Medical Research Council.

SummaryHuman autoantibodies to contactin-associated protein-like 2 (CASPR2) are often associated with neuropathic pain, and CASPR2 mutations have been linked to autism spectrum disorders, in which sensory dysfunction is increasingly recognized. Human CASPR2 autoantibodies, when injected into mice, were peripherally restricted and resulted in mechanical pain-related hypersensitivity in the absence of neural injury. We therefore investigated the mechanism by which CASPR2 modulates nociceptive function. Mice lacking CASPR2 (Cntnap2−/−) demonstrated enhanced pain-related hypersensitivity to noxious mechanical stimuli, heat, and algogens. Both primary afferent excitability and subsequent nociceptive transmission within the dorsal horn were increased in Cntnap2−/− mice. Either immune or genetic-mediated ablation of CASPR2 enhanced the excitability of DRG neurons in a cell-autonomous fashion through regulation of Kv1 channel expression at the soma membrane. This is the first example of passive transfer of an autoimmune peripheral neuropathic pain disorder and demonstrates that CASPR2 has a key role in regulating cell-intrinsic dorsal root ganglion (DRG) neuron excitability.

Antibodies directed against the post-synaptic neuromuscular junction protein, muscle specific kinase (MuSK) are found in a small proportion of generalized myasthenia gravis (MuSK-MG) patients. MuSK is a receptor tyrosine kinase which is essential for clustering of the acetylcholine receptors (AChRs) at the neuromuscular junction, but the mechanisms by which MuSK antibodies (MuSK-Abs) affect neuromuscular transmission are not clear. Experimental models of MuSK-MG have been described but there have been no detailed electrophysiological studies and no comparisons between the MuSK-MG and the typical form with AChR-Abs (AChR-MG). Here we studied the electrophysiology of neuromuscular transmission after immunization against MuSK compared with immunization against AChR, and also after passive transfer of IgG from MuSK-MG or AChR-MG patients. Overt clinical weakness was observed in 6/10 MuSK-immunized and 3/9 AChR-immunized mice but not in those injected with patients' IgG. Miniature endplate potentials (MEPPS) were reduced in all weak mice consistent with the reduction in postsynaptic AChRs that was found. However, whereas there was an increase in the quantal release of acetylcholine (ACh) in the weak AChR-immunized mice, no such increase was found in the weak MuSK-immunized mice. Similar trends were found after the passive transfer of purified IgG antibodies from MuSK-MG or AChR-MG patients. Preliminary results showed that MuSK expression was considerably higher at the neuromuscular junctions of the masseter (facial) than in the gastrocnemius (leg) with no reduction in MuSK immunostaining at the neuromuscular junctions. Overall, these results suggest that MuSK antibodies act in at least two ways. Firstly by indirectly affecting MuSK's ability to maintain the high density of AChRs and secondly by interfering with a compensatory presynaptic mechanism that regulates quantal release and helps to preserve neuromuscular function. These results raise questions about how MuSK is involved in retrograde signaling, and the combination of post-synaptic defects with lack of presynaptic compensation may begin to explain the more severe disease in MuSK-MG patients.

ObjectiveN-methyl-D-aspartate receptor antibody (NMDAR-Ab) encephalitis is a well-recognised clinico-immunological syndrome that presents with neuropsychiatric symptoms cognitive decline, movement disorder and seizures. This study reports the clinical features, management and neurological outcomes of paediatric NMDAR-Ab-mediated neurological disease in the UK.DesignA prospective surveillance study. Children with NMDAR-Ab-mediated neurological diseases were voluntarily reported to the British Neurological Surveillance Unit (BPNSU) from November 2010 to December 2011. Initial and follow-up questionnaires were sent out to physicians.ResultsThirty-one children fulfilled the criteria for the study. Eight presented during the study period giving an incidence of 0.85 per million children per year (95% CI 0.64 to 1.06); 23 cases were historical. Behavioural change and neuropsychiatric features were present in 90% of patients, and seizures and movement disorders both in 67%. Typical NMDAR-Ab encephalitis was reported in 24 children and partial phenotype without encephalopathy in seven, including predominantly psychiatric (four) and movement disorder (three). All patients received steroids, 22 (71%) received intravenous immunoglobulin, 9 (29%) received plasma exchange,and 10 (32%) received second-line immunotherapy. Of the 23 patients who were diagnosed early, 18 (78%) made a full recovery compared with only 1 of 8 (13%) of the late diagnosed patients (p=0.002, Fisher's exact test). Seven patients relapsed, with four needing additional second-line immunotherapy.ConclusionsPaediatric NMDAR-Ab-mediated neurological disease appears to be similar to adult NMDAR-Ab encephalitis, but some presented with a partial phenotype. Early treatment was associated with a quick and often full recovery.