CLASSIFICATION

Myoclonus can originate from either the central nervous system or the peripheral nervous system, but most of myoclonic jerks occur in association with disorders of the central nervous system.¹ It can originate from the motor cortex, brainstem, and spinal cord, and there are some other forms of myoclonus whose source has not been clarified completely (Table 34-1). Cortical myoclonus occurs either spontaneously or through a reflex mechanism in response to external stimulus (cortical reflex myoclonus). Epilepsia partialis continua is a focal, continuous form of cortical myoclonus, usually involving the distal part of the upper or lower limb. Cortical myoclonus is often epileptic in nature and thus is also called epileptic myoclonus. Palatal tremor, reticular reflex myoclonus, and startle syndrome are known to originate from brainstem structures. There are two forms in spinal myoclonus: segmental and propriospinal. Periodic myoclonus and dystonic myoclonus are easily recognized from their unique clinical features, but their underlying mechanisms have not been elucidated precisely.

TABLE 34-1 Classification of Myoclonus

CLINICAL FEATURES

Myoclonic jerks are usually detectable by visual observation without much difficulty. However, when the jerks are small, palpation of the corresponding muscles helps in identifying the myoclonus. Because most myoclonic jerks are associated with co-contraction of agonist and antagonist muscles, it is useful to palpate, in the case of hand myoclonus, the wrist flexors and extensors simultaneously.

Cortical myoclonus appears as brisk, shocklike movements involving fingers, hands, arms, facial muscles, and/or legs, and sometimes trunk muscles, independently (Fig. 34-1). When hand intrinsic muscles are involved, it appears as small twitches of each individual finger or a group of fingers. When, in contrast, proximal muscles of an extremity are involved, it appears as big jerks. When the jerks rapidly spread from proximal to distal muscles of an extremity, it appears as if the whole extremity is involved almost simultaneously. Moreover, a jerk of one hand can be followed by another jerk in the other hand by a very short time interval: in fact, as short as 10 milliseconds, corresponding to the transcallosal conduction time. In this case, it appears as if both upper extremities are almost simultaneously involved. Cortical myoclonus appears rhythmic when it repeats in the same muscle groups at a fast rate (7 to 8 Hz), and thus it often resembles tremor (cortical tremor) (Fig. 34-2). Rhythmic cortical myoclonus is commonly seen in corticobasal ganglionic degeneration, familial adult myoclonic epilepsy, postanoxic myoclonus, and Angelman’s syndrome.

Figure 34-1 Electroencephalographic (EEG)-electromyographic (EMG) polygraph recorded from a patient with progressive myoclonus epilepsy. EMG discharges associated with cortical myoclonus are abrupt and very brief in duration, involving one or more muscles of the right (Rt) upper extremity almost synchronously. There are frequent sharp spikes or multiple spikes on EEG, some of which are associated with the myoclonus. EEG electrode placement is in approximate accordance with the International 10-20 System as indicated by a prime symbol (′). ECR, extensor carpi radialis muscle; 1stDI, first dorsal interosseous muscle.

Figure 34-2 Electromyographic (EMG) polygraph obtained from a patient with clinical diagnosis of corticobasal ganglionic degeneration. Repetitive discharges are seen in the right (RT) biceps and triceps muscles almost synchronously at an approximate rate of 7 to 8 Hz. br., brachii; Lt, left.

Cortical myoclonus is induced or enhanced when the patient attempts to move or actually moves the corresponding part of the body or other parts of the body (action myoclonus). Furthermore, it is often stimulus-sensitive; for example, jerks are elicited by tendon tap during neurological examination. In this case, it appears as if the deep tendon reflex is exaggerated, but the cortical reflexmyoclonus occurs slightly later than the expected time for the monosynaptic spinal reflex. In addition, it can be differentiated from the enhanced deep tendon reflex in that cortical reflex myoclonus spreads to other parts of the corresponding extremity (e.g., from distal to proximal muscles) and even to the contralateral extremity. In patients with spastic paraparesis, the deep tendon reflex in response to the patellar tendon tap may be recognized also in the contralateral leg; a typical example is the crossed adductor reflex. This phenomenon, however, is the result of simultaneous mechanical activation of the proprioceptive input to the contralateral spinal segment by the knee tap, which causes a visible reflex in the contralateral leg as a result of the hyperactive state of the contralateral anterior horn cells.

Furthermore, cortical myoclonus is elicited or enhanced when the corresponding limb is passively moved or when its posture is changed. These maneuvers are thought to induce a kind of proprioceptive reflex myoclonus. Cortical reflex myoclonus is sometimes elicited by flash stimulus and is noticed when the pupillary light reflex is tested (photic cortical reflex myoclonus). Typical examples have been reported in the advanced stage of Creutzfeldt-Jakob disease (CJD).

