Electrophysiological Studies of 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

. Certified for CME credit 2/2008 - 2/2011

AMERICAN ASSOCIATION OF NEUROMUSCULAR & ELECTRODIAGNOSTIC MEDICINE 2621 Superior Dr NW Rochester, MN 55901 The ideas and opinions in this monograph are solely those of the author and do not necessarily represent those of the AANEM.

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.

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INSTRUCTIONS 1. The reader should review this monograph. If further clarification is needed, the references should be consulted. Do not neglect illustrative material. 2. Complete the CME questions document by logging on to www.aanem.org and clicking View Profile, then clicking My Downloads. 3. You can access your CME transcript by logging on to www.aanem.org and clicking View Profile, then clicking My CME. 4. Review those parts of the monograph dealing with the question(s) you answered incorrectly, and read the supplemental materials listed in the references. AANEM MONOGRAPH 30 ABSTRACT: 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. 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- logical studies of myoclonus in a minimonograph for tered involuntary movements, is characterized by the American Association of Electromyography and sudden, brief, jerky, shock-like movements involving Electrodiagnosis, and this was revised in 2000.62 In the extremities, face, and trunk, without loss of con- view of the rapid advance in understanding of the sciousness.22,64 Most myoclonic jerks are caused by pathophysiology of myoclonus, especially owing to abrupt muscle contraction (positive myoclonus), but the clinical application of transcranial magnetic similar jerks are sometimes caused by sudden cessa- stimulation (TMS), it was decided to update the tion of muscle contraction associated with a silent monograph again. Since most myoclonic jerks are period in the ongoing electromyographic (EMG) not pathognomonic of any particular disease, this activity (negative myoclonus) (Fig. 1).1,2,65,93 The monograph discusses the pathophysiological issues term myoclonus is derived from the original report relating to myoclonus in general, but not each indi- by Friedreich,23 who in 1881 reported a 50-year-old vidual disease causing myoclonus. man manifesting involuntary small muscle jerks mostly at rest, and called it “paramyoclonus multi- CLASSIFICATION OF MYOCLONUS 61 plex.” In 1988, Shibasaki reviewed electrophysio- Myoclonus can be classified into three groups (cortical, subcortical, and spinal myoclonus) based on the presumed physiological mechanism underlying This article was prepared and reviewed by the AANEM and did not 64 undergo the separate review process of Muscle & Nerve. its generation. Cortical myoclonus is further classified into three subtypes: spontaneous cortical myoc- Abbreviations: BAFME, benign adult familial myoclonic epilepsy; CBD, cor- 31 ticobasal degeneration; CJD, Creutzfeldt–Jakob disease; DRPLA, denta- lonus, cortical reflex myoclonus, and epilepsia torubral-pallidoluysian atrophy; ECD, equivalent current dipole; EEG, electro- partialis continua (EPC). If EPC is defined as “con- encephalogram; EMG, electromyogram; EPC, epilepsia partialis continua; HFOs, high-frequency oscillations; ISIs, interstimulus intervals; MEG, magne- tinuous muscle jerks of focal cortical origin,” this toencephalogram; MERRF, myoclonus epilepsy with ragged-red fibers; phenomenon is seen in diverse conditions and is OPCA, olivopontocerebellar atrophy; PME, progressive myoclonus epilepsy; PSDs, periodic synchronous discharges; SEPs, somatosensory evoked po- associated with generalized convulsions in many tentials; SSPE, subacute sclerosing panencephalitis; TMS, transcranial mag- cases.17 In this group, however, there is a unique netic stimulation Key words: electrophysiology; jerk-locked back averaging; magnetoen- condition characterized by continuous focal muscle cephalography; myoclonus; transcranial magnetic stimulation jerks not associated with generalized convulsions, Correspondence to: American Association of Neuromuscular & Electro- diagnostic Medicine, 421 First Avenue SW, Suite 300 East, Rochester, MN and in this regard it is distinct from just a focal form 55902; e-mail: [email protected] of spontaneous or reflex cortical myoclonus. In view © 2004 American Association of Neuromuscular & Electrodiagnostic Medi- of the fact that spontaneous or reflex cortical myoc- cine. Published by Wiley Periodicals, Inc. Published online 16 November 2004 in Wiley InterScience (www.interscience. lonus also shares some common features with epi- wiley.com). DOI 10.1002/mus.20234 lepsy,29 the terminology of EPC for this particular

