aanem monograph #30 · 2010-08-11 · progressive myoclonic ataxia or progressive myoclonus...

AANEM Monograph #30

Electrophysiologic Studies of Myoclonus

Hiroshi Shibasaki, MD, PhD and Mark Hallett, MD

At the time of publication, the authors had nothing to disclose.

Reviewed and accepted by the 2003-2004 Education Committee of the American Association of Neuromuscular & Electrodiagnostic Medicine

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Copyright © February 2005

CME STUDY GUIDE AANEM Monograph #30

Electrophysiologic Studies of Myoclonus

Hiroshi Shibasaki, MD, PhD and Mark Hallett, MD EDUCATIONAL OBJECTIVES Myoclonus is one of the most frequently encountered involuntary movements in clinical neurology, but its pathophysiologic mechanisms have not been fully understood. After completion, the reader should be able to compare the currently available electrophyiologic techniques for clinically investigating myoclonus.

CERTIFYING ORGANIZATION The American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education (CME) for physicians and certifies that this CME activity was planned and produced in accordance with ACCME Essentials. CME CREDIT The AANEM designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Monographs published by the AANEM are reviewed every 3 years by the AAEM Education Committee for their scientific relevance. CME credit is granted for 3 years from the date of publish, review, or revision date. Individuals requesting credit for monographs that have been discontinued will be notified that CME credit is no longer available. INSTRUCTIONS

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AANEM MONOGRAPH 30 ABSTRACT: As myoclonus is often associated with abnormally increasedexcitability of cortical structures, electrophysiological studies provide usefulinformation for its diagnosis and classification, and about its generatormechanisms. The electroencephalogram–electromyogram polygraph re-veals the most important information about the myoclonus of interest. Jerk-locked back-averaging and evoked potential studies combined with record-ing of the long-latency, long-loop reflexes are useful to investigate thepathophysiology of myoclonus further, especially that of cortical myoclonus.Recent advances in magnetoencephalography and transcranial magneticstimulation have contributed significantly to the understanding of some of thecortical mechanisms underlying myoclonus. Elucidation of physiologicalmechanisms underlying myoclonus in individual patients is important forselecting the most appropriate treatment.

Muscle Nerve 31: 157–174, 2005

ELECTROPHYSIOLOGICAL STUDIES OF MYOCLONUS

HIROSHI SHIBASAKI, MD, and MARK HALLETT, MD

Human Motor Control Section, National Institute of Neurological Disorders and Stroke (NINDS),National Institutes of Health (NIH), Building 10, Room 5C432A, Bethesda, Maryland 20892-1428, USA

Myoclonus, one of the most commonly encoun-tered involuntary movements, is characterized bysudden, brief, jerky, shock-like movements involvingthe extremities, face, and trunk, without loss of con-sciousness.22,64 Most myoclonic jerks are caused byabrupt muscle contraction (positive myoclonus), butsimilar jerks are sometimes caused by sudden cessa-tion of muscle contraction associated with a silentperiod in the ongoing electromyographic (EMG)activity (negative myoclonus) (Fig. 1).1,2,65,93 Theterm myoclonus is derived from the original reportby Friedreich,23 who in 1881 reported a 50-year-oldman manifesting involuntary small muscle jerksmostly at rest, and called it “paramyoclonus multi-plex.” In 1988, Shibasaki61 reviewed electrophysio-

logical studies of myoclonus in a minimonograph forthe American Association of Electromyography andElectrodiagnosis, and this was revised in 2000.62 Inview of the rapid advance in understanding of thepathophysiology of myoclonus, especially owing tothe clinical application of transcranial magneticstimulation (TMS), it was decided to update themonograph again. Since most myoclonic jerks arenot pathognomonic of any particular disease, thismonograph discusses the pathophysiological issuesrelating to myoclonus in general, but not each indi-vidual disease causing myoclonus.

CLASSIFICATION OF MYOCLONUS

Myoclonus can be classified into three groups (cor-tical, subcortical, and spinal myoclonus) based onthe presumed physiological mechanism underlyingits generation.64 Cortical myoclonus is further classi-fied into three subtypes: spontaneous cortical myoc-lonus, cortical reflex myoclonus,31 and epilepsiapartialis continua (EPC). If EPC is defined as “con-tinuous muscle jerks of focal cortical origin,” thisphenomenon is seen in diverse conditions and isassociated with generalized convulsions in manycases.17 In this group, however, there is a uniquecondition characterized by continuous focal musclejerks not associated with generalized convulsions,and in this regard it is distinct from just a focal formof spontaneous or reflex cortical myoclonus. In viewof the fact that spontaneous or reflex cortical myoc-lonus also shares some common features with epi-lepsy,29 the terminology of EPC for this particular

This article was prepared and reviewed by the AANEM and did notundergo the separate review process of Muscle & Nerve.

Abbreviations: BAFME, benign adult familial myoclonic epilepsy; CBD, cor-ticobasal degeneration; CJD, Creutzfeldt–Jakob disease; DRPLA, denta-torubral-pallidoluysian atrophy; ECD, equivalent current dipole; EEG, electro-encephalogram; EMG, electromyogram; EPC, epilepsia partialis continua;HFOs, high-frequency oscillations; ISIs, interstimulus intervals; MEG, magne-toencephalogram; MERRF, myoclonus epilepsy with ragged-red fibers;OPCA, olivopontocerebellar atrophy; PME, progressive myoclonus epilepsy;PSDs, periodic synchronous discharges; SEPs, somatosensory evoked po-tentials; SSPE, subacute sclerosing panencephalitis; TMS, transcranial mag-netic stimulationKey words: electrophysiology; jerk-locked back averaging; magnetoen-cephalography; myoclonus; transcranial magnetic stimulationCorrespondence to: American Association of Neuromuscular & Electro-diagnostic Medicine, 421 First Avenue SW, Suite 300 East, Rochester, MN55902; e-mail: [email protected]

© 2004 American Association of Neuromuscular & Electrodiagnostic Medi-cine. Published by Wiley Periodicals, Inc.Published online 16 November 2004 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.20234

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 157

condition will be used instead of proposing a newterminology.

