Porphyric neuropathies in an acute intermittent porphyria family

The objective of this study was to investigate two patients with porphyric neuropathy in a family with acute intermittent porphyria. Molecular analysis of the porphobilinogen deaminase (PBGD) gene was performed. We analyzed the clinical course of peripheral neuropathy and serial changes in nerve conduction studies (NCS) of the two patients. We also examined the pathological findings of sural nerve biopsy in one patient. Molecular analysis of the PBGD gene revealed a missense mutation (Arg26His) in exon 2 for two patients and their family members. Distal polyneuropathy was noted in the patients with chronic porphyric neuropathy. In the follow‐up NCS, recovery was relatively poor in the lower limb in one patient with severe polyneuropathy, and NCS evidence of deterioration was found following frequent hormone‐related porphyric attacks in another patient. The sural nerve biopsy showed marked loss of myelinated and unmyelinated fibers in one patient with chronic porphyric neuropathy. In contrast to radial and fibular motor nerves in acute porphyric neuropathy, the sural nerve is vulnerable to involvement in chronic porphyric neuropathy following repeated porphyric attack as seen in the NCS.     

Direct immunofluoresence in vasculitic neuropathy: Specificity of vascular immune deposits

In suspected vasculitic neuropathy, vasculitis is demonstrated in only 30% of superficial peroneal nerve (SPN)/peroneus brevis muscle (PBM) specimens. Pathologic predictors of vasculitis are thus needed for non‐diagnostic cases. Immune deposits in epineurial vessels have an established sensitivity but unknown specificity. In this study we assessed specificity using direct immunofluorescence (DIF) in SPN/PBM biopsies for suspected vasculitic neuropathy. Biopsies from 13 patients with vasculitis, 13 without vasculitis, and 6 with diabetic radiculoplexus neuropathy (DRPN) were stained for immunoglobulin G (IgG), IgM, and complement 3 (C3), and analyzed in a blinded manner. Vascular immunoglobulin or C3 deposits occurred in 12 of 13 nerve or muscle biopsies (11 of 13 nerves, 5 of 13 muscles) in vasculitis vs. 1 of 13 (1 of 13 nerves, 0 of 13 muscles) in controls (P = 0.00003). Specificity was 92%. For DRPN, vascular immune deposits occurred in 5 of 6 nerves or muscles (4 of 6 nerves, 1 of 5 muscles), similar to vasculitis but significantly different from controls. Epineurial/perimysial vascular deposits of immunoglobulin/C3 by DIF are a specific marker of vasculitic neuropathy. Muscle Nerve 000:000–000, 2009     

Expression of capsaicin receptor immunoreactivity in human peripheral nervous system and in painful neuropathies

We describe the expression of the capsaicin receptor (TRPV1) in human peripheral nervous system (PNS) and its changes in sural nerve and skin nerve fibers of patients with painful neuropathy. Dorsal root ganglion (DRG), root, and spinal cord autopsy specimens from subjects without PNS diseases were immunoassayed with anti-TRPV1 antibodies. Bright-field and confocal microscope studies using anti-TRPV1, protein gene product 9.5 (PGP 9.5), and unique-beta-tubulin (TuJ1) antibodies were performed in skin biopsies from 15 healthy subjects and 10 painful neuropathies. The density of intraepidermal nerve fiber (IENF) labeled by each antibody was quantified. Sural nerve biopsies from three patients with painful, one patient with nonpainful diabetic neuropathy, and two patients with multifocal motor neuropathy used as controls were immunoassayed with anti-TRPV1 antibodies and investigated by immunoelectron microscopy. TRPV1 strongly labeled laminae I and II of dorsal horns, most small-size and some medium-size DRG neurons, and small-diameter axons of dorsal roots. In sural nerve, TRPV1 was expressed within the cytoplasm of most unmyelinated and some small myelinated axons, in the muscular lamina of epineural vessels, and in the endothelium of endoneurial vessels. The density of IENF labeled by TRPV1, PGP 9.5, and TuJ1 did not differ. TRPV1 colocalized with TuJ1 in all IENF and dermal nerve bundles. Painful neuropathies showed a diffuse loss of TRPV1-positive axons both in the sural nerve and in the skin. Our findings demonstrated that TRPV1 is normally expressed throughout the nociceptive pathway of PNS and that TRPV1-positive peripheral nerve fibers degenerate in painful neuropathies.     

