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OBJECTIVE: We examined the diagnostic difficulty in thiamine deficiency. METHODS: We report on two patients with polyneuropathy associated with thiamine deficiency (i.e., beriberi neuropathy) that presented with acute motor symptoms mimicking Guillain-Barré syndrome. RESULTS: The cause of the thiamine deficiency was associated with gastrectomy to treat cancer in a 46-y-old man and with dietary imbalance in a 33-y-old man. The thiamine deficiency was not related to alcohol intake in either patient. In both patients, the upper and lower extremities showed a rapidly progressive weakness over the course of 1 mo. Muscle weakness in the first patient progressed even after admission to the hospital, and urinary retention, Wernicke's encephalopathy, lactic acidosis, paralytic ileus, and heart failure appeared subsequently. Clinical symptoms in both patients showed improvement after initiation of thiamine administration, although some residual deficit remained. CONCLUSION: Thiamine deficiency must be actively considered as a possible cause of polyneuropathy, and variability in its clinical features should be taken into consideration. [ABSTRACT FROM AUTHOR]

Vasculitic neuropathy is commonly associated with systemic vasculitis, leading to ischemic damage to the peripheral nerves and axonal degeneration. The typical clinical manifestation of vasculitic neuropathy is a sensory-dominant multiple mononeuropathy often accompanied by pain. Although vasculitic neuropathy is caused by various systemic diseases, ANCA-associated vasculitis, secondary systemic vasculitis linked to various collagen diseases, and non-systemic vasculitic neuropathy hold particular significance. A comprehensive understanding of vasculitic neuropathy is crucial for its early diagnosis, contributing to an improved prognosis for this condition.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic disorder that frequently affects the peripheral nervous system and consists of three distinct conditions: microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA, previously Wegener's granulomatosis), and eosinophilic granulomatosis with polyangiitis (EGPA, previously Churg-Strauss syndrome). The neuropathic features associated with this condition usually include mononeuritis multiplex, which reflects the locality of lesions. Findings suggestive of vasculitis are usually found in the epineurium and occur diffusely throughout the nerve trunk. Nerve fiber degeneration resulting from ischemia is sometimes focal or asymmetric and tends to become conspicuous at the middle portion of the nerve trunk. The attachment of neutrophils to endothelial cells in the epineurial vessels is frequently observed in patients with ANCA-associated vasculitis; neutrophils play an important role in vascular inflammation by binding of ANCA. The positivity rate of ANCA in EGPA is lower than that in MPA and GPA, and intravascular and tissue eosinophils appear to participate in neuropathy. Immunotherapy for ANCA-associated vasculitis involves the induction and maintenance of remission to prevent the relapse of the disease. A combination of glucocorticoids along with cyclophosphamide, rituximab, methotrexate, or mycophenolate mofetil is considered depending on the severity of the condition of the organ to induce remission. A combination of low-dose glucocorticoids and azathioprine, rituximab, methotrexate, or mycophenolate mofetil is recommended to maintain remission. The efficacy of anti-interleukin-5 therapy (i.e., mepolizumab) was demonstrated in the case of refractory or relapsing EGPA. Several other new agents, including avacopan, vilobelimab, and abatacept, are under development for the treatment of ANCA-associated vasculitis. Multidisciplinary approaches are required for the diagnosis and management of the disorder because of its systemic nature. Furthermore, active participation of neurologists is required because the associated neuropathic symptoms can significantly disrupt the day-to-day functioning and quality of life of patients with ANCA-associated vasculitis., (© 2022. The Author(s).)

