Extrapyramidal disorders: interest of myoclonus analysis

Parkinsonism or dystonia are associated with myoclonus in several extrapyramidal diseases. Although the latter symptom is not always prominent, stimulus-sensitive, distal, or focal reflex myoclonus is frequently observed. This review will consider the clinical and electrophysiological features of myoclonus in Parkinson's disease, multiple system atrophy, Lewy body dementia, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, dentatorubral-pallidoluysian atrophy and myoclonus with dystonia. The evidence of a long-latency reflex response, the presence of giant somatosensory evoked potentials, and the demonstration of a back-averaged premyoclonus focal cortical EEG activity often lead to classify myoclonus as a cortical phenomenon. However, a subcortical origin cannot always be ruled out.     

Myoclonus and extrapyramidal diseases

Parkinsonism or dystonia are associated with myoclonus in several extrapyramidal diseases. Although the latter symptom is not always prominent, stimulus-sensitive, distal, or focal reflex myoclonus is frequently observed. This review will consider the clinical and electrophysiological features of myoclonus in Parkinson's disease, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, dentatorubral−pallidoluysian atrophy, Lewy body dementia, and myoclonus with dystonia. The evidence of a long-latency reflex response, the presence of giant somatosensory evoked potentials, and the demonstration of a back-averaged premyoclonus focal cortical EEG activity often lead to classify myoclonus as a cortical phenomenon. However, a subcortical origin cannot always be ruled out.     

Electrophysiological studies of myoclonic jerks provoked by photic stimulation

A patient with a type of myoclonus produced by somatosensory and photic stimuli was studied electrophysiologically. Jerk-locked averaging showed cortical spikes in association with the spontaneous myoclonus. High amplitude somatosensory evoked potentials and high amplitude visual evoked potentials were observed. Somatosensory and photic stimuli produced 2 or 3 successive electromyographic (EMG) discharges. The time interval from the onset of the preceding EMG discharge to that of the following EMG discharge produced by photic stimulation corresponded to the latency of a long-loop reflex. It also corresponded to the time interval from the onset of the preceding EMG discharge to that of the following EMG discharge produced by somatosensory stimulation. Not only somatosensory but also photic stimuli might excite the loop of a long-loop reflex and cause myoclonic jerks.     

Cortical reflex myoclonus. A study of the relationship between giant somatosensory evoked potentials and motor excitability

The excitability cycles of the N1-P1-N2 waveforms of the scalp-recorded somatosensory evoked potential (SEP) and of the long-latency, cortical loop reflex electromyographic (EMG) activity were studied in two patients with cortical reflex myoclonus. Long-latency cortical loop reflex EMG activity in the thenar muscles and giant SEPs occurred following median nerve stimulation. The excitability cycle of the EMG paralleled that of the SEP. There was an initial period of attenuation of SEP and EMG amplitude at interstimulus intervals (ISIs) of less than 40 ms followed by a period of amplitude enhancement at an ISI of up to 200 ms followed by a second period of attenuation. The excitability cycle is abnormal and the SEP and EMG amplitude changes parallel each other. It is therefore likely that a common mechanism determines the abnormal excitability cycle. The substrate for this mechanism is unknown and may be diffuse or restricted. Oral 5-hydroxytryptophan (5-HTP) in therapeutic doses altered the SEP excitability cycle. 5-HTP did not attenuate the giant SEPs but did attenuate the long-latency reflex EMG. Therefore, 5-HTP's site of action may be different from the substrate underlying the mechanism that results in the giant SEPs. Additionally, spinal latency reflex EMG activity occurred following treatment with 5-HTP but was absent when the patient discontinued 5-HTP.     

Myoclonus in Creutzfeldt‐Jakob disease: Polygraphic and video‐electroencephalography assessment of 109 patients

