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Page 332 Breis et al. Neuroimmunol Neuroinflammation 2020;7:330-4 I http://dx.doi.org/10.20517/2347-8659.2020.14

Figure 3. The IgG4 anti-CASPR2 blocking the interaction between CASPR2 and Contactin 2 protein, without activating complement, but
disturbing the expression of the voltage gated potassium channel

specially hyperhidrosis and cardiovascular instability, and neuropathic pain [4,13-15] . Weight loss, skin lesions
or itch, which may result from skin dysautonomia, seizures, fever and SIADH may also be present [12,14] .

[14]
The largest study investigating Morvan’s Syndrome included 29 patients . 93% of them were male and the
median age was 57, varying from 19 to 80. VGKC-complex antibodies were positive in 79%. Tumor was
found in 41% of the patients, and the most prevalent tumor was thymoma in 11 patients, 9 of them had
[14]
history of acetylcholine receptor antibodies .

Most of the patients have both CASPR2 and LGI1 antibodies [4,15] , but CASPR2 antibodies titers are usually
[14]
higher . Antibodies against Contactin-2, a protein expressed in heart conduction tissue, may also be
found, associated with cardiovascular instability . There are also some patients whose sera are not
[14]
consistent with CASPR2, LGI1 or contactin-2, increasing suspicion about an unknown antibody [14,16] .

Isaac’s syndrome is an acquired Peripheral Nerve Hyperexcitability that can include myokymia, muscle
cramps, fasciculation, twitching, stiffness, and pseudomyotonia (slow relaxation of the muscles after
contraction that happens especially in hands, eyes and jaw) [16-18] . Muscle activity persists even when the
[17]
[18]
patient sleeps and it may result in muscle hypertrophy , mainly calf muscles [16,17] , but also forearm and
[17]
hand muscles Cramps are often worsened by voluntary muscle contraction . Dysautonomia (hyperhidrosis,
sialorrhea), Trousseau and Chvostek sign may also be present; sensory manifestations are infrequent ,
[16]
[17]
[16]
strength and reflexes are usually normal . The symptoms are usually insidious, presenting over years .
Antibodies against VGKC complex are found in 38%-50% of the patients. VGKC is associated with
[12]
[17]
repolarization of synaptic membranes and its blockage consequently causes nerve excitability . Other
autoimmune disorders including myasthenia gravis, Addison disease, Hashimoto thyroiditis, are associated,
such as neoplasms, mainly thymoma . Encephalopathy is not present in Isaac’s syndrome .
[17]
[17]
Limbic encephalitis, or limbic encephalopathy, is a reversible cause of cognitive impairment when correctly
[19]
[19]
diagnosed and early treated . The main symptoms suggest infectious encephalitis , but there are many
differential diagnosis besides infection: neurodegenerative dementias, Wernicke-Korsakoff syndrome,
Hashimoto’s encephalopathy, overdose, schizophrenia and others [4,19] . It affects mostly men over 50 years
old and has poor association with tumors .
[4]
The symptoms include amnesia, confusion, psychiatric features, seizures, sleep disturbance and
[22]
[4]
dysautonomia [4,19-21] . The presentation vary from acute to insidious and may be preceded by neuromyotonia .
Focal seizures are the most common type, frequently assuming medial temporal-lobe topography;