Most myoclonic jerks of cortical origin are stimulussensitive, being elicited by stimuli of a single or multi-ple modalities, and are thus called cortical reflex my-oclonus. Most patients presenting with cortical myoc-lonus have both positive and negative myoclonuswhich occur either independently of each other ortogether as a complex of the two kinds of myoclonus(Fig. 1). Cortical myoclonus is not disease-specific.54,64

It is most commonly seen in a group of diseases (“pro-gressive myoclonus epilepsy” or PME), and also seen inother diseases such as juvenile myoclonic epilepsy,post-anoxic myoclonus (Lance-Adams syndrome), cor-ticobasal degeneration (CBD),9,12,44,77,81 Alzheimer’sdisease,88 olivopontocerebellar atrophy (OPCA),58 ad-vanced Creutzfeldt–Jakob diseases (CJD), metabolicencephalopathy (particularly that due to uremia), Rettsyndrome,27 and celiac disease. PME is a heteroge-neous group of inherited disorders,3,46,66 including Un-verricht–Lundborg disease, Lafora disease, neuronalceroid lipofuscinosis, mitochondrial disorders (myoc-lonus epilepsy with ragged-red fibers or MERRF), sia-lidosis, dentatorubral-pallidoluysian atrophy (DRPLA),benign adult familial myoclonic epilepsy (BAFME)92

(also called familial cortical myoclonic tremor79 or fa-milial cortical tremor with epilepsy56), and Angelmansyndrome.28 Among these disorders, DRPLA andBAFME are especially common in Japan, although re-cently they have been reported from Western coun-tries. PME of unknown etiology can be diagnosed asprogressive myoclonic ataxia or progressive myoclonusepilepsy of unknown cause.46 Gene abnormalities havebeen identified in many disorders comprising PME,but the functional relationships with phenotypes suchas myoclonus, epilepsy, and progressive neuronal loss isnot completely understood.43

Subcortical myoclonus includes essential myoclo-nus, periodic myoclonus, dystonic myoclonus, reticularreflex myoclonus, startle syndrome, and palataltremor. Essential myoclonus is a nonprogressive disor-der not associated with any seizures or other neurolog-ical deficits, and probably includes several subtypeshitherto unclassified. Essential myoclonus usually oc-curs irregularly and is not stimulus sensitive. Therehave been a few reports of familial essential myoclonus.Periodic myoclonus is seen typically in patients withCJD, usually in association with periodic synchronousdischarges (PSDs) on electroencephalogram (EEG).Subacute sclerosing panencephalitis (SSPE) is alsocharacterized by periodic movement, but in this con-dition the movement is associated with a much slowermuscle contraction resembling dystonia rather than amyoclonic jerk. Palatal tremor corresponds to an invol-untary vertical oscillation of the soft palate, previouslycalled palatal myoclonus.21 Myoclonus of spinal cordorigin (spinal myoclonus) occurs either irregularly orquasi-periodically, and it can be repetitive at a rapidrate (rhythmic spinal myoclonus). Spinal myoclonus ofslowly repetitive (periodic) form may be stimulus sen-sitive. It tends to involve a group of muscles innervatedby a certain spinal segment (segmental myoclonus).Spinal myoclonus sometimes arises from a certain spi-nal segment and slowly spreads rostrally as well as cau-dally, probably being conducted through the proprio-spinal tract (propriospinal myoclonus).8,16

Clinical features of each group of myoclonus aresummarized in Table 1. This classification is impor-tant especially from the viewpoint of treatment, be-cause, regardless of the underlying diseases or etiol-ogies, cortical myoclonus is usually more severe thanmyoclonus of other categories, and patients withcortical myoclonus often develop generalized con-vulsive seizures.29,64

ELECTROPHYSIOLOGICAL STUDIES

Electrophysiological studies are useful in the evalu-ation of myoclonus, not only for confirming the

FIGURE 1. Electromyogram (EMG) correlates of cortical myoc-lonus, positive, negative, or combination of the two, recordedduring sustained muscle contraction from a patient with progres-sive myoclonus epilepsy (PME).

158 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005

clinical diagnosis but also for understanding the un-derlying physiological mechanisms.32 Since themajority of myoclonic jerks are believed to be causedby hyperexcitability of a group of neurons in certaincerebral structures, the relationship of myoclonicjerks with EEG activity is of primary importance inthe study of myoclonus. Since 1938 when Grinker etal.25 first reported a short train of EEG spikes asso-ciated with myoclonic jerks in two patients with fa-milial myoclonus epilepsy, polygraphic recordings ofEEG and EMG by using either an electroencephalo-graph or cathode ray oscilloscope have been widelyemployed. Since 1975, backward averaging of EEGtime-locked to the myoclonic EMG discharge (jerk-locked back averaging) has been used and foundeffective for detecting EEG correlates of myoclonusthat are otherwise unrecognizable, and also for in-vestigating the temporal and spatial relationship be-tween myoclonus and EEG activities.14,30,69 Negativemyoclonus of cortical origin also can be studied bythe same principle. Namely, the onset of negativemyoclonus can be detected as a sudden cessation ofEMG discharge (the beginning of the silent period)or by the aid of accelerometer, which is then used asa fiducial point for back averaging the simulta-neously recorded EEG (silent period-locked backaveraging).86 More recently, clinical application ofmagnetoencephalogram (MEG) has enabled us toinvestigate the cortical mechanisms involved in my-oclonus generation with relatively higher spatial res-olution than EEG.41,47–49,83,84 These previous studieshave analyzed the electrical or magnetic fields ofcortical potentials time-locked to muscle jerks. Bycontrast, Brown and colleagues6 applied the tech-nique for analyzing the correlation of rhythmic os-cillations of cortical activities with those of EMGdischarges (cortico-muscular coherence) to thestudy of myoclonus.

Since Dawson,19 in 1946, found an exaggeratedEEG response to electrical shocks delivered to theperipheral nerve in a patient with myoclonic epi-lepsy, somatosensory evoked potentials (SEPs) havebeen widely used for the study of myoclonus, and in

particular for stimulus-sensitive myoclonus. The re-flex jerk can often be recognized in the surface EMGas an enhanced, long-latency reflex in response tothe stimulus, referred to as a C reflex.20,78 In corticalreflex myoclonus, the enhanced EMG response ismediated by a transcortical reflex pathway; other“long loops” are possible in other types of myoclo-nus.

The role of the cerebral cortex in the pathogen-esis of myoclonus can be further investigated bystudying the cortical excitability change immediatelyafter a spontaneous myoclonus by employing thetechnique of jerk-locked evoked potentials73 and bycomparing its results with the recovery function ofevoked responses obtained by using a paired stimu-lation paradigm at variable interstimulus intervals(ISIs).60,75,85 The clinical application of TMS hasallowed the excitability changes of the motor cortexto be studied in patients with myoclonus by stimu-lating the cortex more directly than by previousmethods.10,11,45,57,87 This technique, however, shouldbe applied with great caution, especially in patientswith cortical myoclonus, in order to avoid causing ageneralized convulsion.

Electrophysiological techniques currently avail-able to study myoclonus are listed in Table 2, alongwith the main implication of each method.

EMG CORRELATES OF MYOCLONUS

Most myoclonic jerks can be easily diagnosed basedon clinical observation, but some are difficult todistinguish from other involuntary movements suchas tremor, chorea, and dystonia. In this situation,recording EMG discharges associated with involun-tary movements using surface electrodes is extremelyhelpful, because one of the most important charac-teristics of myoclonus is an abrupt and brief musclecontraction. For this purpose, EMGs are recorded byplacing a pair of disc or cup electrodes about 3 cmapart on the skin overlying each muscle. In a smallmuscle like adductor pollicis brevis, only one elec-trode can be placed over the muscle while another

Table 1. Clinical features of myoclonus.

