Classification of myoclonus

Myoclonus can be classified on the basis of its clinical characteristics, its pathophysiology, or its cause (Table 20.1) (Marsden et al., 1982; Hallett et al., 1987; Fahn, 2002).

Table 20.1 Classification schemes for myoclonus

Physiologic myoclonus refers to muscle jerks occurring in certain circumstances in normal subjects. These include sleep jerks (hypnic jerks) and hiccup. Essential myoclonus consists of multifocal myoclonus in which there is no other neurologic deficit or abnormality on investigation. Epileptic myoclonus refers to conditions in which the major clinical problem is one of epilepsy, but one of the manifestations of the epileptic attacks is myoclonic jerks. Symptomatic generalized myoclonus refers to those many conditions in which generalized or multifocal muscle jerking is a manifestation of an underlying identifiable neurologic disease. Psychogenic myoclonus refers to myoclonus produced as a conversion symptom or as “voluntary” or “simulated” myoclonus (Thompson et al., 1992; Monday and Jankovic, 1993).

In the survey by Caviness et al. (1999), symptomatic myoclonus was most common, followed by epileptic myoclonus and essential myoclonus. Dementing illnesses were the commonest cause of symptomatic myoclonus.

Neurophysiologic assessment

Polymyography (recording the duration, distribution, and stimulus sensitivity of EMG activity in affected muscles) is the first step in assessing a patient with myoclonus (Toro and Hallett, 2004; Shibasaki and Hallett, 2005; Hallett and Shibasaki, 2008). Most myoclonic jerks are due to brief EMG bursts of 10–50 ms. EMG bursts in the 100 ms range are seen in some situations such as essential myoclonus. Longer jerks of more than 100 ms are likely to be dystonic. Agonists and antagonists usually fire synchronously (Fig. 20.1).

Figure 20.1 EMG patterns underlying two types of myoclonus. A is from a patient with post-hypoxic myoclonus, and B is from a patient with a type of essential myoclonus (ballistic movement overflow myoclonus). The time scale is the same for both; vertical calibration is 1 mV for A and 0.5 mV for B. In A, the EMG burst is very short and synchronous in antagonist muscles, while in B, the EMG bursts are longer and asynchronous.

From Chadwick D, Hallett M, Harris R, et al. Clinical, biochemical, and physiological features distinguishing myoclonus responsive to 5-hydroxytryptophan, tryptophan with a monoamine oxidase inhibitor, and clonazepam. Brain 1977;100(3):455–487, with permission.

The distribution of muscles involved may suggest that it arises as a result of a lesion of a peripheral nerve, part of a plexus, a spinal root or a restricted number of segments of the spinal cord (segmental myoclonus). Myoclonic muscle jerks affecting axial muscles (neck, shoulders, trunk, and hips) may arise in the brainstem as an exaggerated startle response or brainstem reticular myoclonus, or in the spinal cord as propriospinal myoclonus. In brainstem myoclonus, there is no preceding cortical discharge. Cranial nerve muscles are usually activated from the XI nucleus up the brainstem; limb and axial muscles are activated in descending order. In propriospinal myoclonus, the first muscles activated are usually in the thoracic cord, with slow upward and downward spread. Cortical myoclonus is indicated when somatosensory evoked potentials produced by peripheral nerve stimulation are pathologically enlarged, and a cortical correlate can be back-averaged in the ongoing EEG by triggering from the EMG of the muscle jerk (Hallett et al., 1979; Shibasaki and Hallett, 2005). Stimuli generating giant somatosensory evoked potentials often provoke a subsequent EMG burst of myoclonic activity (the C reflex), at a latency compatible with conduction through fast corticomotoneuron pathways from the motor cortex to muscle. The giant somatosensory evoked potentials usually consist of an enlarged P₂₅/N₃₃ component; the first major cortical negative peak (N₂₀), reflecting arrival of the sensory volley in the cortex, usually is of normal size. The motor volleys in cortical myoclonus activate the cranial and limb musculature in descending order via fast conducting corticospinal pathways. Abnormal corticomuscular and intermuscular coupling can also be a sensitive physiologic feature in cortical myoclonus (Grosse et al., 2003). The increased cortical excitability in cortical myoclonus may well be due to loss of inhibitory interneurons (Hanajima et al., 2008). Cortical reflex myoclonus usually consists of positive EMG discharges, but negative cortical reflex myoclonus also occurs (Shibasaki, 1995; Tassinari et al., 1998), where a giant somatosensory cortical potential is time-locked to EMG silence. Subcortical myoclonus is suggested when reflex myoclonus triggered by peripheral stimuli occurs after a latency that is too short to involve cortical pathways (Thompson et al., 1994; Cantello et al., 1997).