Objective: To clarify whether antiparkinsonian drugs contribute to nocturnal sleep disturbances in patients with Parkinson's disease (PD)., Background: Although the major antiparkinsonian drugs L-dopa and dopamine agonists (DAs) have been found to affect sleep, little is known about the effects of specific drugs on sleep in PD patients., Methods: The study participants consisted of 112 PD patients (median age 72.5 years [inter-quartile range: IQR 65-79]; mean disease duration 8.44 years [standard deviation: 7.33]; median Hoehn and Yahr stage 3 [IQR 2-3.75]) taking one of three types of non-ergot extended-release DAs (rotigotine 32; pramipexole 44; ropinirole 36) with or without L-dopa (median daily total dosage of antiparkinsonian drugs 525.5 mg [IQR 376.25-658] levodopa equivalent dose [LED]). Participants were assessed using the PD Sleep Scale-2 (PDSS-2)., Results: For the whole PD patient cohort, the PDSS-2 sleep disturbance domain score and the scores for item 1 assessing sleep quality and item 8 assessing nocturia were positively correlated with daily total dosage of antiparkinsonian drugs and dosage of L-dopa, but not with the dosage of DAs. Sub-analysis according to DA treatment revealed that DA dosage was not correlated with item 1 or 8 score in any of the subgroups. The LED ratio of rotigotine to the total dosage of antiparkinsonian drugs was inversely correlated with the item 1 score., Conclusions: These data suggest that antiparkinsonian drugs, in particular L-dopa, adversely affect nocturnal sleep in PD patients, especially in terms of sleep quality and nocturia. Thus, adjusting both the total dosage of antiparkinsonian drugs and the dose-ratio of L-dopa might be key actions for alleviating poor sleep quality in patients with PD. Among DAs, we found a clear positive correlation between the dose-ratio of rotigotine and sleep quality. Thus, partial L-dopa replacement with rotigotine could improve sleep quality in patients with PD., Competing Interests: The authors declare that no competing interests exist.

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 Participants: This 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 (r2 = 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 Relevance: This 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.

To clarify the pathogenesis of anti-myelin-associated glycoprotein (MAG) antibody neuropathy associated with IgM monoclonal gammopathy (anti-MAG neuropathy), sural nerve biopsy specimens from 15 patients were investigated. Sodium channels, potassium channels, contactin-associated protein 1 (Caspr1), contactin 1, and neurofascin were evaluated by immunofluorescence in teased-fiber preparations. Immunoreactivity to the pan-sodium channel in both anti-MAG neuropathy patients and in normal controls was concentrated at the node of Ranvier unless there was demyelination, which was defined as the widening of the node of Ranvier. However, this immunoreactivity became weak or disappeared as demyelination progressed. In contrast, KCNQ2 immunostaining was nearly absent even in the absence of demyelination. The lengths of Caspr1, contactin 1, and pan-neurofascin immunostaining sites at the paranode were significantly increased compared with those of normal controls despite the absence of demyelination. The length of paranodal neurofascin staining correlated with the anti-MAG antibody titer, nerve conduction indices, the frequency of de/remyelination in teased-fiber preparations, and the frequency of widely spaced myelin (p < 0.05, p < 0.05, p < 0.01, and <0.05, respectively). These findings suggest that nodal and paranodal molecular alterations occur in early stages preceding the morphological changes associated with demyelination in anti-MAG neuropathy., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

Objective: To describe the pathological features of Guillain-Barré syndrome focusing on macrophage-associated myelin lesions., Methods: Longitudinal sections of sural nerve biopsy specimens from 11 patients with acute inflammatory demyelinating polyneuropathy (AIDP) exhibiting macrophage-associated demyelinating lesions were examined using electron microscopy. A total of 1205 nodes of Ranvier were examined to determine the relationship of the macrophage-associated demyelinating lesions with the nodal regions. Additionally, immunohistochemical and immunofluorescent studies were performed to elucidate the sites of complement deposition., Results: Overall, 252 macrophage-associated myelin lesions were identified in longitudinal sections. Of these, 40 lesions exhibited complete demyelination with no association with the lamellar structures of myelin. In 183 lesions, macrophage cytoplasm was located at internodes without association with the nodes of Ranvier or paranodes. In particular, these internodal lesions were more frequent in one patient (152 lesions). In the remaining 29 lesions, the involvement of nodal regions was obvious. Lesions involving nodal regions were more frequently observed than those involving internodes in four patients. Invasion of the macrophage cytoplasmic processes into the space between the paranodal myelin terminal loops and the axolemma from the nodes of Ranvier was observed in three of these patients. Immunostaining suggested complement deposition corresponding to putative initial macrophage-associated demyelinating lesions., Conclusions: The initial macrophage-associated demyelinating lesions appeared to be located at internodes and at nodal regions. The sites at which the macrophages initiated phagocytosis of myelin might be associated with the location of complement deposition in certain patients with AIDP., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the clinicopathologic features of eosinophilic granulomatosis with polyangiitis (EGPA)-associated neuropathy with a focus on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCAs)., Methods: We examined the clinical features and pathologic findings of sural nerve biopsy specimens from 82 patients with EGPA-associated neuropathy. Of these patients, 32.9% were myeloperoxidase (MPO)-ANCA positive, and 67.1% were MPO-ANCA negative. PR3-ANCA was negative in all of 78 examined patients., Results: Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs 14.6%, p < 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group ( p < 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (i.e., destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group ( p < 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels ( p < 0.01) and epineurial vessels occluded by intraluminal eosinophils ( p < 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group ( p < 0.01)., Conclusions: This study suggests that the pathogenesis of EGPA comprises at least 2 distinct mechanisms: ANCA-associated vasculitis resulting in ischemic effects and inflammation, which is prominent in MPO-ANCA-positive patients, and eosinophil-associated vascular occlusion leading to ischemia and eosinophil-associated tissue damage, which is conspicuous in MPO-ANCA-negative patients., (© 2020 American Academy of Neurology.)