Cortical myoclonus sometimes manifests as negative myoclonus, which is caused by sudden interruption of the ongoing muscle contraction (silent period of the electromyogram [EMG]). Most of the negative myoclonus are either immediately preceded or immediately followed by abrupt muscle contraction (positive myoclonus), but on occasion, the isolated form of negative myoclonus is seen. Thus, the pure negative myoclonus can be easily overlooked unless the extremity is examined during sustained muscle contraction: for example, while the wrists are kept in an extended posture. When the trunk muscles are suddenly involved by negative myoclonus, the patient may fall down abruptly (drop attack). On occasion, negative myoclonus is induced by somatosensory or photic stimulus through a transcortical reflex mechanism (cortical reflex negative myoclonus).

Epilepsia partialis continua manifests as continuous, repetitive focal muscle jerks at the rate of 1 to 6 Hz, localized unilaterally to one finger, several fingers, or a foot.

Palatal tremor used to be called palatal myoclonus, but the name was changed after the first International Congress of Movement Disorders, held in Washington, D.C., in 1990, because of the lack of shocklike features and its resemblance to tremor, especially when other skeletal muscles are also involved. Essential palatal tremor is characterized by repetitive elevation of the soft palate at a rate of 2 to 3 Hz, often associated with ear click. Familial cases of essential palatal tremor have been reported. The movement may be associated with repetitive, brisk muscle contractions of other cranial muscles, which are approximately synchronous with the palatal movement. Symptomatic palatal tremor consists of rhythmic vertical oscillation of the soft palate and is frequently associated with rhythmic vertical oscillation of eyes (ocular myoclonus). This condition is commonly associated with organic lesions of brainstem or cerebellum and often involves other cranial and extremity muscles. In this condition, the movement of extremities is not very shocklike and may resemble real tremor. This form of palatal tremor may be persistent even during sleep.

Reticular reflex myoclonus is a rare form of reflex myoclonus, characterized by shocklike jerks first appearing in the sternocleidomastoid and/or trapezius muscles and then spreading rostrally to the masseter, orbicularis oris, and orbicularis oculi muscles in this order, as well as caudally from proximal to distal muscles of extremities. Diagnosis of this condition requires demonstration of the characteristic spread of jerks by polygraphic recording of surface EMG from different muscles.

Startle syndrome is a group of diseases characterized by exaggerated startle responses to sudden unexpected acoustic or tactile stimuli. Physiologically, this condition is considered to be an exaggerated form of physiological startle reaction. Familial startle disease, or hyperexplexia, is mostly an autosomal dominant disorder characterized by muscular rigidity in the neonatal period and the exaggerated startle responses. This condition has drawn special attention in relation to the discovery of heterogeneous mutation of genes encoding inhibitory glycine receptors.

Segmental spinal myoclonus is seen as brisk contraction of muscles innervated by a certain spinal segment. It is often quasi-rhythmic or periodic and may be stimulus-sensitive. Propriospinal myoclonus involves mainly trunk muscles. Each jerk starts at a certain segmental level, most commonly at the thoracic segments, and spreads rostrally as well caudally at a slow speed of approximately 5-10 m/second. Within each individual patient, the jerk starts always from the same segment, although it may shift one or two segments during the course of illness. The term propriospinal is derived from the propriospinal tract, which connects successive spinal segments. The causative lesion in spinal myoclonus, either segmental or propriospinal, is often difficult to be identified even by extensive laboratory investigation.

Underlying mechanisms have not been disclosed for other kinds of myoclonus, including periodic myoclonus and dystonic myoclonus. There are two representative forms of periodic myoclonus; one seen in CJD and the other seen in subacute sclerosing panencephalitis. Periodic myoclonus seen in CJD is quasi-periodic repetition of shocklike, quasi-synchronous jerks involving extremities and facial muscles at a rate of about 1 Hz. It might shift from one extremity to others and continue during sleep, although the rate and the periodicity might change from time to time. It is often associated with periodic synchronous discharge (PSD) on electroencephalographic (EEG) recording, but there is no fixed time relationship between PSD and periodic myoclonus in this condition (Fig. 34-3).

Figure 34-3 Electroencephalographic (EEG)-electromyographic (EMG) polygraph recorded from a patient with Creutzfeldt-Jakob disease. The rectified EMG discharge associated with jerks involving the left upper limb is relatively long in duration and varies from one to the other jerk in its waveform. The myoclonus is associated with periodic synchronous discharge on the EEG, but their time relationship is not fixed.