Feature Cortical Subcortical Spinal

Movement Shock-like Less shock-like Can be shock-likeCondition Posture, movement Rest RestRhythmicity* Irregular, but often appears rhythmic Tend to be periodic Periodic or rhythmicStimulus sensitivity Highly sensitive Not sensitive Can be sensitive

*Periodic, slowly repetitive with clearly recognizable intervals between successive jerks; rhythmic, fast repetitive without clearly recognizable intervals betweensuccessive jerks.


electrode is placed over a tendon. It is extremelyimportant to discover by clinical observation themost active muscles from which the myoclonic jerkof interest can be recorded. The bandpass filter forEMG recording can be set to, for example, 50–1,000Hz. The use of a relatively high low-frequency filter,corresponding to a time constant of 0.003 s, is forexcluding movement artifacts, most of which are inthe low frequency range. It is useful to record EMGssimultaneously from multiple muscles, if possible,not only to demonstrate the distribution and spreadof myoclonic jerks, but also to discover the bestmuscle for subsequent analysis, especially for thepurpose of the jerk-locked back averaging.

Myoclonic jerks of cortical origin are character-ized by an extremely short duration of the EMGcorrelates, usually less than 50 ms (Fig. 2), whereasthose of subcortical origin (except reticular reflexmyoclonus) have EMG correlates of much longerduration. Cortical myoclonus, with the exception ofEPC, involves a variety of muscles, either indepen-dently or concurrently, and commonly involves ago-nist and antagonist muscles synchronously. In somecases, multichannel EMG recording from an extrem-ity can demonstrate spread of jerks from the proxi-mal to the distal muscles with the conduction veloc-ity approximately corresponding to that of alphamotor fibers5 (Fig. 3). Cortical myoclonus usuallyoccurs irregularly, but not infrequently it appears tobe rhythmic,7 especially in patients with familial cor-

tical myoclonic tremor,79 which was also reported bythe name of BAFME,92 cortical tremor,34,82 or famil-ial cortical tremor with epilepsy,56 and in those withCBD.9,12,44,77,81 When myoclonus consists of fre-quent, independent contraction of multiple smallmuscles of distal limbs, it is called minipolymyoclo-nus.89 Cortical myoclonus is usually stimulus sensi-tive, being elicited most commonly by tendon tap,posturing, and passive or volitional movement, andcan also be elicited by emotional excitation.

Negative myoclonus can also be identified clini-cally without difficulty if special attention is paid toits possibility, but as with positive myoclonus, therecording of its EMG correlates confirms the clinicalimpression. For this purpose, it is always importantto record EMGs not only in the resting condition butalso during isometric contraction of the correspond-ing muscles, most commonly from wrist extensormuscles while the wrists are maintained in extendedposition. In fact, even in a single patient, both posi-tive and negative myoclonus can be seen in variousproportions, either independently or in combina-tion (Fig. 1). When both forms of myoclonus occurin combination, the abrupt increase in muscle dis-charge (positive myoclonus) often precedes the on-set of the silent period (negative myoclonus), butoccasionally follows its offset.

In CJD, myoclonus is usually not stimulus sensi-tive and occurs continuously and quasi-periodicallyin the resting condition with time intervals rangingfrom 600–1,500 ms. It is often overlaid on a dystonicposture or associated with dystonic movement of thecorresponding extremity. The duration of each myo-clonic EMG discharge is usually longer than that ofcortical myoclonus, but it can be as short as in cor-tical myoclonus. The EMG discharges recorded fromthe same muscle may vary considerably in durationamong movements. Patients with CJD may also showtypical cortical reflex myoclonus in advanced stagesof the disease when PSDs tend to disappear and thebackground EEG activity becomes very low in ampli-tude.72 In this case, myoclonus is often elicited notjust by somatosensory stimulation but also by photicstimulation.72

Involuntary movements seen in patients withSSPE are associated with an EMG discharge of ste-reotyped waveform and long duration, resemblingdystonia, and occur periodically with regular inter-vals of 4–13 s.

Essential myoclonus is associated with EMG dis-charge of relatively long duration. Dystonic myoclonus,by definition, is characterized by EMG discharge ofmuch longer duration than cortical myoclonus.

Table 2. Electrophysiological studies of myoclonus.

Technique Implication/utility

EMG correlates Diagnosis and classificationEEG–EMG polygraph Relationship with cortical activityJerk-locked back averaging

of EEG and/or MEGDetection of myoclonus-related

cortical activity, and its temporaland spatial relationship tomyoclonus

Cortico-muscular coherence Relationship of rhythmicoscillations between sensori-motor cortex and muscledischarges

Evoked potentials ormagnetic fields

Cortical sensitivity to various stimuli

Paired stimulation evokedpotentials and long loopreflex

Recovery functions of corticalresponse and reflex myoclonus

Jerk-locked evokedpotentials

Cortical excitability changefollowing spontaneousmyoclonus

Transcranial magneticstimulation

Excitability of motor cortex

EEG, electroencephalogram; EMG, electromyogram; MEG,magnetoencephalogram.


Whether palatal or oculopalatal myoclonus be-longs to myoclonus in the narrow sense has longbeen controversial. The term “palatal tremor” isused more often instead, because the movement inthis condition is rhythmic and associated with anEMG discharge of as long as 400 ms, and hence doesnot appear shock-like. Palatal tremor is classifiedinto essential and symptomatic groups.21 Symptom-atic palatal tremor is caused by various lesions affect-ing the Guillain–Mollaret triangle in the brainstemor cerebellum, and is often associated with verticalocular movements or rhythmic limb movements,which appear to be a rhythmic oscillation ratherthan periodic movements. This involuntary move-

ment continues rhythmically at a rate of 60–180/min, and the symptomatic form is uninterruptedduring sleep whereas the essential form disappearsduring sleep.21 In essential palatal tremor, the in-volved muscle is the tensor veli palatini, whereas insymptomatic palatal tremor, it is the levator palatini.Therefore, the patient with essential palatal tremoroften complains of ear clicks.

Recording EMG from multiple muscles is alsouseful in the study of spinal myoclonus. Segmentalspinal myoclonus is characterized by simultaneousoccurrence of myoclonic jerks in a group of musclesinnervated by a certain spinal segment. Propriospi-nal myoclonus shows spread of myoclonic jerks from

FIGURE 2. Electroencephalogram–electromyogram (EEG–EMG) polygraphic records in a patient with progressive myoclonus epilepsy(PME) manifesting positive myoclonus in the hands at rest. Note that most myoclonic jerks are associated with a spike-and-wave complexon EEG. EEG recorded in reference to ipsilateral earlobe electrode, and negativity shown upward. ECR, extensor carpi radialis muscle;1st DI, first dorsal interosseous muscle; Rt, right.


a certain spinal segment to rostral as well as caudalsegments with a relatively slow speed of approxi-mately 10 m/s.