We herein report the case of a 67-year-old man who presented with the acute onset of limb weakness. Brain magnetic resonance imaging revealed multiple abnormal-signal-intensity lesions. Steroids were administered, and the patient initially responded. Nerve conduction testing findings were consistent with demyelinating polyneuropathy. A sural nerve biopsy specimen revealed fascicles with extensive onion-bulb formation. Although skin and sural nerve biopsies showed no atypical cellular infiltration, the histopathological diagnosis of intravascular large B-cell lymphoma was obtained by a brain biopsy. The neuropathy in this patient may be attributed to a demyelinating process independent of ischemic damage by lymphoma.

Objective: To evaluate the clinical and pathological correlations characterising each clinical subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)., Methods: We assessed 106 consecutive patients who had CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria and had been referred for sural nerve biopsy. Patients with anti-neurofascin 155, anti-contactin 1 and anti-LM1 antibodies were excluded., Results: 55 patients were classified as having typical CIDP. Regarding atypical CIDP, the multifocal acquired demyelinating sensory and motor (MADSAM) (n=15), distal acquired demyelinating symmetric (DADS) (n=16) and pure sensory (n=15) forms were major subtypes, while the pure motor (n=4) and focal (n=1) forms were rare. Nerve conduction studies revealed that distal motor latencies and F-wave latencies were markedly prolonged in the typical CIDP group but relatively preserved in the MADSAM group. Motor conduction velocity was conspicuously slowed in the DADS group, and distal motor latencies were markedly prolonged in the pure sensory group. Sural nerve biopsy specimens from patients with MADSAM, DADS and pure sensory type tended to show extreme variation in myelinated fibre density among fascicles due to focal myelinated fibre loss or onion-bulb formation, whereas patients with typical CIDP tended to show mild fascicular variation. Epineurial lymphocytic infiltration was conspicuous in cases with marked fascicular variation in myelinated fibre density., Conclusions: Preferential involvement of distal and proximal segments and uniform pathological features in typical CIDP indicate a role of humoral factors at sites where the blood-nerve barrier is deficient. By contrast, focal lesions in MADSAM, DADS and pure sensory forms may share neuropathic mechanisms primarily affecting the nerve trunk., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2018 American Academy of Neurology.)

Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val30Met mutations, and information regarding non-Val30Met patients is scarce. The aim of this study was to systematically investigate the cardiac and peripheral vasomotor autonomic functions in non-Val30Met patients. Methods The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test results, noradrenaline infusion test results, and the (123) I-metaiodobenzylguanidine (MIBG) uptake on myocardial scintigraphy were assessed in five patients. The predominant manifestations were neuropathy in three patients (Val94Gly, Val71Ala, and Pro24Ser), cardiomyopathy in one (Thr60Ala), and oculoleptomeningeal involvement in one (Tyr114Cys). Results Although one patient with predominant cardiomyopathy did not manifest orthostatic hypotension during the head-up tilt test, the CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated the presence of cardiac sympathetic and parasympathetic dysfunction in all patients. The total peripheral resistance at 60° tilt did not increase from the baseline values in any of the examined patients. An infusion of low-dose noradrenaline induced an increase in the systolic blood pressure, except in one patient with mild neuropathy. Conclusion Cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non-Val30Met patients, irrespective of their phenotype, suggesting a common pathology of autonomic involvement. However, the vasoconstrictor function was preserved, even in a patient with advanced neuropathy.