We used electroencephalography (EEG)‐polygraphic recordings to classify myoclonus in 109 patients with Creutzfeldt‐Jakob disease (CJD) on the basis of its electromyography (EMG) pattern, time course, distribution, and EEG correlates. We recorded myoclonic jerks in 55 patients (50.4%), and we classified them as periodic myoclonus in 28, rhythmic in 13, and irregular in 20 (6 patients showed two types of myoclonus). Myoclonus occurred as a prominently negative event (interrupting the EMG discharge) in 10. Periodic sharp‐wave complexes (PSWCs) were present in all but one patient with myoclonic jerks but were time‐locked with EMG‐bursts only in case of periodic myoclonus. Jerk‐locked back averaging revealed a variable EEG‐EMG transfer‐time commonly exceeding that characterizing cortical myoclonus. Myoclonus was frequently associated with Met/Met polymorphism at codon 129 of the prion protein gene, but it was also observed in association with Met/Val or Val/Val polymorphisms provided that the EEG showed the presence of the PSWC pattern. The presence of enlarged somatosensory evoked potentials significantly correlated with the myoclonic presentation, as did MR signal hyperintensity involving the cortical mantle. Our observations on the basis of standard polygraphic criteria suggest that CJD associates with a remarkable variety of myoclonic jerks, and therefore different brain structures are probably involved as generators. The significant association between the presence of all myoclonus types with PSWCs suggests that hyperexcitable corticosubcortical loops are always required to generate (or allow) both myoclonus and the EEG complexes, either they are time locked or not. © 2010 Movement Disorder Society     

Cortical myoclonus during lithium exposure

BACKGROUND: Myoclonus can occur in association with lithium therapy at toxic and therapeutic dosages, and can be a predominant and disabling adverse effect. Moreover, myoclonus has been reported when lithium has been combined with cyclic antidepressants and with the neuroleptic clozapine. Although clinical case reports exist, no electrophysiologic data are available that provide a source or a neurophysiological mechanism for the myoclonus seen in lithium therapy. OBJECTIVE: To describe the electrophysiologic characteristics and source of the myoclonus associated with lithium therapy. DESIGN AND METHODS: We retrospectively analyzed 5 cases of myoclonus during lithium therapy. We reviewed the clinical features and results of previous electrophysiologic testing. Four patients received lithium monotherapy; and 1, sertraline hydrochloride and nefazodone hydrochloride in addition to lithium. The electrophysiologic data that had been gathered included multichannel surface electromyographic (EMG) recordings with simultaneous electroencephalography (EEG), somatosensory evoked potentials, and elicitation of long-latency EMG reflexes to median and digital nerve stimulation. RESULTS: All 5 patients showed multifocal action myoclonus without reflex activation and only rare occurrence at rest. In each case, back-averaging created a focal EEG transient over the contralateral sensorimotor area preceding the myoclonus EMG discharge. In 2 of the patients receiving lithium monotherapy, the therapy was discontinued and the myoclonus disappeared. CONCLUSIONS: Lithium, by itself, can be associated with prominent clinical myoclonus, short-duration (<50-millisecond) myoclonus EMG discharges and cortical action myoclonus without the presence of epileptiform abnormalities on the routine EEG. This myoclonus is different from the most common form that is well documented to occur with tricyclic antidepressant therapy by clinical and electrophysiologic means.     

Cortical excitability after myoclonus: jerk-locked somatosensory evoked potentials

Cortical excitability after myoclonus was investigated by electrically stimulating the median nerve just at the time of, or at intervals after, the onset of myoclonus and by averaging the EEG and EMG, using the myoclonus onset pulse as a trigger (jerk-locked somatosensory evoked potential technique). In a patient with "cortical reflex" myoclonus, cortical excitability was relatively enhanced for 20 msec just after the myoclonus, although it was suppressed throughout the postmyoclonus period. In a patient with Creutzfeldt-Jakob disease, cortical excitability was suppressed between periodic myoclonic jerks. In a patient with oculopalatal-somatic myoclonus, there was no change of cortical excitability in relation to myoclonus.     

Abnormal corticomuscular coherence is associated with the small amplitude cortical myoclonus in Parkinson's disease.

Coherence is the degree of time-locked correlation between two signals as a function of frequency. The purpose of this study was to test the following hypotheses: (1) corticomuscular coherence is abnormally increased in those Parkinson's disease (PD) patients with small amplitude cortical myoclonus, and (2) corticomuscular coherence peaks around the time of the myoclonus electromyographic (EMG) discharge. We studied Parkinson's disease patients with and without myoclonus and controls. The data were digitally collected and processed off-line with EMG rectification, creation of 511-msec epochs, Fast-Fourier transform, and coherence analysis. In the 12 to 30 Hz frequency band, but not at 30 to 60 Hz or above, coherence peaks were observed in the PD subjects with myoclonus that were significantly greater than in the control subjects (P < 0.001) and in PD subjects without myoclonus (P < 0.001). The abnormal coherence values are evidence for abnormal rhythmic activity in cortical motor areas in those Parkinson's disease patients with myoclonus. In combination with previous findings on back-averaging, our results show that this myoclonus occurs when neuronal populations are driven to an extreme amount of synchronous activity with higher corticomuscular coherence values. These results have mechanistic implications for cortical dysfunction in Parkinson's disease and for cortical myoclonus in general.     