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 157 (also called familial cortical myoclonic tremor79 or familial cortical tremor with epilepsy56), and Angelman syndrome.28 Among these disorders, DRPLA and BAFME are especially common in Japan, although recently they have been reported from Western coun- tries. PME of unknown etiology can be diagnosed as progressive myoclonic ataxia or progressive myoclonus epilepsy of unknown cause.46 Gene abnormalities have been identified in many disorders comprising PME, but the functional relationships with phenotypes such as myoclonus, epilepsy, and progressive neuronal loss is not completely understood.43 Subcortical myoclonus includes essential myoclonus, periodic myoclonus, dystonic myoclonus, reticular reflex myoclonus, startle syndrome, and palatal tremor. Essential myoclonus is a nonprogressive disor- der not associated with any seizures or other neurological deficits, and probably includes several subtypes hitherto unclassified. Essential myoclonus usually occurs irregularly and is not stimulus sensitive. There have been a few reports of familial essential myoclonus. Periodic myoclonus is seen typically in patients with CJD, usually in association with periodic synchronous FIGURE 1. Electromyogram (EMG) correlates of cortical myoc- discharges (PSDs) on electroencephalogram (EEG). lonus, positive, negative, or combination of the two, recorded Subacute sclerosing panencephalitis (SSPE) is also during sustained muscle contraction from a patient with progres- characterized by periodic movement, but in this con- sive myoclonus epilepsy (PME). dition the movement is associated with a much slower muscle contraction resembling dystonia rather than a myoclonic jerk. Palatal tremor corresponds to an invol- condition will be used instead of proposing a new untary vertical oscillation of the soft palate, previously terminology. called palatal myoclonus.21 Myoclonus of spinal cord Most myoclonic jerks of cortical origin are stimulus origin (spinal myoclonus) occurs either irregularly or sensitive, being elicited by stimuli of a single or multi- quasi-periodically, and it can be repetitive at a rapid ple modalities, and are thus called cortical reflex my- rate (rhythmic spinal myoclonus). Spinal myoclonus of oclonus. Most patients presenting with cortical myoc- slowly repetitive (periodic) form may be stimulus sen- lonus have both positive and negative myoclonus sitive. It tends to involve a group of muscles innervated which occur either independently of each other or by a certain spinal segment (segmental myoclonus). together as a complex of the two kinds of myoclonus Spinal myoclonus sometimes arises from a certain spi- (Fig. 1). Cortical myoclonus is not disease-specific.54,64 nal segment and slowly spreads rostrally as well as cau- It is most commonly seen in a group of diseases (“pro- dally, probably being conducted through the proprio- gressive myoclonus epilepsy” or PME), and also seen in spinal tract (propriospinal myoclonus).8,16 other diseases such as juvenile myoclonic epilepsy, Clinical features of each group of myoclonus are post-anoxic myoclonus (Lance-Adams syndrome), cor- summarized in Table 1. This classification is impor- ticobasal degeneration (CBD),9,12,44,77,81 Alzheimer’s tant especially from the viewpoint of treatment, be- disease,88 olivopontocerebellar atrophy (OPCA),58 ad- cause, regardless of the underlying diseases or etiol- vanced Creutzfeldt–Jakob diseases (CJD), metabolic ogies, cortical myoclonus is usually more severe than encephalopathy (particularly that due to uremia), Rett myoclonus of other categories, and patients with 27 syndrome, and celiac disease. PME is a heteroge- cortical myoclonus often develop generalized con- 3,46,66 neous group of inherited disorders, including Un- vulsive seizures.29,64 verricht–Lundborg disease, Lafora disease, neuronal ceroid lipofuscinosis, mitochondrial disorders (myoc- ELECTROPHYSIOLOGICAL STUDIES lonus epilepsy with ragged-red fibers or MERRF), sia- lidosis, dentatorubral-pallidoluysian atrophy (DRPLA), Electrophysiological studies are useful in the evalu- benign adult familial myoclonic epilepsy (BAFME)92 ation of myoclonus, not only for confirming the

158 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 Table 1. Clinical features of myoclonus. Feature Cortical Subcortical Spinal Movement Shock-like Less shock-like Can be shock-like Condition Posture, movement Rest Rest Rhythmicity* Irregular, but often appears rhythmic Tend to be periodic Periodic or rhythmic Stimulus 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 between successive jerks.

clinical diagnosis but also for understanding the un- particular for stimulus-sensitive myoclonus. The re- derlying physiological mechanisms.32 Since the flex jerk can often be recognized in the surface EMG majority of myoclonic jerks are believed to be caused as an enhanced, long-latency reflex in response to by hyperexcitability of a group of neurons in certain the stimulus, referred to as a C reflex.20,78 In cortical cerebral structures, the relationship of myoclonic reflex myoclonus, the enhanced EMG response is jerks with EEG activity is of primary importance in mediated by a transcortical reflex pathway; other the study of myoclonus. Since 1938 when Grinker et “long loops” are possible in other types of myoclo- al.25 first reported a short train of EEG spikes asso- nus. ciated with myoclonic jerks in two patients with fa- The role of the cerebral cortex in the pathogen- milial myoclonus epilepsy, polygraphic recordings of esis of myoclonus can be further investigated by EEG and EMG by using either an electroencephalo- studying the cortical excitability change immediately graph or cathode ray oscilloscope have been widely after a spontaneous myoclonus by employing the employed. Since 1975, backward averaging of EEG technique of jerk-locked evoked potentials73 and by time-locked to the myoclonic EMG discharge (jerk- comparing its results with the recovery function of locked back averaging) has been used and found evoked responses obtained by using a paired stimu- effective for detecting EEG correlates of myoclonus lation paradigm at variable interstimulus intervals that are otherwise unrecognizable, and also for in- (ISIs).60,75,85 The clinical application of TMS has vestigating the temporal and spatial relationship be- allowed the excitability changes of the motor cortex tween myoclonus and EEG activities.14,30,69 Negative to be studied in patients with myoclonus by stimu- myoclonus of cortical origin also can be studied by lating the cortex more directly than by previous the same principle. Namely, the onset of negative methods.10,11,45,57,87 This technique, however, should myoclonus can be detected as a sudden cessation of be applied with great caution, especially in patients EMG discharge (the beginning of the silent period) with cortical myoclonus, in order to avoid causing a or by the aid of accelerometer, which is then used as generalized convulsion. a fiducial point for back averaging the simulta- Electrophysiological techniques currently avail- neously recorded EEG (silent period-locked back able to study myoclonus are listed in Table 2, along averaging).86 More recently, clinical application of with the main implication of each method. magnetoencephalogram (MEG) has enabled us to investigate the cortical mechanisms involved in my- EMG CORRELATES OF MYOCLONUS oclonus generation with relatively higher spatial resolution than EEG.41,47–49,83,84 These previous studies Most myoclonic jerks can be easily diagnosed based have analyzed the electrical or magnetic fields of on clinical observation, but some are difficult to cortical potentials time-locked to muscle jerks. By distinguish from other involuntary movements such contrast, Brown and colleagues6 applied the tech- as tremor, chorea, and dystonia. In this situation, nique for analyzing the correlation of rhythmic os- recording EMG discharges associated with involun- cillations of cortical activities with those of EMG tary movements using surface electrodes is extremely discharges (cortico-muscular coherence) to the helpful, because one of the most important charac- study of myoclonus. teristics of myoclonus is an abrupt and brief muscle Since Dawson,19 in 1946, found an exaggerated contraction. For this purpose, EMGs are recorded by EEG response to electrical shocks delivered to the placing a pair of disc or cup electrodes about 3 cm peripheral nerve in a patient with myoclonic epi- apart on the skin overlying each muscle. In a small lepsy, somatosensory evoked potentials (SEPs) have muscle like adductor pollicis brevis, only one elec- been widely used for the study of myoclonus, and in trode can be placed over the muscle while another

