Sural Nerve Biopsy Research Articles

Early detection of nerve injury in transthyretin-related familial amyloid polyneuropathy.

This scientific commentary refers to ‘ In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography’ by Kollmer et al. (10.1093/brain/awu344). Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is a severe adult-onset autosomal dominant peripheral neuropathy with a median survival of less than 10 years from symptom onset (Plante-Bordeneuve et al. , 1998). Mutations in the TTR gene facilitate the dissociation of the stable tetrameric TTR protein into pro-amyloidogenic monomers. These misfold, aggregate and are deposited as TTR amyloid fibrils within the endoneurium—the layer of connective tissue surrounding the myelin sheath (Fig. 1)—and other tissues. Common clinical features of TTR-FAP include a peripheral neuropathy (most commonly presenting as a small fibre length-dependent neuropathy), an autonomic neuropathy and a cardiomyopathy. The estimated overall disease prevalence is 1:1 000 000. However, prevalence varies widely and may be as high as 1:1000 in parts of Portugal, Spain and Japan. Diagnosis can be difficult and is often delayed, particularly in non-endemic areas, as a result of the wide spectrum of clinical presentations and incomplete penetrance (Adams et al. , 2014). One of the major ongoing challenges in the disease is to identify early and sensitive biomarkers to allow earlier initiation of therapies and to enable clinical trials in early stage patients, before irreversible axonal neural degeneration has occurred. In this issue of Brain , Kollmer and colleagues address this challenge and show that nerve injury in the lower limbs can be detected, localized and quantified using quantitative MRI in both symptomatic patients and presymptomatic gene carriers (Kollmer et al. , 2014). Figure 1 Morphological appearances of sural nerve biopsy in a patient with amyloid neuropathy. Semi-thin resin preparation ( A ) stained with methylene blue azure–basic fuchsin shows a transverse section of a nerve fascicle in which there is a substantial loss of large and small …

Clinicopathologic features of folate-deficiency neuropathy.

The clinical significance and characteristics of neuropathy caused by folate deficiency remain to be established. 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. 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). 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.

Diagnostic Yield of Sural Nerve Biopsy: Study from a Tertiary Care Referral Centre in India

Background: Peripheral neuropathies are a heterogeneous group of disorders with varying etiologies. A systematic approach is required for patient evaluation for cost effective diagnosis. Aims: Present study conducted at a tertiary care referral centre aimed to evaluate the clinical profile and usefulness of sural nerve biopsy. Material and method: The study was conducted on 75 patients attending the neurology outpatient department/those admitted in the wards. All patients were subjected to a detailed clinical, neurological and necessary biochemical investigations. Those patients with an inconclusive result were subjected to a sural nerve biopsy with the results being interpreted as diagnostic, contributory or noncontributory. Results: Out of the 75 patients enrolled 36 underwent nerve biopsy. Amongst those 18 turned out to have Hansen’s disease, 8 vasculiis, 2 CIDP, 1 diabetes and 7 patients remained undiagnosed. Overall in 15 cases the biopsy was diagnostic, in 14 cases it was contributory, while in 7 cases it was noncontributory. Nerve biopsy proved more beneficial in patients with a multiple mononeuropathy pattern (p<0.003). Overall in about 80% of patients nerve biopsy proved to be worthwhile Conclusion: Nerve biopsy has a good diagnostic yield if done in properly selected cases. This is especially so for the asymmetrical neuropathies particularly infectious causes like leprosy and vasculitis.

MR-Neurography of the sural nerve in patients with hereditary amyloidosis

Background Sural nerve biopsies are often performed in order to detect the underlying disease in patients suffering from unclear polyneuropathic symptoms. In transthyretin familial amyloid-polyneuropathy (TTR-FAP) the diagnostic value of invasive sural nerve biopsies is controversially discussed as it often lacks to detect amyloid deposits [Simmons et al, J Neurol Sci 1993]. As we recently reported, amyloid related nerve-injury in TTR-FAP can be unambiguously determined in large-caliber nerves (sciatic, tibial and common peroneal nerve) by applying high-resolution MR-Neurography (MRN) [Kollmer et al, Brain 2015]. However, the diagnostic yield of MRN of the small-caliber sural nerve, representing the target nerve specimen for biopsies, is still unclear and was subject to this investigation.