EEG CORRELATES OF MYOCLONUS

Simultaneous recording of EEG and EMG is basic yetimportant for the clinical study of any kind of myoc-lonus. This simple study serves as a guide to subse-

quent investigations by providing useful informationin terms of the approximate relationship between themyoclonus and EEG activities. Recording of the EEG–EMG polygraph before carrying out more sophisti-cated investigations is most effective and time-saving,because the polygraph reveals which muscles are mostcommonly involved by the myoclonic jerks of interest.

The EEG can be recorded from electrodesplaced mainly over the central areas, using either abipolar or referential derivation with earlobe refer-ence. The band pass setting may be the same as theone used for recording the conventional EEG (e.g.,0.5–500 Hz). The low-frequency (high-pass) filter ofthis setting corresponds to a time constant of 0.3 s.Since most myoclonic jerks of cortical origin arederived from the sensorimotor cortex, the centralregion should be covered by at least three elec-trodes, including C3, Cz, and C4 of the International10-20 System. It is more efficient to record frommultiple electrodes simultaneously (as far as theequipment allows) because this provides better spa-tial information and helps in distinguishing artifactssuch as eye blinks, EMG, and body movements. DigitalEEG equipment is extremely useful for this kind ofpolygraphic recording because it allows off-line analysisof the stored data after the actual recording by modi-fying various recording conditions such as electrodemontage, paper speed, and filter setting as necessary.

In cortical myoclonus, the EEG usually showsmultifocal or generalized spike-and-wave or multiplespike-and-wave discharges with or without associatedmyoclonus (Fig. 2). On the conventional polygraph,however, the temporal and spatial relationship be-tween myoclonus and its EEG correlate is often dif-ficult to determine quantitatively.

Negative myoclonus of cortical origin may also beassociated with an EEG spike or spike-and-wave com-plex (Fig. 4).1,2,42,53 Again, however, it is difficult todetermine precisely the temporal and spatial rela-tionship between the EMG silent period and theassociated EEG spike on the conventional poly-graph. Furthermore, since the silent period tends tobe preceded or followed by an abrupt EMG dis-charge (positive myoclonus), it is often difficult tojudge whether the detected EEG spike is directlyrelated to the positive or negative component of theEMG discharge.

In CJD, the periodic myoclonus is frequently as-sociated with PSDs in the EEG with somatotopicrelationship of various degrees between the two phe-nomena.70 These two phenomena may appear syn-chronously, but in some cases or at a certain stageof the disease in individual cases, either periodicmyoclonus or PSD alone may be seen; even when

FIGURE 3. Records of jerk-locked back averaging obtained fromthe same patient as shown in Figure 2. Surface electromyograms(EMGs) were recorded from four different muscles of the right(Rt) upper extremity (see Fig. 2 for abbreviations), and the onsetof the EMG discharge from the right thenar muscle was used asa trigger pulse to back average multichannel electroencephalo-grams (EEGs). EEG recorded in reference to ipsilateral earlobeelectrode. A positive–negative, biphasic EEG spike is seen max-imally near the midline vertex, slightly shifted to the left (C1–Cz),and widespread over the scalp. Note that the myoclonic EMGdischarge, which was also averaged with respect to the samefiducial point, spreads rapidly from the proximal muscles to thedistal ones.


they appear concurrently, there may be a signifi-cant amount of jitter between the onset of theEMG discharge and that of the PSD. In SSPE, theinvoluntary movement is constantly associated withperiodic, high-amplitude EEG discharges of stereo-typed waveform. In this condition, the temporal andspatial relationship between the central and periph-eral activities is quite constant among the periodicphenomena in each individual case.55

Essential myoclonus and dystonic myoclonus arenot associated with any EEG abnormality. Patientswith palatal tremor do not show any EEG abnormal-ity, unless accompanied by other cerebral diseases.

JERK-LOCKED BACK AVERAGING

Jerk-locked back averaging is essentially an extensionof the EEG–EMG polygraph, and its principle is toback average the simultaneously recorded EEGs withrespect to myoclonus. Recording can be done withthe patient placed either in the sitting, reclining, orsupine position, depending on the patient’s condi-tion. Surface EMGs are recorded by using exactly thesame method as used for recording with the EEG–EMG polygraph. The filter setting of 50–1,000 Hzcan be used. The amplified EMG is preferably recti-fied or rectified and integrated to obtain a triggerpulse, but the onset of the amplified EMG itself (rawdata) may be also used. In the case of negative

myoclonus, the movement may be monitored by anaccelerometer, so that the onset of its signal can beused as a fiducial point for averaging (Fig. 4).63,86

The recording of EEGs for the purpose of jerk-locked back averaging is also based on the conven-tional EEG–EMG polygraph. When jerks are re-corded from an upper extremity, electrodes shouldbe placed at least over the hand motor-area on eachhemisphere. A point 2 cm in front of the somatosen-sory hand area is used as the hand motor-area, whichfor practical purposes can be substituted by C3 andC4 of the International 10-20 System. Likewise, thevertex electrode (Cz) is used for studying myoclonusof a lower extremity. It is useful to record from theCz electrode regardless of the site of EMG recording,because the midline vertex serves as an importantlandmark for studying the scalp distribution of themyoclonus-related EEG activity. Additional elec-trodes may be applied depending on the location ofthe jerks. The electrode impedance should be keptbelow 5 kohm. Either common referential deriva-tions with reference to the earlobe electrode or bi-polar derivations, or both, can be adopted. Thebandpass filter may be set to 0.5–1,000 Hz.

The analysis window may be freely determineddepending on the purpose of the study, but usually itis set to 200 ms before and 200 ms after the myoc-lonus onset. The number of sweeps is again flexible,

FIGURE 4. Electroencephalogram–electromyogram (EEG–EMG) polygraphic records in a patient with Lennox–Gastaut syndrome,manifesting negative myoclonus in both hands. Note that negative myoclonus documented by accelerometer from the right (Rt) hand isassociated with the silent period on the EMG, and that the negative myoclonus with the longest silent period in this record is associatedwith a clear spike-and-wave on EEG. A1, left earlobe electrode; A2, right earlobe electrode; ECR, extensor carpi radialis muscle; FCR,flexor carpi radialis muscle; Lt, left; Rt, right.


but 50 sweeps per session are usually sufficient todemonstrate the myoclonus-related EEG activity, ifthere is any. Just like conventional evoked potentials,it is recommended to confirm the reproducibility ofthe results by repeating the session at least twice foreach muscle. When the high-frequency filter is set to1,000 Hz, a minimal sampling rate of 2,000 Hz isrequired for analog-to-digital conversion.