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 159 79 Table 2. Electrophysiological studies of myoclonus. tical myoclonic tremor, which was also reported by the name of BAFME,92 cortical tremor,34,82 or famil- Technique Implication/utility ial cortical tremor with epilepsy,56 and in those with EMG correlates Diagnosis and classification CBD.9,12,44,77,81 When myoclonus consists of fre- EEG–EMG polygraph Relationship with cortical activity quent, independent contraction of multiple small Jerk-locked back averaging Detection of myoclonus-related of EEG and/or MEG cortical activity, and its temporal muscles of distal limbs, it is called minipolymyoclo- and spatial relationship to nus.89 Cortical myoclonus is usually stimulus sensi- myoclonus tive, being elicited most commonly by tendon tap, Cortico-muscular coherence Relationship of rhythmic posturing, and passive or volitional movement, and oscillations between sensorimotor cortex and muscle can also be elicited by emotional excitation. discharges Negative myoclonus can also be identified clini- Evoked potentials or Cortical sensitivity to various stimuli cally without difficulty if special attention is paid to magnetic fields its possibility, but as with positive myoclonus, the Paired stimulation evoked Recovery functions of cortical recording of its EMG correlates confirms the clinical potentials and long loop response and reflex myoclonus reflex impression. For this purpose, it is always important Jerk-locked evoked Cortical excitability change to record EMGs not only in the resting condition but potentials following spontaneous also during isometric contraction of the correspond- myoclonus ing muscles, most commonly from wrist extensor Transcranial magnetic Excitability of motor cortex stimulation muscles while the wrists are maintained in extended position. In fact, even in a single patient, both posi- EEG, electroencephalogram; EMG, electromyogram; MEG, tive and negative myoclonus can be seen in various magnetoencephalogram. proportions, either independently or in combination (Fig. 1). When both forms of myoclonus occur in combination, the abrupt increase in muscle dis- electrode is placed over a tendon. It is extremely charge (positive myoclonus) often precedes the on- important to discover by clinical observation the set of the silent period (negative myoclonus), but most active muscles from which the myoclonic jerk occasionally follows its offset. of interest can be recorded. The bandpass filter for In CJD, myoclonus is usually not stimulus sensi- EMG recording can be set to, for example, 50–1,000 tive and occurs continuously and quasi-periodically Hz. The use of a relatively high low-frequency filter, in the resting condition with time intervals ranging corresponding to a time constant of 0.003 s, is for from 600–1,500 ms. It is often overlaid on a dystonic excluding movement artifacts, most of which are in posture or associated with dystonic movement of the the low frequency range. It is useful to record EMGs corresponding extremity. The duration of each myo- simultaneously from multiple muscles, if possible, not only to demonstrate the distribution and spread clonic EMG discharge is usually longer than that of of myoclonic jerks, but also to discover the best cortical myoclonus, but it can be as short as in cor- muscle for subsequent analysis, especially for the tical myoclonus. The EMG discharges recorded from purpose of the jerk-locked back averaging. the same muscle may vary considerably in duration Myoclonic jerks of cortical origin are character- among movements. Patients with CJD may also show ized by an extremely short duration of the EMG typical cortical reflex myoclonus in advanced stages correlates, usually less than 50 ms (Fig. 2), whereas of the disease when PSDs tend to disappear and the those of subcortical origin (except reticular reflex background EEG activity becomes very low in ampli- myoclonus) have EMG correlates of much longer tude.72 In this case, myoclonus is often elicited not duration. Cortical myoclonus, with the exception of just by somatosensory stimulation but also by photic EPC, involves a variety of muscles, either indepen- stimulation.72 dently or concurrently, and commonly involves ago- Involuntary movements seen in patients with nist and antagonist muscles synchronously. In some SSPE are associated with an EMG discharge of ste- cases, multichannel EMG recording from an extrem- reotyped waveform and long duration, resembling ity can demonstrate spread of jerks from the proxi- dystonia, and occur periodically with regular inter- mal to the distal muscles with the conduction veloc- vals of 4–13 s. ity approximately corresponding to that of alpha Essential myoclonus is associated with EMG dis- motor fibers5 (Fig. 3). Cortical myoclonus usually charge of relatively long duration. Dystonic myoclonus, occurs irregularly, but not infrequently it appears to by definition, is characterized by EMG discharge of be rhythmic,7 especially in patients with familial cor- much longer duration than cortical myoclonus.

160 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 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 complex on 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.

Whether palatal or oculopalatal myoclonus be- ment continues rhythmically at a rate of 60–180/ longs to myoclonus in the narrow sense has long min, and the symptomatic form is uninterrupted been controversial. The term “palatal tremor” is during sleep whereas the essential form disappears used more often instead, because the movement in during sleep.21 In essential palatal tremor, the in- this condition is rhythmic and associated with an volved muscle is the tensor veli palatini, whereas in EMG discharge of as long as 400 ms, and hence does symptomatic palatal tremor, it is the levator palatini. not appear shock-like. Palatal tremor is classiﬁed Therefore, the patient with essential palatal tremor into essential and symptomatic groups.21 Symptom- often complains of ear clicks. atic palatal tremor is caused by various lesions affect- Recording EMG from multiple muscles is also ing the Guillain–Mollaret triangle in the brainstem useful in the study of spinal myoclonus. Segmental or cerebellum, and is often associated with vertical spinal myoclonus is characterized by simultaneous ocular movements or rhythmic limb movements, occurrence of myoclonic jerks in a group of muscles which appear to be a rhythmic oscillation rather innervated by a certain spinal segment. Propriospi- than periodic movements. This involuntary move- nal myoclonus shows spread of myoclonic jerks from

