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[22]
(Caspr‑2), which is localized at the juxtaparanodes in due to continuous muscle activity. The main
myelinated axons and associates with Transient axonal electromyographic hallmark of the neuromyotonia
glycoprotein 1，postsynaptic density‑95/discs large/ is the presence of spontaneous, continuous doublet,
zonula occludens‑1, and the ankyrin‑spectrin protein; [4] triplet or multiplet single motor unit discharges,
[23]
leucine‑rich, glioma inactivated 1 (LGI‑1) protein that is firing at a high intraburst frequency (30‑300 Hz).
most strongly expressed in the hippocampus; and the In addition, fibrillation potentials and fasciculations
protein Tag‑1/contactin‑2, associated with Caspr‑2. are often present, the former indicating the discharge
of a single muscle fibers. About 40% of patients with
[5]
Bien et al. demonstrated that T‑cell cytotoxicity is acquired neuromyotonia have detectable anti‑VGKC
not a major contributor for the pathogenesis of the antibodies and the percentage increases to 80% if
[24]
neurological syndromes associated with VGKCs, there is an associated thymoma. Interestingly, the
whereas antibody and complement‑mediated neuronal dysfunction of peripheral nerve VGKCs can be also
cell damage are prevalent. due to genetic cause, that is, episodic ataxia type I. In
fact, episodic ataxia type I is caused by a mutation of
Neoplasms are detected only in a minority of the potassium channel gene KCNA1 on chromosome
seropositive patients for VGKC complex‑IgG (16% 12. [25]
in the experience of Mayo Clinic) [2,4] and do not
significantly associate with Caspr‑2 or LGI‑1. Among The acquired, immune‑mediated form of the
the tumors that are believed to be associated with neuromyotonia has been described in association
VGKC complex‑IgG, lung carcinoma, thymoma and with many autoimmune diseases, such as myasthenia
hematologic malignancies are the most commonly gravis, Addison disease, vitiligo, Hashimoto
described. [2] thyroiditis, pernicious anemia, celiac disease,
and rheumatoid arthritis. It is well established
[26]
We will review all the major neurological conditions that neuromyotonia may also be paraneoplastic.
associated with VGKC complex‑IgG. These include In such cases, the pathophysiology is likely due to
Isaacs’ syndrome, Morvan syndrome (MoS), [7] cross‑reactivity of tumor antigens and VGKCs. Most
[6]
[26]
limbic encephalitis (LE), [8,9] facio‑brachial dystonic cases of paraneoplastic neuromyotonia are related
seizures (FBDS), [10,11] chorea and other movement to small cell lung carcinoma [27,28] and thymoma, [29,30]
disorders, epilepsy, psychosis, gastrointestinal but it has also been reported an association with
[12]
[13]
[14]
neuromuscular diseases, [15,16] a subacute Hodgkin lymphoma, bladder and ovarian
[31]
[32]
encephalopathy that mimics Creutzfeldt‑Jakob prion carcinoma. Membrane‑stabilizing drugs, namely
[33]
[2]
disease both clinically and radiologically and the anticonvulsants carbamazepine, phenytoin,
autoimmune chronic pain. [17] sodium valproic acid, lamotrigine are used for
symptomatic relief in patients with Isaacs’ syndrome
PERIPHERAL NERVE HYPEREXCITABILITY as they usually provide significant improvement of
stiffness, muscle spasms, and pain. Their mechanism
Motor nerves of action helps reducing neuronal repetitive firing
Isaacs’ syndrome (neuromyotonia) Immune‑mediated through interaction with VGKCs. If the response is
neuromyotonia, also known as Isaacs’ syndrome, not sufficient, oral corticosteroid may be prescribed,
is the most severe phenotype of peripheral nerve and nonsteroid immunosuppressive drugs such
hyperexcitability. It is characterized by spontaneous as azathioprine and methotrexate may also be
and continuous muscular activity resulting from considered as treatment. Plasma exchange often
[34]
repetitive motor unit action potentials of peripheral produces clinical improvement lasting about 6 weeks
origin. The syndrome was described for the first with a significant fall in VGKC antibody titers.
[34]
time by Isaacs in 1961. Isaacs also established Intravenous immunoglobulins are also indicated for
[18]
the peripheral nerve origin of the discharges severe neuromyotonia, providing short‑term relief.
by documenting the persistence of abnormal In the paraneoplastic form of the neuromyotonia,
electromyographic activity after proximal nerve block. treatment of malignancy is warranted. [34]
The main clinical features of the neuromyotonia are
muscle twitching at rest (visible myokymia), cramps Sensory nerves
and muscle stiffness, impaired muscle relaxation Chronic pain
after voluntary contraction (pseudomyotonia), along Klein et al. found that the 50% of VGKC‑complex
[17]
with hyperhidrosis. Patients may also suffer from antibody positive patients experience pain in
weakness. Other symptoms include myokymia of isolation (28%) or with accompanying neurologic
[19]
[21]
the limb, trunk, face [20] and tongue muscles. In manifestations (72%), not attributable to an alternative
some patients, hypertrophy of muscles can occur cause. VGKC‑complex antibodies related pain is

70 Neuroimmunol Neuroinflammation | Volume 3 | March 28, 2016