive motor tests and The patient was given clonazepam, val- Progressive myoclonus epilepsy is a clinical myoclonus were scored using established proic acid and trihexyphenidyl without any syndrome with obligate features of myoclo- scales." In patients who were too neuro- relief of symptoms. Carbamazepine lessened nus and epilepsy and variable or inconstant logically impaired to comply with testing, a the palatopharyngolaryngeal movement and features of dementia and . The most simple Likert scale was used to evaluate also the muscle in legs. common is Unverricht-Lundborg disease myoclonus: 0 = absent, + = mild, ++ = Ear clicks and palatopharyngolaryngeal (Baltic or Mediterranean myoclonus) but moderate, +++ = severe. involuntary movements seen in our patient other types include Lafora disease and mito- Myoclonus was unchanged in one patient can be clinically classified into "palatal myo- chondrial myopathy. and worsened in three (table). Patient 3 left clonus",' although the movements were not A serotonergic disturbance is suggested by the study at the starting dose reporting it exactly rhythmic and recurred at a slower rate reduced CSF5- HIAA in Baltic myoclonus made her more unsteady, and therefore she than the usual palatal myoclonus. Needle and the antimyoclonic effect of L- trypto- could not be tested. Patient 1, the only EMG showed myokymic discharges in the phan plus a monoamine oxidase inhibitor or employed patient, could not go to work at 60 palatal and mylohyoideus muscles in syn- 5-hydroxy-L-tryptophan in some patients.' mg/day. On the Myoclonus Evaluation Scale, chrony with the movement. These EMG The problem is that these observations do patient 1 went from 20% abnormality at findings differed from those reported in not point to a specific locus of abnormality in baseline to 33-44% on buspirone; patient 2 symptomatic "palatal myoclonus" showing the 5-HT system. from 43-56% to 47-53%, respectively. There rhythmic discharges at a faster rate,2 Serotonin (5-HT) receptor pharmacology were also no large differences on 10 timed although the previous EMG studies on "pala- has advanced rapidly, identifying multiple motor tasks. Patient 4 was too impaired to tal myoclonus" did not disclose firing pat- 5-HT receptors types. Only a few have been comply with formal testing, but his action- terns of each jerk in detail. Myokymic studied in experimental myoclonus. In rats, and sensory-evoked myoclonus appeared to discharges and muscle cramps in the legs the full 5-HT receptor agonist 8-OH- increase while spontaneous myoclonus was relieved by carbamazepine in the present case DPAT induces myoclonus but partial unchanged. may indicate that they arise from neu- 5-HT,A agonists such as buspirone do not. In all cases, the worsening of myoclonus romuscular hyperexcitability rather than a This pilot study was intended as a prelimi- was transient once the drug was stopped, and central oscillator. nary step in evaluation of the possible role of patients reported returning to their baseline Ephaptic transmission resulting from 5-HT,A receptor abnormalities in progressive level of function. demyelination can cause focal myokymia,3 myoclonus epilepsy. The 5-HT,A receptor is None ofthe patients experienced increased but in our patient there was no evidence of key to the 5-HT containing raphe neurons on seizures compared with their baseline, even organic lesions in the posterior fossa, nor which it is located, because its stimulation those with exacerbation of myoclonus. A other diseases suggesting diffuse injury or decreases cell firing. The activity of these brief head-shaking seizure occurred in hyperirritability of the peripheral nerves, for neurons may be especially important in patient 1 at 45 mg/d buspirone, a generalised example, in association with toxins, brainstem-mediated myoclonus, but the convulsion in patient 2 at 30 mg/d and in thyrotoxicosis, Guillain-Barre syndrome or raphe nuclei also project widely to forebrain patient 4 at 20 mg/d. No new .' Facial myokymia, though and spinal cord. Buspirone (Buspar) is the were evoked. commonly seen in patients with pontine first clinically used 5-HT A agonist of its The incidence of irritability and sedation glioma, or Guillain-Barre class, widely prescribed as an anxiolytic.2 in our patients was higher than the 2% and syndrome, rarely involves the muscles inner- Since increases myoclonus in our 10% of 477 cases in the Physician's Desk vated by lower