A rare case of congenital insensitivity to pain with anhydrosiss

Congenital insensitivity to pain syndrome with anhydrosis (CIPA) is a rare inherited disorder. It is characterized by loss of pain and temperature sensation, lack of sweating and mild mental retardation. This disorder belongs to hereditary sensory and autonomic neuropathy family (type IV). Because of these abnormalities, patients require special anesthetic care. They include titration of intraoperative opioids, an anesthetic to ensure co-operation and immobility and intra-operative temperature monitoring. Here we report a 7-year-old female child with CIPA posted for restoration and cementation for dental caries along with sural nerve and skin biopsy.

Leukoencephalopathy

Just 11 years ago, a new genetic white matter disease, leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate (LBSL), was described in 7 children and 1 teenager.1 Clinical features were dominated by progressive motor deterioration without sphincter dysfunction; half of the patients had loss of position and vibratory sensation and learning problems, but no vision or hearing loss. CSF was acellular without oligoclonal bands. Somatosensory evoked potentials, nerve conduction velocities, and a single sural nerve biopsy were normal. MRI showed a symmetrical leukoencephalopathy (figure, top) with a predilection for the brainstem and spinal cord. Magnetic resonance spectroscopy revealed decreased N -acetylaspartate and elevated lactate levels in brain white matter. Disease was due to a deficiency in mitochondrial aspartyl-tRNA synthetase.2

The Diagnostic Role of Neuromuscular Ultrasound in Chronic Inflammatory Demyelinating Polyneuropathy

The immune-neuropathies are a heterogenous group of peripheral nerve disorders. Their diagnostic classification is mainly based on the documentation of the distribution pattern of peripheral nerve impairment and the results of nerve conduction studies. Nerve conduction studies remain nowadays fundamental not only for the diagnosis of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), but also for the followup and measurement of response to immune-treatment. The challenge though of acquiring the best static and dynamic image of the relevant nerve structures, led to the development of high frequency ultrasound technology. Neuromuscular ultrasound has been able to detect thickened or swollen roots, peripheral nerves or plexus, findings that are consistent with ongoing inflammation, especially in cases of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Similar findings have been described also in other immune-mediated neuropathies such as Guillain–Barre Syndrome (GBS), Multifocal Motor Neuropathy (MMN) and Multifocal Acquired Demyelinating Sensory and Motor Neuropathy (MADSAM). This review provides a timely update on the ultrasound findings of chronic inflammatory demyelinating polyneuropathy. INTRODUCTION Vascular ultrasound has gained a key role in the diagnostics of vascular lesions of the central nervous system. The recent development of high frequency ultrasonography (> 12MHz) provided the neurologist with a valuable tool to study peripheral nerve structures in detail. The first pathological ultrasound findings on peripheral nerve structures have been published in 1985 by Solbiati et al.1 On the other hand, Fornage and Rifkin reported for the first time the pathological findings of carpal tunnel syndrome.2 Immune-mediated neuropathies are a heterogenous group of disorders, with a frequency of 13% on consecutive patients with neuropathy seen at neuromuscular reference centres.3 The diagnosis and classification is based, in typical cases, on the time course, distribution pattern of nerve impairment (predominant involvement of motor/sensory fibers or/and autonomic nerve system), and paraclinical parameters [such as nerve conductions studies and serum antibodies]. On cases, with a typical clinical presentation, an extended diagnostic work-up, including cerebrospinal fluid examination, nerve conductions studies, sural nerve biopsy, laboratory testing, may be needed. The role of neuromuscular ultrasound in the diagnostic workup of CIDP remains in the literature less well defined and parallels the beginning of research on entrapment neuropathies. Only a few studies in the literature have used ultrasound to examine the pathological changes *Corresponding author: Antonios Kerasnoudis, MD Neuroimmunological Department St. Luke Hospital, Thessaloniki Private Practice: Ethnikis Antistasis 18, Serres, Greece Tel: 0030-6974994379 E-mail: antonis.kerasnoudis@gmail.com Article History: Received: March 19th, 2014 Accepted: March 31st, 2014 Published: April 8th, 2014 Citation: Kerasnoudis A, Yoon MS. The Diagnostic Role of Neuromusclar Ultrasound in Chronic Inflammatory Demyelinating Polyneuropathy. Neuro Open J. 2014; 1(1): 1-6. Copyright: © 2014 Kerasnoudis A. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Volume 1 : Issue 1 Article Ref. #: 1000NOJ1101 Review

A family with axonal sensorimotor polyneuropathy with TUBB3 mutation.

