Dopamine agonists suppress visual-cortical reflex myoclonus · Dopamine agonists abolished cortical reflex myoc-lonus to flash stimulation in two patients with olivo-ponto-cerebellar

Journal of Neurology, Neurosurgery, and Psychiatry 1985;48: 1277-1283

Dopamine agonists suppress visual-cortical reflexmyoclonusJA OBESO, J ARTIEDA, T TUNON,* MR LUQUIN, JM MARTINEZ LAGEFrom the Movement Disorders Unit, Department ofNeurology, Clinica Universitaria, University ofNavarra,Pamplona, Spain.

SUMMARY Two patients with a diagnosis of olivo-ponto-cerebellar atrophy developed corticalreflex myoclonus to visual (flash) and somaesthetic stimuli. Oral treatment with levodopa-carbidopa (1000/100 mg) or subcutaneous administration of apomorphine (1 mg) abolished thevisually-triggered myoclonus, without modifiying reflex myoclonus to electrical or tactile stimula-tion. Intravenous administration of lisuride (0-1 mg) produced a marked reduction in both typesof reflex myoclonus. These results indicate a selective inhibitory effect of dopamine agonist drugson visual reflex myoclonus of cortical origin.

In recent years the pharmacological basis of myo-clonus has been focused on a disorder of cerebralserotoninergic mechanisms. This followed the dis-covery by Lhermitte et al,' 2 later confirmed byothers,36 that oral treatment with5-hydroxytryptophan (5-HTP) plus carbidopa pro-duced a reduction in post-anoxic action myoclonus,and the findings of low CSF levels of5-hydroxyindolacetic acid in similar patients whoresponded to treatment with 5-HTP orclonazepam.78 However, a deficit of serotonin maynot be important in other myoclonic disorders9 10 inwhich other neurotransmitters may be involved. Theanti-myoclonic effect of clonazepam, valproic acidor primidone might be due at least partially, toenchancement of cerebral gamma aminobutyric acid(GABA) activity." A protective effect of apomor-phine against visually induced myoclonus has beendemonstrated in the baboon.'2 Quesney et al'3 foundthat in patients with generalised epilepsy, apomor-phine produced transient inhibition of spike andwave EEG activity induced by photic stimulation,suggesting a dopamine influence on certain types ofmyoclonus.

Cortical reflex myoclonus results from abnormal

*Present address: Neuropathology section, Hospital de Navarra,Pamplona.

Address for reprint requests: Dr JA Obeso, Neurologia, ClinicaUniversitaria, Apartado 192, Pamplona, Spain.

Received 23 January 1985 and in revised form 9 May 1985.Accepted 17 May 1985

motor cortex activity triggered by sensory input.'4 '5Electrophysiological characteristics of cortical myo-clonus are the presence of enhanced cortical evokedpotentials, EEG activity time-locked to the musclejerks and brief EMG discharges.4 12 Clinical andelectrophysiological studies indicate the existence ofseparate mechanisms underlying different types ofcortical myoclonus in man.'6 Such pathophysiologi-cal discrimination may also indicate different phar-macological characteristics. For example, corticalreflex myoclonus to somaesthetic stimulation ishighly responsive to serotonin agonists, but is notimproved by dopaminergic drugs.'7 We now report aselective effect of levodopa-carbidopa and apomor-phine on cortical reflex myoclonus induced by photicstimulation in two patients with olivo-ponto-cerebellar-atrophy. These two cases were includedin a previous report on the pathophysiology of corti-cal myoclonus.'6

Method

Electrophysiological technique A Medelec MS 6 machinewas used for electrophysiological investigations.Somatosensory evoked potentials (SEPs) to digital nervestimulation were recorded from a scalp electrode placed onthe hand area (7 cm lateral and 2 cm posterior to thevertex) with the reference electrode on Fz (10-20 EEGinternational system). Visual evoked potentials (VEPs) toflash stimulation recorded from the scalp over the occipitalcortex also were recorded. For reasons explained previ-ously,'8 we have designated the major cortical potentialpeaks by their polarity and sequence (Ni, P1, N2, etc).The electromyographic (EMG) reflex responses elicited byelectrical or flash stimulation were recorded simultane-

