Myoclonus

Pathophysiology

In most types of myoclonus, the pathophysiology is unclear, although abnormalities or deficiencies in neurotransmitter receptors, including serotonin1, GABA2, opiate, glycine, and dopamine, seem to be likely.3

Cortical
In specific types of myoclonus, certain aspects of the pathophysiology are more defined. In cortical myoclonus, a dysfunction at the level of the sensorimotor cortex may arise due to the distant effect of cerebellar pathology, resulting in decreased cortico-cortical inhibition; pathologic involvement of the cortex is not necessary. In postmortem examination in 3 patients with cortical myoclonus, Tijssen et al. found significant Purkinje cell loss symmetrically involving all lobules of the cerebellum.4 Larner et al. reported cerebral amyloid beta-peptide angiopathy to be the cause of pronounced action- and startle-induced movements in a patient with cortical myoclonus.5 Damaged or partially damaged structures in the cerebral cortex can also be due to infarct.6 Posthypoxic myoclonus may be modulated by estrogen.7

In studying corticobasal ganglionic degeneration, Grosse et al. found evidence of differences between corticobasal ganglionic degeneration and cortical myoclonus.8 They demonstrated an inflated EMG-EMG coherence over a broad band, without exaggeration in the EEG-EMG coherence, thus highlighting an atypically robust drive to the involved muscles. These results indicate that myoclonus due to corticobasal ganglionic degeneration may be due to reafference rather than corticospinal drive, which points to a subcortical origin of the movements with a disturbed interaction between sensorimotor cortex and subcortical structures.

Essential
The pathophysiology of essential palatal myoclonus is unknown; however, secondary or symptomatic palatal myoclonus may be immunologic, psychogenic, or genetic in origin, or it may be related to trauma9 or a localized lesion within the brainstem or upper cerebellar peduncle. In the latter case, olivary hypertrophy occurs about 3 weeks after the lesion, with symptomatic palatal myoclonus following from 2 to 49 months later.

(Mollaret's triangle: available here)

Peripheral
As mentioned previously, recent work has hypothesized peripheral myoclonus to result from lesions of the peripheral nerves that alter sensory input and induce central reorganization, with abnormal sensory spinal afferences causing loss of local inhibitory spinal interneurons.10

Spinal
A variety of mechanisms have been proposed for spinal myoclonus, including a dysfunction of segmental spinal-cord circuitry11; deficient inhibitory glycinergic transmission in the spinal cord and subsequent "release" of synchronous motor neuron oscillations within segments of the cord12; and vitamin B12 deficiency causing vacuolar swelling of the myelin layers in the midthoracic cord, resulting in degeneration of the descending pyramidal and ascending posterior column tracts.13 Simon has highlighted a critical role for GABAA receptors in the premotoneuronal circuitry responsible for generation or transmission of the sinusoidal oscillations.11 In an MRI study of patients with spinal myoclonus caused by siderosis, the imaging technique demonstrated a deposition of hemosiderin on the surface of the brainstem, cerebellum, and spine.14 Approximately 16% of patients with syringomyelia have spinal or propriospinal myoclonus with increased H-reflex responses.15

Opsoclonus-Myoclonus
The mechanism of opsoclonus-myoclonus is not clearly known but is thought to be an autoimmune-mediated dysfunction of the brainstem (involving a disordered interaction of "burst" and "omnipause" cells16) against a paraneoplastic17, paraviral18, or idiopathic encephalopathy.19 Although imaging studies of patients with opsoclonus-myoclonus do not usually identify a structural change in the brain, according to SPECT results18, most of the cerebellum is involved, including the vermis, nearby structures, or both. Hyperperfusion of these areas decreases with clinical improvement. Another proposed mechanism is related to a dysfunction of the glycinergic omnipause neurons in the nucleus raphe interpositus.20

The antibodies found in patients with opsoclonus-myoclonus have included those against the neurofilament protein, 210 kDa21, and IgM and IgG binding to the cytoplasm of cerebellar Purkinje cells.22 The parainfectious and idiopathic forms of opsoclonus-myoclonus account for about 50% of cases, with the Epstein-Barr, Coxsackie B, St. Louis encephalitis, and other viruses causing most of the infections. The primary neoplastic cause in children is either a neuroblastoma or ganglioneuroblastoma. In adults, cancers of the lung, breast, or uterus or a neuroblastoma account for most cases. Patients with neuroblastomas who have opsoclonus-myoclonus are more like to have antineuronal antibodies than if they do not have opsoclonus-myoclonus.23

Genetics
A variety of genes have been implicated in the cause of myoclonus, particularly those cases that include myoclonus as one feature of a disorder.

• Myoclonus dystonia
  • 7q21—DYT11, SCGE
  • 18p11—DYT15
• Myoclonic epilepsy
  • 8q24—Familial adult myoclonic epilepsy
  • G8363A mutation—MERRF
  • 21q22.3—CSTB gene—Unverricht-Lundborg disease
  • 6p24— EPM2A, EPM2B—Lafora progressive myoclonic epilepsy
• Other
  • PRNP H187R—Hereditary Creutzfeldt-Jakob disease
  • 3242A>G—MELAS
  • 22q11—DiGeorge syndrome