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 161 quent investigations by providing useful information in terms of the approximate relationship between the myoclonus 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 most commonly involved by the myoclonic jerks of interest. The EEG can be recorded from electrodes placed mainly over the central areas, using either a bipolar or referential derivation with earlobe reference. The band pass setting may be the same as the one used for recording the conventional EEG (e.g., 0.5–500 Hz). The low-frequency (high-pass) filter of this setting corresponds to a time constant of 0.3 s. Since most myoclonic jerks of cortical origin are derived from the sensorimotor cortex, the central region should be covered by at least three electrodes, including C3, Cz, and C4 of the International 10-20 System. It is more efficient to record from multiple electrodes simultaneously (as far as the equipment allows) because this provides better spatial information and helps in distinguishing artifacts such as eye blinks, EMG, and body movements. Digital EEG equipment is extremely useful for this kind of polygraphic recording because it allows off-line analysis of the stored data after the actual recording by modi- fying various recording conditions such as electrode montage, paper speed, and filter setting as necessary. In cortical myoclonus, the EEG usually shows multifocal or generalized spike-and-wave or multiple spike-and-wave discharges with or without associated myoclonus (Fig. 2). On the conventional polygraph, FIGURE 3. Records of jerk-locked back averaging obtained from however, the temporal and spatial relationship be- the same patient as shown in Figure 2. Surface electromyograms tween myoclonus and its EEG correlate is often dif- (EMGs) were recorded from four different muscles of the right (Rt) upper extremity (see Fig. 2 for abbreviations), and the onset ficult to determine quantitatively. of the EMG discharge from the right thenar muscle was used as Negative myoclonus of cortical origin may also be a trigger pulse to back average multichannel electroencephalo- associated with an EEG spike or spike-and-wave com- grams (EEGs). EEG recorded in reference to ipsilateral earlobe plex (Fig. 4).1,2,42,53 Again, however, it is difficult to electrode. A positive–negative, biphasic EEG spike is seen max- determine precisely the temporal and spatial rela- imally near the midline vertex, slightly shifted to the left (C1–Cz), and widespread over the scalp. Note that the myoclonic EMG tionship between the EMG silent period and the discharge, which was also averaged with respect to the same associated EEG spike on the conventional poly- fiducial point, spreads rapidly from the proximal muscles to the graph. Furthermore, since the silent period tends to distal ones. be preceded or followed by an abrupt EMG discharge (positive myoclonus), it is often difficult to judge whether the detected EEG spike is directly a certain spinal segment to rostral as well as caudal related to the positive or negative component of the segments with a relatively slow speed of approxi- EMG discharge. mately 10 m/s. In CJD, the periodic myoclonus is frequently associated with PSDs in the EEG with somatotopic relationship of various degrees between the two phe- EEG CORRELATES OF MYOCLONUS nomena.70 These two phenomena may appear syn- Simultaneous recording of EEG and EMG is basic yet chronously, but in some cases or at a certain stage important for the clinical study of any kind of myoc- of the disease in individual cases, either periodic lonus. This simple study serves as a guide to subse- myoclonus or PSD alone may be seen; even when

162 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 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 is associated with the silent period on the EMG, and that the negative myoclonus with the longest silent period in this record is associated with 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. they appear concurrently, there may be a signifi- myoclonus, the movement may be monitored by an cant amount of jitter between the onset of the accelerometer, so that the onset of its signal can be EMG discharge and that of the PSD. In SSPE, the used as a fiducial point for averaging (Fig. 4).63,86 involuntary movement is constantly associated with The recording of EEGs for the purpose of jerk- periodic, high-amplitude EEG discharges of stereo- locked back averaging is also based on the conven- typed waveform. In this condition, the temporal and tional EEG–EMG polygraph. When jerks are re- spatial relationship between the central and periph- corded from an upper extremity, electrodes should eral activities is quite constant among the periodic be placed at least over the hand motor-area on each phenomena in each individual case.55 hemisphere. A point 2 cm in front of the somatosen- Essential myoclonus and dystonic myoclonus are sory hand area is used as the hand motor-area, which not associated with any EEG abnormality. Patients for practical purposes can be substituted by C3 and with palatal tremor do not show any EEG abnormal- C4 of the International 10-20 System. Likewise, the ity, unless accompanied by other cerebral diseases. vertex electrode (Cz) is used for studying myoclonus of a lower extremity. It is useful to record from the JERK-LOCKED BACK AVERAGING Cz electrode regardless of the site of EMG recording, Jerk-locked back averaging is essentially an extension because the midline vertex serves as an important of the EEG–EMG polygraph, and its principle is to landmark for studying the scalp distribution of the back average the simultaneously recorded EEGs with myoclonus-related EEG activity. Additional elec- respect to myoclonus. Recording can be done with trodes may be applied depending on the location of the patient placed either in the sitting, reclining, or the jerks. The electrode impedance should be kept supine position, depending on the patient’s condi- below 5 kohm. Either common referential derivation. Surface EMGs are recorded by using exactly the tions with reference to the earlobe electrode or bi- same method as used for recording with the EEG– polar derivations, or both, can be adopted. The EMG polygraph. The filter setting of 50–1,000 Hz bandpass filter may be set to 0.5–1,000 Hz. can be used. The amplified EMG is preferably recti- The analysis window may be freely determined fied or rectified and integrated to obtain a trigger depending on the purpose of the study, but usually it pulse, but the onset of the amplified EMG itself (raw is set to 200 ms before and 200 ms after the myoc- data) may be also used. In the case of negative lonus onset. The number of sweeps is again flexible,

