Forms Of Myoclonus Research Articles

Myoclonus

Myoclonus remains a challenging movement phenotype to characterize, evaluate, and treat. A systematic assessment of the temporal sequence, phenomenology, and distribution of movements can assist in the rational approach to diagnosis and management. Cortical forms of myoclonus are increasingly recognized as primarily cerebellar disorders. A syndrome of orthostatic myoclonus has been recognized by electrophysiology in patients with neurodegenerative disorders, mainly in Alzheimer disease, accounting for impairments in gait and balance previously mischaracterized as normal pressure hydrocephalus or orthostatic tremor. Tyrosine hydroxylase deficiency and Silver-Russell syndrome (uniparental disomy of chromosome 7) have been established as two novel causes of the myoclonus-dystonia syndrome. Mutations in the glycine receptor (GlyR) α1-subunit gene (GLRA1) explain the major expression of hyperekplexia, an inherited excessive startle disorder, butnewly identified mutations in GlyR β-subunit (GLRB) and glycine transporter 2 (GlyT2) genes (SLC6A5) account for "minor" forms of this disorder manifested as excessive startle and hypnic jerks. The entity previously known as palatal myoclonus has been reclassified as palatal tremor in recognition of its clinical and electromyographic features and no longer enters the differential diagnosis of myoclonic disorders. Increasing documentation of psychogenic features in patients previously characterized as having propriospinal myoclonus has cast doubts on the existence of this distinctive disorder. Myoclonus can be a prominent manifestation of a wide range of disorders. Electrophysiologic testing aids in distinguishing myoclonus from other mimics and classifying them according to cortical, subcortical, or spinal origin, which assists the choice of treatment. Despite the lack of randomized clinical trials, levetiracetam appears most effective in patients with cortical myoclonus, whereas clonazepam remains the only first-line therapeutic option in subcortical and spinal myoclonus.

A landmark publication in movement disorders

I went to do a fellowship with David Marsden in July 1975, after finishing my neurology residency, because I was fascinated by the work that he was doing together with Pat Merton and Bert Morton on the long-latency stretch reflex. This was landmark work that laid the groundwork for reflex loops that involved the brain, much beyond the spinal reflexes of Sherrington. Sherrington’s work was primarily in the spinalized cat; therefore, he could not appreciate that some reflexes might involve higher centres. The long-latency stretch reflexes required not only an intact nervous system but also a voluntary background contraction. Pat Merton was a physiologist who had been studying how movement might be controlled by feedback mechanisms and the long-latency reflexes seemed appropriate for the task. Bert Morton was a clever engineer who built the equipment that was housed in a special laboratory at the National Hospital in Queen Square. The three Ms would get together, often on the weekend, to do their experiments, typically with Pat or David as the experimental subject. Pat was a meticulous experimenter. In one experiment that I conducted with him, he corrected his reaction time to auditory stimulation taking into account the speed of sound from the speaker on one side of the room to his ear. It was likely that David, the neurologist of the group, recognized that hyperexcitability of the long loop might be responsible for certain forms of myoclonus. They spent considerable time studying the myoclonus of a single patient with post-hypoxic myoclonus. They collected huge amounts of data and David wanted to publish them, but Pat, being typically meticulous, did not allow it, as he wanted to make sure that the calibration of the data was correct; they could never finish the calibration, and the article was never published. There is …

Classifying myoclonus: A riddle, wrapped in a mystery, inside an enigma

Myoclonus is complex, and is likely to encompass a number of relatively disparate phenomena. A widely used approach to the classification of myoclonus is a physiological one, in which the major forms are cortical and subcortical. In this classification, cortical forms of myoclonus are defined by the presence of enlarged somatosensory evoked potentials (SEP), back-averaged potentials, and enhanced long latency reflexes, whereas subcortical forms are largely delineated by the absence of these features. In addition to cortical and subcortical types, the presence of generalized spike and wave discharges on EEG indicate the presence of cortical-subcortical interactions, analogous to absence seizures of idiopathic generalized epilepsy. However, a number of difficulties arise in applying these criteria to many forms of myoclonus: One can conclude that it is likely that many forms of myoclonus lie on a spectrum between myoclonus and tremor. Some have clearcut evidence for being of cortical origin, whereas others are cortical-subcortical or purely subcortical. The role of subcortical structures in influencing electrophysiological phenomena is poorly understood, and merits further investigation.

