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subacute in onset, chronic in course, neuropathic, postinfective irritable bowel syndrome associated with
[43]
nociceptive, regional, or diffuse. It is significantly inflammatory enteric neuropathy, chronic intestinal
associated with Caspr‑2 antibody positivity, but pseudo obstruction, and esophageal and colonic
[44]
not with LGI‑1 antibody, and occurs in isolation dysfunction secondary to infection by the protozoan
[17]
or with recognized neurologic manifestations of parasite trypanosoma cruzi (Chagas’ disease).
[45]
VGKC‑complex autoimmunity. [11,35,36] It is characterized The presence of VGKC‑Ab (or other antineuronal
by prominent morbidity and in some cases may require antibodies) in the early phases of gastrointestinal
to be treated by narcotics. It has been hypothesized neuromuscular diseases still remains contentious.
that pain related to VGKC antibodies is due to the However, if present, early detection, followed by
hyperexcitability of nociceptive pathways, although proper immunotherapy could be important in order to
such involvement is difficult to be demonstrated, prevent the progressive deterioration of gut function.
and patients’ symptoms are often disproportionate to
objectively measured neuropathic dysfunction. It has CENTRAL NERVOUS SYSTEM MANIFESTATIONS
been demonstrated that VGKCs act synergistically with
the potassium/sodium hyperpolarization‑activated LE
cyclic nucleotide‑gated ion channel 2 (HCN2), LE is generally characterized by a subacute and
that is an inward rectifying channel acting as a progressive onset of episodic memory deficits,
regulator of nociceptive pain. VGKC and HCN2 disorientation, and recurrent seizures. Additional
[37]
act synergistically to maintain nociceptive afferent features are hallucinations, sleep‑cycle disturbances,
sensory neural thresholds, [38,39] and it is reasonable agitation, and delusions. There is histological
to hypothesize that VGKC‑complex antibodies may evidence of mesial temporal lobe inflammation.
interfere with their functional activity. LE can be associated with several antibodies
including anti‑Hu, anti‑CV2/CRMP5, anti‑Ri, [47,48]
[46]
[2]
Membrane‑stabilizing antiepileptic drugs may anti‑Ma2, [49,50] and anti‑amphiphysin. [51,52] Antibodies
have some benefit in patients with VGKC‑complex targeting neuronal cell surface antigens, such as
autoimmune chronic pain. Interestingly, 81% of ion channels and ligand‑gated ion channels have
patients described by Klein et al. experienced been recently identified. VGKC complex‑IgG are a
[17]
improvement in their pain by immunotherapy, good example of the second category of antibodies.
allowing narcotics to be discontinued in some cases. VGKC antibodies were first reported in 2001 in two
patients affected by reversible LE [53] and then in two
More recently, Rosch et al. reported two series in 2004. [8,9] VGKC‑LE has been described in
[40]
cases of ganglioside antibody‑negative pediatric association with antibodies against LGI‑1 in 80‑90%
Guillain‑Barrè syndrome associated with Caspr‑2 of patients or Caspr‑2 in 5‑10%. Very few patients
[54]
[55]
antibodies. Both patients experienced a full recovery. have contactin‑2 antibodies, and some patients
Thus, Caspr‑2 might be a possible autoimmune target have no specific target. VGKC‑LE is frequently
[56]
in Guillain‑Barrè syndrome. Certainly, further studies diagnosed in the absence of associated tumors. [57,58] In
are needed in order to fully understand the relevance a recent study, only the 21.4% of the patients showed
of Caspr‑2 as an autoantigen in the pathophysiology of malignancies. Hyponatremia is a characteristic
[59]
Guillain‑Barrè syndrome. feature of VGKC‑LE. It is present in about 60% of
patients, and it is initially resistant to treatment, but
Autonomic nerves it usually resolves as the VGKC complex‑IgG titers
Gastrointestinal neuromuscular disorders described decline. The serum hyponatremia usually follows
[9]
in association with VGPC complex‑IgG a syndrome of inappropriate antidiuretic hormone
Gastrointestinal neuromuscular diseases are (SIADH) secretion pattern. Intermittent and episodic
characterized by symptoms of intestinal neuromuscular hypothermia, along with neuropathic pain, both
dysfunction. These disorders may be attributable to responsive to immunotherapy, have been reported
[41]
congenital or, more frequently, acquired conditions. in patients affected by VGKC‑LE. [60] A severe sleep
An autoimmune pathophysiology has been proposed disorder, characterized by insomnia, deep diurnal
to explain acquired gastrointestinal neuromuscular drowsiness and complete disappearance of rapid
diseases. Interestingly, inflammatory neuropathy eye movement sleep has also been associated with
is common in patients affected by gastrointestinal VGKC‑LE. Autonomic dysfunctions have been
[61]
neuromuscular diseases and autoantibodies directed extensively described in VGKC‑LE patients. Vincent
against neuronal antigens are present in some et al. reported sweating and hypersecretion due
[9]
patients. VGKC complex‑IgG have been detected in to an effect of the antibodies on the postganglionic
the sera of patients with primary and paraneoplastic sympathetic neurons. More recently, episodic
slow‑transit constipation, [15,16] primary achalasia, bradycardia has been recognized as a prodrome
[42]

Neuroimmunol Neuroinflammation | Volume 3 | March 28, 2016 71