Russell L. Chin

Non-length dependent small fibre neuropathy/ganglionopathy

Objective: To describe the clinical and laboratory features of a painful non-length dependent, small fibre ganglionopathy (SFG). Background: The syndrome of generalised SFG with early involvement of the face, trunk or proximal limbs is not well recognised and contrasts with the burning feet syndrome of small fibre neuropathy (SFN) and classical large fibre features of sensory ganglionopathy. Methods: Retrospective case review including skin biopsies from four neuromuscular centres. Patients with pre-existing diseases associated with ganglionopathies were excluded. Results: 12 men and 11 women, with an average age of 50 years, were studied. Neuropathic pain developed over days in eight and over months in the other patients. The face (n = 12), scalp (n = 10), tongue (n = 6), trunk (n = 15) and acral extremities (n = 21) were involved. Symptoms began in the hands or face before the legs in 10. The pain was characterised as burning (n = 22), prickling (n = 13), shooting (n = 13) or allodynic (n = 11). There was loss of pinprick sensation in affected regions in 19, with minimal or no loss of large fibre sensibility. Laboratory findings included abnormal glucose metabolism in six patients, Sjögren syndrome in three and monoclonal gammopathy, sprue and hepatitis C infection in one each, with the remainder idiopathic. Sensory nerve action potentials were normal in 12 and were reduced in the hands but normal in the legs in six. Skin biopsy in 14 of 17 showed reduced nerve fibre density in the thigh equal to or more prominent than in the calf. Two of seven patients improved with immune therapies, 13 symptomatically with analgesic medications and the remainder had little improvement. Ten considered the pain disabling at the last follow-up (mean 2 years). Conclusion: The pattern of symmetric, non-length dependent neuropathic pain with face and trunk involvement suggests a selective disorder of the dorsal ganglia cells subserving small nerve fibres. It can be distinguished from distal SFN. A potential metabolic or immune process was detected in half of the cases and the disorder was often refractory to treatment.

Etanercept (Enbrel®) therapy for chronic inflammatory demyelinating polyneuropathy

Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and/or variants who were refractory or intolerant of standard therapies were treated with etanercept, 25 mg twice per week. Ten patients underwent treatment, and manual muscle strength, sensory thresholds and functional abilities were tested prior to and 4-6 months after initiating therapy. Three patients had significant improvement and three others had possible improvement. Based on these preliminary observations, treatment with etanercept may be considered in patients with CIDP, who cannot undergo standard therapies, although its efficacy in CIDP needs to be examined in a double-blinded, controlled clinical trial.

Mechanisms underlying celiac disease and its neurologic manifestations

Abstract.The extra-intestinal manifestations of celiac disease (CD), including ataxia and peripheral neuropathy, are increasingly being recognized as the presenting symptoms of this autoimmune disease. Although there is a greater understanding of the pathogenesis of the intestinal lesions in CD the mechanisms behind the neurologic manifestations of CD have not been elucidated. In this article, the authors review the cellular and molecular mechanisms behind the histopathologic changes in the intestine, discuss the presentation and characteristics of neurologic manifestations of CD, review the data on the mechanisms behind these manifestations, and discuss the diagnosis and treatment of CD. Molecular mimicry and intermolecular help may play a role in the development of neurologic complications.

Cerebellar ataxia and coeliac disease

A 37-year-old woman presented in July, 2002, with a 12-year history of progressive dysarthria and ataxia. Her symptoms became noticeably worse during pregnancy in 1999 and 2001. She had also been anaemic for the past 7 years, and coeliac disease had been diagnosed in 1997. At that time, she had high serum concentrations of IgG and IgA antibodies to gliadin, an endomysial titre of 1:32, and duodenal atrophy on endoscopy; a duodenal biopsy showed subtotal villous atrophy. Neurological tests were done at the same time; median somatosensory evoked potentials showed a delay between the lower brainstem and cortex. She underwent tests for spinocerebellar ataxia, 1–3 brainstem auditory and visual evoked potentials, and cerebral MRI, none of which showed any abnormalites. Cervical spine MRI showed mild degenerative changes. For 5 years, she had followed a strict gluten-free diet, but on examination in 2002 she had severe dysarthria, left finger-to-nose dysmetria, poor right rapid-alternating and fine-finger movements, diminished pedal pin-perception, ankle areflexia, and a severely ataxic, wide-based gait. A modified (without Archimedes Spiral) International Cooperative Ataxia Rating scale (ICARS) score was 31/96. 4 We did many serological tests for autoimmune disease including IgG and IgA antibodies to gliadin, purkinje cells, and voltage-gated calcium channels. The only abnormal results were increased IgA antibodies to transglutaminase, and glutamic acid decarboxylase (GAD). Cerebral MRI showed superior vermis atrophy, whereas lumbosacral MRI was normal. Sensory nerve conduction amplitudes were low. H reflexes were absent. Electromyography showed prolonged durations of motor unit potentials distally. We did not do a nerve biopsy, and we do not have the facilities to do indirect immunohistochemistry or immunofluoresence. We treated her with intravenous immunoglobulin (IVIg) 2 g/kg initially, and 0.5 g/kg 2 weeks later. Within a month, she reported substantial improvements in her speech and gait. She was able to safely hold her children. Acquaintances noted that the audible slap of her walk CASE REPORT disappeared. Squatting, walking, stair-climbing, tandem gait, and standing on one leg all became much easier, and she no longer spilt cups of liquid. On examinaton, we found that all the neurological signs had improved; she still had slight dysarthria and left finger-nose dysmetria, an unsteady gait with a widened base and very slight slapping, and impaired tandem walking, and we calcuated a modified ICARS score of 3/96. She developed a slight rash, so we stopped IVIg and gave her a single dose of methylprednisolone. However, 5 …

Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibres on skin biopsy

Clinical, laboratory and electrodiagnostic (EDX) characteristics of 62 patients with sensory neuropathy with abnormal skin biopsies were reviewed. Reduced epidermal nerve fibre density (ENFD) was seen in 71% and morphological changes with normal ENFD were seen in 29% of the patients. Patients with small fibre sensory neuropathy may have associated large fibre loss undetected by routine EDX. Identified associations included abnormal glucose metabolism, Lyme vaccination, monoclonal gammopathy, vitamin B12 deficiency, coeliac disease, and diseases of the connective tissue, inflammatory bowel and thyroid. Sensory neuropathy remained undetermined in 50% of the patients.

Effect of intravenous immunoglobulin on cerebellar ataxia and neuropathic pain associated with celiac disease

Background:  Cerebellar syndrome and small fiber neuropathy may complicate celiac disease (CD) and may be resistant to a strict gluten‐free diet.

Neurologic Complications of Celiac Disease

Neurologic complications of celiac disease (CD) include ataxia and peripheral neuropathy, which can be the presenting symptoms and signs. Early diagnosis and intervention could prevent development of further neurologic and systemic complications. Questions remain regarding the prevalence of the neurologic complications, the pathophysiological mechanisms, and the effectiveness of therapy or response to a gluten-free diet.

Demyelinating findings in typical and atypical chronic inflammatory demyelinating polyneuropathy: sensitivity and specificity.

Objective: The objective of this study was to evaluate how the number of demyelinating findings (DF) on nerve conductions affects sensitivity and specificity of electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Electrodiagnostic findings of 26 consecutive patients with CIDP were compared with amyotrophic lateral sclerosis (ALS) and diabetic polyneuropathy controls. Patients with CIDP were divided into typical and atypical CIDP, as defined elsewhere. Results: Depending on the minimal required number (MRN) of DF on nerve conductions, sensitivities decreased from an arbitrary 100% to 58% and 54%, for an MRN of 1, 2, and 3, respectively, as specificities increased, from 48% to 81% and 95%, respectively. The number of DF per patient was higher in typical CIDP than in atypical CIDP. Conclusions: The considerable gap between specificity and sensitivity is the reason for controversy regarding the MRN for the diagnosis of CIDP. Requiring 2 or more DFs to identify CIDP increases specificity from 48% to 81% but lowers sensitivity from 100% to 58%. For patients with other potential causes of neuropathy, the requirement of 2 or more DFs could further increase specificity.

Differential gene expression in chronic inflammatory demyelinating polyneuropathy (CIDP) skin biopsies

Gene expression analysis previously identified molecular markers that are up-regulated in sural nerve biopsies from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To determine whether the same or additional genes are also up-regulated in skin, we applied gene microarray profiling and quantitative real-time PCR (qPCR) analysis to skin punch biopsies from patients with CIDP and controls. Five genes, allograft inflammatory factor 1 (AIF-1), lymphatic hyaluronan receptor (LYVE-1/XLKD1), FYN binding protein (FYB), P2RY1 (purinergic receptor P2Y, G-protein-coupled, 1), and MLLT3 (myeloid/lymphoid or mixed-lineage leukemia translocated to, 3), all associated with immune cells or inflammatory processes, were elevated in punch skin biopsies from patients with CIDP as compared to normal subjects or patients with Charcot-Marie-Tooth Type 1 (CMT1). The average fold change of the 5 genes over normal expression, as determined by qPCR, was significantly elevated in skin biopsies from patients with CIDP in comparison to CMT1 or diabetic neuropathy, and similar to that seen in Lyme disease. The findings indicate the presence of inflammatory changes in the skin of patients with CIDP.

Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi.

Abstract  Neurological syndromes that follow vaccination or infection are often attributed to autoimmune mechanisms. We report six patients who developed neuropathy or cognitive impairment, within several days to 2 months, following vaccination with the OspA antigen of Borrelia burgdorferi. Two of the patients developed cognitive impairment, one chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy, one both cognitive impairment and CIDP, and one cognitive impairment and sensory axonal neuropathy. The patients with cognitive impairment had T2 hyperintense white matter lesions on magnetic resonance imaging. The similarity between the neurological sequelae observed in the OspA‐vaccinated patients and those with chronic Lyme disease suggests a possible role for immune mechanisms in some of the manifestations of chronic Lyme disease that are resistant to antibiotic treatment.