Granuloma, vasculitis, and demyelination in sarcoid neuropathy.

BACKGROUND: Despite the suggestion that direct compression by granuloma and ischemia resulting from vasculitis can cause nerve fiber damage, the mechanisms underlying sarcoid neuropathy have not yet been fully clarified. METHODS: We examined the clinicopathological features of sarcoid neuropathy by focusing on electrophysiological and histopathological findings of sural nerve biopsy specimens. We included 18 patients with sarcoid neuropathy who had non-caseating epithelioid cell granuloma in their sural nerve biopsy specimens. RESULTS: Although electrophysiological findings suggestive of axonal neuropathy were observed, particularly in the lower limbs, all but three patients showed ≥1 abnormalities in nerve conduction velocity or distal motor latency. Additionally, a conduction block was observed in 11 of the 16 patients for whom waveforms were assessed; five of them fulfilled motor nerve conduction criteria strongly supportive of demyelination as defined in the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guideline for chronic inflammatory demyelinating polyneuropathy (CIDP). In most patients, sural nerve biopsy specimens revealed a mild to moderate degree of myelinated fiber loss. Fibrinoid necrosis was observed in one patient, and electron microscopy analysis revealed demyelinated axons close to granulomas in six patients. CONCLUSIONS: Patients with sarcoid neuropathy may meet the EAN/PNS electrophysiological criteria for CIDP due to the frequent presence of conduction blocks. Based on our results, in addition to the ischemic damage resulting from granulomatous inflammation, demyelination may play an important role in the mechanism underlying sarcoid neuropathy.

Aberrant Expression of Nodal and Paranodal Molecules in Neuropathy Associated With IgM Monoclonal Gammopathy With Anti-Myelin-Associated Glycoprotein Antibodies.

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.

Distinct pathogenesis in nonsystemic vasculitic neuropathy and microscopic polyangiitis.

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.

Vasculitic Neuropathy Following Exposure to a Glyphosate-based Herbicide.

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.

Alcoholic Myelopathy and Nutritional Deficiency.

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.

Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy.

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.

Intraepidermal nerve fibre density in POEMS (Crow-Fukase) syndrome and the correlation with sural nerve pathology.

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.

Uncompacted Myelin Lamellae and Nodal Ion Channel Disruption in POEMS Syndrome.

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.

Immunoglobulin G4-related pathologic features in inflammatory neuropathies.

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.

Clinicopathologic features of folate-deficiency neuropathy.

OBJECTIVE: The clinical significance and characteristics of neuropathy caused by folate deficiency remain to be established. METHODS: We examined the clinicopathologic features of 18 consecutive patients with neuropathy caused by folate deficiency who presented with low serum folate levels but normal blood thiamine and serum cobalamin levels in the absence of chronic alcoholism. RESULTS: Symptoms were relatively uniform, characterized by slowly progressive polyneuropathy with predominant involvement of the lower extremities, with a tendency to manifest as sensory rather than motor neuropathy and predominant deep rather than superficial sensory loss. The electrophysiologic features were consistent with axonal neuropathy. The histopathologic features of sural nerve biopsy specimens indicated large fiber-predominant axonal loss without segmental demyelination. Although macrocytosis was found in 7 patients, only 3 patients exhibited hemoglobin levels less than 10 g/dL. During the same study period, we found 12 patients who had low blood thiamine levels but normal serum folate and cobalamin levels without chronic alcoholism. Compared with patients who had thiamine-deficiency neuropathy, patients with a folate deficiency showed significantly slower progression (p < 0.01), a tendency to manifest sensory neuropathy (p < 0.05), predominant deep sensory loss (p < 0.01), and preservation of biceps tendon reflexes (p < 0.05). CONCLUSIONS: Folate-deficiency neuropathy was characterized by a slowly progressive and sensory-dominant pattern, which was different from thiamine-deficiency neuropathy (i.e., beriberi neuropathy). This study demonstrates the importance of folate deficiency in the differential diagnosis of neuropathy, particularly in countries where folic acid fortification has not yet been practiced.

[Clinicopathological features of neuropathy associated with IgG4-related disease].

The newly recognized entity IgG4-related disease (IgG4-RD) is characterized by an elevated IgG4 serum concentration, swelling of organ, and tissue infiltration by IgG4-positive plasma cells with fibrosis. IgG4-RD has been reported in various organs. In the field of neurology, hypophysitis and hypertrophic pachymeningitis have been known to be related to IgG4-RD, while reported patients with neuropathy manifesting features compatible to IgG4-RD. The features of IgG4-related neuropathy are characterized by sensory-motor neuropathy, mononeuritis multiplex pattern, and predominant involvement of distal portions of the lower extremities. In the sural nerve biopsy specimens, fibrosis and IgG4-positive plasma cell infiltration in the epineurium and decreased myelinated fiber density due to axonal degeneration were observed. IgG4-RD should be considered as the differential diagnosis of neuropathy.

Comprehensive health education combining hot spa bathing and lifestyle education in middle-aged and elderly women: one-year follow-up on randomized controlled trial of three- and six-month interventions.

BACKGROUND: This study attempted to clarify the duration of effects of 3- and 6-month comprehensive health education programs based on hot spa bathing, lifestyle education and physical exercise for women at 1-year follow-up. METHODS: We examined middle-aged and elderly women who were randomly divided into two groups and followed up them for one year. Spa programmers instructed subjects for one hour in lifestyle education and physical exercise and for one hour in a half bath (salt spring, temperature at 41.5 degrees C) once a week. The program for the 3-month group (n=19) was repeated in the 6-month group (n=14). The evaluation items were body mass index, PWC75%HRmax (by a bicycle ergometer as aerobic capacity), blood profiles (total cholesterol, HDL cholesterol, arteriosclerotic index, uric acid, and hemoglobin A1c), profile of mood states, self-rating depression scale, subjective happiness, pains in the knee and back, and active modification of lifestyle. RESULTS: There were significant interactions between groups and response over time to aerobic capacity, hemoglobin A1c, back pain, vigor, fatigue and self-rating depression (respectively, p<0.05). Duration of effects was longer for the 6-month intervention than for the 3-month intervention. CONCLUSIONS: Beneficial effects of 6-month intervention on hemoglobin A1c, aerobic capacity, pains in the back, vigor, fatigue and depression remained significant at the 1-year follow-up. Duration of effects was longer in the 6-month intervention than in the 3-month intervention.