Mutations in the β‑tubulin isotype III (TUBB3) gene result in TUBB3 syndrome that includes congenital fibrosis of the extraocular muscle type 3 (CFEOM3), intellectual impairments and/or an axonal sensorimotor neuropathy. In the present study, a TUBB3 D417N mutation was identified in a family with axonal sensorimotor polyneuropathy by whole exome sequencing. The proband exhibited gait disturbance at the age of 12 years and was wheelchair bound at 40 years. However, the proband's cousin exhibited gait disabilities at 45 years of age and was still able to walk when he was 60 years old. Ophthalmoplegia and intellectual impairment were not observed in either patient. A sural nerve biopsy identified an absence of large myelinated fibers without demyelinating degeneration. Based on these clinical features, the two patients exhibited an axonal peripheral neuropathy without CFEOM3. These results therefore suggested that certain TUBB3 mutations may predominantly be associated with axonal peripheral neuropathy. Furthermore, the results also suggested that TUBB3 mutations may be implicated in modulating the inter‑ and intra‑familial heterogeneity of clinical phenotypes.

Axonal loss influences the response to rituximab treatment in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibody

Polyneuropathy associated with anti-Myelin-Associated Glycoprotein (MAG) antibody is a well-defined immune-mediated disease that develops in individuals with IgM monoclonal gammopathy. Factors related to response to rituximab treatment in anti-MAG neuropathy have not been clarified so far. We prospectively evaluated the clinical status, immunological changes, and electrophysiological parameters before and 12months after rituximab treatment in 7 patients with anti-MAG neuropathy. Pathological indices of sural nerve biopsy specimens before rituximab treatment were investigated. Overall, 4 patients improved by more than 5% either clinical scale, expressed according to the Medical Research Council (MRC) sum score or sensory sum score (SSS) 12months after rituximab treatment. The modified Rankin Scale (mRS) scores improved in 2 patients. With respect to the relationship between the response to rituximab treatment and the clinicopathological findings, short disease duration and preservation of nerve fiber density were significantly related. The immunohistochemical assessment suggested that low-intensity binding of anti-IgM antibody to the myelin sheath may contribute to the degree of response to rituximab treatment. The degree of axonal loss and the deposition of pathogenic autoantibodies in myelinated fibers may determine the therapeutic response to rituximab treatment in anti-MAG neuropathy.

Sural nerve biopsy and functional studies support the pathogenic role of a novel MPZ mutation

Our patient is a 65-year-old woman presenting with bilateral pes cavus, pronounced distal muscle wasting, weakness and areflexia. Electrophysiological findings included diffuse unrecordable motor and sensory responses. While the CMT phenotype was evident, the lack of family history and the severe, but unspecific electrophysiological impairment, was a challenge for genetic diagnosis. A sural nerve biopsy was performed, showing a severe loss of myelinated fibers with residual axons surrounded by myelin outfoldings. Whereas myelin outfoldings are a pathological hallmark of autosomal recessive CMT4B1 and CMT4B2, due to mutations in myotubularin-related 2 (MTMR2) and 13 (MTMR13) genes respectively, they may also occur in nerve biopsies from CMT1B patients. By direct sequencing, a novel heterozygous transversion c.410G>T in MPZ gene was demonstrated, producing an amino acid change from glycine to valine in position 108 (p.G108V). In HeLa cells the fusion P0G108V-EGFP was normally trafficked to the cell membrane, but with decreased P0 adhesion function, compared with wild-type P0, thus supporting a pathogenic role of the new variant. In conclusion this case highlights the relevance, in selected cases, of sural nerve biopsy to orient the genetic/molecular tests, while in vitro analyses may strengthen the pathogenic role of novel mutations.

Differential gene expression of cytokines and neurotrophic factors in nerve and skin of patients with peripheral neuropathies.