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Fig 1 Case 1. Transverse sections of the cerebellum, ponsand medulla. Cerebellar white matter is considerablyreduced in volume; both dentate nuclei appear normalmacroscopically. There is severe atrophy ofthe pons andmiddle cerebellar penduncles (single arrow). The brachiumconjuctivum is normal bilaterally. In the medulla the normalprotusion ofthe inferior olive has disappeared (doublearrow).

ously by surface electrodes placed on biceps brachii orfinger flexors. The amplitude of the reflex EMG dischargeswas measured as the maximum interpeak value on averagerecords before and after each pharmacological test. Theduration of the EMG bursts usually remained constantthroughout each session.

Case reportsCase 1 M. R. (Clinica Universitaria No 136647)A 65-year-old woman with a history of unsteadinessof gait beginning in 1978 was investigated in 1979for a cerebellar syndrome, but no cause was found.There was no family history of neurological disease.By 1982 the patient had lost facial expression, haddifficulty in performing normal daily motor tasksand had frequent falls. She was also incontinent ofurine and could not swallow solid food. Examinationshowed marked rigidity and akinesia as well as dys-metria of the limbs. She could not stand or walkalone. Pursuit eye movements were interrupted andthere were ocular dysmetria and "square wave"jerks. Mentation was intact. Cranial nerves, tendonjerks and sensation were all normal. There was noorthostatic hypotension. Brief light touch or pin-prick of the skin area innervated by the medial plan-tar nerve of either foot provoked repetitive jerkingof the toes lasting up to 1 second. When the stimuluswas applied to the great-toe, or to the second toe oradjacent area, the jerk consisted of extension of thegreat toe and flexion of the other toes. There was novisible muscle jerking when the patient voluntarilymoved the foot or toes. A few months later, whenher general condition had deteriorated, it wasnoticed that touch and particularly pin-prick to the

Obeso, Artieda, Tufz6n, Luquin, Lage

dorsal region of the thumb or forefinger producedbrief and repetitive jerks of the forearm and bicepmuscles. A CT scan revealed severe brainstem andcerebellar atophy, but the cerebral hemisphereswere normal. The clinical diagnosis of sporadicolivo-ponto-cerebellar atrophy was made. In Janu-ary 1984 EEG showed diffuse theta rhythm at rest,but flash stimulation provoked generalised musclejerking which blurred the EEG trace, without loss ofconsciousness. The patient was treated withlevodopa-carbidopa ( 1000/100 mg/day), bromocrip-tine (30 mg/day), lisuride (5 mg/day) and thyroxinereleasing hormone (TRH) iv (10 mg/day) with noimprovement in her akinesia and ridigity. She diedof pneumonia in March 1984.On post-mortem examination the brain weighed

1180 g. The brainstem and cerebellum weighed120 g (normal control values 160 + 10 g). Macros-copic examination after fixation showed severeatrophy of the pons, inferior and middle cerebellarpeduncles and cerebellum (fig 1). The substantianigra and locus coeruleus appeared mildly depig-mented. The putamen was shrunken bilaterally andthe cerebral hemispheres were normal. The spinalcord was normal macroscopically. For histologicalstudies, the whole cerebellum, blocks of severalother brain regions and the spinal cord were embed-ded in paraffin wax. Sections were stained withhaematoxylin-eosin, luxol fast-blue, Bielchowsky,Nissl, Holsen and Spilmeyer.Microscopic examination of the pre-trontal,

sensory-motor and visual cortex did not reveal anyhistological abnormality (fig 2A). Neuronal loss andfibrillary gliosis were very severe in the putamen(fig 2B) and moderate in the external globus pal-lidus. The internal globus pallidus, caudate,thalamus, subthalamus, hypothlamus, red nucleusand geniculate bodies were normal. In the mesence-phalon (fig 2C), the substantia nigra (pars reticulataand compacta) and locus coeruleus showed intensegliosis and 20% decrease of pigmented neurons.Lewy bodies and neurofibrillary tangles were notpresent. The superior cerebral peduncle was normal.In the pons, neuronal loss and gliosis was wide-spread and very severe (fig 2-D), sparing only partof the raphe nuclei. The middle and inferior cerebel-lar peduncles were thin and severely demyelinated.The arcuate fibres also were damaged. The cortico-spinal tract was slightly pale, but the medial lon-gitudinal fascicle and the central tegmental tractwere normal. In the cerebellum (fig 2E) the whitematter was severely demyelinated. Purkinje cellswere markedly reduced in number and there wasBergmann glia proliferation. The molecular layershowed moderate gliosis; the granular layer wasslightly thinner than normal. Within this latter layer,