cranial nerves.' patient population, we also hypothesised that Reference, respectively. There may have been Myokymic discharges, also called grouped they may benefit from an anxiolytic. Much less dizziness (12% in PDR). , usually cause vermicular evidence suggests buspirone exerts its clinical This uncontrolled observational study in movements,3 but involvement of the dorsal effect by stimulating pre-synaptic 5- HT,A a small number of patients suggests that interosseous muscles may cause tremor-like receptors. buspirone does not help and may exacerbate http://jnnp.bmj.com/ or flickering movements of the fingers." Two male and two female patients, aged myoclonus in progressive myoclonus epi- Myokymic discharges in the palatal muscles 15-22 years, with progressive myoclonus lepsy. Worsening of myoclonus was not could therefore cause movements resembling epilepsy who had failed conventional therapy explained by decreased anticonvulsant levels, "palatal myoclonus" or "tremor". Needle were identified. Standard diagnostic tests had and there are no experimental data to sup- EMG is important to differentiate palato- been performed including muscle enzyme port an interaction between buspirone and pharyngolaryngeal myokymia from the histochemistry. All were taking one or more anticonvulsants. Although a fluctuating base- essential "palatal myoclonus",' which has a anticonvulsants (valproic acid, clonazepam, line of patients with progressive myoclonus slower rate of movement than symptomatic lorazepam, or phenobarbital) for control of epilepsy could give the false impression of on September 25, 2021 by guest. Protected copyright. "palatal myoclonus". seizures, but none of the drug doses were drug-induced exacerbation, the patients JUNKO ITO the Each had improved when buspirone was discontin- JUN KIMURA changed during study. patient Department of Neurology prominent action myoclonus, some sponta- ued. HIROSHI SHIBASAKI neous myoclonus, and little or no cerebellar The data should be viewed as positive Department of Pathophysiology ataxia. None of the patients were seizure-free findings for several reasons. Any response to Kyoto University School ofMedicine, Sakyoku, Kyoto, for more than a few months before the start buspirone suggests that the 5- somato- _Japan. HTIA of the study. All had therapeutic anticon- dendritic autoreceptors are intact, and by Correspondence to: Dr Ito, Department of Neurol- vulsant levels before and during the study. inference, that 5-HT-containing raphe neu- ogy, Kyoto University Hospital, 54 Kawaracho Shogoin, Sakyo-ku, Kyoto 606-1, Japan. Table on and seizures 1 Deuschl G, Mischke G, Schenck E, Schulte- Effects of buspirone myoclonus Montig J, Liicking CH. Symptomatic and Days Threshold Max. Best Effect of myoclonus essential rhythmic palatal myoclonus. Brain on dose dose dosel Side Seizure 1990;113: 1645-72. Patient 2 Tahmoush AJ, Brooks JE, Keltner JL. Palatal Diagnosis drug mglday mglday day Subjective Obective effects frequency myoclonus associated with abnormal ocular 1 Baltic 60 15 60 35 worse No change Sedation 1 and extremity movements. A polygraphic Irritability study. Arch Neurol 1972;27:431-40. Mood swings 3 Gutmann L. AAEN minimonograph 37:facial 2 Baltic 18 25 30 20 worse worse Sedation 1 and limb myokymia. Muscle Nerve 1991;14: Lightheadedness 1043-9. 3 Baltic 3 15 15 - worse worse - 0 4 Kaeser HE, Skorpil V. Myokymia involving the 4 Lafora 13 5 20 - worse worse Sedation 1 muscles innervated by the Vth, VIth, VIIth, Irritability IXth, Xth, Xlth and XIIth cranial nerves with brain stem tumor. Eur Neurol 1976;14: 408-12. Best dose/day may indicate merely least side effects. Letters to the Editor 115

rons are also present. It also implies that the droxy-2-(Di-q-propylamino) tetralin in differ- matter' and would explain the findings in our J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.1.114 on 1 January 1993. Downloaded from ent rodent models of epilepsy Neurosci Letts 5-HT terminal is functional enough to medi- 1985;60:201-6. patient. The differential diagnosis was not ate decreased 5-HT tone. This interpretation elaborated in our article as it was not the is supported by the finding of reduced CSF primary objective. We favoured the former 5-HIAA in some patients. diagnosis because the MRI appearance with The second observation was that buspir- bilateral, extended, confluent lesions on one did not exacerbate seizures unrelated to T2-weighted images appeared