In spontaneous cortical myoclonus or corticalreflex myoclonus, this technique can disclose a my-oclonus-related EEG activity that may not be recog-nizable on the conventional polygraph.63,69 Morecommonly, this technique is used to study the pre-cise interval from the EEG activity to the myoclonusas well as to study the scalp distribution of the my-oclonus-related EEG activity based on simultaneousmultichannel recordings.30,74,75 Epilepsia partialiscontinua is a good clinical indication for applyingthis technique.13,15,18

In myoclonus of cortical origin, the jerk-lockedback averaging technique commonly discloses a posi-tive–negative, biphasic spike at the central electrodessomatotopically corresponding to the muscle fromwhich the myoclonus is recorded (Fig. 3). The initialpositive peak of the EEG spike precedes the onset ofmyoclonic EMG discharge of a hand muscle by ap-proximately 20 ms. The more distal the muscle fromwhich the myoclonus is recorded, the longer is theEEG–EMG time interval, and vice versa.74,75 Thewidespread distribution of the myoclonus-relatedEEG activity, as seen in Figure 3, may be related, atleast partially, to the involvement of multiple mus-cles by the myoclonus with a short time delay. In thisregard, Brown and colleagues5 postulated, based onclinical electrophysiological studies, that the myoc-lonus-related cortical discharge may spread throughthe motor cortex within one hemisphere as well as tothe homologous area of the contralateral motor cor-tex transcallosally.

Another cause of the widespread distribution ofthe myoclonus-related EEG activity is, as with anyother high-voltage EEG activity, the shunt effect dueto different electrical conductivity of the tissues cov-ering the cerebral cortex, such as spinal fluid andskull. In this respect, since magnetic fields generatedfrom the cerebral cortex theoretically are not influ-enced by those surrounding structures, MEG oftenenables the source of the myoclonus-related corticalactivities to be investigated more easily and moreaccurately than EEG. Uesaka and colleagues83 stud-ied seven patients with cortical reflex myoclonusincluding one with EPC by using an MEG systemequipped with 37 channel axial gradiometers, andshowed that the cortical activity preceding myoclo-

nus was localized in the postcentral gyrus in fivepatients; exceptions were a patient with EPC whoshowed the source in the precentral gyrus and an-other patient with cortical reflex myoclonus whoshowed two sources, one in the precentral and theother in the postcentral gyrus. Mima and col-leagues47 studied six patients with cortical myoclo-nus by applying the technique of jerk-locked backaveraging to the magnetic fields which were re-corded by using a whole-head MEG system with pla-nar gradiometers, and also to the simultaneouslyrecorded EEGs. They detected the pre-myoclonuscortical activity on MEG in all cases (Fig. 5). In fact,

FIGURE 5. Magnetic fields back averaged with respect to the onsetof myoclonus of the left hand in a patient with progressive myoclo-nus epilepsy (PME). Note that the myoclonus-related activity islocalized at the right central region (a). A biphasic cortical activityprecedes the myoclonus onset (vertical line) followed by post-my-oclonus activity (b). The onset and peak of the spike precede theonset of EMG recorded from the left wrist extensor muscle by 21and 11 ms, respectively. The contour map of the earliest peak (c)suggests the location of the equivalent current dipole (ECD) in the rightcentral area with the intracellular current flow directed posteriorly. JLF,jerk-locked field. (From Mima and colleagues47 with permission.)


in two cases including a case of corticobasal degen-eration, the myoclonus-related activity was detectedonly on the back-averaged MEG, and not on theEEG. They further identified the equivalent currentdipole (ECD) for the myoclonus-related activity inthe precentral gyrus in all cases. The discrepantresults between these studies47,83 might be due to thedifferent gradiometers used (axial vs. planar), differ-ent methods of data analysis, and different popula-tion of patients. As Mima and colleagues47 recordedMEG and EEG simultaneously, and thus could cor-relate the averaged waveforms between the two, andas they could estimate the direction of intracellularcurrent flow in the apical dendrite of pyramidalneurons for each dipole source, it is reasonable topostulate based on their data that cortical myoclonusin most cases is generated in the primary motorcortex.

Theoretically, MEG can record only the currentflow which is oriented tangentially with respect tothe head surface, whereas EEG can record both thetangentially and radially oriented current sources.However, MEG allows us to estimate the direction ofthe intracellular current flow or, in other words, thesite of depolarization in the apical dendrite of largepyramidal neurons in the cerebral cortex. In thereport by Mima and colleagues,47 in four cases whoseEEG showed a positive–negative biphasic activity, theMEG demonstrated a posteriorly directed currentflow in the precentral gyrus, suggesting the depolar-ization in the deep layer of the apical dendrite of thepyramidal neurons in the anterior bank of the cen-tral sulcus (area 4). In the remaining two cases,whose EEG showed a monophasic negative activitylocalized to the contralateral central region, theMEG showed an anteriorly directed current flow inthe precentral gyrus, suggesting the depolarizationin the superficial layer of the apical dendrite (Fig. 6of Mima and colleagues47).

Periodic myoclonus seen in CJD seems to be linkedonly loosely with PSD, if any, because a negative sharpwave demonstrated by back-averaging EEGs time-locked to the myoclonus is much smaller than the PSDwhich is seen on the raw EEG. As described previously,this is most likely due to significant time jitter betweenthe central and peripheral activities. Moreover, thePSD precedes the onset of myoclonus of an upperextremity by 50 to 85 ms, which is too long for impulseconduction from the primary motor cortex to the pe-ripheral muscle via the corticospinal tract.70 In an au-topsy-proven case of Gerstmann–Straussler–Scheinkerdisease which clinically manifested myoclonus but didnot show any PSD on the routine EEG, jerk-lockedback averaging disclosed a sharp negative potential

time-locked to the myoclonus, which seems to corre-spond to PSD in terms of the waveform and scalpdistribution.70

Wilkins and colleagues89 reported a group ofpatients whose myoclonic jerks were generally ofsmall amplitude and multifocal (minipolymyoclo-nus), preceded by a bilaterally synchronous, fronto-centrally predominant, negative slow wave. They pro-posed the term “primary generalized epilepticmyoclonus” for this condition.

Essential myoclonus is not associated with anyspecial EEG activity, even if the jerk-locked averagingtechnique is applied.74 Dystonic myoclonus is usuallynot accompanied by any EEG correlates with anexception of that seen in SSPE, in which case thequasi-periodic dystonic myoclonus is closely linkedwith the EEG complexes.55 Palatal or oculopalatalmyoclonus (palatal tremor) and spinal myoclonushave no special EEG correlates.