Introduction: We evaluated the morphology of amyloid fibrils in the peripheral nervous system using biopsy or autopsy specimens from hereditary transthyretin amyloidosis patients. The impact of amyloid fibril formation on neighboring tissues was also investigated., Methods: Sural nerve biopsy specimens from 34 patients were examined using electron microscopy. Twenty-eight patients had Val30Met mutations, and the remaining 6 patients had non-Val30Met mutations (i.e., Glu54Lys, Pro24Ser, Thr49Ala, Val71Ala, Val94Gly, and Ala97Gly). The patients with the Val30Met mutation included a case from Brazil (supposedly of Portuguese origin), 6 early-onset cases from endemic foci in Japan, and 21 late-onset cases from non-endemic areas in Japan., Results: Long amyloid fibers were abundant in the early-onset Val30Met cases from the Japanese endemic foci and Brazil, whereas the amyloid fibrils were generally short in the late-onset Val30Met and non-Val30Met cases. The amyloid fibrils seemed to mature from dotty structures among amorphous electron-dense extracellular materials and pull surrounding tissues during the maturation process. The distortion of Schwann cells close to amyloid fibril masses was conspicuous, particularly in cases with long amyloid fibrils. Atrophy was conspicuous in non-myelinating Schwann cells and bands of Büngner (i.e., Schwann cell subunits that previously contained myelinated axons), particularly those completely surrounded by amyloid fibrils. In contrast, the myelinated fibers tended to be only partially surrounded by amyloid fibrils and morphologically preserved due to their large size. Only a few demyelinated axons were found., Conclusion: Pre-fibrillar amyloid precursors appear to play a pivotal role during the initial phase of amyloid fibril formation. The mechanical distortion and subsequent atrophy of Schwann cells resulting from the elongation of amyloid fibrils may be related to small-fiber predominant loss, which is a classical characteristic of amyloid neuropathy. Although rather rare, the destruction of myelin (i.e., demyelination) resulting from amyloid deposition may relate to nerve conduction abnormalities mimicking chronic inflammatory demyelinating polyneuropathy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We herein report a woman with chronic inflammatory demyelinating polyneuropathy (CIDP) in whom positivity for anti-neurofascin 155 antibodies was revealed 23 years after the onset of neuropathy. The patient initially reported numbness in the face at 50 years of age and subsequently manifested features compatible to typical CIDP. Steroid administration initiated at 54 years of age ameliorated her neuropathic symptoms. Although the nerve conduction indices at 59 years of age deteriorated, those at 68, 72, and 73 years of age showed a gradual recovery. The deterioration and subsequent restoration of compound muscle action potential amplitudes was the most dramatic, suggesting that a conduction block can be reversed earlier than other electrophysiological indices.

The objective of this study was to systematically investigate cardiac and peripheral vasomotor autonomic functions in late-onset transthyretin Val30Met familial amyloid polyneuropathy (FAP ATTR Val30Met) patients from non-endemic areas. The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test with impedance cardiography, noradrenaline infusion test, and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy were assessed in eight patients. Although only four patients manifested orthostatic hypotension during the head-up tilt test, CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated a higher prevalence of cardiac sympathetic and parasympathetic dysfunction. Total peripheral resistance at 60° tilt did not increase from baseline values in five of six examined patients. An infusion of low-dose noradrenaline induced an increase in systolic blood pressure in all patients. The extent of the change in systolic blood pressure negatively correlated to that in total peripheral resistance (p < 0.05). Patients with poor vasoconstrictor responses to orthostatic stress tended to exhibit severe reduction of unmyelinated fibres in sural nerve biopsy specimens. In conclusion, both cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in late-onset FAP ATTR Val30Met patients from non-endemic areas, even in those without orthostatic intolerance. However, vasoconstriction by alpha-adrenoceptor agonists was preserved even after denervation, carrying important implications for the management of orthostatic hypotension in FAP.