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200msFig 3 Case 1. Visual evoked potentials (VEP) to flashstimulation (arrows) at a frequency of10 Hz,somatosensory evoked potentials (SEP) to digital nervestimulation ofthe right forefinger and electromyographic(EMG) recording of the reflex jerks from right finger flexormuscles. Each trace is the average of32 responses. (A) and(C) control records. (B) and (D) after 1 mg ofsubcutaneousapomorphine. Reflex myoclonus to flash stimulation wasabolished by apomorphine, but electrically elicitedmyoclonus was not decreased. Notice that the amplitude ofthe primary complex of the VEPs remains constant. Thebaseline ofthe cortical record changed slightly afterapomorphine; this variation was probably due to theabsence ofmuscle artefact once the reflex myoclonus haddisappeared. Vertical calibration bars are 50 ,uV for VEPs,25 ,uV for SEP and 200 ,uV for EMG potentials.

axonal swelling (" torpedoes") from Purkinje cellswere observed. The dentate nucleus and its ribbonas well as the other deep cerebellar nuclei were pre-served. At the level of the medulla (fig 2-F) relevantabnormalities comprised severe neuronal loss andfibrillary gliosis of the inferior olives and arciformnucleus, the dorsal motor nucleus of the vagus, andthe hypoglosal nucleus. Moderate demyelination ofthe spino-cerebellar tracts was present. The spinalcord sections showed marked neuronal loss andgliosis of the anterior and lateral horns with mildgliosis of Clarke's columns.

Pharmacological and physiological studies1 Control Flash stimulation at a frequency of 10to 20 Hz elicited rhythmical myoclonus. At thesefrequencies each flash produced a large VEP (50,uV) followed by a generalised jerk which caused anartifact in the scalp (occipital) electrode (fig 3A).

Obeso, Artieda, Tunion, Luquin, LageThe latency of the first positive peak of the VEP was32 ms and the time interval between this peak andthe onset of the reflex EMG discharge recordedfrom biceps brachii was 28 ms. SEPs were alsoenlarged (35 ,uV, P1-N2) and were followed by areflex EMG discharge with a latency of 40 ms afterthe stimulus recorded from biceps brachii (fig 3C).2 Apomorphine A single subcutaneous dose of1 mg of apomorphine was given prior to intravenousadministration of 40 mg of domperidone. Clinicaland electrophysiological evaluation of myoclonuswas repeated 30 minutes after apomorphine. Themyoclonic jerking previously provoked by flashstimulation at a frequency of 10 to 20 Hz wasabolished following apomorphine, but the amplitudeand morphology of the primary complex of the VEPremained constant (fig 3B). The slight change inmorphology of the cortical record was probably dueto the absence of muscle artefact. On this occasionthe flash could be kept on indefinitely without elicit-ing any reflex myoclonus. In contrast, the amplitudeof the EMG myoclonic discharge produced by elec-trical stimulation of the fingers was not modified byapomorphine (fig 3D).

3 Lisuride A single intravenous dose of 0-1 mgof lisuride was given on a different day. Twentyminutes later, a striking reduction in visual reflexmyoclonus was observed. However, rhythmicaleye-blinking at the flash frequency was still present.Reflex myoclonic jerking following touch or pin-prick was decreased and the size of the EMG reflexdischarge elicited by electrical stimulation wasdiminished to half of the control value.