CORTICO-MUSCULAR COHERENCE

This analysis is also based on the simultaneous re-cording of EEG and EMG while myoclonic jerks inquestion are frequently occurring, and is expressedas a correlation of rhythmic activities of certain fre-quency bands between EEG and EMG. By applyingthis analysis method to patients with cortical myoc-lonus, Brown and colleagues6 found an abnormallyincreased coherence for a much higher frequencyrange. In addition, EEG–EMG coherence for thefrequency band of around 20 Hz, which is seen innormal subjects during sustained muscle contrac-tion, was also found. By contrast to the conventionalmethod of jerk-locked back averaging, which re-quires averaging of a considerable number of sweepsand hence takes a relatively long time (although itdepends on the patient’s condition), this analysismethod can be applied to a relatively short segmentof the EEG–EMG polygraph. However, since therecording is usually performed during sustainedmuscle contraction, the results of analysis inevitablycontain the background activities due to voluntarymuscle contraction in addition to the activities di-rectly related to myoclonic jerks. Brown and col-leagues6 have reported that an abnormal EEG–EMGcoherence can be found in some cases where backaveraging was unrevealing. They applied this tech-nique to five patients with clinically probable CBD,and found negligible cortico-muscular coherencedespite a dramatically exaggerated EMG–EMG co-herence up to approximately 60 Hz between fingerextensors and first dorsal interosseous muscles onthe more affected side.26 Based on this finding, they


proposed that myoclonus in this condition might notbe due to an exaggerated cortical drive.

EVOKED RESPONSES

For recording SEPs, the conventional method can beadopted. Electrical shocks are delivered to the me-dian nerve at the wrist as a square-wave pulse of0.2–0.5 ms duration at a rate of, for example, 1–2Hz. The stimulus strength is adjusted to 10%–15%above the motor threshold, but in some patients with

cortical reflex myoclonus, the motor threshold isdifficult to determine accurately because of signifi-cantly lowered threshold of the long-latency reflex,which obscures the direct motor response (M wave).

In most patients with cortical reflex myoclonus,the SEP to electrical stimulation of the peripheralnerve shows a characteristic waveform, its main fea-ture being an extreme enlargement of early corticalcomponents (Fig. 6). Actually, a marked enlarge-ment of SEP in those patients enables its constituent

FIGURE 6. Somatosensory evoked potential (SEP) waveforms following electrical stimulation of the left median nerve (LMN Stim) at wristin a patient with Lafora disease presenting with progressive myoclonus epilepsy (PME) (top), and the scalp topography of two peaks(bottom). Four peaks are clearly distinguishable: N20/P20, P25, N30/P30, and N35. N30/P30 shows a similar distribution to N20/P20 (notshown here), although with opposite polarity. A1, left earlobe electrode. Negativity shown upward. (From Ikeda and colleagues35 withpermission.)


components to be distinguished more easily than thenormal SEP.35,71 The initial component, which con-sists of a postcentral negative peak N20 and a pre-central positive peak P20, is usually not en-hanced.38,59,74,75 In MEG recording, however, themagnetic field corresponding to this initial SEP peak(N20m) is also enlarged in some cases, although to amuch lesser degree than other components.41,48 Thesubsequent components are clearly enlarged to avariable degree depending on the patient. The sec-ond identifiable peak (P25) shows a single positivefield at the contralateral central region, suggesting acurrent flow which is radially oriented with respectto the head surface (Fig. 6). The third component isa complex consisting of a precentral negative peak(N30) and a postcentral positive peak (P30), suggest-ing a probable current flow situated in the posteriorbank of the central sulcus and tangentially orientedwith respect to the head surface. The fourth compo-nent is a negative peak (N35) which shows a similarscalp distribution to that of P25. In fact, the ampli-tude of these components in patients with corticalmyoclonus can be more than 10 times as large as thenormal value.38,74,75 Scalp topography of each com-ponent suggests that the giant SEP may result froman excessive enhancement of physiological compo-nents of the normal SEP, instead of occurrence of anabnormal component.38,71

The study of the somatosensory evoked magneticfields in patients with cortical or cortical reflex my-oclonus discloses abnormalities of the somatosen-sory areas with relatively high temporal and spatialresolution.41,48,80,84 Among the somatosensory areas,only the primary somatosensory cortex (SI) is hyper-excitable in those cases, whereas the second somato-sensory area (SII), located in the upper bank of thesylvian fissure with bilateral innervation, is not.48

Furthermore, within the SI, area 3b, which receivesmainly a tactile input, is most sensitive. By applyingan instrument devised to activate proprioceptive re-ceptors selectively,50 Mima and colleagues49 showedthat area 3a, which receives a proprioceptive input, isalso sensitive in those patients. As for nociceptiveinput, by applying a CO2 laser beam, which selec-tively activates the nociceptive receptors, Kakigi andcolleagues39 showed that the pain SEP is not en-hanced in patients with cortical reflex myoclonuseven when they show giant SEP in response to elec-trical stimulation of peripheral nerves. Until re-cently, it has been believed that the nociceptive in-puts are received mainly in the SII.51,90,91 RecentMEG as well as electrocorticographic studies clearlydemonstrate that the SI also receives the nociceptiveinput.37,40 It is especially noteworthy that, within the

SI, its crown (probably the area 1) was shown to bethe main receptive field of the nociceptive input.37,40

Thus the current consensus is that areas 3b and 3a,but not area 1, are hyperexcitable in cortical reflexmyoclonus.

The ECD of the initial peak of the somatosensoryevoked magnetic fields (N20m) is localized in theposterior bank of the central sulcus, most likely inarea 3b. As for the next SEP component (P25) or itsMEG counterpart (P25m), which is clearly enlargedin the patients with cortical or cortical reflex myoc-lonus (Fig. 7), its dipole source is usually identifiedin the precentral gyrus (Fig. 8).48 In this case, theintracellular current flow in the apical dendrite ofthe pyramidal neurons is estimated to be directedposterolaterally, suggesting that it represents the de-polarization in the deep layer of the apical dendritesituated either in the anterior bank of the centralsulcus (area 4) or in the crown of the precentralgyrus. As for the mechanism of detection by MEG ofa radially oriented dipole in the crown (which theo-retically cannot be recorded as magnetic fields fromthe head surface), it is conceivable that the tangen-tial vector of the radially oriented dipole is picked upas an MEG signal as a result of its extreme enlarge-ment.48 This contrasts with the generator mecha-nism of N20 or N20m which shows anteromediallydirected intracellular current flow in the postcentralgyrus (area 3b), indicating depolarization occurringin the deep layer of the tangentially oriented apicaldendrite of the somatosensory neurons in that area.

Since the giant SEP is not seen in other types ofmyoclonus, its demonstration is clinically significantfor supporting the clinical diagnosis of cortical orcortical reflex myoclonus. However, short-latencySEP components, which occur within 20 ms aftermedian nerve stimulation at the wrist and are knownto be generated in subcortical structures, are notenhanced in any type of myoclonus.

Patients with photosensitive myoclonus show gi-ant evoked potentials at occipital as well as fronto-central electrodes in response to flash stimulation.72

Questions as to where in the frontal lobe this ante-rior response is generated, and whether the anteriorresponse is mediated by the primary occipital re-sponse or the result of direct input from the thala-mus to the frontal cortex remain to be elucidated.

