Neuronal intranuclear inclusion disease (NIID) has highly variable clinical manifestations. Sone et al. describe the clinical and pathological features of 57 adult-onset cases diagnosed by postmortem dissection/antemortem skin biopsy. They report ‘dementia dominant’ and ‘limb weakness’ subtypes, and recommend consideration of NIID in the differential diagnosis of leukoencephalopathy and neuropathy.

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Objective: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. Methods:In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested.Results: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155-negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n 5 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes.Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments. Neurology ® 2016;86:800-807 GLOSSARY Caspr1 5 contactin-associated protein-1; CCPD 5 combined central and peripheral demyelination; CI 5 confidence interval; CIDP 5 chronic inflammatory demyelinating polyneuropathy; CNTN1 5 contactin 1; GBS 5 Guillain-Barré syndrome; IgG4 5 immunoglobulin G4; IVIg 5 IV immunoglobulin; MS 5 multiple sclerosis; NF155 5 neurofascin-155; OR 5 odds ratio; PNS 5 peripheral nervous system.Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common acquired immune-mediated neuropathy worldwide and is clinically heterogeneous.1 Proven treatments for CIDP include corticosteroids, plasma exchange, and IV immunoglobulin (IVIg). However, the response rates to treatments are highly heterogeneous between patients. This emphasizes that patients and clinicians require biomarkers to identify CIDP subgroups and guide specific immunotherapeutic options.Immunoglobulin G4 (IgG4) autoantibodies to neurofascin-155 (NF155) were recently documented in patients with CIDP.2,3 NF155 belongs to the L1 family of adhesion molecules and is expressed at paranodes by the terminal loops of myelin and associates with the axonal cell adhesion molecules CNTN1 and contactin-associated protein-1 (Caspr1). 4 This ternary complex of glycoproteins is required for the rapid propagation of the nerve impulses along myelinated axons. 5,6 Three of 4 patients with anti-NF155 IgG4 showed disabling tremor and all showed poor response to IVIg. 3 This suggested that IgG4 autoantibodies participate in CIDP pathogenesis; nonetheless, the low number of reactive patients precluded statistical correlation.

Guillain-Barré syndrome is divided into two major subtypes, acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy. The characteristic electrophysiological features of acute motor axonal neuropathy are reduced amplitude or absence of distal compound muscle action potentials indicating axonal degeneration. In contrast, autopsy study results show early nodal changes in acute motor axonal neuropathy that may produce motor nerve conduction block. Because the presence of conduction block in acute motor axonal neuropathy has yet to be fully recognized, we reviewed how often conduction block occurred and how frequently it either reversed or was followed by axonal degeneration. Based on Ho's criteria, acute motor axonal neuropathy was electrodiagnosed in 18 patients, and repeated motor nerve conduction studies were carried out on their median and ulnar nerves. Forearm segments of these nerves and the across-elbow segments of the ulnar nerve were examined to evaluate conduction block based on the consensus criteria of the American Association of Electrodiagnostic Medicine. Twelve (67%) of the 18 patients with acute motor axonal neuropathy had definite (n=7) or probable (n=5) conduction blocks. Definite conduction block was detected for one patient (6%) in the forearm segments of both nerves and probable conduction block was detected for five patients (28%). Definite conduction block was present across the elbow segment of the ulnar nerve in seven patients (39%) and probable conduction block in two patients (11%). Conduction block was reversible in seven of 12 patients and was followed by axonal degeneration in six. All conduction blocks had disappeared or begun to resolve within three weeks with no electrophysiological evidence of remyelination. One patient showed both reversible conduction block and conduction block followed by axonal degeneration. Clinical features and anti-ganglioside antibody profiles were similar in the patients with (n=12) and without (n=6) conduction block as well as in those with (n=7) and without (n=5) reversible conduction block, indicating that both conditions form a continuum; a pathophysiological spectrum ranging from reversible conduction failure to axonal degeneration, possibly mediated by antibody attack on gangliosides at the axolemma of the nodes of Ranvier, indicating that reversible conduction block and conduction block followed by axonal degeneration and axonal degeneration without conduction block constitute continuous electrophysiological conditions in acute motor axonal neuropathy.

To assess the significance of distal compound muscle action potential (CMAP) duration for diagnosis of demyelinating neuropathies, electrophysiologic data were reviewed from 471 subjects, including 145 normal controls, 60 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 205 with other neuropathy, and 61 with amyotrophic lateral sclerosis (ALS). The duration of distally evoked CMAP was measured in the median, ulnar, tibial, and peroneal nerves. Optimal cut-off values were calculated with receiver-operating characteristic (ROC) curves. In comparison of normal controls and CIDP patients, ROC analyses showed the sufficient area under the curves (82-93%). When the cut-off values in the detection of demyelination were determined as the point with 98% specificity vs. normal on the ROC curves (median, 6.6 ms; ulnar, 6.7 ms; peroneal, 7.6 ms; tibial, 8.8 ms), the sensitivity was 77% for CIDP, with a specificity of 90% vs. ALS and 95% vs. diabetic neuropathy. The distal CMAP duration is a useful index for the detection of distal demyelination. We suggest the above cut-off values for each nerve as one of the electrodiagnostic criteria for demyelinating neuropathies, preferentially affecting the distal nerve terminals, such as CIDP.