Myoclonic disorders: a practical approach for diagnosis and treatment

Myoclonus is a sudden, brief, involuntary muscle jerk. It is caused by abrupt muscle contraction, in the case of positive myoclonus, or by sudden cessation of ongoing muscular activity, in the case of negative myoclonus (NM). Myoclonus may be classified in a number of ways, although classification based on the underlying physiology is the most useful from the therapeutic viewpoint. Given the large number of possible causes of myoclonus, it is essential to take a good history, to clinically characterize myoclonus and to look for additional findings on examination in order to limit the list of possible investigations. With regards to the history, the age of onset, the character of myoclonus, precipitating or alleviating factors, family history and associated symptoms and signs are important. On examination, it is important to see whether the myoclonus appears at rest, on keeping posture or during action, to note the distribution of jerks and to look for the stimulus sensitivity. Electrophysiological tests are very helpful in determining whether myoclonus is cortical, subcortical or spinal. A single pharmacological agent rarely control myoclonus and therefore polytherapy with a combination of drugs, often in large dosages, is usually needed. Generally, antiepileptic drugs such as valproate, levetiracetam and piracetam are effective in cortical myoclonus, but less effective in other forms of myoclonus. Clonazepam may be helpful with all types of myoclonus. Focal and segmental myoclonus, irrespective of its origin, may be treated with botulinum toxin injections, with variable success.

Nonepileptic motor phenomena in the neonate

The newborn infant is prone to clinical motor phenomena that are not epileptic in nature. These include tremors, jitteriness, various forms of myoclonus and brainstem release phenomena. They are frequently misdiagnosed as seizures, resulting in unnecessary investigations and treatment with anticonvulsants, which have potentially harmful side effects. Unfortunately, there is a paucity of literature about many of these phenomena in the newborn, and some of the major textbooks refer to these events as nonepileptic seizures, leading to further confusion for the practitioner. The present paper aims to review these phenomena with special emphasis on differentiating them from epileptic seizures, and offers information on treatment and prognosis wherever possible.

Clinical and neurophysiological characterization of myoclonus in complex regional pain syndrome

The origin of myoclonus in patients with complex regional pain syndrome (CRPS) is unknown. Eight patients with CRPS related myoclonus were clinically evaluated and studied with intermuscular and corticomuscular coherence analysis. Jerks were present at rest, aggravated during action and were frequently associated with tremulousness or dystonia. Electromyography demonstrated a burst duration ranging from 25 to 240 ms with burst frequencies varying from <1 jerk/s during rest to 20 Hz during action. Coherence studies showed increased intermuscular coherence in 4 patients in the 6 to 12 Hz band, as reported in patients with enhanced physiological tremor. In 2 patients side-to-side coherence was observed, pointing to a central oscillatory drive. Significant coherence entrainment was detected in 5 patients. We conclude that the characteristics of myoclonus in CRPS are different from other forms of myoclonus.

Myoclonus and transcranial magnetic stimulation

The neural dysfunction at the origin of myoclonus may locate at various anatomical levels within the central nervous system, including the motor cortices. Transcranial magnetic stimulation (TMS) can be used to assess the balance between inhibitory and excitatory processes involved in the regulation of motor cortex activity and thereby, may be of value to determine the pathophysiological mechanisms of myoclonus. Using paired-pulse paradigms with various interstimulus intervals, TMS studies showed that intracortical inhibition (ICI) was reduced in progressive myoclonic epilepsy (PME). In contrast, ICI was decreased only for short interstimulus intervals in patients with juvenile myoclonic epilepsy (JME). Transcallosal inhibition and sensorimotor integration were also both altered in PME but not in JME. Actually, the loss of inhibitory regulation within the central nervous system might represent an intrinsic mechanism of myoclonus, whether of epileptic origin or not. Finally, the other TMS parameters of excitability (motor threshold, silent period, intracortical facilitation) were found normal in most cases of myoclonus. According to these observations, it was quite conceivable that the application of repetitive trains of TMS (rTMS) at inhibitory low-frequency (around 1 Hz) might be able to relieve myoclonus by restoring ICI. A few reported cases illustrate the efficacy of low-frequency rTMS to alleviate myoclonic symptoms. Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI.