Pathophysiologically relevant alterations in cytokine and neurotrophic factor levels have been reported in neuropathy subtypes. We characterized gene expression profiles of pro- and anti-inflammatory cytokines and neurotrophic factors in nerve and skin samples of patients with neuropathies of different etiologies. We prospectively studied 133 patients with neuropathies and compared data between subtypes and with healthy controls. All patients underwent sural nerve and/or skin punch biopsy at the lateral thigh and lower leg; controls received skin punch biopsies. Gene expression of pro- and anti-inflammatory cytokines (IL-1β, IL-2, IL-6, TNF, IL-10), neurotrophic factors (BDNF, NGF, NT3, TrkA), and erythropoietin with the erythropoietin receptor (Epo, EpoR) was analyzed. Sural nerve gene expression of the investigated cytokines and neurotrophic factors did not differ between neuropathies of different etiologies; however, IL-6 (p < 0.01) and IL-10 (p < 0.05) expression was higher in painful compared to painless neuropathies. Skin IL-6 and IL-10 gene expression was increased in patients compared to controls (p < 0.05), and IL-10 expression was higher in lower leg skin of patients with non-inflammatory neuropathies compared to inflammatory neuropathies (p < 0.05). Proximal and distal skin neurotrophic factor and Epo gene expression of patients with neuropathies was reduced compared to controls (NGF, NT3, Epo; p < 0.05). Neuropathies are associated with an increase in cytokine expression and a decrease in neurotrophic factor expression including nerve and skin.

Pentraxin-3 and VEGF in POEMS syndrome: a 2-year longitudinal study.

Circulating Pentraxin 3 (PTX3) and vascular endothelial growth factor (VEGF) levels were measured longitudinally (mean follow-up 2 years) by ELISA in 6 patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes (POEMS) syndrome and 16 controls. Expression of PTX3 was also assessed (immunohistochemistry) on sural nerve biopsies from POEMS and vasculitic neuropathy patients. No correlation was found between PTX3 and VEGF levels in POEMS or controls. Sural nerve biopsies from vasculitic neuropathy patients, but not those from POEMS syndrome, showed strong PTX3 staining. PTX3, expression of vessel inflammation/remodeling, and VEGF, crucial pro-angiogenic cytokine, appear to be independently regulated in POEMS syndrome.

Pure sensory Guillain-Barré syndrome: A case report and review of the literature.

Sensory Guillain-Barré syndrome (GBS) is an acute demyelinating neuropathy that presents clinically with involvement of the sensory peripheral nerve only. To date, <10 cases of pure sensory GBS have been reported; thus, the clinical and pathological features of sensory variant GBS are yet to be well characterized. The current study reports the case of a 43-year-old female that presented with acute, symmetric and monophasic sensory neuropathy, without motor weakness. Patient history, clinical examination, routine nerve conduction studies and sural nerve biopsy were reviewed. All the observations were consistent with a diagnosis of pure sensory GBS. In particular, the pathological features of the sural nerve biopsy revealed that the form of regenerated nerve fibers have complete structure of myelinated nerve fascicles, and these myelinated nerve fibers are thicker than other parts of the biopsy. The patient received small-dose (20 mg/day) prednisone initially, but without any benefit. Satisfactory improvements were observed with one course of intravenous immunoglobulin.

CARDIAC AND EXTRACARDIAC AMYLOIDOSIS IN V122I ATTR

IntroductionHereditary transthyretin-related amyloidosis (ATTR) is a genetically heterogenous disease which may present with a predominant peripheral and autonomic neuropathy, a cardiac myopathy, or with both neurological and cardiac involvement. The...

G.P.59: Muscle pathology as a diagnostic clue to Allgrove syndrome

Allgrove or triple A syndrome is an autosomal-recessive disorder caused by mutations in the AAAS gene, coding for the nucleoporin ALADIN. While the eponymous combination of Achalasia, Addisonianism and Alacrimia seems hard to miss, these cases are a diagnostic challenge when this trias is incomplete and other neurological signs from a broad range of associated symptoms predominate. This was the case with a 15year old boy from a consanguineous family suffering from progressive distal limb muscle weakness and atrophy as well as mild learning disability, whose muscle and sural nerve biopsy samples we received. No abnormalities of the sural nerve were found, but the gastrocnemius muscle sample showed considerable fatty replacement, increased endo- and perimysial connective tissue, rounded fibre profiles, increased fibre size variability, increased internalised myonuclei and nuclear clumps, numerous degenerating and some regenerating fibres, massive fibre splitting and many whirled fibres as well as some rimmed vacuoles, few target fibres, but more frequent targetoid/ core-like lesions. Conspicuous nuclear inclusions in electron microscopy and particularly reduced immunoreactivity with an antibody against lamin A/C led us to suspect a nuclear pathology. When he developed dysphagia due to achalasia, sequencing of the AAAS gene was initiated, revealing homozygous c.762delC mutations in exon 8 leading to a premature stop of translation due to frameshift (p.S255V fs ∗ 35). Adrenal deficiency and autonomic dysfunction can result in life threatening situations for these patients, but can be addressed by symptomatic medication. Thus making the diagnosis in time is important. Triple A syndrome with its variable, multi-system symptoms including optic atrophy, cerebellar ataxia, upper and lower motoneuron signs and various neuropathic presentations is a differential diagnosis for mixed pathologies with signs of nuclear changes that myopathologists need to be aware of.

