Sleep, Morvan's Syndrome, and Potassium channels

http://med.ege.edu.tr/~norolbil/2001/NBD14801.html

Morvan’s syndrome (Ms) is a rare disease characterised by neuromyotonia, autonomic, central nervous system (CNS) involvement and endocrine dysfunction. Although existence of antibodies against voltage-gated potassium channels (VGKCs) has been recently established, their causative role in disease etiology has not been investigated.

Sleep and VGKCs:

Kv3.1 is a voltage-gated, fast activating/deactivating potassium channel and is expressed in fast-spiking, parvalbumin-containing interneurons in cortex, hippocampus, striatum, the thalamic reticular nucleus and in several nuclei of the brain stem. They are known to get involved in generation and maintenance of cortical fast gamma and slow delta oscillations recorded by EEG during sleep (15). This seems to be the only well-defined contribution of VGKC to sleep physiology.

Sleep and calcium activated potassium channels:

The most direct evidence of potassium channels in sleep physiology comes from apamin. Intraventricular injections of low doses of apamin, a specific blocker of a class of calcium-activated potassium channels, induce experimental insomnia, a long-lasting suppression of deep slow sleep and paradoxical sleep. Apamin especially suppresses REM sleep period (4,8). These features are quite reminiscent of the specific sleep disorder observed in Ms patients. Moreover, basal forebrain cholinergic neurons express neurotensin receptors and neurotensin blockade of calcium activated potassium channels, in this location, is a potential physiological mechanism whereby this peptide may evoke alterations in the cortical arousal, sleep-wake cycle, and theta rhythm (14). Calcium activated potassium channels of thalamic reticular nuclei neurons are also known to play role in production of spindles (a hallmark of sleep observed on EEG recordings) during sleep via thalamocortical projections (6,10). However, antibodies against this kind of potassium channel has not been reported to be detected in serum samples of Ms cases.

a suggested explanation for this situation could be as follows: Inhibition of potassium channels in the habenulointerpeduncular system may presumably result in increased acetylcholine secretion (just as it does in neuromuscular junction) and this may continously activate the interpeduncular nucleus. The extraordinary hyperactivity of this nucleus may give rise to increased activation of monoaminergic system (especially median raphe), overwhelm the cholinergic system and thus cause an increased vigilance state distinguished by stage 1 non-REM sleep characteristics. However, information about the exact role of VGKCs in this region is currently lacking and excitatory effects of acetylcholine on interpeduncular nucleus is questionable

endocrine dysfunction of Ms cases may be caused by antibodies against peripheral VGKCs rather than thalamic nuclei. It has well been established that potassium channels are major constituents of both melatonin and norepinephrine secretion mechanisms and inhibition of these channels may dramatically alter the serum levels of both hormones

Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels (2001 Brain)

Morvan's ‘fibrillary chorea’ or Morvan's syndrome is characterized by neuromyotonia (NMT), pain, hyperhydrosis, weight loss, severe insomnia and hallucinations. We describe a man aged 76 years with NMT, dysautonomia, cardiac arrhythmia, lack of slow-wave sleep and abnormal rapid eye movement sleep. He had raised serum antibodies to voltage-gated K⁺ channels (VGKC), oligoclonal bands in his CSF, markedly increased serum norepinephrine, increased serum cortisol and reduced levels and absent circadian rhythms of prolactin and melatonin. The neurohormonal findings and many of the clinical features were very similar to those in fatal familial insomnia, a hereditary prion disease that is associated with thalamic degenerative changes. Strikingly, however, all symptoms in our MFC patient improved with plasma exchange. The patient died unexpectedly 11 months later. At autopsy, there was a pulmonary adenocarcinoma, but brain pathology showed only a microinfarct in the hippocampus and no thalamic changes. The NMT and some of the autonomic features are likely to be directly related to the VGKC antibodies acting in the periphery. The central symptoms might also be due to the direct effects of VGKC antibodies, or perhaps of other autoantibodies still to be defined, on the limbic system with secondary effects on neurohormone levels. Alternatively, changes in secretion of neurohormones in the periphery might contribute to the central disturbance. The relationship between VGKC antibodies, neurohormonal levels, autonomic, limbic and sleep disorders requires further study.