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 163 but 50 sweeps per session are usually sufficient to nus was localized in the postcentral gyrus in five demonstrate the myoclonus-related EEG activity, if patients; exceptions were a patient with EPC who there is any. Just like conventional evoked potentials, showed the source in the precentral gyrus and an- it is recommended to confirm the reproducibility of other patient with cortical reflex myoclonus who the results by repeating the session at least twice for showed two sources, one in the precentral and the each muscle. When the high-frequency filter is set to other in the postcentral gyrus. Mima and col- 1,000 Hz, a minimal sampling rate of 2,000 Hz is leagues47 studied six patients with cortical myoclo- required for analog-to-digital conversion. nus by applying the technique of jerk-locked back In spontaneous cortical myoclonus or cortical averaging to the magnetic fields which were re- reflex myoclonus, this technique can disclose a my- corded by using a whole-head MEG system with pla- oclonus-related EEG activity that may not be recog- nar gradiometers, and also to the simultaneously nizable on the conventional polygraph.63,69 More recorded EEGs. They detected the pre-myoclonus commonly, this technique is used to study the pre- cortical activity on MEG in all cases (Fig. 5). In fact, cise interval from the EEG activity to the myoclonus as well as to study the scalp distribution of the myoclonus-related EEG activity based on simultaneous multichannel recordings.30,74,75 Epilepsia partialis continua is a good clinical indication for applying this technique.13,15,18 In myoclonus of cortical origin, the jerk-locked back averaging technique commonly discloses a positive–negative, biphasic spike at the central electrodes somatotopically corresponding to the muscle from which the myoclonus is recorded (Fig. 3). The initial positive peak of the EEG spike precedes the onset of myoclonic EMG discharge of a hand muscle by approximately 20 ms. The more distal the muscle from which the myoclonus is recorded, the longer is the EEG–EMG time interval, and vice versa.74,75 The widespread distribution of the myoclonus-related EEG activity, as seen in Figure 3, may be related, at least partially, to the involvement of multiple muscles by the myoclonus with a short time delay. In this regard, Brown and colleagues5 postulated, based on clinical electrophysiological studies, that the myoclonus-related cortical discharge may spread through the motor cortex within one hemisphere as well as to the homologous area of the contralateral motor cortex transcallosally. Another cause of the widespread distribution of the myoclonus-related EEG activity is, as with any other high-voltage EEG activity, the shunt effect due to different electrical conductivity of the tissues cov- ering the cerebral cortex, such as spinal fluid and skull. In this respect, since magnetic fields generated from the cerebral cortex theoretically are not influ- FIGURE 5. Magnetic fields back averaged with respect to the onset of myoclonus of the left hand in a patient with progressive myoclo- enced by those surrounding structures, MEG often nus epilepsy (PME). Note that the myoclonus-related activity is enables the source of the myoclonus-related cortical localized at the right central region (a). A biphasic cortical activity activities to be investigated more easily and more precedes the myoclonus onset (vertical line) followed by post-my- accurately than EEG. Uesaka and colleagues83 stud- oclonus activity (b). The onset and peak of the spike precede the ied seven patients with cortical reflex myoclonus onset of EMG recorded from the left wrist extensor muscle by 21 and 11 ms, respectively. The contour map of the earliest peak (c) including one with EPC by using an MEG system suggests the location of the equivalent current dipole (ECD) in the right equipped with 37 channel axial gradiometers, and central area with the intracellular current flow directed posteriorly. JLF, showed that the cortical activity preceding myoclo- jerk-locked field. (From Mima and colleagues47 with permission.)

164 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 in two cases including a case of corticobasal degen- time-locked to the myoclonus, which seems to corre- eration, the myoclonus-related activity was detected spond to PSD in terms of the waveform and scalp only on the back-averaged MEG, and not on the distribution.70 EEG. They further identified the equivalent current Wilkins and colleagues89 reported a group of dipole (ECD) for the myoclonus-related activity in patients whose myoclonic jerks were generally of the precentral gyrus in all cases. The discrepant small amplitude and multifocal (minipolymyoclo- results between these studies47,83 might be due to the nus), preceded by a bilaterally synchronous, fronto- different gradiometers used (axial vs. planar), differ- centrally predominant, negative slow wave. They pro- ent methods of data analysis, and different popula- posed the term “primary generalized epileptic tion of patients. As Mima and colleagues47 recorded myoclonus” for this condition. MEG and EEG simultaneously, and thus could cor- Essential myoclonus is not associated with any relate the averaged waveforms between the two, and special EEG activity, even if the jerk-locked averaging as they could estimate the direction of intracellular technique is applied.74 Dystonic myoclonus is usually current flow in the apical dendrite of pyramidal not accompanied by any EEG correlates with an neurons for each dipole source, it is reasonable to exception of that seen in SSPE, in which case the postulate based on their data that cortical myoclonus quasi-periodic dystonic myoclonus is closely linked in most cases is generated in the primary motor with the EEG complexes.55 Palatal or oculopalatal cortex. myoclonus (palatal tremor) and spinal myoclonus Theoretically, MEG can record only the current have no special EEG correlates. flow which is oriented tangentially with respect to the head surface, whereas EEG can record both the CORTICO-MUSCULAR COHERENCE tangentially and radially oriented current sources. However, MEG allows us to estimate the direction of This analysis is also based on the simultaneous re- the intracellular current flow or, in other words, the cording of EEG and EMG while myoclonic jerks in site of depolarization in the apical dendrite of large question are frequently occurring, and is expressed pyramidal neurons in the cerebral cortex. In the as a correlation of rhythmic activities of certain fre- report by Mima and colleagues,47 in four cases whose quency bands between EEG and EMG. By applying EEG showed a positive–negative biphasic activity, the this analysis method to patients with cortical myoc- MEG demonstrated a posteriorly directed current lonus, Brown and colleagues6 found an abnormally flow in the precentral gyrus, suggesting the depolar- increased coherence for a much higher frequency ization in the deep layer of the apical dendrite of the range. In addition, EEG–EMG coherence for the pyramidal neurons in the anterior bank of the cen- frequency band of around 20 Hz, which is seen in tral sulcus (area 4). In the remaining two cases, normal subjects during sustained muscle contrac- whose EEG showed a monophasic negative activity tion, was also found. By contrast to the conventional localized to the contralateral central region, the method of jerk-locked back averaging, which re- MEG showed an anteriorly directed current flow in quires averaging of a considerable number of sweeps the precentral gyrus, suggesting the depolarization and hence takes a relatively long time (although it in the superficial layer of the apical dendrite (Fig. 6 depends on the patient’s condition), this analysis of Mima and colleagues47). method can be applied to a relatively short segment Periodic myoclonus seen in CJD seems to be linked of the EEG–EMG polygraph. However, since the only loosely with PSD, if any, because a negative sharp recording is usually performed during sustained wave demonstrated by back-averaging EEGs time- muscle contraction, the results of analysis inevitably locked to the myoclonus is much smaller than the PSD contain the background activities due to voluntary which is seen on the raw EEG. As described previously, muscle contraction in addition to the activities di- this is most likely due to significant time jitter between rectly related to myoclonic jerks. Brown and col- the central and peripheral activities. Moreover, the leagues6 have reported that an abnormal EEG–EMG PSD precedes the onset of myoclonus of an upper coherence can be found in some cases where back extremity by 50 to 85 ms, which is too long for impulse averaging was unrevealing. They applied this tech- conduction from the primary motor cortex to the pe- nique to five patients with clinically probable CBD, ripheral muscle via the corticospinal tract.70 In an au- and found negligible cortico-muscular coherence topsy-proven case of Gerstmann–Straussler–Scheinker despite a dramatically exaggerated EMG–EMG co- disease which clinically manifested myoclonus but did herence up to approximately 60 Hz between finger not show any PSD on the routine EEG, jerk-locked extensors and first dorsal interosseous muscles on back averaging disclosed a sharp negative potential the more affected side.26 Based on this finding, they

