Small vessel platelet thrombosis in the peripheral nerves in POEMS syndrome.

INTRODUCTION/AIMS: Vascular thrombosis is prevalent among patients with polyneuropathy, organomegaly, endocrinopathy M-protein, and skin changes (POEMS) syndrome. The endothelial cells in the endoneurium are often hypertrophied and the lumen is frequently occluded. Consequent local hypoxia may increase vascular endothelial growth factor (VEGF), which induces hypercoagulation and vascular permeability. METHODS: This study presents two patients in the fifth decade of life, who had rare nerve biopsy findings of vascular occlusion mainly by platelets. Before the cases presented here, we encountered nine confirmed POEMS patients whose nerve biopsies did not show similar findings. RESULTS: A small artery and a vein were occluded, but no atherosclerotic changes were observed. The endothelial cells that adhered to the packed platelets lost their junctions. DISCUSSION: Platelet aggregation, degranulation, and ischemia may cause a loose endothelial barrier and leak proinflammatory cytokines, such as interleukin-12. This may increase production of VEGF and may cause nerve demyelination. Small vessel platelet thrombosis may contribute to the pathogenesis of this disorder.

Distinct features of hypereosinophilic syndrome with neuropathy from eosinophilic granulomatosis with polyangiitis.

Background and objectives: Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) have overlapping clinical considerations, which frequently involve peripheral neuropathy. The current study aimed to discriminate between the clinicopathological features of HES and EGPA, focusing on the mechanism of peripheral nerve damage. Methods: A total of 53 patients who underwent nerve biopsies at our laboratory were examined: nine patients with idiopathic HES (iHES), three patients with reactive HES, 14 patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA)-positive EGPA, and 27 patients with negative EGPA. Nerve biopsies were performed using light and electron microscopy. Results: Polyneuropathy was more common than mononeuritis multiplex in iHES, which differed from that in ANCA-negative EGPA groups (p = 0.012). Nerve biopsies showed that iHES was associated with neuropathy features such as rare vasculitis and non-vasculitic eosinophilic infiltrates, which differed from those of ANCA-negative EGPA. Fibrinoid necrosis was found only in the reactive HES and ANCA-positive groups. The percentage of endoneurial vessels occluded with eosinophils tended to be higher in iHES (1.8%) than in ANCA-positive EGPA (0%) and negative EGPA (0.7%). In a patient with ANCA-negative EGPA, the endoneurial vessels were occluded with platelets, fibrinoid materials, and eosinophils, demonstrating the morphology of eosinophil extracellular traps. Conclusion: iHES with neuropathy showed a pattern more similar to polyneuropathy than mononeuritis multiplex, which is dominant in ANCA-negative EGPA, and tended to show vasculitis in the peripheral nerves less frequently compared with EGPA. Eosinophilic infiltration and endoneurial vascular occlusion by eosinophils may cause nerve damage.

Soluble TREM2 and Alzheimer-related biomarker trajectories in the blood of patients with diabetes based on their cognitive status.

AIM: We aimed to elucidate the dynamics of blood biomarkers according to the severity of cognitive impairment in patients with type 2 diabetes mellitus (DM) and to identify useful biomarkers for diabetes-related dementia. METHODS: This was a cross-sectional, nested case-control study of 121 Japanese DM and non-DM patients with different levels of cognitive functioning. We evaluated participants' cognitive functions, blood biomarkers related to Alzheimer's disease, and soluble triggering receptors expressed on myeloid cells 2 (sTREM2). We then compared these biomarkers between the DM and non-DM and across the different cognitive strata. RESULTS: In all cognitive strata, significantly lower levels of serum sTREM2 were observed in the DM than in the non-DM. We also found that plasma levels of phosphorylated tau (p-tau) increased with increasing levels of cognitive decline in both the DM and non-DM. However, this was accompanied by a decrease in plasma amyloid-ß(Aß42/Aß40 ratios in non-DM only. CONCLUSION: This study revealed novel characteristic trajectories of dementia-related blood biomarkers in diabetes-related dementia, suggesting the pathological involvement of molecular cascades initiated by impaired microglial activation. This results in decreased serum sTREM2, followed by tauopathy without substantial amyloid plaques, reflected by plasma p-tau elevation with no decrease in the Aß42/Aß40 ratio. Clinical trials (the unique trial number and the name of the registry): UMIN000048032, https://www.umin.ac.jp.