Immunohistochemical characteristics of polymyositis in patients with HTLV-1–associated myelopathy and HTLV-I carriers

The immunohistochemical characteristics of polymyositis in patients with HTLV-I-associated myelopathy (HAM) and HTLV-I carriers were studied. Infiltrating cells were predominantly T cells and were not different from in the control group. All specimens contained positively staining muscle fibers for MHC class I antigens, but class II antigens were also expressed in some muscle fibers in 1 patient with HTLV-I-negative polymyositis, 3 patients with HTLV-I-positive polymyositis, and all 5 HAM patients with polymyositis. Expression of the neural cell adhesion molecule was lowest in the HAM patients. These findings may suggest a different immune environment in polymyositis with HAM. © 1993 John Wiley & Soncs, Inc.     

The yield of sural nerve biopsy in the evaluation of peripheral neuropathies

The diagnostic yield of sural nerve biopsy was evaluated in 120 peripheral neuropathy patients. In 58 (48%) a final diagnosis was reached without biopsy, while 14 (11.5%) remained undiagnosed. Nerve biopsy contributed to the final diagnosis in 20 of the 53 biopsies (38%). In patients with motor conduction velocity below 30 m/s, sural nerve histology was helpful in 65% of biopsies. In patients with milder reduction in conduction biopsy contributed in only 11%. It is concluded that in general neurological population, nerve biopsy is of limited value as a routine diagnostic procedure. However, in patients with marked slowing of conduction velocity, in whom the diagnosis is not immediately apparent, sural nerve biopsy is indicated.     

Peripheral neuropathy in Cockayne syndrome

Two siblings with Cockayne syndrome are reported. In one case a sural nerve biopsy showed a demyelinating peripheral neuropathy with occasional inclusions in Schwann cells made up of electron dense finely granular material intermingled with vacuoles or lamellar structures. The significance, if any, of this accumulated material remains unclear. The presence, in addition, of small finely lamellar intra-axonal osmiophilic bodies suggests an associated axonal involvement

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Sommario Vengono descritti due casi di Sindrome di Cockayne. In un caso è stata effettuata una biopsia del nervo surale che ha evidenziato una neuropatia periferica di tipo demielinizzante con rare inclusioni nelle cellule di Schwann, formate da materiale osmiofilo finemente granulare, vacuoli e strutture lamellari. Il significato di tali inclusioni è molto incerto. La presenza inoltre di corpi osmiofili lamellari intrassonali suggerisce una associata compromissione assonale.

     

Sequelae following sural nerve biopsy in type 1 diabetic subjects

Objectives –  To detect post-operative sequelae of sural nerve biopsy.
Materials and methods––  A questionnaire mailed to type 1 diabetic patients ( n  = 24; male/female 23/1; reply n  = 23) 2 years after biopsy.
Results –  Type 1 diabetic patients (age 56 [11]; median [interquartile range]) had a long duration of diabetes (DM; 20 [19] years) and all had neuropathy. Three out of 24 patients developed infection (two superficial and one deep) and one had a post-operative bleeding. Less frequent pain among the patients were reported from one centre. About one-third or more of the patients still complained of pain, mostly mild, in the biopsy area and paraesthesia in the foot 2 years after surgery. More than two-thirds of the patients were reluctant for further biopsy; a crucial information in drug trial planning.
Conclusions –  Sequelae of a sural nerve biopsy occur in type 1 DM. The risk for wound infections should be considered.     

CO2 laser-induced pain-related somatosensory evoked potentials in peripheral neuropathies: correlation between electrophysiological and histopathological findings.