In contrast, periodic myoclonus seen in subacute sclerosing panencephalitis is really periodic, with almost constant interval of 6 to 8 seconds, and associated with PSD with a fixed time relationship. The muscle contraction in this condition is rather slow and is characterized by twisting nature of the movement, resembling dystonia rather than myoclonus. Therefore, the involuntary movement in this condition might be called periodic dystonic myoclonus.

Myoclonus can be seen in association with other involuntary movements, such as tremor and/or dystonia, either concurrently or independently. For example, patients with writer’s cramp, as a typical example of focal hand dystonia, might exhibit a combination of muscle cramp, tremor, and myoclonic jerks. The term dystonic myoclonus is used when myoclonus has a twisting feature. In this regard, periodic dystonic myoclonus seen in patients with subacute sclerosing panencephalitis is a representative form of dystonic myoclonus. The term myoclonic dystonia is used to indicate almost the same condition as dystonic myoclonus. However, inherited myoclonus-dystonia syndrome is characterized by independent occurrence of myoclonus and dystonia in the same patient. In this case, myoclonic jerks commonly involve the proximal limb muscles and trunk, and they respond to ethanol in just the same way as essential tremor. Autosomal dominant trait with mutation of the gene encoding ε-sarcoglycan is one of the diseases that causes this condition.

UNDERLYING DISEASES

Myoclonus can be caused by a number of different diseases. Representative diseases causing cortical myoclonus are listed in Table 34-2. Progressive myoclonus epilepsy is a group of diseases manifesting postural/action myoclonus and generalized convulsive seizures. Most of them are hereditary, and gene abnormalities have been identified for many of these diseases (Table 34-3).² Among other diseases, postanoxic myoclonus (Lance-Adams syndrome) is most commonly encountered. In this condition, myoclonus develops in patients who survived the acute phase of anoxic encephalopathy, and it is often refractory to various drug treatments. Most jerks are of cortical origin, although reticular reflex myoclonus has been described in this condition. In contrast with progressive myoclonus epilepsy, generalized convulsive seizures are rather rare in this condition.

TABLE 34-2 Diseases Causing Cortical Myoclonus

TABLE 34-3 Major Forms of Progressive Myoclonus Epilepsy and Their Gene Abnormality

DRPLA, dentatorubral-pallidoluysian atrophy; MERFF, myoclonic epilepsy associated with ragged-red fibers.

Modified from Lehesjoki A-E: Molecular background of progressive myoclonus epilepsy. EMBO J 2003; 22:3473-3478, with help from Dr. Lehesjoki.

It is noteworthy that cortical myoclonus can be present in metabolic encephalopathy, such as the disease caused by uremia. Thus, this condition is not necessarily associated with organic brain lesions and is reversible when the underlying cause is successfully treated. In relation to this, hepatic encephalopathy characteristically shows rhythmic negative myoclonus (asterixis), although the mechanism of this condition is not known.

The diagnosis of essential myoclonus is made when myoclonus is not found to be associated with generalized convulsive seizures or other neurological deficits in spite of clinical observation over a long period of time. It is often familial and may be related to the inherited dystonia-myoclonus syndrome (see previous discussion). The physiological mechanism of essential myoclonus has not been elucidated, but at least some of them might be of cortical origin.

Many drugs can cause myoclonus as a side effect (drug-induced myoclonus). Myoclonus of this category is often of negative form, associated with the EMG silent period (Fig. 34-4). Thus, whenever negative myoclonus develops in a patient who takes anticonvulsants, this possibility has to be considered. In other words, some cases of negative myoclonus in patients with cortical myoclonus may be, in fact, a side effect of anticonvulsants that they are taking. The physiological mechanisms underlying drug-induced myoclonus may not be homogeneous. It is most likely that some of them may be of cortical origin and the others subcortical.

Figure 34-4 Polygraphic record consisting of accelerometer (Acceler.), electromyographic (EMG), and electroencephalographic (EEG) recordings from a patient with anticonvulsant-induced negative myoclonus. There are frequent interruptions of EMG discharges of the right extensor carpi radialis (R-ECR) muscle, associated with the wrist drop as shown in the accelerometer record. The longer the EMG silent period, the more conspicuous is the asterixis. There is no special EEG activity associated with the negative myoclonus. R-FCR, right flexor carpi radialis.

