ObjectiveTo investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes.MethodsWe assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti-contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings.ResultsCharacteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti-neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo–glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p<0.05).ConclusionsParanodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with CIDP with autoantibodies to paranodal axo–glial junctional molecules.

Objective The objective of this study was to elucidate the natural history of late-onset transthyretin Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) in non-endemic areas. Methods The authors retrospectively assessed the development of major clinical landmarks and abnormalities of nerve conduction and cardiac examination indices in 50 patients with an age of onset older than 50 years and no relationship to endemic foci.

Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkin's lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain.

These findings suggest that direct insult of amyloid fibrils causes Schwann cell damage, resulting in the predominant loss of small-fiber axons characteristic of early-onset cases. In addition, vasculopathy may participate in the pathogenesis of neuropathy, particularly in late-onset cases.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a form of chronic neuropathy that is presumably caused by heterogeneous immune-mediated processes. Recent advances in the search for autoantibodies against components expressed at nodal regions, such as the nodes of Ranvier and paranodes, have substantially contributed to clarifying the pathogenesis of CIDP in a subpopulation of patients. In particular, immunoglobulin G4 (IgG4) antibodies to paranodal junction proteins, including neurofascin-155 and contactin-1, have attracted the attention of researchers. Paranodal dissection resulting from the attachment of IgG4 at paranodal junctions and the absence of macrophage-induced demyelination are characteristic pathologic features in patients who have these antibodies. By contrast, the mechanisms of neuropathy in cases with classical macrophage-induced demyelination remain unclear despite the long-standing recognition of this process in CIDP. In addition to complement-dependent damage provoked by autoantibodies, recent studies have shed light on antibody-dependent phagocytosis by macrophages without participation of complements. However, a direct association between specific autoantibodies and macrophage-induced demyelination has not been reported. Electron microscopic examination of longitudinal sections of sural nerve biopsy specimens suggested that macrophages recognize specific sites of myelinated fibers as the initial target of demyelination. The site that macrophages select to initiate myelin breakdown is located around the nodal regions in some patients and internode in others. Hence, it seems that the components that distinguish between the nodal regions and internode play a pivotal role in the behavior of macrophages that initiate phagocytosis of myelin. Further studies are needed to elucidate the mechanisms underlying macrophage-induced demyelination from this perspective.

Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP and is now prevalent in areas other than those seen within conventional endemic foci. We investigated 15 patients with FAP ATTR Val30Met without a family history of FAP who were referred for sural nerve biopsy. Initial symptoms included somatic neuropathy in all patients, while sensory dissociation and autonomic symptoms were apparent only in two and seven patients, respectively. Nonspecific neuropathic features and slight abnormalities in cerebrospinal fluid protein levels and in electrophysiological indices related to nerve conduction led clinicians to initially suspect chronic inflammatory demyelinating polyneuropathy (CIDP) in some patients. Small-fiber predominant loss was observed in a minority of patients. In terms of cardiac involvement, findings suggestive of subclinical cardiomyopathy due to amyloid deposition, such as cardiomegaly on chest X-ray, thickening of the interventricular septum, and granular sparkling echo on echocardiography, were seen alone or in combination in 11 of 14 examined patients. In conclusion, clinicians should consider the possibility of FAP ATTR Val30Met in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis. Detecting subclinical cardiac involvement may help to diagnose late-onset FAP ATTR Val30Met in those without a family history of the disease.

No abstract

and the OPDM_LRP12 Study Group IMPORTANCE Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown.OBJECTIVE To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. DESIGN, SETTING, AND PARTICIPANTSThis case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot.MAIN OUTCOMES AND MEASURES Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics.RESULTS Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r 2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. CONCLUSIONS AND RELEVANCEThis study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.