Pain-related somatosensory evoked potentials (pain SEPs) following CO2 laser stimulation as well as conventional electrically stimulated SEPs (electric SEPs) were examined in 10 patients with peripheral neuropathies in whom the histopathological examination of the sural nerve was done. Results of pain SEPs showed a positive relationship with clinical impairment of pain sensation and densities of small myelinated fibers of the sural nerve. In contrast, results of electric SEPs showed a positive relationship with clinical impairment of deep and tactile sensations and with densities of large myelinated fibers of the sural nerve. Therefore, pain SEPs are considered to be generated by ascending signals mediated through nociceptive receptors and A delta fibers. The pain SEP is only one noninvasive and objective method currently available to investigate a physiological condition of the sensory pathway responsible for pain sense, and is especially useful when combined with the conventional electric SEPs.     

The additional yield of combined nerve/muscle biopsy in vasculitic neuropathy

Background: Vasculitic neuropathy can be confirmed by demonstrating vasculitis in a nerve biopsy, but it is uncertain to what extent combined (i.e. nerve/muscle) biopsy improves the yield. Methods: A random‐effects meta‐analysis was performed to assess the additional yield of combined biopsy in vasculitic neuropathy. Medline, Embase, LILACS and ISI were searched from January 1980 until January 2009 for relevant articles on the yield of nerve, muscle or combined biopsy to diagnose vasculitic neuropathy. Fourteen (15%) studies were included. Methodological quality was scored using a modified Quality Assessment for Diagnostic Accuracy Studies tool. Results: In patients clinically suspected of vasculitic neuropathy, the additional yield of definite vasculitis in combined biopsy was 5.1% (95% CI 1.1–9.2%; P = 0.013). In patients diagnosed with vasculitic neuropathy, the additional yield of definite vasculitis in combined biopsy was 15% (95% CI 2.1–28%; P = 0.023). Conclusions: There is a modest additional yield of definite vasculitis in combined biopsy compared to nerve biopsy alone. Because of methodological flaws in analysed studies, the findings should be validated in a prospective study.     

Major histocompatibility complex class II expression and macrophage responses in genetically proven Charcot–Marie–Tooth type 1 and hereditary neuropathy with liability to pressure palsies

This study examined major histocompatibility complex (MHC) class II expression and macrophage infiltration in sural nerve biopsies from patients with genetically proven Charcot–Marie–Tooth (CMT) 1A and 1B and hereditary neuropathy with liability to pressure palsies (HNPP) by immunocytochemistry. In both young and older patients with duplication of the PMP22 gene, MHC class II expression was consistently up-regulated and not closely related to the extent of macrophage infiltration. On the other hand, MHC class II expression was more variable in CMT1A and CMT1B caused by point mutations and in HNPP. The extent of nerve pathology as assessed by teased fiber preparations or electron microscopy was not predictive for the degree of MHC class II expression in CMT1/HNPP. We conclude that MHC class II up-regulation is a common feature in hereditary neuropathies. As shown for the animal model of globoid cell dystrophy, it is conceivable that increased expression of MHC class II molecules in CMT1 and HNPP accelerates nerve pathology. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1419–1427, 1998     

The distribution and abundance of MHC and ICAM-1 on Schwann cells in vitro

Schwann cells, the myelin forming glial cells of peripheral nerves, have been implicated as having an immunoregulatory role in inflammatory demyelinating neuropathies (IDNs) such as Guillain Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We employed rat IFN-γ, a cytokine released by macrophages and CD4⁺ T-cells during inflammatory demyelination of the peripheral nervous system, to examine the distribution and abundance of MHC class I, MHC class II and ICAM-1 on Lewis rat Schwann cells and fibroblasts in vitro. MHC class I, class II and ICAM-1 molecules were immunolabelled with 30 nm colloidal gold and observed by scanning electron microscopy. Incubation with IFN-γ for 24 and 72 h, resulted in the clustering of MHC class I and ICAM-1 on Schwann cells and fibroblasts with MHC class II randomly distributed as single particles. MHC class I and ICAM-1 were upregulated after 24 h incubation in the presence of IFN-γ, whereas MHC class II was upregulated after 72 h. The difference in the rate of upregulation may indicate differences in the recycling and/or synthesis of these molecules. Changes in distribution such as clustering, in conjunction with the upregulation of these molecules, suggest a role for Schwann cells in the restimulation of specifically primed CD4⁺ T-cells in IDNs.     