Clinical and morphological variability of the E396K mutation in the neurofilament light chain gene in patients with Charcot-Marie- Tooth disease type 2E.

Mutations in the neurofilament light chain (NEFL) gene mostly cause autosomal dominant axonal Charcot-Marie- Tooth neuropathy (CMT2E). The mutation c.1186G>A, p.E396K has been reported in seven unrelated families so far, however, the phenotypic spectrum has not been fully elucidated. Here we describe nine patients with the E396K mutation who had a strikingly discordant clinical severity. The clinical picture in family I (patients I,1-II,8) was characterized by childhood onset, distal and proximal pareses, and loss of ambulation in the 6th decade of life, whereas onset was at age 50 years in patient 9, who had no affected relatives. Electrophysiology and sural nerve biopsy revealed a mixed axonal and demyelinating neuropathy, along with probably coincidental inflammatory small vessel disease in patient 9. Biopsy results in family I suggest that not only axons but also Schwann cells may be primary disease targets in CMT2E. Considerably elevated CK levels in all affected adults of family I as well as pronounced myopathic changes in skeletal muscle biopsies point towards an accompanying muscle involvement as a primary target. Our findings reveal an extended phenotype of CMT2E caused by an identical missense mutation of the NEFL gene.

P627: Is precautionary neurophysiological monitoring useful for beta-thalassemia patients?

P627: Is precautionary neurophysiological monitoring useful for beta-thalassemia patients?

A case of congenital insensitivity to pain with anhidrosis.

A case of congenital insensitivity to pain with anhidrosis.

Cryoglobulinemic vasculitis in a patient with CREST syndrome

Cryoglobulinemic vasculitis is a rare entity. Although it has been reported in diffuse systemic sclerosis, it has not been reported in calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly and telangiectasia (CREST) syndrome. We report a patient with cryoglobulinemic vasculitis with CREST syndrome who did not have typical clinical features of vasculitis. This 58-year-old woman presented with mild generalized weakness and a diagnosis of CREST syndrome, which included Raynaud’s syndrome, dysphagia and telangiectasias. She was positive for serum cryoglobulins, which led to a sural nerve biopsy. The biopsy results were consistent with cryoglobulinemic vasculitis. Cryoglobulinemic vasculitis has not been previously reported in CREST syndrome to our knowledge. Additionally, the patient also had limited clinical symptoms. Our patient displays the importance of checking for cryoglobulins and obtaining a nerve biopsy when the serum is positive. Both of these diagnostic tests were integral for directing appropriate treatment for this patient.

Heterogeneity of axonal pathology in chinese patients with giant axonal neuropathy

Giant axonal neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the GAN gene. Herein we report ultrastructural changes in Chinese patients with GAN. General clinical assessment, sural nerve biopsy, and genetic analysis were performed. Sural biopsy revealed giant axons in 3 patients, 2 with a mild phenotype and 1 with a classical phenotype. Ultrastructurally, all patients had giant axons filled with closely packed neurofilaments. In addition, the classical patient had some axons containing irregular tubular-like structures. GAN mutation analysis revealed novel compound heterozygous c.98A>C and c.158C>T mutations in the BTB domain in 1 mild patient, a novel homozygous c.371T>G mutation in the BACK domain in another mild patient, and a novel c.1342G>T homozygous mutation in the Kelch domain in the classical patient. Closely packed neurofilaments in giant axons are common pathological changes in Chinese patients with GAN, whereas irregular tubular-like structures appear in the classical type of this neuropathy.