more typical myoclonus in progressive myoclonus epi- MATTERS of subacute encephalits' and because of the lepsy. Drug-induced exacerbation of myoclo- response to zidovudine treatment.5 In the nus may precipitate myoclonus-associated ARISING absence of a biopsy or necropsy, the histology seizures, perhaps as in our case 2. This of our patient's lesions remains conjectural supports the clinical observation that myo- and we agree with Dr Berger that PML is a clonus and epilepsy respond differently to Balint's syndrome in subacute HIV serious consideration in this patient. drugs in progressive myoclonus epilepsy and encephalitis ARMIN SCHNIDER the hypothesis that they have different reg- THEODOR LANDIS ulatory mechanisms. The 5-HT,A agonist MARIANNE REGARD I was interested to read the report of Dr Departmient of Neurology, University Hospital, 8-OH-DPAT has not been found to be an CH-8091 Zurich, Schnider et al on a 45 year old woman with Switzerland anticonvulsant in standard experimental Balint's syndrome complicating subacute 1 Schnider A, Landis T, Regard M. Balint's models of epilepsy.5 Anticonvulsants could HIV encephalitis.' Attributing her cognitive syndrome in subacute HIV-encephalitis. . have masked a proconvulsant effect of Neurol Neurosurg Psychiatry 1991 ;54:822-25. disorder to subacute HIV encephalitis in the buspirone since anticonvulsants are better 2 Damasio AR. Disorders of complex visual pro- absence of biopsy confirmation is presump- able to block seizures than myoclonus in cessing: agnosias, achromatopsia, Balint's tuous and likely to be incorrect. Focal neuro- syndrome, and related difficulties of orienta- these disorders. There are no data to support tion and construction. In: Mesulam logical findings are distinctly unusual with MM, a proconvulsant effect of buspirone, however, ed.Principles of behavioral neurology. Philadel- this disorder. It is far more likely that phia: FA Davies, 1985;259-88. 8-OH-DPAT has a proconvulsant effect in progressive multifocal leukoencephalopathy 3 Gray F, Gherardi R, Scaravilli F. The neu- mice5 and extremelv high doses induce seiz- (PML) was responsible. PML affects approx- ropathology of the acquired immune defi- ures in rats2 which may be unrelated to 5-HT ciency syndrome. A review. Brain 1988; imately 4% of all AIDS patients.2 A neurotransmission. predilec- 111:245-66. tion for the parieto-occipital region is typical 4 Jarvik JG, Hesselink Kennedy It would be premature to conclude that JR, C, et al. and visual symptoms are a presented mani- Acquired immunodeficiency syndrome. Mag- drugs acting at 5-HT,A receptors are ineffec- netic resonance patterns of brain involvement festation in 35% of patients.' The radio- tive in progressive myoclonus epilepsy. A with pathologic correlation. Arch Neurol graphic characteristics of the white matter 1988;45:731-6. post-synaptically acting 5-HT A agonist lesions in PML" mirror those observed in 5 Yarchoan R, Berg G, Brouwers P, et al. might have a different effect on myoclonus their patient. Furthermore, the improvement Response of human-immunodeficiency-vi- from buspirone. Different partial 5-HT, A with zidovudine hardly dispels the diagnosis rus-associated neurological disease to 3'-azi- agonists, such as gepirone or ipsapirone do-3'-deoxythymidine. Lancet 1987;1:132-5. of PML. Spontaneous recovery5 and without buspirone's weak D. dopamine improvement following the use of zidovu- receptor antagonism, may also have a differ- dine' have both been reported with HIV- ent effect on myoclonus. Continuous treat- associated PML. Anti-acetylcholine receptor antibody ment with buspirone has effects on other JOSEPH R BERGER neurotransmitter receptors such as 5-HT, THOMAS E WHIGHAM measurement in myasthenia gravis receptors which could have influenced myo- Universitn of Miami, School of Medicine, Department of Neurology In a recent study,' Clarke et al reported a clonus. Pre- or post-synaptic 5-HTIA antago- (D4-5), nists are other therapeutic possibilities. PO Box 016960, "deficiency of anti-acetylcholine receptor Further studies on the role of 5-HT Miami, Florida 33101, USA (AChR) antibodies measurement in myas- receptor subtype involvement in myoclonus thenia gravis (MG)". In their retrospective I Schnider are indicated, particularly in Lance-Adams A, Landis T, Regard M. Balint's study, antibodies were detected in only 38% syndrome in subacute HIV-encephalitis. of 86 patients with MG, compared with syndrome (post-hypoxic myoclonus) for Neurol Neurosurg Psychiatry 1991;554:822-5. which evidence is best for involvement of 2 Berger JR, Kaszowitz B, Dickinson G, Post 66-93% in other reports. The unusually low 5-HT systems. MJD. Progressive multifocal leukoencepah- antibody detection rate is attributed by the loapthy associated with human immunodefi- authors to the use of staphylococcal protein- This work was in part by FDA ciency virus infection: a review of the lit- supported Orphan http://jnnp.bmj.com/ erature and report of cases. A for immunoprecipitation rather than anti- Products and Development grant FD- 16 Ann Intern t-000747-01-1 and the Children's Research Med 1987;107:78-87. human IgG antiserum. To support their 3 Brooks BR, Walker DL. Progressive multifocal claim, the authors cite our early report of Institute. leukoencephalopathy. Neurol Ctlin 1984;2: M R PRANZATELLI 299-313. 36% detection in an assay employing protein- Departmlents of Neurology, Paediatrics, Pharmacology. A.2 In that study, however, we used dener- DC. 4 Sze G, Lee SH. Infectious diseases. In: Lee SH, The George Washington University, Washington, Rao K, Zimmerman RA, eds. Cranial MRI vated rat muscle AChR as the antigen. Later, D FRANZ and CT, 3rd ed, New York: McGraw Hill, we modified the system using human amiputa- Departments of Neurology and Paediatrics, Wright 1992;539-88. tion muscles AChR which increased the detec- State University, School of Medicine, OH. 5 Berger JR, Mucke L. Prolonged survival and Dayton, partial recoverv in AIDS associated pro- tion rate to 88%, still using protein-A as the

E TATE gressive multifocal leukoencephalopathy. precipitating agent.3 4 These results agree on September 25, 2021 by guest. Protected copyright. J M MARTENS Neurology 1988;38: 1060-4. with most ' 6 Conway B, Halliday CWC, Brunham RC. reported series,5 which stress the Department of Neurology, Children's National Medical notion that the assay efficiencv (sensitivity Center, Washington DC, USA. Human immunodeficiency virus-associated progressive multifocal leukoencephalopathy: and antibody titres) depends primarily on the Correspondence to: Dr Pranzatelli, Neurology apparent response to 3'-azido-3'-deoxythymi- quality of the antigen preparation. Thus Department, Children's National Medical Center, dine. Rev Infect Dis 1990;12:479-82. protein-A is similar to anti-human IgG anti- 111 Michigan Avenue NW, Washington DC, sera for in the 20010, USA. immunoprecipitation anti- Schnider et al reply: AChR antibody assay and we feel that the 1 Koskiniemi M, Hyyppa M, Sainio K, Salmi T, We appreciate the comments by Dr Berger authors should look for other methodological Sarna S, Uotila L. Transient effect of L-tryp- regarding the histological nature of the flaws to account for the low sensitivity of their tophan in progressive myoclonus epilepsy without Lafora bodies. Clinical and electro- lesions in our patient who presented with assay. Finally, we completely agree with the physiological study. Epilepsia 1980;21 :351-7. Balint's syndrome as the first neurological authors that all laboratories engaged in rou- 2 Yocca FD. Neurochemistry and neurophysiol- manifestation of AIDS.' Unlike some tine antibody assays should be subject to a of and interactions at ogy buspirone gepirone: patients with Balint's due to stroke quality control audit, and we refer the presynaptic and postsynaptic 5-HT,A re- syndrome ceptors. _7 Clin Psychopharmacol 1990;1O: in whom visual movement perception is authors to consult with "EuroEQAS for 65-125. impaired,2 she perceived movement partic- AChR antibodies". 3 Trouillas P. Brudon F, Adeleine P. Improvement ularly well. We ascribed this variant to a TALMA BRENNER of with levorotatory form of ITZHAK WIRGUIN 5-hydroxytryptophan. Arch Neurol 1988;45: subcortical lesion site, as shown by MRI, that ODED ABRAMSKY 1217-22. spares cortico-cortical connections between Neuroimlmunology Laboratorv, 4 Marsden CD, Schacker M. Assessment of primary visual cortex and visual association Departnment of Neurology, Hadassah Medical Center, extrapyramidal disorders. BrJ Clin Pharmacol POB 12000, J7erusalemt 91120, Israel. 1981,11:129-51. areas. Both subacute HIV encephalitis and 5 Loscher W, Czuczwar SJ. Evaluation of the progressive multifocal leucoencephalopathy 1 Clarke CE, Shepherd DI, Yuill GM, Smaje JC, 5-hydroxytryptamine receptor agonist 8-hy- (PML) primarily involve subcortical white Wilson PB. Deficiencies in anti-acetylcholine