Anti-voltage-gated potassium channel antibodies and autoimmune neuromyotonia
The discovery of an autoimmune basis for neuromyotonia, coupled with the finding of increased nerve terminal excitability, led to the supposition that voltage-gated potassium channels(VGKCs) were the primary target for the pathogenic antibodies (Sinha et al. 1991). The phenotypic and electrophysiological similarities between the Shaker mutant of the fruit fly Drosophilia melanogaster and patients with neuromyotonia further suggested that VGKCs were functionally blocked by antibodies. However, it wasn't until the neurotoxin dendrotoxin was first used in radiolabelled form in an immunoprecipitation assay that the nature of the putative antibody was identified.
Dendrotoxin is an eastern green mambasnake (Dendroaspis, Fig. 1) venom peptide that is capable of occluding the pore of VGKCs. Dendrotoxin homologueues specifically bind toand block some isoforms of VGKCs. A radioimmunoassayusing 125I-?-dendrotoxin-labelledextracts of human frontal cortex was developed that detected anti-VGKC antibodies in about half the patients with acquired autoimmune neuromyotonia (Shillito et al. 1995). However, as dendrotoxinis not capable of blocking all membersof the Shaker-related VGKC family, a more sensitive molecular immunohistochemical assay was developed that showed VGKC antibody binding in every one of 12 neuromyotonia patients but not in any controls (Hart et al. 1997).
Neuromyotonia appears sporadically and can occur at any age. It has even been reported in newborn babies of mothers without the condition; these babies all died of respiratory complications in infancy. Muscle twitching or 'visible myokymia' is observed as a continuous, undulating, wave-like rippling of muscles, likened to a bag of worms under the skin. This is usually the commonest symptom, seen in over 90% of patients. Twitching generally occurs in the limbs but can also be seen in the trunk muscles and the face, including the tongue. Rarely, the laryngeal muscles are involved, causing hoarseness and exertional dyspnoea. Occasionally, there is no visible muscle twitching at all, but needle EMG reveals continuous motor unit activity. However, muscle rippling can sometimes be felt on palpation, even when it is invisible to the naked eye.
Muscle cramps that can be painful at times are a prominent feature in over 70% of cases and are sometimes the first symptom that is noticed. They may be associated with spasms and are sometimes worsened by attempted voluntary muscle contraction or electrical nerve stimulation. Cold weather can also precipitate muscle cramps.
This can occur in association with cramps, and can be severe enough to affect walking and manual dexterity. As a result, patients may adopt an abnormal posture and may be unable to stand on their heels due to stiffness in the lower limbs. Stiffness can also occur in the muscles of respiration resulting in breathlessness. Occasionally, stiffness can improve with repeated exercise. It is sometimes impossible to elicit the tendon re-flexes due to the increased muscle tone.
Central nervous system symptoms
There are occasional reports of hallucinations, delusional episodes and insomnia, sometimes referred to as Morvan's fibrillary chorea (Liguori et al. 2001). Although oligoclonal bands have been found in the cerebrospinal fluid (CSF) of patients with autoimmune neuromyotonia, there is no correlation with disease severity or central symptoms. Detectable levels of antivoltage-gated potassium channel antibodies in the CSF have not been demonstrated.
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Figure 1 Dendroaspis, the green mamba snake.
© Martin Overton
Muscle twitching or 'visible myokymia' is observed as a continuous, undulating, wave-like rippling of muscles, likened to a bag of worms under the skin; muscle rippling can sometimes be felt on palpation, even when it is invisible to the naked eye