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Page 2 of 5 Orsucci et al. Neuroimmunol Neuroinflammation 2018;5:7 I http://dx.doi.org/10.20517/2347-8659.2017.67

immunomodulatory approaches, but no clinical trial is available to date and the optimal treatment approach
[1]
is unknown . Here, we report the case of a patient with Isaacs’ syndrome tested positive for anti-contactin-
associated protein-2 (Caspr2) antibodies.

CASE REPORT
A 74-year-old Italian man, with unremarkable family history and without any significant comorbidities,
reported diffuse muscle pain for the last three weeks. In the previous year he had occasionally presented
muscle cramps. The pain had gradually worsened so that required the use of morphine intravenously and
carbamazepine (400 mg/day) and pregabalin (225 mg/day) oral administration. Neurological examination
revealed continuous muscle twitches in upper and lower limbs and in the facial muscles [Video 1]. The
remaining examination was unremarkable.

Routine laboratory testing showed increased creatine kinase (CK) levels (579 U/L; normal < 190), mild
anemia (haemoglobin ≈ 10 g/dL), increased erythrocyte sedimentation rate (74 mm/h; normal < 40) and
C-reactive protein levels (13.6 mg/dL; normal < 0.5). Serological studies were negative for HIV, syphilis and
Borrelia. Autoantibodies associated with rheumatic diseases, acetylcholine receptor and MuSK antibodies,
anti-gangliosides, anti-Hu/Yo/Ri/CV2/Ma2, anti-amphiphisin and anti-GAD antibodies were not detected
in the patient’s serum. Cerebrospinal fluid examination (CSF) showed moderately increased protein levels
(73 mg/dL; reference range 15-40 mg/dL), without any signs of intrathecal immunoglobulin synthesis.

Total-spine and brain magnetic resonance imaging (MRI) and electroencephalography were normal. An
extensive screening search for malignancies, including chest/abdomen computed tomography, gastroscopy,
colonoscopy, and tumour markers measurement resulted negative, whereas a segmental Crohn’s disease
was diagnosed. Sensory and motor evoked potentials and nerve conduction studies were normal, whereas
electromyography (EMG) showed continuous spontaneous activity in all the examined muscles [Figure 1],
suggesting the diagnosis of Isaacs’ syndrome. At last, this diagnosis was confirmed by the finding of anti-
Caspr2 antibodies in the patient’s serum.

Therefore, the patient was treated with high-dose corticosteroids (intravenous methylprednisolone
1000 mg/day × 5 days and consecutive tapering to prednisone 25 mg/day) followed by 5 sessions (about 2 h
every other day) of plasma exchange (PEX), with immediate remission of the muscle twitches and pain at
the end of the corticosteroid cycle and after the first PEX session [Video 2]. EMG confirmed this excellent
improvement [Video 2]. At discharge, CK levels were normal. One year after discharge, the disease was
still well controlled with low-dose oral corticosteroids (prednisone 25 mg/day) and symptomatic therapy
with carbamazepine and pregabalin. Five years after discharge, the disease is excellently controlled
by azathioprine 125 mg/day, which was prescribed as a corticosteroid-sparing treatment. Prednisone
administration was interrupted. An extensive screening search for malignancies was repeated and was still
normal.

DISCUSSION
Neuromyotonia is a syndrome of spontaneously occurring muscle activity of peripheral nerve origin, which
[2]
can be triggered by voluntary or induced muscle contraction . It is one among several causes of visible
myokymia. The abnormal activity is characterized electromyographically by doublet, triplet or multiplet
single unit discharges that have a high intraburst frequency, the frequency of the bursts themselves being
[2]
irregular . Our patient fulfilled these EMG criteria [Figure 1].
Anti-VGKC autoantibodies have been identified in patients with acquired neuromyotonia, limbic
encephalitis, or a combination of both (Morvan’s syndrome). However, recent studies have shown that in fact