Besides the analysis of evoked electrical or mag-netic fields following peripheral stimulation, thechange of cortical rhythmic oscillations followingstimulation can also be analyzed. Silen and col-leagues76 studied rhythmic oscillations over the handarea of the sensorimotor cortex following electricalstimulation of the median nerve. In normal subjects,


they found a small transient decrease followed by arebound increase of 20 Hz oscillations, but this re-bound increase was absent in patients with Unver-richt–Lundborg type PME.76 They ascribed the lackof 20 Hz rebound to decreased cortical inhibition.Recently, high-frequency oscillations (HFOs) of sev-eral hundred hertz and their abnormality in variousmovement disorders have drawn increasing atten-tion. Mochizuki and colleagues52 studied the so-matosensory evoked HFOs in four patients with my-oclonus epilepsy, and found enhancement of lateHFOs of 600–750 Hz frequency range.

LONG-LOOP REFLEX

The long-latency, long-loop reflex can be recordedusing the same EMG electrode placement as used forjerk-locked back averaging. Modality of the stimulusis selected based on clinical observation, but electri-cal shocks delivered to the median nerve at the wristare most commonly used. In this case, the EMGresponse is best recorded from the thenar muscle ofthe stimulated hand, but can be recorded also from

other muscles of the stimulated upper extremity oreven from those of the nonstimulated extremitieswith different latencies. When studying the long-loop reflex, it is extremely important and effective torecord cortical evoked potentials simultaneously.

In cortical reflex myoclonus, a markedly en-hanced long-latency reflex is usually recorded fromthe thenar muscle at a latency of around 45 ms afterstimulation of the median nerve at the wrist.75 Thisenhanced long-loop reflex corresponds to the C re-flex named by Sutton and Mayer.78 Most patientsshow both giant SEPs and C reflex. In most cases ofcortical reflex myoclonus, the larger the SEP, themore conspicuous and widespread is the C reflex. Insome cases, however, these two phenomena do notnecessarily correlate with each other in terms ofmagnitude.59

In some patients, the enhanced C reflexes can berecorded also from more proximal muscles of thestimulated upper extremity with shorter latency andeven from the opposite (nonstimulated) hand mus-cle. In the latter case, the latency difference of C

FIGURE 7. Somatosensory evoked magnetic fields (MEG, magnetoencephalogram) and potentials (EEG, electroencephalogram)following electrical stimulation of the right median nerve at wrist in a patient with familial cortical myoclonic tremor. Lt, left. (By courtesyof Dr. Tatsuya Mima.)


reflexes between the left and right hand muscles is10 to 15 ms.74 This time lag seems to be compatiblewith the conduction time of the impulse between thehomologous cortical areas of two hemispheresthrough the corpus callosum.5

The time interval from the P25 peak of the giantSEP to the onset of the enhanced C reflex is similarto or slightly longer than the interval from the initialpositive peak of the myoclonus-related cortical spiketo the onset of the spontaneous myoclonus.74,75

Based on the similarity in time intervals as well as thescalp topography, the giant SEP and myoclonus-re-lated cortical spike are postulated to share at leastsome common physiological mechanisms.68,74,75

Long-latency, long-loop reflexes can be recordedfollowing the stimulus presentation of other modal-ities such as flash. Photic reflex myoclonus seems tobe mediated by the cerebral cortex. Because theonset latency of the occipital and frontal responses isaround 35 and 40 ms, respectively, and because theoccipital response is also enlarged, it is most likelythat the reflex arc involves the occipitofrontal path-way.72

Shibasaki and colleagues67 reported that in somepatients with cortical reflex myoclonus, electrical

stimulation of the median nerve at the extendedwrist elicited abrupt wrist drop associated with ashort interruption of the EMG discharges. Further-more, it was found that the larger the SEP, thelonger was the elicited EMG silent period, thus caus-ing more conspicuous wrist drop. Moreover, the si-lent period was also induced in the EMG of theopposite (nonstimulated) hand, particularly whenthe giant SEP was also recognized over the centralregion ipsilateral to the stimulus (Fig. 9). Thus, it wassuggested that this phenomenon might be a negativemyoclonus induced via the transcortical reflex path-way, and it was called “cortical reflex negative myoc-lonus” as a negative counterpart of the more con-ventional form of cortical reflex myoclonus, corticalreflex positive myoclonus.67 Negative myoclonus canbe induced by stimulation of other modalities aswell. Gambardella and colleagues24 reported a caseof photically induced epileptic negative myoclonus.

In reticular reflex myoclonus, the long-latencyreflex is enhanced, but cortical evoked potentials arenot enhanced. In this condition, the reflex myoclo-nus first involves bulbar muscles such as the sterno-cleidomastoid and trapezius muscles, and subse-quently the more rostral cranial muscles (such as thefacial muscles) and caudal muscles (such as limbmuscles) are involved.14,30 A great variability of thereflex latency among myoclonic jerks within an in-dividual subject seems to be characteristic of thisform of reflex myoclonus, indicating the necessityfor looking at individual responses to a single stim-ulus rather than averaging.

Spinal myoclonus, whether segmental or propri-ospinal, can be stimulus sensitive. In spinal myoclo-nus, therefore, it is worthwhile presenting variousmechanical stimuli, such as tapping the muscle ortendon, while recording EMGs from multiple mus-cles.

PAIRED STIMULATION EVOKED POTENTIALS ANDLONG-LOOP REFLEX

By employing a paired median nerve stimulationSEP technique with various ISIs in a patient withcortical reflex myoclonus, Dawson20 found a depres-sion of cortical excitability at a latency between 10and 30 ms, enhancement between 60 and 100 ms,and then another depression. Sutton and Mayer78

found a mild enhancement of cortical excitabilitybetween 32 and 63 ms and also between 130 and atleast 250 ms in a patient with focal cortical reflexmyoclonus. Simultaneous recording of long-latencyreflexes in a paired stimulation paradigm providesfurther information regarding the mechanism of

FIGURE 8. Equivalent current dipoles (ECDs) for the two peaks ofsomatosensory evoked magnetic fields (N20m and P25m) (see Fig.10) and for the cortical activity preceding myoclonus of the left hand(JLF, jerk-locked field), superimposed on the patient’s own MRI, inthe same patient as shown in Figure 10. The myoclonus-relatedcortical activity is located in the contralateral precentral gyrus, withits current flow directed posterolaterally, and so is the P25m of thesomatosensory response. The N20m is located in the postcentralgyrus, with its current flow directed anteriorly. C, central sulcus; L,left; R, right. (By courtesy of Dr. Tatsuya Mima.)


the reflex myoclonus. Demonstration of a shortperiod of enhanced cortical excitability following asingle stimulus supports the participation of the ce-rebral cortex in generation of that particular reflexmyoclonus,75,85 and furthermore, it may explain theoccurrence of two successive giant positive peaks ofSEPs and two successive C reflexes following a singlestimulus in some patients.