Psychogenic myoclonus is suggested if stimulus-evoked jerks are of very variable latency and longer than a voluntary reaction time (Thompson et al., 1992; Brown, 2006), and when the Bereitschaftspotential is evident prior to EMG bursts on jerk-locked back-averaging of the EEG, as in voluntary movement (Terada et al., 1995). Monday and Jankovic (1993) reported the clinical features of 18 such patients. There were 13 women and 5 men with an age range of 22–75 years. The myoclonus was present for 1–110 months; and it was segmental in 10, generalized in 7, and focal in 1. Stress precipitated or exacerbated the myoclonic movements in 15 patients; 14 had a definite increase in myoclonic activity during periods of anxiety. The following findings helped to establish the psychogenic nature of the myoclonus: clinical features incongruous with “organic” myoclonus, evidence of underlying psychopathology, an improvement with distraction or placebo, and the presence of incongruous sensory loss or false weakness. Over half of all patients with adequate follow-up improved after gaining insight into the psychogenic mechanisms of their movement disorder.

Making the diagnosis

It is convenient to consider myoclonus according to its clinical distribution, for this is how neurologists first assess the patient. Thus, we will first describe focal myoclonus restricted to one body part, for example, a limb or brainstem-innervated muscles. Then we will describe axial (neck, trunk, and proximal limb muscles) myoclonus, followed by generalized multifocal myoclonus.

Focal myoclonus

Jerking of one body part may arise anywhere from the peripheral nerve to the motor cortex (Table 20.3). With peripheral nerve lesions, the myoclonus may well arise because of secondary central nervous system changes (Shin et al., 2007). Another possibility is that there is a peripheral ectopic generator that triggers the myoclonus (Tyvaert et al., 2009). Spontaneous rhythmic focal myoclonus is likely to be epilepsia partialis continua or spinal segmental myoclonus. Stimulus-sensitive myoclonus, particularly affecting the distal limbs, is most likely to arise in the cerebral cortex. Polymyography, somatosensory evoked potentials, and back-averaging from spontaneous jerks will usually suffice to define the site of origin.

Table 20.3 Causes of focal myoclonus

A variety of lesions of the peripheral nerve and spinal cord have been described as causing focal myoclonus (Frenken et al., 1976; Jankovic and Pardo, 1986; Massimi et al., 2009). These include peripheral nerve tumors, trauma or radiation, and spinal cord trauma, tumor, vascular lesions, multiple sclerosis and other inflammatory myelitis. Such spinal segmental myoclonus characteristically is rhythmic (0.5–3 Hz), is confined to muscles innervated by a few spinal segments, and persists during sleep (Fig. 20.2 and Video 20.3). Spinal segmental myoclonus appears to be due to loss of inhibitory interneurons in the posterior horns, which may be demonstrated physiologically (Di Lazzaro et al., 1996). As a result, there is spontaneous bursting of groups of anterior horn cells. Usually it is not stimulus-sensitive, but it can be (Davis et al., 1981). Clonazepam is most likely to help. One case was responsive to topiramate (Siniscalchi et al., 2004).

Figure 20.2 Spinal segmental myoclonus. Myoclonic jerking of right leg: surface recording of EMG activity in both legs. This 75-year-old man developed involuntary jerking of the right leg 8 days prior to investigation. He had an abdominal aortic aneurysm, and died 3 months later. Autopsy showed ischemic loss of interneurons in the thoracolumbar cord.

From Davis SM, Murray NM, Diengdoh JV, et al. Stimulus-sensitive spinal myoclonus. J Neurol Neurosurg Psychiatry 1981;44(10):884–888, with permission.

Palatal myoclonus (alternately referred to as palatal tremor) describes the syndrome of rhythmic palatal movements at about 1.5–3 Hz, sometimes synchronously affecting the eyes, face, tongue and larynx, and even the head, trunk, intercostal muscles and diaphragm (Deuschl et al., 1990, 1994a, 1994b). The movements usually are bilateral and symmetric, occurring between 100 and 150 times per minute, and, in some circumstances, persist during sleep. There are two forms, essential palatal myoclonus and symptomatic palatal myoclonus (Table 20.4 and Video 20.4). The main symptom caused by these movements, seen only in the essential form, is clicking in the ear due to rhythmic contractions of tensor veli palatini which opens the eustachian tube. The tensor veli palatini is innervated by the trigeminal nerve.