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 165 FIGURE 6. Somatosensory evoked potential (SEP) waveforms following electrical stimulation of the left median nerve (LMN Stim) at wrist in 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 (not shown here), although with opposite polarity. A1, left earlobe electrode. Negativity shown upward. (From Ikeda and colleagues35 with permission.)

proposed that myoclonus in this condition might not cortical reflex myoclonus, the motor threshold is be due to an exaggerated cortical drive. difficult to determine accurately because of significantly lowered threshold of the long-latency reflex, EVOKED RESPONSES which obscures the direct motor response (M wave). For recording SEPs, the conventional method can be In most patients with cortical reflex myoclonus, adopted. Electrical shocks are delivered to the me- the SEP to electrical stimulation of the peripheral dian nerve at the wrist as a square-wave pulse of nerve shows a characteristic waveform, its main fea- 0.2–0.5 ms duration at a rate of, for example, 1–2 ture being an extreme enlargement of early cortical Hz. The stimulus strength is adjusted to 10%–15% components (Fig. 6). Actually, a marked enlarge- above the motor threshold, but in some patients with ment of SEP in those patients enables its constituent

166 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 components to be distinguished more easily than the SI, its crown (probably the area 1) was shown to be normal SEP.35,71 The initial component, which con- the main receptive field of the nociceptive input.37,40 sists of a postcentral negative peak N20 and a pre- Thus the current consensus is that areas 3b and 3a, central positive peak P20, is usually not en- but not area 1, are hyperexcitable in cortical reflex hanced.38,59,74,75 In MEG recording, however, the myoclonus. magnetic field corresponding to this initial SEP peak The ECD of the initial peak of the somatosensory (N20m) is also enlarged in some cases, although to a evoked magnetic fields (N20m) is localized in the much lesser degree than other components.41,48 The posterior bank of the central sulcus, most likely in subsequent components are clearly enlarged to a area 3b. As for the next SEP component (P25) or its variable degree depending on the patient. The sec- MEG counterpart (P25m), which is clearly enlarged ond identifiable peak (P25) shows a single positive in the patients with cortical or cortical reflex myoc- field at the contralateral central region, suggesting a lonus (Fig. 7), its dipole source is usually identified current flow which is radially oriented with respect in the precentral gyrus (Fig. 8).48 In this case, the to the head surface (Fig. 6). The third component is intracellular current flow in the apical dendrite of a complex consisting of a precentral negative peak the pyramidal neurons is estimated to be directed (N30) and a postcentral positive peak (P30), suggest- posterolaterally, suggesting that it represents the de- ing a probable current flow situated in the posterior polarization in the deep layer of the apical dendrite bank of the central sulcus and tangentially oriented situated either in the anterior bank of the central with respect to the head surface. The fourth compo- sulcus (area 4) or in the crown of the precentral nent is a negative peak (N35) which shows a similar gyrus. As for the mechanism of detection by MEG of scalp distribution to that of P25. In fact, the ampli- a radially oriented dipole in the crown (which theo- tude of these components in patients with cortical retically cannot be recorded as magnetic fields from myoclonus can be more than 10 times as large as the the head surface), it is conceivable that the tangen- normal value.38,74,75 Scalp topography of each com- tial vector of the radially oriented dipole is picked up ponent suggests that the giant SEP may result from as an MEG signal as a result of its extreme enlarge- an excessive enhancement of physiological compo- ment.48 This contrasts with the generator mecha- nents of the normal SEP, instead of occurrence of an nism of N20 or N20m which shows anteromedially abnormal component.38,71 directed intracellular current flow in the postcentral The study of the somatosensory evoked magnetic gyrus (area 3b), indicating depolarization occurring fields in patients with cortical or cortical reflex my- in the deep layer of the tangentially oriented apical oclonus discloses abnormalities of the somatosen- dendrite of the somatosensory neurons in that area. sory areas with relatively high temporal and spatial Since the giant SEP is not seen in other types of resolution.41,48,80,84 Among the somatosensory areas, myoclonus, its demonstration is clinically significant only the primary somatosensory cortex (SI) is hyper- for supporting the clinical diagnosis of cortical or excitable in those cases, whereas the second somato- cortical reflex myoclonus. However, short-latency sensory area (SII), located in the upper bank of the SEP components, which occur within 20 ms after sylvian fissure with bilateral innervation, is not.48 median nerve stimulation at the wrist and are known Furthermore, within the SI, area 3b, which receives to be generated in subcortical structures, are not mainly a tactile input, is most sensitive. By applying enhanced in any type of myoclonus. an instrument devised to activate proprioceptive re- Patients with photosensitive myoclonus show gi- ceptors selectively,50 Mima and colleagues49 showed ant evoked potentials at occipital as well as fronto- that area 3a, which receives a proprioceptive input, is central electrodes in response to flash stimulation.72 also sensitive in those patients. As for nociceptive Questions as to where in the frontal lobe this ante- input, by applying a CO2 laser beam, which selec- rior response is generated, and whether the anterior tively activates the nociceptive receptors, Kakigi and response is mediated by the primary occipital re- colleagues39 showed that the pain SEP is not en- sponse or the result of direct input from the thala- hanced in patients with cortical reflex myoclonus mus to the frontal cortex remain to be elucidated. even when they show giant SEP in response to elec- Besides the analysis of evoked electrical or mag- trical stimulation of peripheral nerves. Until re- netic fields following peripheral stimulation, the cently, it has been believed that the nociceptive in- change of cortical rhythmic oscillations following puts are received mainly in the SII.51,90,91 Recent stimulation can also be analyzed. Silen and col- MEG as well as electrocorticographic studies clearly leagues76 studied rhythmic oscillations over the hand demonstrate that the SI also receives the nociceptive area of the sensorimotor cortex following electrical input.37,40 It is especially noteworthy that, within the stimulation of the median nerve. In normal subjects,

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 167 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 courtesy of Dr. Tatsuya Mima.)

