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epilepsy group. Three patients with antiepileptic The demographic, clinical and neuroradiological
drug‑resistant epilepsy had anti‑LGI‑1 antibodies. characteristics of the patients positive for VGKC
Twelve patients received immunotherapy and 9 (75%) complex‑IgG (except for FBDS, dysautonomia,
achieved a > 50% reduction in seizure frequency. and hyponatremia) are not distinguishable from
Interestingly, LGI‑1 is also linked to seizures of genetic CJD [36,77] and most patients fulfilled the World Health
etiology. Mutations in the LGI‑1 gene are responsible Organization diagnostic criteria for sCJD. [36,79] Thus,
for autosomal dominant temporal lobe epilepsy it is critical to consider autoimmune encephalitis in
with auditory features (buzzing and tinnitus). [74‑76] the differential diagnosis of sCJD in order to promptly
Indeed, the identification of autoantibodies, such test for the relevant antibodies.
as those targeting VGKC‑complex, has changed
paradigms in the diagnosis and management of MORVAN’S SYNDROME
epilepsy and has expanded the phenotypic spectrum
of autoimmune disorders. In future, the discovery Morvan’s “fibrillary chorea” or MoS was first described
of new autoantibodies may also further expand the by the French physician Augustin Marie Morvan [80] in
range of the autoimmune epilepsies. 1890 in a patient who exhibited myokymia combined
with excessive sweating and disordered sleep. It is a
Psychiatric manifestations rare entity characterized by peripheral and central
Several psychiatric manifestations have been described nervous system (CNS) involvement, specifically,
in patients with VGKC‑complex antibodies. [12,14] neuromyotonia, hallucinations, delirium, insomnia,
These are often affective‑predominant and include and autonomic disturbance [Table 2]. [80,81] Peripheral
confusion, memory impairment, personality changes, nerve involvement is mainly characterized by
depression, agitation, hallucinations, and anxiety. A neuromyotonia, but neuropathic pain in the feet and/
clinical improvement has been reported in the majority or legs and back, areflexia and a stocking‑type sensory
of the patients who received immunotherapy. loss may also be present. In some cases, insomnia
[81]
[12]
Neuropsychiatric presentations are significantly may be severe, amounting to not less than complete
more common in patients with higher autoantibody lack of sleep (agrypnia) for weeks or months in a row.
[82]
values, and clinical improvements are more likely in Common encephalopathic manifestations are spatial
patients treated early. Further studies are needed in and temporal disorientation, confusion, amnesia,
order to clarify the exact prevalence of VGKC‑complex hallucinations and agitation. Epileptic seizures,
antibodies in patients from the general population including generalized tonic‑clonic seizures and
with psychiatric manifestations. partial seizures consistent with FBDS, are present in
[11]
about one‑third of the cases. Compulsive behaviors,
Subacute encephalopathy that mimics Creutzfeldt‑Jakob stereotypies, and reduplicative paramnesias can
prion disease associated with VGKC complex‑IgG be part of the CNS involvement. Autonomic
[83]
[77]
Rossi et al. described three patients that were disturbance includes hyperhidrosis, pruritus,
referred with possible prion disease. Their drooling, severe constipation, urinary incontinence,
clinical picture was in keeping with autoimmune excessive lacrimation, and cardiac arrhythmias.
[84]
encephalitis, and they had very high VGKC‑complex/ Autonomic system dysfunction has been described
LGI‑1 antibodies. Otherwise, low titers of neuronal in the 93% of MoS patients, being hyperhidrosis
antibodies occurs rarely in suspected patients with and cardiovascular instability the most common
sporadic Creutzfeldt‑Jakob disease (sCJD) and when [81]
present should be interpreted with caution. Atypical manifestations. Weight loss, skin lesions or itching,
and hyponatremia due to the SIADH secretion are
features in sCJD, such as FBDS, hyponatremia [36] and
autonomic dysfunction, may suggest an autoimmune Table 2: Symptoms and signs of Morvan’s syndrome
[77]
disorder. A high titer of VGKC‑complex Ab (LGI‑1 Peripheral Central nervous Autonomic Systemic
negative) was also identified in a 61‑year‑old Caucasian nervous system system features
system
man with a novel prion protein (PRNP) gene mutation Neuromyotonia Insomnia Hyperhidrosis Weight loss
and Gerstmann‑Straüssler‑Scheinker disease, but Neuropathic pain Disorientation/ Tachycardia Skin lesions
despite 1 year of aggressive immunosuppressive confusion
treatment the patient died. [78] Areflexia Amnesia Blood pressure Hyponatremia
abnormalities
Stocking‑type Hallucinations Drooling
Interestingly, nonspecific markers of neuronal sensory loss
degeneration in CSF such as 14.3.3 and S100B proteins Agitation Constipation
may test positive in patients with VGKC complex‑IgG Delusions Urinary
incontinence
encephalitis, thus being not completely reliable for Seizures Excessive
the definite diagnosis of sCJD. [77] lacrimation

74 Neuroimmunol Neuroinflammation | Volume 3 | March 28, 2016