Table 20.4 Differences between essential and symptomatic palatal myoclonus

In many cases, a focal brainstem lesion can be identified (symptomatic palatal myoclonus/tremor), usually a stroke, encephalitis, multiple sclerosis, tumor, trauma, or degenerative disease (Table 20.5). Often the palatal myoclonus appears some months after the acute lesion. Such patients will have symptoms appropriate to the brainstem damage and to the underlying cause, in addition to the palatal myoclonus. They also may have pendular vertical nystagmus (ocular myoclonus), as well as facial, intercostal, and diaphragmatic jerks in synchrony with the palatal myoclonus. The pathology in symptomatic palatal myoclonus damages the dentato-olivary pathway, often in the brainstem central tegmental tract (Fig. 20.3); the resulting denervation of the inferior olive leads to hypertrophy (Fig. 20.4), which can be seen on brain MRI (Deuschl et al., 1994b). In this situation, the palatal movement is due to contractions of the levator veli palatini (innervated by the nucleus ambiguus). Only rarely can the ear clicking be caused by spontaneous contractions of the levator veli palatini (Jamieson et al., 1996).

Table 20.5 Causes of palatal myoclonus in 287 patients

From Deuschl G, Mischke G, Schenck E, Schulte-Monting J, Lucking CH. Symptomatic and essential rhythmic palatal myoclonus. Brain 1990;113(Pt 6):1645–1672.

Figure 20.3 Palatal myoclonus. Dentato-olivary somatotopic relationships in humans are crossed in both horizontal and vertical planes; somatotopic relationships between the dentate nucleus and homolateral superior cerebellar peduncle are direct. The dentato-olivary pathway (continuous dark line) passes from the dentate nucleus through the superior cerebellar peduncle and joins the contralateral central tegmental tract on its way to the inferior olive; in the red nucleus region, this pathway (broken line) passes by the internal and dorsal surfaces of this structure.

Modified from Lapresle J. Palatal myoclonus. Adv Neurol. 1986;43:265–273, with permission.

Figure 20.4 Unilateral hypertrophy of the inferior olive in a patient with unilateral symptomatic palatal myoclonus.

From Deuschl G, Toro C, Valls-Solé J, et al. Symptomatic and essential palatal tremor. 1. Clinical, physiological, and MRI analysis. Brain 1994;117:775–88, with permission.

In other cases, no cause is evident (essential palatal myoclonus/tremor). The complaint of these patients is the clicking; the eye and other structures are not involved; and there are no other symptoms or signs. These patients tend to be younger and do not appear to develop other diseases. Clonazepam, anticholinergics, or carbamazepine may help some patients with palatal myoclonus (Sakai and Murakami, 1981; Jabbari et al., 1987). Sumatriptan can be effective (Scott et al., 1996), but not in patients with symptomatic palatal myoclonus. Ear clicking can be relieved by injection of botulinum toxin into the appropriate muscles (Deuschl et al., 1991; Jamieson et al., 1996). Ear clicking occasionally may be due to simple partial seizures (Ebner and Noachtar, 1995). Some of these patients may be psychogenic (Pirio Richardson et al., 2006).

Cortical myoclonus produces spontaneous muscle jerks (spontaneous cortical myoclonus), jerks triggered by external stimuli (cortical reflex myoclonus), or jerks on movement (cortical action myoclonus) (Hallett et al., 1979; Obeso et al., 1985). Such patients have neurophysiologic evidence of an abnormal discharge in the sensory motor cortex generating the myoclonic jerks via fast conducting corticomotoneuron pathways (Figs 20.5 and 20.6). Myoclonus arising in the cerebral cortex can be focal affecting one body part, such as a hand or foot, but multiple cortical discharges can cause multifocal jerks, each jerk being due to a discrete discharge in one part of the motor cortex. In addition, cortical discharges can cause generalized muscle jerks, either by intracortical and transcallosal spread to activate both motor cortices (Brown et al., 1991a, 1996; Brown and Marsden, 1996), or by cortico-reticular pathways activating brainstem myoclonic generators. Such multifocal and generalized cortical myoclonus is discussed below. Patients with focal cortical myoclonus also exhibit epilepsia partialis continua (Juul-Jensen and Denny-Brown, 1966), partial motor seizures, and secondary generalization with tonic-clonic grand mal seizures (Cowan et al., 1986) (Fig. 20.7). Focal slow-frequency repetitive transcranial magnetic stimulation has suppressed focal cortical myoclonus in a patient with cortical dysplasia (Rossi et al., 2004).