Case 2. PRL (Clinica Universitaria, No 73247).This 67-year-old lady was diagnosed as having Par-kinson's disease in 1971. She responded initially tolevodopa therapy and levodopa plus benserazidesubsequently. In 1975, akinesia and rigidity hadbecome prominent and a "wearing off phenomenon"was present. Bromocriptine and amantadine wereadded but did not produce any greater improve-ment. When examined in 1983, she was unable tospeak, required assistance to walk a few metres andwas severely rigid. There was also marked dys-phagia. Tendon jerks were exaggerated and a rightBabinski sign was present. Pursuit ocular move-ments were abnormal (cogwheeling) and oculardysmetria was observed upon attempted saccadicmovements of the eyes. Dysmetria of the upperlimbs in the finger-to-nose test was noticed, evalua-tion of coordination in the lower limbs was madedifficult by severe akinesia. Light touch or pin-prickto the fingers and toes, or tapping the wrist or toeswith a tendon hammer, provoked repetitive musclejerks localised to the stimulated limb. In the arm

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-_-Fig 4 CT brain scan ofpatient No 2. Marked brainstemand cerebellar atrophy, the latter mainly due to atrophy ofthe vermis, is observed (A and B). There is also slightdilatation ofthe third ventricle and anterior horns (C),without cortical atrophy (D).

these were characterised by flexion of fingers, wristand elbow; in the legs by flexion of the toes, andflexion/extension of the great toe. Treatment withlevodopa-carbidopa was discontinued for a few dayswith only slight deterioration in her motor capacity.At this time, the flashing stimulus employed forroutine EEG recording elicited repetitive general-ised myoclonic jerking unaccompanied by loss ofconciousness. The CT scan showed mark atrophy ofthe brainstem and cerebellar vermis with only mod-erate cortical atrophy (fig 4). A clinical diagnosis ofsporadic olivo-ponto-cerebellar atrophy was made.

ms later by a generalised jerk. SEPs were alsoincreased in amplitude 25 ,uV (P1-N2) and wereassociated with reflex EMG discharges occurringwith a latency of 40 ms in finger flexors.

2 On levodopa therapy The electrophysiologi-cal studies were repeated three days after Sinemet275 (levodopa 250 mg, carbidopa 25 mg) (4tablets/day) had been restarted. At that time, flash-ing at any frequency (3 to 50 Hz) during a prolongedperiod of time (up to 30 seconds) failed to elicit anyreflex myoclonus. However VEPs were still enlarged(fig SB). Reflex myoclonic jerking triggered by elec-trical stimulation was unchanged.

3 Lisuride 0 15 mg of lisuride was given IVwhen the patient was taking her usual dose ofSinemet. Accordingly only the effect of lisuride onsomaesthetically induced myoclonus could bestudied. A marked reduction (90%) in the amp-litude of the EMG reflex discharges recorded infinger flexors following digital nerve stimulation wasfound, which corresponded with diminution in reflexmyoclonus in the limbs observed clinically.

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She was treated with lisuride (3 mg/day p.o.) and Fig 5 Case 2. (A) Visual evoked potentials (VEPs) andlevodopa-carbidopa 275 (4 tablets/day p.o.) without reflex EMG discharges recorded from right biceps brachii tofurther improvement. A few months later she died flash stimulation (arrows) at a frequency of6 Hz, while theof aspiration pneumonia at home. patient was not receiving any dopamine agonist. (B)

Following oral treatment with levodopa-carbidopaPharmacological and physiological studies (1000/100 mglday). The reflex muscle responses were1 Off levodopa therapy. Flash stimulation at a abolished after levodopa without change in the amplitude ofthe VEPs. The late positive wave observed in the controlfrequency of 3 Hz (or greater) induced generalised VEP represented a muscle artefact due to the reflexand rhythmical myoclonus (fig SA). Each flash pro- myoclonus; accordingly it is not present after treatment.duced a large VEP (50 gV) which was followed 30 Vertical bar is SO uV for VEP and 500 ,uV for EMG trace.