Objective: To investigate the mechanisms of vasculitis in nonsystemic vasculitic neuropathy (NSVN) and microscopic polyangiitis (MPA), focusing on complement- and antineutrophil cytoplasmic antibody (ANCA)-associated pathogenesis., Methods: Sural nerve biopsy specimens taken from twenty-four patients with NSVN and 37 with MPA-associated neuropathy (MPAN) were examined. Twenty-two patients in the MPAN group tested positive for ANCA., Results: Immunostaining for complement component C3d deposition showed more frequent positive staining of epineurial small vessels in NSVN than in MPAN ( p = 0.002). The percentages of C3d-positive blood vessels were higher in the NSVN group than those in the ANCA-positive MPAN and ANCA-negative MPAN groups ( p = 0.002 and p = 0.009, respectively). Attachment of neutrophils to the endothelial cells of epineurial small vessels was frequently observed in the MPAN groups, irrespective of the presence or absence of ANCA, but was scarce in the NSVN group. Immunohistochemistry using antimyeloperoxidase (MPO) antibodies revealed that the number of MPO-positive cells attached to the endothelial cells of epineurial vessels was lower in the NSVN group than that in the ANCA-positive MPAN and ANCA-negative MPAN groups ( p < 0.001 and p = 0.011, respectively)., Conclusions: NSVN and MPA have distinct mechanisms of vasculitis. In MPA, the attachment of neutrophils to vascular endothelial cells seems to be an initial lesion of vasculitis, regardless of the presence or absence of ANCA. Complement participated in the pathogenesis of vasculitis in NSVN.

Objective: To 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., Methods: We 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., Results: Characteristic 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)., Conclusions: Paranodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with CIDP with autoantibodies to paranodal axo-glial junctional molecules., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

We herein report a case of peripheral neuropathy following exposure to large amounts of glyphosate-based herbicide. A 70-year-old man suffered from pain and purpura in the left sole following exposure to glyphosate-based herbicide. Pain and purpura spread to the opposite side and increased in severity. Mild weakness of the lower limbs was also observed. A sural nerve biopsy revealed the infiltration of lymphocytes around small vessels in the epineurium with numerous eosinophils, deposition of hemosiderins and focal axonal degeneration, compatible with findings of vasculitic neuropathy. Glyphosate-based herbicides should be recognized as a causative agent of vasculitic neuropathy.

A patient with chronic alcoholism presented with myelopathy and low serum folate and cobalamin levels. A 42-year-old alcoholic man had gait disturbance for 4 months. A neurological examination revealed marked spasticity with increased deep tendon reflexes and extensor plantar responses of the lower limbs. His cobalamin level was decreased and his serum folate level was particularly low. His plasma ammonia level was not increased. Abstinence and folic acid and cobalamin supplementation stopped the progression of his neurological deficits. This case indicates that nutritional deficiency should be monitored closely in patients with chronic alcoholism who present with myelopathy.

Objective: To examine the morphology of Schwann cells and endoneurial microvessels with electron microscopy., Methods: Sural nerve biopsy specimens from 49 patients with familial amyloid polyneuropathy (FAP) with transthyretin Val30Met mutation were assessed. Patients included 11 early-onset cases from endemic foci and 38 late-onset cases from nonendemic areas., Results: Loss of nerve fibers with or without neighboring amyloid deposition was a common feature. The amount of amyloid deposition was greater relative to the extent of nerve fiber loss in early-onset cases than in late-onset cases. The atrophy of Schwann cells, particularly nonmyelinating Schwann cells, that were apposed to amyloid fibrils was more conspicuous in early-onset cases than in late-onset cases. The numbers of endothelial cell nuclei, endothelial cell profiles, and occluded microvessels were significantly increased in the patients with FAP compared with 37 patients with nutritional/alcoholic neuropathies (p < 0.05, 0.01, and 0.01, respectively). Findings suggestive of the disruption of blood-nerve barriers such as the loss of tight junctions and the fenestration of endothelial cells were also found more frequently in the patients with FAP (p < 0.001), regardless of the presence or absence of amyloid deposition., Conclusions: 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., (© 2016 American Academy of Neurology.)