Symptomatic myoclonus

A huge number of neurological disorders are associated with myoclonus. This paper describes these disorders whose diagnosis partly relies on the presence of myoclonus. The diagnostic approach is related to certain clinical features of myoclonus, which, after their integration in the clinical context, help orientate towards diagnosis. Myoclonus is frequent during dementia. Although its presence is well-known to take part in the diagnosis of Creutzfeldt–Jakob disease (CJD), myoclonus can also be present to a significant degree in Alzheimer's disease and Lewy body dementia (LBD), which raises a diagnostic issue. Both its clinical and electrophysiological features may help differential diagnosis, given that myoclonus with fast-evolving dementia and focal neurological signs should favor the diagnosis of CJD. Myoclonus in a context of progressive ataxia suggests one clinical form of the Ramsay–Hunt syndrome (progressive myoclonic ataxia, PMA), whose most frequent causes are: coeliac disease, mitochondriopathies, some spino-cerebellar degenerations, and some late metabolic disorders. In addition to ataxia and myoclonus, the presence of opsoclonus directs diagnosis toward the opsoclonus–myoclonus syndrome (OMS), whose origin, in adult, is idiopathic or paraneoplastic. Palatal tremor (myoclonus) with ataxia may represent either a sporadic pattern, which often reflects the evolution of degenerative or lesional disorders, or a familial pattern in some degenerative affections or metabolic diseases. Of more recent knowledge is the association of progressive ataxia, myoclonus, and renal failure, which corresponds to a recessive autosomic disease. In a context of encephalopathy, myoclonus is frequent in metabolic or hydro-electrolytic disorders, and in brain anoxia. One should distinguish these various forms of myoclonus which may occur in the acute post-anoxic phase, from those occurring as sequels at a later stage, i.e. the Lance and Adams syndrome whose clinical aspects are also multiple. Myoclonus is less frequent during toxic or drug exposures. Irrespective of its acute or insidious onset, Hashimoto's encephalopathy is accompanied by myoclonus and tremor. Myoclonus may also be present during encephalic and/or spinal infectious disorders. Myoclonus with focal neurological signs may be observed in thalamic lesions, responsible for unilateral asterixis or unilateral myoclonus superimposed on dystonic posture. Segmental spinal myoclonus or propriospinal myoclonus may be associated with several spinal-cord disorders. Myoclonus associated with peripheral nerve lesions is exceptional or even questionable for some of these.

Spinal Myoclonus After Spinal Cord Injury

Background/Objective: In the course of examining spinal motor function in many hundreds of people with traumatic spinal cord injury, we encountered 6 individuals who developed involuntary and rhythmic contractions in muscles of their legs. Although there are many reports of unusual muscle activation patterns associated with different forms of myoclonus, we believe that certain aspects of the patterns seen with these 6 subjects have not been previously reported. These patterns share many features with those associated with a spinal central pattern generator for walking.Methods: Subjects in this case series had a history of chronic injury to the cervical spinal cord, resulting in either complete (ASIA A; n = 4) or incomplete (ASIA D; n = 2) quadriplegia. We used multi-channel electromyography recordings of trunk and leg muscles of each subject to document muscle activation patterns associated with different postures and as influenced by a variety of sensory stimuli.Results: Involuntary contractions spanned multiple leg muscles bilaterally, sometimes including weak abdominal contractions. Contractions were smooth and graded and were highly reproducible in rate for a given subject (contraction rates were 0.3-0.5 Hz). These movements did not resemble the brief rapid contractions (ie, "jerks") ascribed to some forms of spinal myoclonus. For all subjects, the onset of involuntary muscle contraction was dependent upon hip angle; contractions did not occur unless the hips (and knees) were extended (ie, subjects were supine). In the 4 ASIA A subjects, contractions occurred simultaneously in all muscles (agonists and antagonists) bilaterally. In sharp contrast, contractions in the 2 ASIA D subjects were reciprocal between agonists and antagonists within a limb and alternated between limbs, such that movements in these 2 subjects looked just like repetitive stepping. Finally, each of the 6 subjects had a distinct pathology of their spinal cord, nerve roots, distal trunk, or thigh; in 4 of these subjects, treatment of the pathology eliminated the involuntary movements.Conclusion: The timing, distribution, and reliance upon hip angle suggest that these movement patterns reflect some elements of a central pattern generator for stepping. Emergence of these movements in persons with chronic spinal cord injury is extremely rare and appears to depend upon a combination of the more rostrally placed injury and a pathologic process leading to a further enhancement of excitability in the caudal spinal cord.

