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also possible symptoms. MoS usually presents with CONCLUSION
a slow, insidious onset over months to years and is
[85]
almost exclusively seen in males. In about the 90% of The clinical spectrum of the neurological disorders
cases, it spontaneously goes into remission, while in associated with VGKC complex‑IgG is rapidly
the remaining 10% of cases leads to death. [86] expanding, and new associated conditions have
been described in the last years. The vast majority
Patients with MoS may have an associated underlying of these disorders are reversible by immunotherapy,
tumor, including thymoma, that is the most common, and it is becoming increasingly recognized that
lung cancer, sigmoid cancer, testicular cancer early diagnosis and detection of VGKC complex‑IgG
[88]
[87]
and lymphoma, thus indicating the paraneoplastic is critical in order to rapidly start the treatment.
nature of the disease. On the other hand, patients As a result, VGKC complex‑IgG are now part of the
[89]
without an associated tumor have been also been investigation of patients with unexplained subacute
studied, and they generally experience a good clinic onset of epilepsy, memory or cognitive problems, or
response to immunotherapy. Interestingly, it has peripheral nerve hyperexcitability syndromes. It is still
[81]
been described the occurrence of MoS after scrotal not fully understood how VGKC complex‑IgG could
tap and injection of sclerosing agent for the treatment cause such a range of different clinical presentations.
of hydrocele in 5 males. [90] Some MoS cases associated The accelerated development that the research on
with thymomas and myasthenia gravis have also been antibody‑mediated syndrome has had in the last
[91]
reported. VGKC‑complex antibody serum levels are period has been exciting and has made possible to
increased in the 90% of the patients [Figure 1] and diagnose and to treat clinical syndromes that would
although these are directed against LGI‑1, Caspr‑2, or have otherwise been poorly defined. Certainly, the
commonly both, Caspr‑2 antibodies predominate and development and validation of experimental models
are always associated with thymoma. Fewer patients of VGKC autoimmunity will represent the next
have been reported also with contactin‑2 antibodies. critical challenge in order to clearly elucidate how
[81]
It is intriguing that low levels of Caspr‑2 mRNA the antibodies get into the CNS and understand if
have been detected in the human prostate: although also antibody‑binding, internalization and loss of
Caspr‑2 is predominantly expressed in the nervous the target surface antigens, along with complement
system, the male reproductive system may be a source activation, are involved in the physiopathology. In
of the antigen and MoS onset after scrotal drainage [90] fact, there is a need to extend our understanding of the
may be a crucial factor to break the immune tolerance. pathophysiological mechanisms of these syndromes
in order to improve their diagnosis, and ultimately, to
Moreover, thymectomy and thymoma chemotherapy
may act as disease triggers, thus suggesting that
thymic tumors may also harbor the antigenic targets,
in particular, Caspr‑2. CSF analysis in MoS usually
shows normal protein, glucose, white cell count, and
IgG index. Oligoclonal bands may be detected. Marked
changes in circadian serum levels of neurohormones
have been described, with serum levels of melatonin
and prolactin substantially lower than normal and
without a circadian rhythm of release. Plasma levels
[87]
of norepinephrine were found to be high throughout
the 24 h period, without the physiological nocturnal
decrease. [83,87] Increased serum levels of cortisol were
[87]
also observed. A negative MRI is a characteristic
finding in MoS, [81,88] but frontal T2 hyperintensity in
one patient and bilateral hippocampal T2 high signal
in another patient have also been reported and
[81]
in these cases the diagnosis of “LE associated with
neuromyotonia” should be more appropriate. MoS
treatment is based on immunotherapies, including
plasma exchange, intravenous immunoglobulin,
corticosteroids, azathioprine, cyclosporine, and
cyclophosphamide. In the paraneoplastic forms of
MoS, the management of the underlying malignancy Figure 1: Indirect immunofluorescence showing IgG in the serum of a patient
with Morvan’s syndrome binding to the surface of a live rat hippocampal
is mandatory. neurons

Neuroimmunol Neuroinflammation | Volume 3 | March 28, 2016 75