Electrophysiological studies of myoclonus

As myoclonus is often associated with abnormally increased excitability of cortical structures, electrophysiological studies provide useful information for its diagnosis and classification, and about its generator mechanisms. The electroencephalogram-electromyogram polygraph reveals the most important information about the myoclonus of interest. Jerk-locked back-averaging and evoked potential studies combined with recording of the long-latency, long-loop reflexes are useful to investigate the pathophysiology of myoclonus further, especially that of cortical myoclonus. Recent advances in magnetoencephalography and transcranial magnetic stimulation have contributed significantly to the understanding of some of the cortical mechanisms underlying myoclonus. Elucidation of physiological mechanisms underlying myoclonus in individual patients is important for selecting the most appropriate treatment.     

A case of neuronal ceroid-lipofuscinosis (Jansky-Bielshowsky type): morphological, biochemical and electrophysiological studies (author's transl)

We reported a case of late infantile neuronal ceroid-lipofuscinosis. The patient was an 8-year-old boy presenting with marked psychomotor deterioration, progressive visual failure due to retinal degeneration and optic atrophy, startle reaction to auditory stimuli, frequent myoclonus and generalized convulsions. The routine laboratory examinations were all normal. EEG was markedly abnormal because of poorly organized background activity and frequent paroxysmal spike-and-wave complexes. CT scan showed evidence of severe atrophy of the cerebrum, cerebellum and brainstem. Electron microscopic examination of the biopsied rectum revealed fingerprint profiles in the neurons and pericytes beneath the muscularis mucosa. Cultured skin fibroblasts also contained electron dense inclusions, some of which showed fingerprint profiles. Urinary glycopeptides were normal. Lyscsomal enzyme activities in leukocytes and cultured fibroblasts were normal. Neurophysiological studies revealed giant cortical potentials evoked by the auditory as well as somatosensory stimulation. Simultaneous recording of the somatosensory evoked EEG and EMG potentials disclosed that the myoclonus in this patient was stimulus-sensitive and compatible with the cortical reflex myoclonus. With regard to hypothetical pathogenesis of this disease, we studied lipoperoxide in the blood before and after anti-oxidant therapy. We also measured vitamin A and carotene, since these substrates are related to retinoic acid. Although vitamin A and carotene were normal, lipoperoxide was slightly elevated. However, it was not influenced by the treatment with anti-oxidant. Significance of elevated lipoperoxide to the pathogenesis of this diseases has not solved.     

Unilateral involuntary movement associated with streptococcal infection: neurophysiological investigation

Two boys developed rhythmic involuntary movements in the extremities on one side of the body after febrile illness. They also showed behavioral disturbances. In both patients, serum antistreptolysin-O and antistreptokinase titers were elevated in acute illness and decreased a few months later. One patient showed tremorous movement, and the other choreiform movement. In the former, a surface EMG showed short-duration (30 to 60 ms), highly frequent (6 to 8 Hz) and synchronous discharges of multiple muscles, including the antagonists, suggesting myoclonic jerk. In the latter, a surface EMG showed long-duration (0.5 to 1 s), repetitive (about 0.5 Hz) and synchronous or asynchronous discharges of the antagonists, suggesting choreoathetosis. In both patients, giant somatosensory evoked potentials and high-voltage slow EEG activities were observed predominantly in the hemisphere contralateral to the involuntary movement. In the myoclonic patient, long-latency EMG responses were enhanced and cortical potentials preceding the myoclonus were present by jerk-locked back averaging technique. The present data suggest that unilateral rhythmic involuntary movements occur secondary to streptococcal infection. The pathophysiology of the involuntary movements may be associated with sensorimotor cortex hyperexcitability.     