多发性硬化脊髓型合并周围神经病变

目的：评价多发性硬化（MS）脊髓型的临床特征,脊髓磁共振成像（MRI）,神经电生理检查和腓肠神经活检的诊断价值。方法：分析14例MS脊髓型临床表现,脊髓MRI,神经电生理和腓神经活组织病理检查。结果：其临床表现为两侧肢体不对称性运动和感觉障碍的脊髓内部损害,可伴有发作性症状,有缓解和复发,脊髓MRI可以明确脱髓鞘部位,表现髓内纵行条带状或斑片状长T1长T2信号,脊髓略增粗,诱发电位有极高的敏感性,肌电图和腓肠神经病理提示周围神经脱髓鞘改变。结论：MRI、神经电生理检查及周围神经活检对MS脊髓型的早期诊断和治疗起重要作用。     

Influence of impaired T- and B-cell compartments on efficacy of IVIg in dysimmune neuropathies

Autoimmune mechanisms are postulated to play a role in the development and progression of dysimmune neuropathies (DN). We investigated the relation between lymphocyte number and marker expression, and disease activity in 20 patients with DN under intravenous immunoglobulins (IVIg) treatment. B- and T-lymphocyte markers were studied by flow cytometry of the expression of CD5, CD25, CD23 and CD38 markers on B cells and of CD3, CD4 and CD8 markers, respectively. These parameters were compared with those obtained from matched healthy volunteers. The proportions of CD38+ B cells were higher in patients compared with those of controls. Proportions of activated CD4+ and CD8+ T cells were comparable in peripheral blood mononuclear cells of patients and controls, but a significant reduction of the absolute numbers of CD3+, CD4+ and CD8+ cells were observed in DN patients. The percentages of CD25+ memory T cells were instead significantly increased in DN patients. Lastly, T-cell reduction and the CD19/CD38 ratio over total B (CD19+) cells directly correlated with a poor response to IVIg therapy. In DN, whereas T-cell number is reduced, activated T and B cells are increased, thus suggesting an intrinsic defect of the immune response.     

Demyelinating Peripheral Neuropathy in Devic Disease

Abstract: This is a report of a 20-year-old man with typical features of Devic disease (neuromyelitis optica) associated with demyelinating peripheral neuropathy. A sural nerve biopsy showed markedly decreased myelinated fibers of a large diameter. Teased fiber preparations showed segmental remyelination in 50% of examined fibers, as well as a few demyelination. Demyelination of bilateral optic nerves, spinal cord, and peripheral nerves at the same time suggests a possibility of common pathogenetic mechanisms in both the central and peripheral nervous systems.     

Diagnostic validity of epidermal nerve fiber densities in painful sensory neuropathies

In this prospective study, intraepidermal nerve fiber densities (IENFD) and subepidermal nerve plexus densities (SENPD) were quantified by immunostaining in skin punch biopsies from the distal calf in 99 patients with clinical symptoms of painful sensory neuropathy and from 37 age-matched healthy volunteers. The clinical diagnosis was based on history and abnormal thermal thresholds on quantitative sensory testing (QST). In patients with neuropathy, IENFD and SENPD were reduced to about 50% of controls. Elevated warm detection thresholds on QST correlated with IENFD but not with SENPD. Using receiver-operating characteristic (ROC) curve analysis of IENFD values, the diagnostic sensitivity for detecting neuropathy was 0.80 and the specificity 0.82. For SENPD, sensitivity was 0.81 and specificity 0.88. With ROC analysis of both IENFD and SENPD together, the diagnostic sensitivity was further improved to 0.92. The combined examination of IENFD and SENPD is a highly sensitive and specific diagnostic tool in patients suspected to suffer from painful sensory neuropathies but with normal values on clinical neurophysiological studies.     