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Discussion

Dopamine agonists abolished cortical reflex myoc-lonus to flash stimulation in two patients witholivo-ponto-cerebellar atrophy. These results ex-tend the findings of Quesney et al'3 1' ofapomorphine-induced suppression of photosensitiveepileptic discharges in humans, and support experi-mental work indicating a strong inhibitory action ofdopamine agonists upon the photomyoclonicresponse in the baboon Papio papio.'2 The site andmechanism of action of dopamine agonist inhibitionof the abnormal cortical discharges producing myo-clonus is not clear. Dopamine agonists did notreduce the amplitude of the VEPs preceding themyoclonic jerks in either of the two patients, indicat-ing that the antimyoclonic effect of these drugs wasnot due to inhibition of the afferent visual impulsesat the retina or lateral geniculate bodies. Theabnormal occipital discharges evoked by flash stimu-lation could have spread via occipito-reticular path-ways or utilising the dense visuo-motor (occipital-premotor cortex) connections.20 The former possi-bility seems unlikely in view of (a) the short latency(30 ms) between the primary complex of the VEPsand the myoclonic jerking in the arms, and (b), thesmall size and significance of visuo-reticular path-ways in humans.2' On the other hand a cortico-cortical link is favoured by experimental findings inthe photosensitive baboon22 23 and in a recentpatient with visual reflex myoclonus studied byShibasaki,24 in whom evidence for occipito-frontaltransmission of the abnormal discharges generatedby flash stimulation was obtained. Interestingly, theoccipito-frontal conduction time (10 ms) recordedin Shibasaki's patient coincided almost exactly withour indirect calculations (10-12 ms) in the twopatients reported here. In addition, in these twopatients, cortical reflex myoclonus to somaestheticstimuli was not modified by apomorphine orlevodopa. It is therefore unlikely that dopamineagonists suppressed visual reflex myoclonus by wayof a nonspecific inhibitory action or by decreasingthe excitability of cortico-spinal motoneurons.Accordingly we propose that the antimyocloniceffect of the dopamine agonist was probably due to aselective inhibition of visual cortex output neurons(area 19) projecting onto the premotor cortex orinhibiting the "premotor" cortex neurons by whichvisual cortex neurons communicate withmotoneurons in area 4.2022The main source of cortical dopamine arises from

the basal ganglia via the meso-cortical dopaminergicpathway.25 In patient 1, and probably in patient 2,there was severe damage of the entire substantianigra and surrounding structures. It is therefore

Obeso, Artieda, Tunion, Luquin, Lage

likely that the dopaminergic meso-cortical pathwaywas damaged as part of the multisystem atrophythey suffered. Direct microiontophoretic applicationof dopamine mainly produces neuronal inhibition26and endogenous dopamine activity in the visual cor-tex is reduced by rhythmic flash (15 Hz) stimulationin cats.27 Thus, dopamine agonists in these patientscould have restored an intracortical inhibitorydopaminergic defect, made clinically overt duringrepetitive visual stimulation, by post-synaptic stimu-lation of the meso-cortical connections. On theother hand, reflex myoclonus of any type is not afeature of untreated Parkinson's disease, the besthuman model of dopaminergic deficiency. Someother factor(s) must be taken into consideration toexplain the origin and response to dopamine agon-ists of visual reflex myoclonus. In the two patientsdescribed here there was evidence of marked cere-bellar damage. Indeed, in many patients with corti-cal myoclonus, clinical and CT scan features raisethe possibility that a defect of cerebellar inhibitoryoutput is responsible for the pathological corticalreflex mechanisms.'6 At present however, anyattempt to explain how cerebellar and meso-corticaldysfunction interact to provoke visual corticol myoc-lonus would be mere speculation.The findings reported here confirm previous

results indicating that pure dopamine agonists arenot active against somaesthetic cortical reflex myoc-lonus.'7 Unfortunately, it was not possible to test theeffect of 5-HTP plus carbidopa upon the visualreflex myoclonus present in our two patients.Experimental evidence suggests that serotonin agon-ists are also capable of suppressing photomyoclonicand photoconvulsive responses.28 Whether or notthis is the case in humans requires further investiga-tion.

Cortical reflex myoclonus is difficult to treat andmay be associated with generalised seizures.'6Appropiate control of visually triggered myoclonusoften improves the standard of living of patientswith myoclonic epilepsy. Dopamine agonists mightbe considered as an additional therapeutic tool inpatients with photic epilepsy.

The authors are grateful to Mrs MA Garcia and MrsM Obeso for technical help. Mrs ML Sola patientlytyped the manuscript.

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Dopamine agonists suppress visual-cortical reflex myoclonus · Dopamine agonists abolished cortical reflex myoc-lonus to flash stimulation in two patients with olivo-ponto-cerebellar