PHYSIOLOGICAL MECHANISMS

As far as cortical myoclonus is concerned, its physiological mechanisms have been elucidated to some extent. This is because most activities of the sensorimotor cortex are remarkably exaggerated in this condition, which makes it easier to assess those activities physiologically by EEG or magnetoencephalographic recording from the head surface. Cortical myoclonus is characterized by increased excitability of the primary motor cortex, extreme enhancement of cortical response to somatosensory stimulus, and enhanced long-loop, transcortical reflex (Fig. 34-5). When a part of the primary motor cortex is suddenly involved by epileptic activity, the muscles innervated by that particular cortical area show sudden contraction at a latency of about 20 milliseconds for a hand and 40 milliseconds for a foot. The cortical activity related to myoclonus may be actually recognized as a spike on EEG recording. In this condition, the somatosensory cortex reacts to tactile or proprioceptive input with magnitude of 10 times or more in comparison with the physiological reaction. This activity can be recorded as an enormously enhanced (giant) somatosensory evoked potential (SEP). Furthermore, tapping of a hand, for example, elicits reflex muscle contraction in that hand at a latency of about 45 milliseconds. This response can be recorded as an EMG response (long-loop reflex or C reflex) through the use of the surface electrodes.

Figure 34-5 Schematic diagrams illustrating the hypothesized impulse flow for cortical reflex myoclonus and spontaneous cortical myoclonus. In the latter case (right), excessive discharge arising from the hand area of the motor cortex, seen as a spike on electroencephalographic (EEG) recording, causes abrupt muscle contraction in the corresponding hand in 20 milliseconds via the fast conducting corticospinal tract. In cortical reflex myoclonus (left), the somatosensory input (Stim.) generates giant somatosensory evoked potential (SEP) at a latency of 20 to 25 milliseconds in the sensorimotor cortex, which then gives rise to a reflex muscle contraction (C reflex) at a latency of 45 milliseconds.

LABORATORY TESTS

The main laboratory test is aimed at confirming and classifying the myoclonus and understanding its pathophysiology, by using a battery of electrophysiological tests (Table 34-4).^3,4 The most essential test for any kind of myoclonus is the EMG recording of myoclonic jerks with the surface electrodes. In order to find the distribution and spread of myoclonus, it is more effective to record simultaneously from as many muscles as possible. This is also useful for finding the most appropriate muscle for carrying out other physiological studies as described later. For recording EMG from a large muscle, a pair of disk electrodes are placed on the skin overlying the muscle belly about 3 cm apart from each other; for recording from a small muscle such as hand intrinsic muscles, one electrode is placed over the muscle, and the other electrode on the skin covering the adjacent bone. A band-pass filter of 30 to 1000 Hz is adequate. Application of low-frequency filter (high-pass filter) is mainly for eliminating movement artifacts.

TABLE 34-4 Essential Physiological Tests of Myoclonus

EEG, electroencephalogram; EMG, electromyogram.

Cortical myoclonus is associated with an EMG discharge of abrupt onset and of short duration, lasting less than 50 milliseconds (see Fig. 34-1). Usually, agonist and antagonist muscles contract simultaneously. The contraction may spread from proximal to distal muscles at the speed of about 50 m/second, which corresponds approximately to the conduction velocity of α motor fibers. In case of hand myoclonus, it may be seen in the homologous muscles of the contralateral upper extremity 10 to 15 milliseconds later.

Simultaneous EEG recording with the surface EMG is especially useful for the confirmation of cortical myoclonus. EEG recording is accomplished by placing electrodes in accordance with the International 10-20 System recommendations. Referential derivation with ipsilateral earlobe reference or bipolar derivation is used. Usually a band-pass filter of 1 to 500 Hz is used. When the number of EEG channels, the recording time, or both are limited, EEG may be recorded from a limited number of electrodes: for example, from C3, Cz, and C4 of the International 10-20 System in reference to the ipsilateral earlobe. Demonstration of spikes or multiple spikes on EEG is highly suggestive of the cortical origin of myoclonus. The spikes may or may not be associated with myoclonic jerks (see Fig. 34-1). Absence of EEG spikes, however, does not rule out the cortical myoclonus, because small spikes may not be detected by the scalp recording as a result of attenuation of the electric potential by the skull. Demonstration of PSD is almost pathognomonic of either CJD or subacute sclerosing panencephalitis, depending on the waveform. EEG findings similar to the CJD type of PSD are sometimes encountered in anoxic encephalopathy, but PSD in this condition is not persistent.