they found a small transient decrease followed by a other muscles of the stimulated upper extremity or rebound increase of 20 Hz oscillations, but this re- even from those of the nonstimulated extremities bound increase was absent in patients with Unver- with different latencies. When studying the long- richt–Lundborg type PME.76 They ascribed the lack loop reflex, it is extremely important and effective to of 20 Hz rebound to decreased cortical inhibition. record cortical evoked potentials simultaneously. Recently, high-frequency oscillations (HFOs) of sev- In cortical reflex myoclonus, a markedly en- eral hundred hertz and their abnormality in various hanced long-latency reflex is usually recorded from movement disorders have drawn increasing atten- the thenar muscle at a latency of around 45 ms after 52 tion. Mochizuki and colleagues studied the so- stimulation of the median nerve at the wrist.75 This matosensory evoked HFOs in four patients with my- enhanced long-loop reflex corresponds to the C re- oclonus epilepsy, and found enhancement of late flex named by Sutton and Mayer.78 Most patients HFOs of 600–750 Hz frequency range. show both giant SEPs and C reflex. In most cases of cortical reflex myoclonus, the larger the SEP, the LONG-LOOP REFLEX more conspicuous and widespread is the C reflex. In The long-latency, long-loop reflex can be recorded some cases, however, these two phenomena do not using the same EMG electrode placement as used for necessarily correlate with each other in terms of jerk-locked back averaging. Modality of the stimulus magnitude.59 is selected based on clinical observation, but electri- In some patients, the enhanced C reflexes can be cal shocks delivered to the median nerve at the wrist recorded also from more proximal muscles of the are most commonly used. In this case, the EMG stimulated upper extremity with shorter latency and response is best recorded from the thenar muscle of even from the opposite (nonstimulated) hand mus- the stimulated hand, but can be recorded also from cle. In the latter case, the latency difference of C

168 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 stimulation of the median nerve at the extended wrist elicited abrupt wrist drop associated with a short interruption of the EMG discharges. Further- more, it was found that the larger the SEP, the longer was the elicited EMG silent period, thus causing more conspicuous wrist drop. Moreover, the silent period was also induced in the EMG of the opposite (nonstimulated) hand, particularly when the giant SEP was also recognized over the central region ipsilateral to the stimulus (Fig. 9). Thus, it was suggested that this phenomenon might be a negative myoclonus induced via the transcortical reflex pathway, and it was called “cortical reflex negative myoclonus” as a negative counterpart of the more conventional form of cortical reflex myoclonus, cortical reflex positive myoclonus.67 Negative myoclonus can be induced by stimulation of other modalities as well. Gambardella and colleagues24 reported a case of photically induced epileptic negative myoclonus. FIGURE 8. Equivalent current dipoles (ECDs) for the two peaks of In reticular reflex myoclonus, the long-latency somatosensory evoked magnetic fields (N20m and P25m) (see Fig. reflex is enhanced, but cortical evoked potentials are 10) and for the cortical activity preceding myoclonus of the left hand not enhanced. In this condition, the reflex myoclo- (JLF, jerk-locked field), superimposed on the patient’s own MRI, in nus first involves bulbar muscles such as the sterno- the same patient as shown in Figure 10. The myoclonus-related cortical activity is located in the contralateral precentral gyrus, with cleidomastoid and trapezius muscles, and subse- its current flow directed posterolaterally, and so is the P25m of the quently the more rostral cranial muscles (such as the somatosensory response. The N20m is located in the postcentral facial muscles) and caudal muscles (such as limb gyrus, with its current flow directed anteriorly. C, central sulcus; L, muscles) are involved.14,30 A great variability of the left; R, right. (By courtesy of Dr. Tatsuya Mima.) reflex latency among myoclonic jerks within an individual subject seems to be characteristic of this reflexes between the left and right hand muscles is form of reflex myoclonus, indicating the necessity 10 to 15 ms.74 This time lag seems to be compatible for looking at individual responses to a single stim- with the conduction time of the impulse between the ulus rather than averaging. homologous cortical areas of two hemispheres Spinal myoclonus, whether segmental or propri- 5 through the corpus callosum. ospinal, can be stimulus sensitive. In spinal myoclo- The time interval from the P25 peak of the giant nus, therefore, it is worthwhile presenting various SEP to the onset of the enhanced C reflex is similar mechanical stimuli, such as tapping the muscle or to or slightly longer than the interval from the initial tendon, while recording EMGs from multiple mus- positive peak of the myoclonus-related cortical spike cles. to the onset of the spontaneous myoclonus.74,75 Based on the similarity in time intervals as well as the PAIRED STIMULATION EVOKED POTENTIALS AND scalp topography, the giant SEP and myoclonus-re- LONG-LOOP REFLEX lated cortical spike are postulated to share at least some common physiological mechanisms.68,74,75 By employing a paired median nerve stimulation Long-latency, long-loop reflexes can be recorded SEP technique with various ISIs in a patient with following the stimulus presentation of other modal- cortical reflex myoclonus, Dawson20 found a depres- ities such as flash. Photic reflex myoclonus seems to sion of cortical excitability at a latency between 10 be mediated by the cerebral cortex. Because the and 30 ms, enhancement between 60 and 100 ms, onset latency of the occipital and frontal responses is and then another depression. Sutton and Mayer78 around 35 and 40 ms, respectively, and because the found a mild enhancement of cortical excitability occipital response is also enlarged, it is most likely between 32 and 63 ms and also between 130 and at that the reflex arc involves the occipitofrontal path- least 250 ms in a patient with focal cortical reflex way.72 myoclonus. Simultaneous recording of long-latency Shibasaki and colleagues67 reported that in some reflexes in a paired stimulation paradigm provides patients with cortical reflex myoclonus, electrical further information regarding the mechanism of

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 169 FIGURE 9. Giant somatosensory evoked potentials (SEPs) and surface electromyogram (EMG) silent periods induced by electrical stimulation of the left median nerve (LMN) at wrist during the sustained wrist extension in the same patient as shown in Figure 9. A single sweep record. Note that the giant SEP is seen not only over the contralateral central (C4) and parietal (P4Ј) electrodes (N35c) but also over the ipsilateral central (C3) electrode (N35i) about 15 ms later, and the silent period (SP) is included not only in the wrist ﬂexor and extensor muscles of the left upper limb (LFCU and LECR, respectively), but also in the right wrist extensor muscle (RECR). A1, left earlobe electrode; C, C reﬂex. (From Shibasaki and colleagues67 with permission.)

