Continuous muscle activity, Morvan's syndrome and limbic encephalitis: ionic or non ionic disorders?

The early pathophysiologic study showed increasing evidence that autoimmunity is implicated in the pathogenesis of neuromyotonia. Antibodies to voltage gated potassium channel were detected in the serum of patients who had peripheral nerves hyperexcitability and also Morvan's disease or limbic encephalitis. These discoveries offered new approaches to treatments. Recently, antibodies previously attributed to VGKC recognise 2 surface antigens LGI1 and CASPR2 into the VGKC complex. Finally, VGKC antibodies are directed to 2 proteins the first one is a key hippocampic protein containing pre and post synaptic proteins. The second one CASPR2 is an hippocampic and paranodal protein. There clinical significance is different: hyperexcitability, limbic encephalitis without thymoma for LGI1, hyperexcitability, Morvan limbic encephalitis and frequent thymoma for CASPR2. In conclusion, the term NMT--LE--VGKC should be changed to NMT--LE with LGII and CASPR2 antibodies and classified as auto immune synaptic disorders. Mutations in genes encoding both these proteins are found in hereditary epilepsy and other syndromes. Various potassium channelopathies are closely linked to Morvan's syndromes. A new classification of antibodies will be necessary.

Continuous muscle activity or Isaac’s syndrome (1) or neuromyotonia (a misnamed disorder because of the lack of myotonia) are one of a family of disorders characterized by peripheral nerves hyperexcitability. The earliest clinical description (2) gathers five patients with “la chorée fibrillaire”. All of them had muscle quivering characteristic of neuromyotonia. In Morvan’s syndrome, symptoms of neuromyotonia are associated with autonomic and central nervous system dysfunction with frequent insomnia (3, 4).These cases are close to limbic encephalitis (with short memory disturbances, confusion, seizures, personality changes, hyponatremia, hyppocampal abnormalities on brain MRI) (5, 6). Both neuromyotonia and Morvan’s syndrome can be associated with tumours, particularly thymomas or with dysimmune disease (myasthenia gravis). For these reasons and taking into consideration the improvement with anti dysimmune therapy, the following hypothesis was suggested (7). Antibodies anti potassium voltage dependant (VGKC) could lead to a depolarization and muscle hyperactivity.

VGKC antibodies were detected by immunoprecipitation of iodinated α-dendrotoxin (125 I α DTX) in brain homogenates. The VGKC antibody titers are higher (≥ pM) compared to controls (< 100 pM), mainly to KV1.1 subunits. In addition to the previous syndrome VGKC antibodies have also been identified (8) in epilepsies, type 1 primary episodic ataxia (9) long QT syndrome, paroxysmal dystonia, Shaker group, and others (10).

However most VGKC antibodies don’t bind directly to KV1.1 subunits and it was recognized that VGKCs are not the targets for the VGKC antibodies (11) and the question was: are these syndromes due to antiVGKC antibodies (K+ ionic channelopathy) or to anti non ionic secreted protein antibodies (12). Thus “the term limbic encephalitis” – VGKC should be changed to LE with LGI1 antibodies and classified as autoimmune synaptic encephalopathy” (12).

In fact, most VGKC-antibodies bind to associate VGKC complex proteins. This complex gathers 2 target proteins:

LGI1 (Leucin-rich Glioma Inactived 1), key hippocampic protein of synaptic organisation with a large extra cellular sequence and multiple domains (13), associated with KV1.1 subunits, connecting pre (Adam23) and post (Adam22) synaptic proteins forming a bridge (14)

CASPR2 (Contactin Associated Protein2) hippocampic and paranodal (Ranvier node) membrane protein (15).

Mutations in genes encoding both these proteins are found in hereditary epilepsia and other syndromes (16). These mutations reflect the fact that genetic and autoimmune conditions often target the same proteins (11).

Interest in Morvan’s disease or syndromes has grown, owing to its close links with various potassium channelopathies and now disorders classified as autoimmune synaptic syndromes. Many new antibodies against neuronal cell surface antigens will probably be described in the future (17). A new classification of antibodies will certainly be necessary.