Figure 20.5 Focal cortical myoclonus. Details of short-latency components of somatosensory evoked potentials in cervical (C5; top traces) and cortical hand area of the left and right hand (LHA, RHA; bottom traces) following electrical stimulation of the index finger of the left (A) and right (B) hand. The patient, a 34-year-old woman, had an undiagnosed left hemisphere lesion. For some 6 years she had experienced rare grand mal seizures but continuous flexor jerking of the right hand and forearm while awake. These jerks occurred spontaneously, on action, or in response to touch of the fingers or a tap with a tendon hammer. On examination, apart from the focal myoclonus of the right hand, there were no other neurologic signs. Brain imaging was normal, as was a carotid arteriogram and CSF examination. Routine EEG showed a focal abnormality over the region of the left sensorimotor area, with spike-sharp-wave discharges. The early cervical potentials, with a peak latency of 13 ms, and the first major cortical response (N1), with a latency of 20 ms, are the same size on both sides. The later components are much enlarged after right hand stimulation (B). Traces are the average of 999 sweeps, with the stimulation given at the beginning of the sweep. Electrodes referred to a reference at Fz. The apparent large late responses recorded at the cervical electrode in B are due to activity at the Fz reference.

From Rothwell JC, Obeso JA, Marsden CD. Electrophysiology of somatosensory reflex myoclonus. Adv Neurol 1986;43:385–398, with permission.

Figure 20.6 Focal cortical myoclonus. Average (of 128) EMG and EEG events associated with spontaneous (left traces) and reflex-evoked (right traces) cortical myoclonus in a patient with a focal dysplastic lesion of the right sensorimotor cortex. The EEG during spontaneous jerks was back-averaged from a trigger point on the rectified EMG record. Reflex jerks were elicited by giving electrical stimuli (stim) to the left forefinger, 50 ms after the start of the recording sweep. The time interval between the large P1 positive wave in the EEG and the start of the myoclonic EMG burst is indicated. EMGs taken from the left first dorsal interosseous; EEG records from the contralateral sensorimotor hand area, referred to a linked mastoid reference.

From Rothwell JC, Obeso JA, Marsden CD. On the significance of giant somatosensory evoked potentials in cortical myoclonus. J Neurol Neurosurg Psychiatry 1984;47(1):33–42, with permission.

Figure 20.7 Cortical myoclonus. The various manifestations of spike discharges in the motor cortex, and their interrelationships are depicted. The physiologic correlate of the focal cortical myoclonic jerk is a cortical positive wave (an interictal spike) which represents a volley of pyramidal cell discharge in motor cortex. This can occur spontaneously, on voluntary movement, or in response to stimuli. Multiple spikes can cause multifocal myoclonus. The cortical discharge can also spread throughout the motor strip and, via the corpus callosum, to the opposite motor cortex to cause multifocal or generalized cortical myoclonus. If the spike discharge occurs repetitively, the result is epilepsia partialis continua. If it propagates locally it may cause a simple Jacksonian motor seizure, or if it becomes secondarily generalized, a tonic-clonic grand mal seizure occurs.

Epilepsia partialis continua is defined clinically as a syndrome of continuous focal jerking of a body part, usually localized to a distal limb, occurring over hours, days or even years, due to a cerebral cortical abnormality (Cockerell et al., 1996) (Fig. 20.8). The most common etiologies now are Rasmussen encephalitis and cerebrovascular disease. Most, but not all patients, have epileptic or other EEG abnormalities, and over half have identifiable cortical lesions on brain MRI. A similar clinical picture can occur with subcortical lesions, in which case it is suggested that the term “myoclonia continua” be employed (Cockerell et al., 1996). Cortical myoclonus sometimes is so rhythmic as to produce a tremor (Ikeda et al., 1990; Toro and Hallett, 2004) (Video 20.5). A focal cortical lesion produces focal myoclonus in the opposite appropriate body part. Such lesions include those due to vascular disease, tumor, granulomas, and focal encephalitis (Table 20.6) (Thomas et al., 1977; Cockerell et al., 1996). Chronic, prolonged focal myoclonic jerking in children suggests the possibility of Rasmussen encephalitis.