The technique of jerk-locked back averaging can be used for detecting spikes associated with myoclonus that are not detectable on the conventional EEG-EMG polygraph and for investigating the time and spatial relationship between the EEG spikes and myoclonus. EEG and EMG are recorded simultaneously, just as for the conventional polygraph, and the onset of EMG discharges associated with myoclonus is used as a fiducial point for back averaging the EEG (Fig. 34-6). The EMG may be rectified to avoid the canceling effect of averaging, and integrated. The onset of the rectified, integrated EMG waveform is used as a fiducial point for back averaging, as well as for obtaining the averaged EMG waveforms. Averaging of 100 sweeps is usually sufficient, but it is important to confirm the reproducibility of the results. In order to obtain a record of high quality, it is important to choose the most appropriate muscle for obtaining the fiducial point, to distinguish the myoclonic discharges from the background EMG activities, and to avoid artifacts such as head movements. When the myoclonic jerks occur infrequently in the resting condition, passive or active movement of the corresponding limb might help increase the number of jerks. In case of hand myoclonus, the positive peak or the onset of the negative peak of the EEG spike precedes the myoclonus by 20 milliseconds, on average, and it is localized to the central region of the contralateral head.

Figure 34-6 Diagram showing the method of jerk-locked back averaging for demonstrating an electroencephalographic (EEG) correlate of myoclonus. The electromyogram (EMG) associated with myoclonus is recorded simultaneously with EEG, and the onset of the rectified EMG is used as a fiducial point for back averaging the EEG as well as the rectified EMG.

SEPs are recorded by stimulating the median nerve at wrist by electric shock of 0.2 to 0.3 milliseconds duration with the stimulus intensity 10% above the motor threshold delivered at a frequency of 1 Hz. Averaging of 100 sweeps is usually sufficient, but it is important to confirm the reproducibility of the results. The initial peak of the cortical SEP, N20/P20, is not significantly enlarged, but the subsequent peaks (P25, N30/P30, N35) are extremely enlarged in the majority of patients with cortical reflex myoclonus.

It is convenient to record the long-loop reflex at the time of SEP recording. When the median nerve is electrically stimulated for recording SEP, the surface EMG can be recorded from the thenar muscle of that hand by a pair of surface electrodes. The transcortical reflex (C reflex) is seen at the latency of about 45 milliseconds. In case of severe cortical reflex myoclonus, the reflex EMG response is seen not only in the thenar muscle but also in other muscles of the same limb and also in the thenar muscle of the contralateral hand. In this case, the C reflex of the contralateral hand occurs 10 to 15 milliseconds later than that of the stimulated hand.

When the patient is likely to have reflex myoclonus that is sensitive to visual stimulus, it is worthwhile to record photic evoked responses and photically evoked long-loop reflex, just as in the case of SEP and somatosensory evoked long-loop reflex.

In addition to these electrophysiological tests, other tests such as magnetic resonance imaging and chemical tests of blood should be performed, depending on the underlying diseases that are possible according to the history and physical findings in each case.

EXPERIMENTAL MODEL

The rat model of posthypoxic myoclonus has been extensively studied by Truong’s group.⁵ They observed auditory stimulus-induced myoclonus in the rats that survived the acute stage of coma and seizures caused by mechanically induced cardiac arrest. The myoclonus was thought to be of brainstem origin, but in contrast to startle response, the acoustic reflex myoclonus did not show habituation. It was maximal about 4 days after the anoxic insult, and it subsided in 3 to 4 weeks.

Histologically, neuronal degeneration was seen extensively in the motor cortex, somatosensory cortices, thalamic reticular nucleus, hippocampus, and cerebellum. Hypofunction of serotonergic system in the frontal cortex was found in this experimental condition, and clonazepam, sodium valproate, and piracetam were found to reduce the myoclonus. Most human cases of posthypoxic myoclonus are of cortical origin, although reticular reflex myoclonus is occasionally encountered.

Dichlorodiphenyltrichloroethane (p,p′-DDT) causes spontaneous myoclonus in rats, but in this condition, hyperfunction of 5-hydroxyindole acetic acid (5-HIAA) was demonstrated. Injection of picrotoxin, a γ-amino butyric acid type A (GABA_A) antagonist, into the reticular nucleus of the thalamus in rats induces rhythmic, spontaneous myoclonus, which is also evoked by acoustic stimulus. Complex neuropharmacological abnormalities seem to be involved in these experimental conditions, mainly involving serotonergic and GABAergic systems.

TREATMENT

Symptomatic treatment of cortical myoclonus is achieved by anticonvulsants such as clonazepam, sodium valproate, and, on occasion, primidone to a variable degree, depending on the patient (Table 34-5). In addition, piracetam or levetiracetam may be effective for cortical myoclonus. This can be given either in combination with those anticonvulsants or alone. L-5-hydroxytryptophan (5-HTP) has been reported to be effective, especially for posthypoxic myoclonus. Other forms of myoclonus also respond to clonazepam.

TABLE 34-5 Treatment of Cortical Myoclonus

Prepared with help from Dr. Akio Ikeda.