Neutrophil extracellular traps in neuropathy with anti-neutrophil cytoplasmic autoantibody-associated microscopic polyangiitis.

To clarify the roles of neutrophils in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitic neuropathy, we studied neutrophil extracellular traps (NETs) in peripheral nerve vasculitis. Stored nerve samples from 17 patients with microscopic polyangiitis (MPA) were immunohistochemically analyzed using antibodies for citrullinated histone H3 (citH3) and various neutrophil enzymes. We defined merged citH3 and extracellularly released myeloperoxidase (MPO) as NET formation. We also compared NET formation between MPO-ANCA-positive/negative MPA and rheumatoid arthritis (RA)-associated vasculitic neuropathy. NETs were identified mostly in vasculitic small arterioles of 6 of 12 MPO-ANCA-positive MPA patients, and their frequency was higher (p < 0.05) than in ANCA-negative patients. NETs were not found in vasculitic neuropathy with RA or patients with chronic inflammatory demyelinating polyradiculoneuropathy. NETs were also observed in the peripheral nervous system of MPA patients as well as in the lung and kidney. These results suggest that NETs may be involved in the pathogenesis of MPA neuropathy.

Different profiles of onion bulb in CIDP and CMT1A in relation to extracellular matrix.

Hypertrophic neuropathy is usually intractable, and chronic inflammatory demyelinating polyneuropathy (CIDP) and Charcot-Marie-Tooth disease Type 1A (CMT1A) are the representative disorders. The two disorders are sometimes confused both clinically and pathologically. The aim of this study was to clarify the differences in the pathology of large onion bulbs, focusing on the extracellular matrix (ECM) proteins. Nine patients with CIDP and 14 with CMT1A were included. The opened interspaces in OB were frequently shown in CMT1A patients. In CIDP, interspaces of OB packed with collagen fibers were prominent. The mean ratio of opened OB was significantly increased in CMT1A (37.9%) compared to CIDP patients (10.6%) (p = 0.003). Among the ECM examined, tenascin-C (TNC) showed a distinct difference in the pattern of immunoreactivity of OB. The mean ratio of OB showing TNC immunoreactivity was significantly larger in CIDP (29.7%, p = 0.005) than in CMT1A (5.0%). TNC immunoreactivity was confined to the area around myelin sheaths in CMT1A. The increased deposition of collagen fibers in CIDP suggests the activity of nerve regeneration. TNC expression in Schwann cell lamellae comprising OB may also suggest the activity of regeneration. Schwann cell phenotypes in CIDP may be different from CMT1A regarding the production of ECM proteins.

Two subtypes of Churg-Strauss syndrome with neuropathy: the roles of eosinophils and ANCA.

The aim of this study was to clarify the differences in the pathogenesis of neuropathy between myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive and -negative patients with Churg-Strauss syndrome (CSS). Eight MPO-ANCA-positive and 14 MPO-ANCA-negative patients were included. In addition to the standard histology, nerve biopsies were examined, employing immunohistochemistry for eosinophil major basic protein and electron microscopy. The groups did not differ significantly in clinical profiles, including the peak disability score and number of blood eosinophils. In nerve biopsies, necrotizing vasculitis was found in 63% (5/8) of the ANCA-positive and 21% (3/14) of the ANCA-negative patients. Fibrinoid necrosis of vessel walls was noted in 4 ANCA-positive patients (50%), and in one ANCA-negative patient (p = 0039). In contrast, a large number of eosinophilic infiltrations in the epineurium was shown in 36% (5/14) of the ANCA-negative patients, with no eosinophilic infiltrations shown in ANCA-positive patients. In 3 ANCA-negative patients, endoneurial eosinophils were seen where focal axonal loss and capillary dilatation were occasionally noted. There may be 2 pathogenetic mechanisms of neuropathy with CSS: ANCA-related vascular fibrinoid necrosis, and a toxic eosinophilic effect on nerve fibers which is independent of ANCA. Therapy targeting activated eosinophils may be a possible treatment for intractable neuropathy of CSS.