Figure 20.8 Epilepsia partialis continua. A1 Pattern of spontaneous jerking in the left arm of a case due to cerebral infarction. Hypersynchronous bursts of EMG activity occur at the same time in virtually all muscles of the arm (Delt, deltoid; Bic, biceps: Tri, triceps; F. flex., flexor muscles in the forearm; F.ext., extensor muscles in the forearm; APB, abductor pollicis brevis). The jerks occur in short runs with pauses of 0.5 s or so between each. A2 Shows the start of a run of activity after one of these pauses. Note that the first jerk of the run occurs only in forearm and hand muscles; the second jerk involves most of the muscles of the left arm (B). Lack of enlarged somatosensory evoked potential (SEP) and reflex muscle jerk following stimulation of the left median nerve at the elbow. The top two traces are average (of 256 trials) EEG records from the right central (C4) and left central (C3) electrodes, referenced to linked earlobes. The bottom trace is the EMG from abductor pollicis brevis (APB). The N20 component of the SEP is present and of normal size and latency. C Lack of any back-averaged EEG correlate preceding spontaneous jerks of the left APB muscle (rectified EMG record in bottom trace); 350 trials averaged. Linked earlobe reference. D Effect of a sub-motor threshold magnetic stimulus over the right motor cortex on an ongoing run of spontaneous jerking. The stimulus occurs at the time of the stimulus artifact. No short-latency muscle response is evident (on this time scale it would merge into the stimulus artifact). A spontaneous jerk of all arm muscles follows the stimulus, but then the upper arm muscles pause for the following two jerks.

From Cockerell OC, Rothwell J, Thompson PD, et al. Clinical and physiological features of epilepsia partialis continua. Cases ascertained in the UK. Brain 1996;119(Pt 2):393–407, with permission.

Table 20.6 Causes of focal cortical myoclonus and epilepsia partialis continua

Rasmussen encephalitis is a disorder of childhood and adolescence in which a unilateral focal seizure disorder is accompanied by a progressive hemiplegia due to focal cortical inflammation and destruction (Hart, 2004; Freeman, 2005). The seizures are severe, often with epilepsia partialis continua, partial motor seizures, and secondary generalization. The EEG may show focal epileptiform activity, or periodic lateralized discharges (PLEDs), or both. In addition to the progressive hemiplegia, there often is cognitive decline. The cause appears due to an autoimmune process, specifically to the glutamate receptor (GluR) 3 subunit, with such antibodies acting as a GluR agonist to cause an excitotoxic cascade (Gahring et al., 2001). Immunotherapy (steroids, plasmapheresis, or intravenous human immunoglobulin (IVIg)) may help some, but hemispherectomy may be necessary.

Axial myoclonus

Typically axial myoclonus consists of neck and trunk flexion with abduction of the arms and flexion of the hips.

Axial myoclonic jerks may arise in the spinal cord or brainstem. Propriospinal myoclonus involves long propriospinal fibers in the spinal cord distributed to axial muscles (Brown et al., 1991c) (Fig. 20.9). The most prominent movement of propriospinal myoclonus is truncal flexion, and it can be either spontaneous or stimulus induced (Video 20.6). A review of 60 patients noted a middle-aged male predominance (Roze et al., 2009). The myoclonus tended to be worse when lying down and at wake–sleep transitions. A premonitory sensation might be present before the jerks. The etiology of many of these cases is not clear, although injury to the spinal cord from trauma, infection, tumor, and disk herniation has been described (Capelle et al., 2005; Shprecher et al., 2010). Diffusion tensor imaging with fiber tracking of the spinal cord may reveal abnormalities (Roze et al., 2009). The EMG pattern of propriospinal myoclonus can be mimicked voluntarily, indicating that psychogenic myoclonus should be in the differential diagnosis in these cases (Kang and Sohn, 2006), and several such cases have now been reported (Williams et al., 2008; Slawek et al., 2010). In a series of 35 patients referred with axial jerks, 34 of them were considered to be psychogenic (van der Salm et al., 2010). More work is needed in this area to understand this disorder better. The most effective drug for treatment has been clonazepam (Roze et al., 2009).

Figure 20.9 Propriospinal myoclonus. EMG record of a single spontaneous jerk in a patient with propriospinal myoclonus. Muscles are sternocleidomastoid, deltoid, biceps, rostral aspect of rectus abdominis, caudal aspect of rectus abdominis, and quadriceps. EMG activity occurred first in rectus abdominis. Contraction of sternocleidomastoid, rectus abdominis, and quadriceps occurred in all jerks, but activity in deltoid and biceps (evident here) was variable. Vertical calibration line = 200 µV and 100 µV for bottom and top three channels, respectively.

From Brown P, Thompson PD, Rothwell JC, et al. Axial myoclonus of propriospinal origin. Brain 1991;114:197–214., with permission.

Brainstem reticular myoclonus (Table 20.7 and Fig. 20.10