Myoclonus and its disorders

This article defines myoclonus, describes the numerous causes of myoclonus, and summarizes various classification schemes. The electrodiagnostic characteristics and pathophysiology of this movement disorder are described. Treatment of the various forms of myoclonus is also discussed.

Gamma-hydroxybutyrate in experimental myoclonus.

In Swiss mice, muscimol (3 mg per kilogram, intraperitoneally) caused myoclonic jerks of the hindquarters. These jerks were strong, repetitive, more or less regular, and of high frequency (peak response, 76 per minute). Pretreatment with sodium gamma-hydroxybutyrate (50 to 200 mg per kilogram) caused a dose-dependent blockade of these jerks. This drug also nullified an already developed muscimol response. All of the drugs currently being used in the management of postanoxic action myoclonus (Lance-Adams syndrome) block this response of muscimol. Gamma-hydroxybutyrate may be of value in the management of Lance-Adams syndrome and other forms of myoclonus.

Modification of central serotonergic and dopaminergic behaviors in the course of chronic corticosteroid administration

The effect of chronic cortisol administration (12.5 mg/kg per day p.o.) was studied in guinea pigs using two behavioral models; apomorphine-induced stereotypy (SB) and 1-5-HTP-induced myoclonus (MJB). Diurnal variations in behavioral sensitivity were evaluated by behavioral testing at five time points over a 24 h period at bi-weekly intervals. Cortisol succinate administration suppresses 1-5-HTP myoclonus in all animals and abolishes diurnal fluctuations in sensitivity during the first two weeks of therapy. At four weeks, a subgroup is observed which is behaviorally hypersensitive to 1-5-HTP. These changes occur in association with a reduction in the behavioral response to apomorphine but in the absence of major disruption in diurnal behavioral threshold variation to apomorphine. Chronic cortisol administration appears to induce major alterations in central serotonin-mediated behaviors. This observation may explain the therapeutic effect of corticosteroids in certain forms of myoclonus and the role of cortisol rhythm disturbances in the context of a variety of psychiatric disorders.

Possible Value of Baclofen in Myoclonus

To the Editor.— Myoclonus, characterized by repetitive involuntary movements of skeletal muscle, is observed in several neurological conditions. 1,2 The anatomic origin of the neurochemical aspects of myoclonus is not fully understood. Certain forms of myoclonus are effectively treated with the serotonin precursor tryptophan 3 or by antianxiety drugs belonging to the benzodiazepine group. 4 The nonavailability of a suitable animal model restricted the development of new drugs in the treatment of myoclonus. Recently we observed that administration of the putative γ-aminobutyric acid (GABA) agonist muscimol, 3 mg/kg, intraperitoneally resulted in the development of myoclonic jerks in male Swiss mice. These jerks involving their hindquarter developed within ten minutes after injection, were rhythmic, and occurred at a rate of 50 to 76 per minute and lasted for 60 to 90 minutes. Both the serotonin precursor 5-hydroxytryptophan, 200 mg/ kg, intraperitoneally, in mice pretreated with a decarboxylase inhibitor, benserazide, 50 mg/kg

L-5-hydroxytryptophan in treatment of several different syndromes in which myoclonus is prominent.

The serotonin precursor L-5-hydroxytryptophan is useful therapy for patients with posthypoxic intention myoclonus. L-5-hydroxytryptophan plus carbidopa was administered to eight patients with this disorder or other syndromes in which myoclonus is prominent. This treatment (1) decreased the frequency of occurrence and amplitude of intention myoclonus in two patients with posthypoxic intention myoclonus and in one with idiopathic myoclonus, (2) had no effect in one patient with congenital encephalopathy and myoclonus, and (3) increased the frequency of occurrence and amplitude of myoclonus in two patients with lipid storage disease, one with myoclonic epilepsy, and in an additional patient with idiopathic myoclonus. Therefore, L-5-hydroxytryptophan does not effect improvement in all forms of myoclonus; it should be given with caution because it produces a high incidence of side effects. A patient's response to L-5-hydroxytryptophan therapy may be important in a diagnostic classification of myoclonic syndromes based on differences in indoleamine neurotransmitter function.