Photic cortical reflex myoclonus

Three patients with flash-evoked myoclonus were studied electrophysiologically. Myoclonic jerks were elicited at a fixed latency after the application of photic stimuli and were always preceded at a fixed time interval by extremely enhanced cortical evoked potentials. The enhanced electroencephalographic (EEG) responses to flash were widely distributed over the scalp and were maximal at the central region; the occipital response preceded the frontocentral response by 3.4 to 5.1 msec. The interval from the frontocentral EEG response to the flash-evoked myoclonus was similar to that from the giant somatosensory evoked potential to the electrically evoked myoclonus. Investigation of recovery of evoked cortical responses and of myoclonic jerks showed a period of extremely enhanced excitability of both central and peripheral phenomena following stimulus. All of these findings suggest a cortical reflex mechanism. The role of the occipital cortex in the pathogenesis of photic cortical reflex myoclonus remains to be elucidated.     

Cortical reflex myoclonus

Three patients with a type of myoclonus produced by intention and somatosensory stimulation were studied with electrophysiologic techniques. Each jerk typically affected only a few contiguous muscles; agonist and antagonist muscles were activated simultaneously with a simple electromyographic (EMG) burst lasting 10 to 30 msec. Cranial nerve muscles were activated in an order indicating that the signal to produce the myoclonus traveled down the brainstem. In action-induced jerks a negative transient in the electroencephalogram (EEG) from the contralateral sensorimotor cortex consistently preceded the jerk with a fixed latency. In reflex-induced jerks this negative transient could be recognized as a component of the sensory evoked potential. The types of myoclonus are reviewed and it is argued that this type of myoclonus is mediated in cerebral cortex and that the negative transient represents a paroxysmal depolarization shift (PDS). The myoclonus may result from hyperactivity of a component of the long-latency stretch reflex.     

Cortical tremor: a variant of cortical reflex myoclonus

Two patients with action tremor that was thought to originate in the cerebral cortex showed fine shivering-like finger twitching provoked mainly by action and posture. Surface EMG showed relatively rhythmic discharge at a rate of about 9 Hz, which resembled essential tremor. However, electrophysiologic studies revealed giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex and premovement cortical spike by the jerk-locked averaging method. Treatment with beta-blocker showed no effect, but anticonvulsants such as clonazepam, valproate, and primidone were effective to suppress the tremor and the amplitude of SEPs. We call this involuntary movement "cortical tremor," which is in fact a variant of cortical reflex myoclonus.     

Neurophysiological evaluation of sensorimotor functions of the leg: comparison of evoked cortical potentials following electrical and mechanical stimulation,long-latency muscle responses,and transcranial magnetic stimulation

Summary Twenty-two patients with localized lesions of the central nervous system (unilateral cerebral ischaemia, cervical myelopathy, spinal tumour, familial spastic paraplegia) underwent neurophysiological evaluation of sensorimotor deficits of the leg. Functional methods using muscle stretch as stimulus, i.e. long-latency muscle responses and cortical potentials evoked by dorsiflection of the foot, were compared with transcranial magnetic stimulation and somatosensory evoked cortical potentials following electrical stimulation of the posterior tibial nerve. The functional neurophysiological methods yielded no diagnostic superiority with respect to the procedures using artificial (i.e. magnetic and electrical) stimulation. However, in most cases of missing compound motor action potentials following transcranial magnetic stimulation or missing electrically evoked cortical potentials, the long-latency muscle responses still allowed quantitative assessment of sensorimotor function.     

Cortical reflex myoclonus in adult onset Huntington's disease]

We report a case of cortical reflex myoclonus in adult onset Huntington's disease (HD). The patient is a 51-year-old woman. Chorea and myoclonus were observed on her face and extremities. Neurophysiological tests showed C reflex and abnormal waves preceding myoclonus by jerk-locked back averaging method but no giant somatosensory evoked potential. Gene analysis revealed the prolongation of CAG repeats (13/44) in IT15 gene. Oral administration of clonazepam was transiently effective for myoclonus. We should inscribe that the cortical reflex myoclonus may exceptionally manifest in HD.     