Objective: To examine intraepidermal nerve fibre densities (IENFDs) in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin change (POEMS) syndrome., Methods: The IENFDs of 11 patients with POEMS syndrome were estimated. We determined whether IENFD was associated with patient clinical features or the estimated number of nerve fibres on complete cross-sections of biopsied sural nerves., Results: IENFD was significantly reduced (9.7±4.4fibres/mm) compared with normal controls (p<0.05), although the individual values varied from 1.4 to 14.4fibres/mm. The presence of glucose intolerance was significantly associated with a reduction of IENFD (p<0.05). The number of unmyelinated fibres was preserved at the sural nerve level and was not correlated with IENFD. In contrast, the number of myelinated fibres was correlated with IENFD (p<0.05)., Conclusions: Some of the patients presented with a severe IENFD reduction. Because the number of unmyelinated fibres was well preserved at the level of the sural nerve biopsy, this severe reduction may indicate involvement at the most distal nerve terminals of unmyelinated fibres. Although the reduction of IENFD becomes evident as polyneuropathy becomes severe, the effects of glucose intolerance should also be considered in patients with moderate to severe reductions., (Copyright © 2016. Published by Elsevier B.V.)

To elucidate the significance of uncompacted myelin lamellae (UML) and ion channel disruption at the nodes of Ranvier in the polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, we evaluated sural nerve biopsy specimens from 33 patients with POEMS syndrome and from 7 control patients. Uncompacted myelin lamellae distribution was assessed by electron microscopy and immunofluorescence microscopy. In the POEMS patient biopsies, UML were seen more frequently in small versus large myelinated fibers. Paranodes and Schmidt-Lanterman incisures, where normal physiologic UM is located, were frequently associated with UM. Widening of the nodes of Ranvier (i.e. segmental demyelination) was not associated with UML. There was axonal hollowing with neurofilament condensation at Schmidt-Lanterman incisures with abnormal UML, suggesting axonal damage at those sites in the POEMS patient biopsies. Myelin sheath irregularity was conspicuous in large myelinated fibers and was associated with abnormally widened bizarrely shaped Schmidt-Lanterman incisures. Indirect immunofluorescent studies revealed abnormalities of sodium (pan sodium) and potassium (KCNQ2) channels, even at nonwidened nodes of Ranvier. Thus, UML was not apparently associated with segmental demyelination but seemed to be associated with axonal damage. These observations suggest that nodal ion channel disruption may be associated with functional deficits in POEMS syndrome patient nerves.

Objective: To evaluate the pathologic significance of immunoglobulin G4 (IgG4) in patients with inflammatory peripheral neuropathy., Methods: We clinicopathologically examined 149 consecutive patients with peripheral neuropathy who had clusters of inflammatory cells with or without vasculitis in sural nerve biopsy specimens and in whom we were able to assess the serum IgG4 levels., Results: Elevation of serum IgG4 levels and infiltration of IgG4-positive plasma cells, which are currently defined as the diagnostic criteria for IgG4-related disease, were found in 35 and 29 patients, respectively. In the 44 patients exhibiting either elevated serum IgG4 levels or IgG4-positive cell infiltration, the diagnoses prior to the examination of IgG4 in serum and pathologic samples included microscopic polyangiitis (12 patients) and eosinophilic granulomatosis with polyangiitis, or Churg-Strauss syndrome (19 patients). Thirty-four patients (77%) had findings of vasculitis as indicated by the destruction or obstruction of the vessel walls. Sixteen (36%) of these patients had fibrinoid necrosis. Axonal degeneration without evidence of demyelination was observed irrespective of the presence of vasculitis. The extent of fibrosis, assessed as the fibrotic area in the epineurium, significantly correlated with the grade of IgG4-positive cell infiltration (p < 0.01)., Conclusions: Elevated serum IgG4 levels and infiltration of IgG4-positive plasma cells were observed in a subgroup of patients with inflammatory neuropathy, particularly in patients diagnosed with primary systemic vasculitis, including microscopic polyangiitis. Epineurial IgG4-positive plasma cell infiltration correlated with the extent of epineurial fibrosis., (© 2015 American Academy of Neurology.)