For recording the paired stimulation SEPs andlong-latency reflex, the same set-up used for record-ing the SEP and long-latency EMG reflex can beused. Any ISI can be chosen; for example, an initialinterval of 5 ms followed by a stepwise increase by 10ms up to 50 ms and then by 25 to 50 ms up to 200 ms.Paired stimulation in other modalities, such as flash,can also be employed.72

Subtraction of the response to a single stimulusfrom that to paired stimuli is usually necessary forobtaining a recovery function of cortical excitabil-ity, but when dealing with a giant evoked poten-tial, subtraction may not be needed except at veryshort ISIs.

JERK-LOCKED EVOKED POTENTIALS

This technique can be used to study whether there isany change in cortical excitability following a spon-taneous myoclonic jerk.73 The stimulus is presentedjust at the time of, or at varying intervals after, theonset of the EMG discharge associated with sponta-neous myoclonus. EEGs and the rectified EMG arethen averaged by using the EMG onset as a trigger. Acortical excitability curve after myoclonus can beobtained by comparing the amplitude of a certaincomponent of the evoked potentials thus recordedwith that of control evoked potentials obtained bypresenting the same stimulus with a random timerelationship to the myoclonus.

By using this technique in a patient with PME,Shibasaki and colleagues73 reported a similar en-hancement of cortical excitability of 20-ms durationimmediately after the myoclonus-related corticalspike, as well as after the giant SEP; the latter is beingstudied by the paired stimulation SEP technique.This finding supports the hypothesis that the myoc-

FIGURE 9. Giant somatosensory evoked potentials (SEPs) and surface electromyogram (EMG) silent periods induced by electricalstimulation of the left median nerve (LMN) at wrist during the sustained wrist extension in the same patient as shown in Figure 9. A singlesweep record. Note that the giant SEP is seen not only over the contralateral central (C4) and parietal (P4�) electrodes (N35c) but alsoover the ipsilateral central (C3) electrode (N35i) about 15 ms later, and the silent period (SP) is included not only in the wrist flexor andextensor muscles of the left upper limb (LFCU and LECR, respectively), but also in the right wrist extensor muscle (RECR). A1, leftearlobe electrode; C, C reflex. (From Shibasaki and colleagues67 with permission.)


lonus-related cortical activity in cortical reflex myoclo-nus is generated by a mechanism common to that ofthe giant SEP.75 In a patient with CJD, cortical excit-ability was suppressed between periodic myoclonicjerks or between consecutive PSDs, suggesting that theperiodicity might be related, at least partially, to arefractoriness of the cerebral cortex.73 In a patient withoculopalatal-somatic myoclonus (tremor) due to apontine lesion, there was no change of cortical excit-ability in relation to the rhythmic movements, suggest-ing that this type of involuntary movement is not re-lated to the excitability change of the cerebral cortex.73

TRANSCRANIAL MAGNETIC STIMULATION

For the last 15 years, the technique of TMS has beenapplied extensively to the investigation of pathophys-iology of various movement disorders.10 Since theexcitability change of the sensorimotor cortex is in-volved in many cases of cortical or cortical reflexmyoclonus as its physiological background, TMS isespecially useful for directly investigating the excit-ability change of the motor cortex. Reutens andcolleagues57 applied TMS preceded by electricalstimulation of the median nerve at various intervalsto patients with PME and found increased excitabil-ity at approximately 50 ms after the peripheral nervestimulation. Later, Cantello and colleagues11 usedthe same technique and found MEP facilitation at

ISIs of 34–60 ms. In order to elucidate the modalityspecificity of the peripheral stimulation, Manganottiand colleagues45 used electrical stimulation of digitalnerve delivered at three times the sensory thresholdfollowed by TMS in patients with PME. They foundfacilitation at ISI of 25–40 ms, whereas a significantMEP inhibition was seen from 25–50 ms in normalsubjects (Fig. 10). In contrast, Valzania and col-

FIGURE 10. Motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) following electrical stimulation of thedigital nerve by various interstimulus intervals (ISIs) in a healthy control subject (left) and in a patient with progressive myoclonus epilepsy(PME) (right). Note the enhancement of MEP by the conditioning stimulus given 20–50 ms before the TMS in the patient versus itssuppression in the normal subject. (From Manganotti and colleagues45 with permission.)

FIGURE 11. Motor evoked potentials (MEPs) elicited by pairedpulse transcranial magnetic stimulation (TMS) at interstimulusinterval (ISI) of 50 ms in a normal subject (upper trace) and in apatient with progressive myoclonus epilepsy (PME) (lower trace).Note a remarkable enhancement of excitability at 50 ms after theconditioning stimulus in the patient. (From Valzania and col-leagues87 with permission.)


leagues87 applied paired-pulse TMS at 110% of theresting motor threshold for both stimuli to patientswith PME, and found facilitation at 50 ms, in con-trast with normal subjects (Fig. 11). Brodtmann andcolleagues4 applied paired-pulse TMS to patientswith generalized epilepsy and found markedly en-hanced excitability in a patient with juvenile myo-clonic epilepsy when the second stimulus was given250 ms after the first. Hanajima and colleagues33

studied the supra-threshold conditioning TMS deliv-ered to the primary motor cortex’s effect on theexcitability of the opposite hemisphere’s primarymotor cortex in five patients with benign myoclonusepilepsy. They found an absence of the transcallosallate inhibition which is seen at ISI of 8–20 ms innormal subjects, suggesting an abnormal cortical in-hibitory mechanism in cortical myoclonus. Thus,TMS clearly shows abnormal excitability of the mo-tor cortex in cortical myoclonus.

CONCLUSION

Just like other involuntary movements, the study ofmyoclonus should start with careful clinical observa-tion with special attention directed to the site ofinvolvement, rhythmicity or periodicity, provokingfactors, stimulus sensitivity, mode of effective stimuliif stimulus sensitive, and accompanying neurologicalsigns. Electrophysiological studies as describedabove are useful to delineate further characteristicsof the myoclonus. The EEG–EMG polygraph is themost useful technique because it provides the mostimportant information about the myoclonus in eachpatient. Jerk-locked back averaging and evoked po-tential studies combined with recording of the long-latency, long-loop reflexes are then useful to clarifythe pathophysiology of myoclonus, especially that ofcortical myoclonus. Furthermore, these techniquescan be combined to investigate the precise role ofthe cerebral cortex in the generation of myoclonus.Recent advances in MEG techniques have contrib-uted significantly to the elucidation of some of thecortical mechanisms underlying myoclonus. Recentadvances in the application of TMS have greatlycontributed to the understanding of the motor cortexexcitability change in cortical myoclonus. Elucidationof physiological mechanisms underlying myoclonus ineach individual patient is important for selecting themost appropriate treatment of choice.36

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