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The animal model presented here resembles several of the key features of human myoclonus. Further study of the neuropathology and pharmacology of this animal model will hopefully increase our knowledge of the brain structures and systems affected in this disease and permit testing of therapeutic agents for the significant number of patients who do not respond to current treatments.

A 72-year-old woman suffered a respiratory arrest following intoxication with barbiturates. Her examination 27 months after the anoxic incident revealed involuntary jerks of trunk and limb muscles triggered by willed movements. On a regimen of 1 g L-5-HTP and 100 mg l-alpha-methyldopa hydrazine (carbidopa), action myoclonus disappeared completely. This medication had to be discontinued because of a regressive hysterical reaction. Two months later, she was found unconscious; resuscitation efforts were unsuccessful. Autopsy showed death was caused by choking on food. Coronal slices of the cerebral hemispheres and transverse section of the brainstem and cerebellum revealed no lesion. No evidence of hypoxic damage could be demonstrated in the cerebral cortex, hippocampus, striatum, pallidum, subthalamus, thalamus, or other diencephalic structures. In the caudal half of the midbrain tegmentum, a marked astrocytic reaction of some duration was encountered in the lateral parts of the supratrochlearis nucleus, the lateral subnucleus of the mesencephalic gray, and the immediately adjacent cuneiform and subcuneiform nuclei. In the former nucleus, sites of presumed nerve cell disintegration were found, but the neuronal populations of this nucleus and of the other raphe nuclei were well maintained. The other brainstem structures and the cerebellum were normal. Our neuropathological findings suggest that hypoxic myoclonus (a) does not seem to be explained by demonstrable neuronal loss in motor structures, such as cerebellum, thalamus, or basal ganglia and (b) does not appear to be causally related to a detectable reduction in the serotonin-containing neurons of the brain but rather to a functional derangement of anatomically intact serotonergic pathways originating perhaps from other, as yet unidentified, damaged neuronal structures.

The CNS diseases that are associated with mitochondrial myopathy have been reviewed in this chapter. The disorders causing myoclonus have been compared to those in which myoclonus has been reported. Both groups have been associated with lactate and pyruvate accumulation, and both have a wide spectrum of clinical and pathologic findings. Deficiency of components of the respiratory chain has been offered as an explanation for the mitochondrial accumulation in the muscles of these patients. Skeletal muscle respiratory-chain components may be deficient, and there is experimental evidence that indicates that mitochondria will proliferate in muscle and other tissues when vital nutrients are withheld. There are two features of these patients that separate them from other patients with myoclonus. The first is the elevation of serum lactate and pyruvate due to deficient oxidative phosphorylation. The second is a pedigree that indicates maternal inheritance.

In two cases of action myoclonus following hypoxic or shock encephalopathy, neuropathological examination disclosed mild or moderate scattered changes involving thalamus, griseum centrale mesencephali, and nucleus centralis superior. Other areas were affected only in one of these cases (striatum, nucleus subthalamicus or hippocampus, nuclei pontis, and cerebellar cortex). In another case (an alcoholic patient), the changes, which involved only corpus mamillare and thalamus, were those of Wernicke-Korsakoff encephalopathy. In one case of oscillatory myoclonus following septic shock, there were marked cerebellar changes involving deep nuclei and mild abnormalities in the thalamus and inferior olive. The last case of action myoclonus following acute methyl bromide intoxication was characterized by marked changes in the inferior colliculi and moderate or mild abnormalities of thalamus, griseum centrale mesencephali, nucleus centralis superior, nucleus reticularis tegmenti pontis, nuclei pontis, and dentatus. The findings are compared with the data of seven previously reported neuropathological examinations in action myoclonus following hypoxic encephalopathy.

Action myoclonus, reviewed in this chapter, is the term applied to arrhythmic muscular jerking induced by voluntary movement. It is made worse by attempts at precise or coordinated movement (intention myoclonus) and may also be provoked by certain sensory stimuli. The effective stimuli for action myoclonus is probably feedback from muscle afferents, although it may be initiated by corollary discharge from motor cortex to reticular formation before or at the onset of voluntary movement. The condition is usually associated with diffuse neuronal disease such as post-hypoxic encephalopathy, uremia, and the various forms of PME, although action myoclonus may be limited to one limb in some cases of focal cerebral damage. It is caused by hyperexcitability of the sensorimotor cortex (cortical reflex myoclonus) or reticular formation (reticular reflex myoclonus), or both. No consistent pathological change has been reported in autopsied cases of action myoclonus. The underlying disorder appears to be a loss of inhibitory mechanisms involving serotonin and possibly GABA as transmitter agents. The term PME is used for the association of myoclonus with degenerative changes in the nervous system which are commonly diffuse but may predominate in certain systems. There may or may not be associated tonic-clonic seizures, other manifestations of epilepsy, or dementia. Those cases of PME associated with Lafora inclusion bodies and cerebral storage diseases can be distinguished from the system degenerations. Systems which may be involved in the latter group include cerebellodentatorubral, pyramidal, extrapyramidal, optic, auditory, posterior columns and gracile and cuneate nuclei, spinocerebellar pathways, motor neurons of cranial nerves and anterior horns, and muscle fibers. Confronted with this diversity of pathological change, it seems unnecessary to make any clinical distinction between Ramsay Hunt syndrome and Unverricht-Lundborg syndrome (Baltic myoclonus) because cerebellar signs are found in patients described under both headings. Additional systems may be involved in individuals or families who are otherwise typical. All three names could well be joined in an eponymous title (Unverricht-Lundborg-Hunt disease) or the condition simply known as the systems degeneration type of PME, as Halliday (43) suggested. The cause of the condition (or spectrum of conditions) is at present unknown. Action myoclonus usually responds to sodium valproate or clonazepam, and some individuals, particularly those with posthypoxic myoclonus, improve with the administration of serotonin precursors.