Shunt-responsive parkinsonism and reversible white matter lesions in patients with idiopathic NPH.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially treatable dementia and gait disorder with abnormal CSF dynamics. OBJECTIVE: To investigate and characterize the changes in motor symptoms and CT and MRI features of iNPH before and after a shunt operation using specific evaluation criteria. METHODS: We studied 17 definitive iNPH patients, diagnosed according to the clinical guidelines of both the Japanese Society of NPH and the International NPH Consultant Group, with ventricular enlargement (Evan's index > 0.3) and narrowed CSF spaces at the high convexity on CT scan and /or MRI. The pre- and post-operative evaluation criteria for the gait and motor disturbances included the Japanese NPH Grading Scale-Revised (JNPHGSR), the Timed "Up and Go" test and the motor sections of the Unified Parkinson Disease Rating Scale. For cognitive impairments, the JNPHGSR, Mini Mental State Examination, Frontal Assessment Battery and Trail Making Test were used. White matter lesions were rated from the CT and/or MRI using a validated visual rating scale. RESULTS: All patients showed specific CT and MRI findings, consisting of diffusely-dilated Sylvian fissure, as well as narrowed CSF space at the high convexity. Fifteen patients (88%) showed white matter lesions on their CT or MRI images. These signs were ameliorated in all patients after the shunt operation. Evan's index and the mean total scores on the visual scale for white matter lesions also improved significantly. Clinically, the patients had frequent parkinsonism (71%), but relatively few had a history of either small-vessel diseases (29%), hypertension (41%) or diabetes (35%). All patients showed gait disturbances, and these symptoms, including postural instability and body bradykinesia, improved significantly after the operation. Over half also showed signs of cognitive impairment and urinary incontinence, and all such symptoms and signs improved significantly. CONCLUSION: iNPH often appears as a shunt-responsive type of parkinsonism and reversible white matter lesions among the geriatric population.

Hypoxia-inducible factor 1alpha may be a marker for vasculitic neuropathy.

Neuromuscular biopsy is still an essential method for diagnosing vasculitic neuropathy, although its diagnostic sensitivity is at most 60%. Our objective was to examine the expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in peripheral nerves and to evaluate its usefulness in diagnosing vasculitic neuropathy, especially for discrimination from other axonal neuropathies. Forty-one patients with vasculitic neuropathy consisting of 20 definite, 14 probable and seven possible diagnoses, 15 patients with metabolic neuropathy, five with motor neuron disease and six with chronic inflammatory demyelinating polyneuropathy were included. Nerve biopsy specimens were immunohistochemically examined for HIF-1alpha and various cell markers. Distinct immunoreactivity (IR) was observed in nuclei of endoneurial cells in 54% (22/41) of vasculitic patients, while specimens from metabolic neuropathies showed less nuclear IR and the difference of mean density of HIF-1alpha-positive nuclei was significant. Two patients with possible vasculitis who showed HIF-1alpha-positive nuclei in endoneurium, were later confirmed to have vasculitis by skin biopsies. Most of the cells expressing HIF were demonstrated to be Schwann cells. There was a trend in the vasculitic patients with early phase nerve damage to display higher endoneurial HIF-1alpha-IR. HIF-1alpha may be an immunohistochemical marker for vasculitic neuropathy, especially when the observed section contains no vasculitic lesions.

[Falls in peripheral neuropathy].