the reflex myoclonus. Demonstration of a short JERK-LOCKED EVOKED POTENTIALS period of enhanced cortical excitability following a This technique can be used to study whether there is single stimulus supports the participation of the ce- any change in cortical excitability following a spon- rebral cortex in generation of that particular reflex taneous myoclonic jerk.73 The stimulus is presented myoclonus,75,85 and furthermore, it may explain the just at the time of, or at varying intervals after, the occurrence of two successive giant positive peaks of onset of the EMG discharge associated with sponta- SEPs and two successive C reflexes following a single neous myoclonus. EEGs and the rectified EMG are stimulus in some patients. For recording the paired stimulation SEPs and then averaged by using the EMG onset as a trigger. A long-latency reflex, the same set-up used for record- cortical excitability curve after myoclonus can be ing the SEP and long-latency EMG reflex can be obtained by comparing the amplitude of a certain used. Any ISI can be chosen; for example, an initial component of the evoked potentials thus recorded interval of 5 ms followed by a stepwise increase by 10 with that of control evoked potentials obtained by ms up to 50 ms and then by 25 to 50 ms up to 200 ms. presenting the same stimulus with a random time Paired stimulation in other modalities, such as flash, relationship to the myoclonus. can also be employed.72 By using this technique in a patient with PME, Subtraction of the response to a single stimulus Shibasaki and colleagues73 reported a similar en- from that to paired stimuli is usually necessary for hancement of cortical excitability of 20-ms duration obtaining a recovery function of cortical excitabil- immediately after the myoclonus-related cortical ity, but when dealing with a giant evoked poten- spike, as well as after the giant SEP; the latter is being tial, subtraction may not be needed except at very studied by the paired stimulation SEP technique. short ISIs. This finding supports the hypothesis that the myoc-

170 Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 FIGURE 10. Motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) following electrical stimulation of the digital 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 its suppression in the normal subject. (From Manganotti and colleagues45 with permission.) lonus-related cortical activity in cortical reflex myoclo- ISIs of 34–60 ms. In order to elucidate the modality nus is generated by a mechanism common to that of specificity of the peripheral stimulation, Manganotti the giant SEP.75 In a patient with CJD, cortical excit- and colleagues45 used electrical stimulation of digital ability was suppressed between periodic myoclonic nerve delivered at three times the sensory threshold jerks or between consecutive PSDs, suggesting that the followed by TMS in patients with PME. They found periodicity might be related, at least partially, to a facilitation at ISI of 25–40 ms, whereas a significant refractoriness of the cerebral cortex.73 In a patient with MEP inhibition was seen from 25–50 ms in normal oculopalatal-somatic myoclonus (tremor) due to a subjects (Fig. 10). In contrast, Valzania and col- pontine lesion, there was no change of cortical excitability in relation to the rhythmic movements, suggesting that this type of involuntary movement is not related to the excitability change of the cerebral cortex.73

TRANSCRANIAL MAGNETIC STIMULATION For the last 15 years, the technique of TMS has been applied extensively to the investigation of pathophysiology of various movement disorders.10 Since the excitability change of the sensorimotor cortex is involved in many cases of cortical or cortical reﬂex myoclonus as its physiological background, TMS is especially useful for directly investigating the excitability change of the motor cortex. Reutens and colleagues57 applied TMS preceded by electrical FIGURE 11. Motor evoked potentials (MEPs) elicited by paired stimulation of the median nerve at various intervals pulse transcranial magnetic stimulation (TMS) at interstimulus to patients with PME and found increased excitabil- interval (ISI) of 50 ms in a normal subject (upper trace) and in a patient with progressive myoclonus epilepsy (PME) (lower trace). ity at approximately 50 ms after the peripheral nerve Note a remarkable enhancement of excitability at 50 ms after the stimulation. Later, Cantello and colleagues11 used conditioning stimulus in the patient. (From Valzania and col- the same technique and found MEP facilitation at leagues87 with permission.)

Electrophysiological Studies of Myoclonus MUSCLE & NERVE February 2005 171 leagues87 applied paired-pulse TMS at 110% of the 2. Baumgartner C, Podreka I, Olbrich A, Novak K, Serles W, Aull S, et al. Epileptic negative myoclonus: an EEG-single-photon resting motor threshold for both stimuli to patients emission CT study indicating involvement of premotor cor- with PME, and found facilitation at 50 ms, in con- tex. Neurology 1996;46:753–758. trast with normal subjects (Fig. 11). Brodtmann and 3. Berkovic SF, So NK, Andermann F. Progressive myoclonus colleagues4 applied paired-pulse TMS to patients epilepsies: clinical and neurophysiological diagnosis. J Clin Neurophysiol 1991;8:261–274. with generalized epilepsy and found markedly en- 4. Brodtmann A, Macdonell RA, Gilligan AK, Curatolo J, Berk- hanced excitability in a patient with juvenile myo- ovic SF. Cortical excitability and recovery curve analysis in clonic epilepsy when the second stimulus was given generalized epilepsy. Neurology 1999;53:1347–1349. 33 5. Brown P, Day BL, Rothwell JC, Thompson PD, Marsden CD. 250 ms after the first. Hanajima and colleagues Intrahemispheric and interhemispheric spread of cerebral studied the supra-threshold conditioning TMS deliv- cortical myoclonic activity and its relevance to epilepsy. Brain ered to the primary motor cortex’s effect on the 1991;114:2333–2351. excitability of the opposite hemisphere’s primary 6. Brown P, Farmer SF, Halliday DM, Marsden J, Rosenberg JR. Coherent cortical and muscle discharge in cortical myoclo- motor cortex in five patients with benign myoclonus nus. Brain 1999;122:461–472. epilepsy. They found an absence of the transcallosal 7. Brown P, Marsden CD. Rhythmic cortical and muscle dis- late inhibition which is seen at ISI of 8–20 ms in charge in cortical myoclonus. Brain 1996;119:1307–1316. 8. Brown P, Rothwell JC, Thompson PD, Marsden CD. 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