Broadening the spectrum of controls for skin biopsy in painful neuropathies

Epidermal nerve fiber density (ENFD) is useful in the evaluation of small‐fiber neuropathies (SFSNs). A recent evidence‐based review highlighted the need to broaden the spectrum of ENFD controls to include lower limb pain states other than polyneuropathy. We studied epidermal innervation in multiple sclerosis (MS) and distal lower limb burning pain (DLLBP). Distal‐leg ENFD/morphology in MS DLLBP patients did not differ significantly from that of healthy controls. This study extends the range of ENFD controls and further supports use of ENFD assessment in SFSN. Muscle Nerve, 2010     

Endoneurial edema in sural nerve may indicate recent onset inflammatory neuropathy

Introduction: Sural nerve biopsy is an important means of establishing the diagnosis of inflammatory neuropathies. We investigated the diagnostic value of endoneurial edema. Methods: Diagnostic sural nerve biopsies from 42 patients with inflammatory and 28 patients with noninflammatory neuropathies were re‐evaluated for the presence of endoneurial edema. Edema was assessed on hematoxylin‐eosin stained paraffin and frozen sections and on azure II‐methylene blue stained semithin sections. We determined the area of endoneurial edema on digitized images in relation to the entire endoneurial area of each fascicle. Results: Edema was more extensive in neuropathies with short disease duration (≤12 months) as compared to long duration (>12 months; P < 0.01). Edema in inflammatory neuropathies of ≤12 months duration covered a larger area than in noninflammatory neuropathies (P < 0.01), and the extent of edema correlated negatively with disease duration (P < 0.05). Conclusions: Endoneurial edema may be a useful additional disease marker in inflammatory neuropathies of recent onset. Muscle Nerve 53 : 705–710, 2016     

Cockayne syndrome: report of two siblings and review of literature in Japan

Typical Cockayne syndrome was seen in a boy and his younger sister and these two cases are reported here, and reported cases of the syndrome in Japan are summarized. Both cases (an 11-year-old boy and a 7-year-old girl) had dwarfism, a senile face, retinitis pigmentosa, photosensitivity, and mental retardation. Calcium deposition in the basal ganglia was seen by CT scan. In both cases nerve conduction velocities were reduced suggesting peripheral neuropathy, but segmental demyelination on sural nerve biopsy was not demonstrated. Twenty seven cases of the syndrome has now been reported in Japan in 21 families (including the above two cases), consisting of 14 males and 12 females (the sex of one case was unknown): consanguineous marriage was confirmed in 14 families. Eleven cases in five families were siblings. The estimated ages of onset were from 1 month to 3 years, and in most cases photosensitivity was the initial symptom. Clinical manifestations were mental retardation in 25 cases (93%), dwarfism in 24 cases (89%), photosensitivity in 23 cases (85%), articular contracture in 22 cases (81%), sunken eyes in 20 cases (74%), retinitis pigmentosa in 17 cases (63%), deafness in 16 cases (59%), and intracranial calcification in 14 cases (51%). Intracranial calcification will be more often detected in future following the development of CT scanning.     

Neurofibromatosis 2 with peripheral neuropathies: Electrophysiological,pathological and genetic studies of a Taiwanese family

The objective of this study was to assess peripheral nerve involvement and DNA mutation of the neurofibromatosis type 2 (NF2) gene (NF2) in a Taiwanese family with classic NF2. Eleven members (six symptomatic and five asymptomatic) of a family carrying NF2 underwent clinical examination, neuroimaging, and electrophysiological analysis. Mutation and linkage analyses were conducted on DNA samples prepared from peripheral blood (all individuals), a sural nerve biopsy specimen (one symptomatic member), and a tumor specimen (another symptomatic member). Six of the 11 members were diagnosed with classic NF2. DNA sequencing of the tumor specimen demonstrated a frameshift mutation with 756delC on exon 8 of NF2. Three affected subjects showed clinical variability of the neuropathic disorders. Electrophysiological studies demonstrated variation in the disease pattern and severity of peripheral nerve involvement in five affected subjects. The morphometric assessment of the sural nerve biopsy specimen showed a marked reduction in both large myelinated and unmyelinated fibre density and increased density of non‐myelinating Schwann cell nuclei. Apart from numerous pathological nuclei of isolated Schwann cells, multiple profiles of non‐myelinating Schwann cell subunits were apparent in the endoneurium. Schwann cell proliferation in association with first‐hit mutation of the merlin gene might be responsible for the NF2‐associated neuropathy. Sural nerve biopsy showed a progressive neuropathy in the disease. Further, we suggest nonmyelinating Schwann cells are involved in NF2 neuropathy.