Falling accidents are predisposing factors in worsening the quality of life. Causes of falls included gait and balance problems, visual disorder, cognitive impairment and drugs. However, falls in neuropathic patients are not often investigated. We studied the actual condition and causes of falls associated with neuropathy. One hundred and ninety-three patients (122 males and 71 females, ages 57 +/- 15 years) with neuropathy were selected for evaluation. In all patients, more than half a year had passed since the onset of symptoms and the present condition was considered comparatively stable. We divided the patients into 2 groups: falling or non-falling. Patients experiencing accident accompanied by external injury once or more in the past year, or patients who answered "often fell" (1 time or more per month) on flat ground or in their residence comprised the fall group. The severity of disease was evaluated by modified Rankin Scale (0 to 5). The relationship between falls and neuropathic symptoms (proximal muscle weakness, distal muscle weakness, aching or numbness, and the position and vibration sensory loss) was statistically examined. The distribution of patients in the fall group according to modified Rankin Scale of neuropathy was scale 5: 0/0 (0%), scale 4: 5/36 (14%), scale 3: 24/72 (33%), scale 2: 7/56 (13%), and scale 1: 1/19 (5%). There were six fractures among all patients. Regarding the etiology, the fall group showed a high level of axonal neuropathies (44%). On analysis according to condition and symptoms in the patients with a score of 2, 3, or 4 who demonstrated a high rate of falls, there was a strong correlation between deep sensory loss and fall (p < 0.05). However, as independent factors, there were no correlations between falling and proximal muscle weakness, distal muscle weakness or aching numbness, respectively. We thought it necessary to add ataxic gait resulting from deep sensory loss to one of the fall risks.

The mechanisms of recovery from cerebellar infarction: an fMRI study.

Patients with cerebellar infarction frequently make an excellent functional recovery. However, the mechanisms of functional recovery from cerebellar infarction remain unclear. Thus, functional MRI was used to investigate these mechanisms in six right-handed patients with complete recovery after cerebellar infarction, and nine right-handed normal subjects. The non-infarcted side of the cerebellum and the sensorimotor cortex contralateral to the non-infarcted side of the cerebellum were significantly activated during the infarcted-side hand movement. In the infarcted side of the cerebellum, intact regions were activated. Our results indicate that recovery from cerebellar infarction depends on reorganization in the infarcted side of the cerebellum, and recruitment of the cerebellocortical loop involving the cerebrum ipsilateral to the movement and the cerebellum contralateral to the movement.

Oct6, a transcription factor controlling myelination, is a marker for active nerve regeneration in peripheral neuropathies.

Three transcription factors, Krox20 (EGR2), Oct6 (SCIP/Tst1) and Sox10, are considered necessary for transition from the nonmyelinating to the myelinating stage of Schwann cell development. We immunohistochemically studied Oct6 expression in peripheral nerve specimens from 25 patients with various diseases including Charcot-Marie-Tooth disease type 1A (CMT1A). Oct6 was present in cytoplasm of Schwann cells associated with normal-appearing myelinated nerve fibers, but not in nuclei. Expression was seen in nuclei of Schwann cells in the early phase of acute axonal degeneration; nuclear expression peaked at the regenerative stage. Schwann cells forming "onion bulbs" expressed Oct6 in chronic inflammatory demyelinating polyneuropathy (CIDP), but showed minimal expression in CMT1A, reflecting their proliferative activity in CIDP. Nerves showing chronic axonal loss had no expression. Oct6, then, may be a marker for dedifferentiation of adult Schwann cells and active nerve regeneration.

New cyclooxygenase-2 inhibitors for treatment of experimental autoimmune neuritis.

We analyzed two new cyclooxygenase-2 (COX-2) inhibitors, celecoxib (SC-58635) and meloxicam, for the treatment of experimental autoimmune neuritis (EAN) in rats. Celecoxib and meloxicam significantly reduced clinical EAN score and histopathological damage of the sciatic nerve. They induced no serious side effects, whereas indomethacin used as a control caused severe intestinal ulceration and dysfunction of liver and kidney. These findings suggest that the new COX-2 inhibitors may be useful as additional therapeutic agents for patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.