Neurophysiology of myoclonus and progressive myoclonus epilepsies

The high temporal resolution of neurophysiological recordings makes them particularly suited to faithfully describing the time course of rapid events such as myoclonus and to precisely measure its time relationship with other related activities. In progressive myoclonus epilepsies (PMEs) polygraphy with simultaneous EMG‐EEG recordings is a crucial tool for defining the characteristic of myoclonic jerks their topography over different muscles (namely antagonists), their time course and relationship with vigilance muscle activation and stimulations. Moreover on polygraphic recordings it is possible to detect EEG activities associated to myoclonic jerks and define their time relationship with myoclonus thus differentiating cortical types of myoclonus from subcorticallly generated ones. Tanks to the back averaging technique non obvious time‐locked EEG potentials can be detected on polygraphy, furthermore in stimulus sensitive myoclonus the analysis can include the potential evoked by the somatosensory stimulus (SEP). The polygraphic recording also gives information on muscle activity suppression occurring after jerk or as pure negative myoclonus. Besides the time domain analysis, techniques based on frequency analysis have been developed to evaluate EEG‐EMG coherence. The neurophysiological techniques provide investigators and clinicians with an invaluable information to define the type of myoclonus and its generating circuitry thus substantially contributing in the diagnosis and management of PMEs.     

Negative myoclonus in Creutzfeldt-Jakob disease.

OBJECTIVE: To describe electrophysiological findings in a patient with Creutzfeldt-Jakob disease (CJD) showing negative myoclonus. METHODS AND RESULTS: We studied this CJD patient electrophysiologically, in comparison with two patients with cortical reflex positive myoclonus due to benign adult familial myoclonic epilepsy (BAFME). Spontaneous negative myoclonus was associated with periodic synchronous discharges (PSDs) on the electroencephalogram, but negative myoclonus could also be induced by electrical stimulation of the median nerve in the CJD patient. This patient showed giant somatosensory evoked potentials (SEPs) and enhanced C reflexes, and the duration of the induced EMG silences was found to be significantly correlated with the amplitude of cortical SEPs. The duration of silent periods (SPs) produced by magnetic stimulation of the motor cortex was extremely long. The study of recovery function of SEPs suggested that the excitability of the somatosensory cortex was decreased during a long post-stimulus period. These findings were clearly different from those of patients with BAFME. CONCLUSIONS: This CJD patient had two types of negative myoclonus; one was associated with PSDs and the other was cortical reflex negative myoclonus. The long-lasting decrease in excitability of the sensorimotor cortices after stimulation could be related to the occurrence of both types of negative myoclonus.     

Somatosensory evoked potentials in progressive supranuclear palsy

We report median and digital nerve somatosensory evoked potentials (SEPs) in 14 patients with probable progressive supranuclear palsy (PSP) along with transcortical long-loop reflexes, motor evoked potentials, and auditory startle responses. Enlarged cortical responses were found in 14 median and 13 digital nerve SEP studies, while long-loop reflexes were increased in only one patient. All motor evoked potential studies were normal. Auditory startle responses were either absent or reduced in 11 patients. The observed neurophysiological abnormalities may reflect cortical hyperexcitability but are distinct from those in other disorders associated with giant SEPs, such as progressive myoclonus epilepsy. A number of groups reported widespread cortical changes in addition to the characteristic subcortical neurofibrillary degeneration in post-mortem confirmed PSP. However, clinical features reflecting cortical dysfunction such as ideomotor apraxia and cortical sensory loss are uncommon in classical PSP. Furthermore, frontal lobe dementia which is frequently present in PSP patients, is thought to be of subcortical origin resulting from striato-frontal deafferentation. We propose that cortical neurofibrillary pathology may lead to subclinical intracortical disinhibition accounting for the enlarged cortical SEPs in PSP.     

Cortical reflex myoclonus in patients with the mitochondrial DNA transfer RNALys(8344) (MERRF) mutation

Five patients from three families with the syndrome of myoclonic epilepsy and ragged red fibres (MERRF), associated with the mitochondrial DNA point mutation at position 8344, were studied neurophysiologically to determine the characteristics of their myoclonus. The findings were those of cortical reflex myoclonus, with enlarged cortical somatosensory evoked potentials and late reflex responses to peripheral nerve stimulation. Electroencephalography showed paroxysmal spike and polyspike and wave discharges, with photic sensitivity. This pattern of electrophysiological abnormalities was uniform, despite considerable variation in severity of myoclonus. Although a consistent finding, cortical reflex myoclonus is not specific to MERRF amongst myoclonic syndromes.