Sensory neuronopathies: A case series and literature review.

Sensory neuronopathies are heterogeneous disorders of dorsal root ganglia. The clinical and laboratory features in a single-centre series, including response to treatment and outcome have been described. They retrospectively included 54 patients meeting Camdessanché et al (2009) criteria for sensory neuronopathy. The patients were classified according to their likely aetiology and analysed their demographic, clinical, neurophysiological, histological and spinal MRI features. The outcome with the modified Rankin Scale (mRS) was evaluated, and the response to treatment was assessed. About 54 patients were included (18 male; median age 54.5 years). The most common initial symptoms were hypoaesthesia, paraesthesia, ataxia and pain. Half of patients had a slow onset, greater than 12 months before seeing a neurologist. The aetiology as possibly inflammatory (meaning nonspecific laboratory evidence of immune abnormality) in 18 patients (33%), paraneoplastic 8 (15%), autoimmune 7 (13%) and idiopathic 6 (11%) was classified. About 31 patients received immune therapy of which 11 (35%) improved or stabilised. Corticosteroids were the most used treatment (24 patients) and cyclophosphamide had the highest response rate (3/6, 50%). At the final follow up (median 24 months) 67% had mRS ≥3 and 46% mRS ≥4, including 15% who died. Worse outcome was associated with generalised areflexia and pseudoathetosis by logistic regression, and with motor involvement and raised CSF protein by univariate analysis. Sensory neuronopathies caused severe disability, especially in patients with generalised areflexia and pseudoathetosis. Of those without an obvious cause, most had some evidence of dysimmunity. Some patients had a positive response to immunotherapy, but rarely enough to improve disability much.

Catatonia with GABAA receptor antibodies.

A 22-year-old African woman developed acute behavioural change, against a background of sickle cell disease with strokes requiring a ventriculoperitoneal shunt. She alternated between mutism with prolonged staring and posturing, and a state of agitation with elation and echolalia. Cerebrospinal fluid (CSF) protein was elevated and electroencephalogram showed mild slowing with bitemporal slow and sharp waves. We suspected catatonia secondary to possible autoimmune encephalitis but her condition persisted despite intravenous methylprednisolone. After identifying a positive serum anti-gamma-aminobutyric acid-A (GABAA) antibody, treatment with intravenous immunoglobulin, oral corticosteroids and rituximab led to gradual improvement. Patients with catatonia may show reduced GABAA receptor density and there are two other reports of catatonia with anti-GABAA antibodies. This patient's treatment response supports the antibody's causative role.

Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease that causes progressive or relapsing and remitting weakness and numbness. It is probably caused by an autoimmune process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. This review was first published in 2003 and has been updated most recently in 2016. OBJECTIVES: To assess the effects of immunomodulatory and immunosuppressive agents other than corticosteroids, immunoglobulin, and plasma exchange in CIDP. SEARCH METHODS: On 24 May 2016, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 4) in the Cochrane Library, MEDLINE, Embase, CINAHL, and LILACS for completed trials, and clinical trial registers for ongoing trials. We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials. SELECTION CRITERIA: We sought randomised and quasi-randomised trials of all immunosuppressive agents, such as azathioprine, cyclophosphamide, methotrexate, ciclosporin, mycophenolate mofetil, and rituximab, and all immunomodulatory agents, such as interferon (IFN) alfa and IFN beta, in participants fulfilling standard diagnostic criteria for CIDP. We included all comparisons of these agents with placebo, another treatment, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We wanted to measure the change in disability after one year as our primary outcome. Our secondary outcomes were change in disability after four or more weeks (from randomisation); change in impairment after at least one year; change in maximum motor nerve conduction velocity and compound muscle action potential amplitude after one year; and for participants who were receiving corticosteroids or intravenous immunoglobulin (IVIg), the amount of this medication given during at least one year after randomisation. Participants with one or more serious adverse events during the first year was also a secondary outcome. MAIN RESULTS: Four trials fulfilled the selection criteria: one of azathioprine (27 participants), two of IFN beta-1a (77 participants in total) and one of methotrexate (60 participants). The risk of bias was considered low in the trials of IFN beta-1a and methotrexate but high in the trial of azathioprine. None of the trials showed significant benefit in any of the outcomes selected by their authors. The results of the outcomes which approximated most closely to the primary outcome for this review were as follows.In the azathioprine trial there was a median improvement in the Neuropathy Impairment Scale (scale range 0 to 280) after nine months of 29 points (range 49 points worse to 84 points better) in the azathioprine and prednisone treated participants compared with 30 points worse (range 20 points worse to 104 points better) in the prednisone alone group. There were no reports of adverse events.In a cross-over trial of IFN beta-1a with 20 participants, the treatment periods were 12 weeks. The median improvement in the Guy's Neurological Disability Scale (range 1 to 10) was 0.5 grades (interquartile range (IQR) 1.8 grades better to zero grade change) in the IFN beta-1a treatment period and 0.5 grades (IQR 1.8 grades better to 1.0 grade worse) in the placebo treatment period. There were no serious adverse events in either treatment period.In a parallel group trial of IFN beta-1a with 67 participants, none of the outcomes for this review was available. The trial design involved withdrawal from ongoing IVIg treatment. The primary outcome used by the trial authors was total IVIg dose administered from week 16 to week 32 in the placebo group compared with the IFN beta-1a groups. This was slightly but not significantly lower in the combined IFN beta-1a groups (1.20 g/kg) compared with the placebo group (1.34 g/kg, P = 0.75). There were four participants in the IFN beta-1a group and none in the placebo group with one or more serious adverse events, risk ratio (RR) 4.50 (95% confidence interval (CI) 0.25 to 80.05).The methotrexate trial had a similar design involving withdrawal from ongoing corticosteroid or IVIg treatment. At the end of the trial (approximately 40 weeks) there was no significant difference in the change in the Overall Neuropathy Limitations Scale, a disability scale (scale range 0 to 12), the median change being 0 (IQR -1 to 0) in the methotrexate group and 0 (IQR -0.75 to 0) in the placebo group. These changes in disability might have been confounded by the reduction in corticosteroid or IVIg dose required by the protocol. There were three participants in the methotrexate group and one in the placebo with one or more serious adverse events, RR 3.56 (95% CI 0.39 to 32.23). AUTHORS' CONCLUSIONS: Low-quality evidence from randomised trials does not show significant benefit from azathioprine or interferon beta-1a and moderate-quality evidence from one randomised trial does not show significant benefit from a relatively low dose of methotrexate for the treatment of CIDP. None of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for randomised controlled trials to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures relevant to people with CIDP, and longer treatment durations.

Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disease causing progressive or relapsing and remitting weakness and numbness. It is probably due to an autoimmune process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. This review was first published in 2003 and has been most recently updated in 2013. OBJECTIVES: We aimed to review systematically the evidence from randomised trials of immunomodulatory and immunosuppressive agents other than corticosteroids, immunoglobulin and plasma exchange for CIDP. SEARCH METHODS: On 9 July 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register (July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1977 to July 2012), EMBASE (January 1980 to July 2012), CINAHL (January 1982 to July 2012) and LILACS (January 1982 to July 2012). We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials. SELECTION CRITERIA: We sought randomised and quasi-randomised trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, ciclosporin, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as interferon alfa and interferon beta, in participants fulfilling standard diagnostic criteria for CIDP. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged their risk of bias and extracted data. We wanted to measure the change in disability after one year as our primary outcome. Our secondary outcomes were change in disability after four or more weeks (from randomisation), change in impairment after at least one year, change in maximum motor nerve conduction velocity and compound muscle action potential amplitude after one year and for those participants who were receiving corticosteroids or intravenous immunoglobulin, the amount of this medication given during at least one year after randomisation. Participants with one or more serious adverse events during the first year was also a secondary outcome. MAIN RESULTS: Four trials fulfilled the selection criteria, one of azathioprine (27 participants), two of interferon beta-1a (77 participants in total) and one of methotrexate (60 participants). The risk of bias in the two trials of interferon beta-1a for CIDP and the trial of methotrexate was assessed to be low but bias in the trial of azathioprine was judged high. None of these trials showed significant benefit in the primary outcome (measured only in the methotrexate study) or secondary outcomes selected for this review. Severe adverse events occurred no more frequently than in the placebo groups for methotrexate and interferon beta-1a, but participant numbers were low. There was no adverse event reporting in the azathioprine study. AUTHORS' CONCLUSIONS: The evidence from randomised trials does not show significant benefit from azathioprine, interferon beta-1a or methotrexate but none of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for randomised controlled trials to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures and longer durations.

Investigating genotype-phenotype relationship of extreme neuropathic pain disorders in a UK national cohort.

The aims of our study were to use whole genome sequencing in a cross-sectional cohort of patients to identify new variants in genes implicated in neuropathic pain, to determine the prevalence of known pathogenic variants and to understand the relationship between pathogenic variants and clinical presentation. Patients with extreme neuropathic pain phenotypes (both sensory loss and gain) were recruited from secondary care clinics in the UK and underwent whole genome sequencing as part of the National Institute for Health and Care Research Bioresource Rare Diseases project. A multidisciplinary team assessed the pathogenicity of rare variants in genes previously known to cause neuropathic pain disorders and exploratory analysis of research candidate genes was completed. Association testing for genes carrying rare variants was completed using the gene-wise approach of the combined burden and variance-component test SKAT-O. Patch clamp analysis was performed on transfected HEK293T cells for research candidate variants of genes encoding ion channels. The results include the following: (i) Medically actionable variants were found in 12% of study participants (205 recruited), including known pathogenic variants: SCN9A(ENST00000409672.1): c.2544T>C, p.Ile848Thr that causes inherited erythromelalgia, and SPTLC1(ENST00000262554.2):c.340T>G, p.Cys133Tr variant that causes hereditary sensory neuropathy type-1. (ii) Clinically relevant variants were most common in voltage-gated sodium channels (Nav). (iii) SCN9A(ENST00000409672.1):c.554G>A, pArg185His variant was more common in non-freezing cold injury participants than controls and causes a gain of function of NaV1.7 after cooling (the environmental trigger for non-freezing cold injury). (iv) Rare variant association testing showed a significant difference in distribution for genes NGF, KIF1A, SCN8A, TRPM8, KIF1A, TRPA1 and the regulatory regions of genes SCN11A, FLVCR1, KIF1A and SCN9A between European participants with neuropathic pain and controls. (v) The TRPA1(ENST00000262209.4):c.515C>T, p.Ala172Val variant identified in participants with episodic somatic pain disorder demonstrated gain-of-channel function to agonist stimulation. Whole genome sequencing identified clinically relevant variants in over 10% of participants with extreme neuropathic pain phenotypes. The majority of these variants were found in ion channels. Combining genetic analysis with functional validation can lead to a better understanding as to how rare variants in ion channels lead to sensory neuron hyper-excitability, and how cold, as an environmental trigger, interacts with the gain-of-function NaV1.7 p.Arg185His variant. Our findings highlight the role of ion channel variants in the pathogenesis of extreme neuropathic pain disorders, likely mediated through changes in sensory neuron excitability and interaction with environmental triggers.

Immunomodulatory treatment other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy is a disease causing progressive or relapsing and remitting weakness and numbness. It is probably due to an autoimmune process. Immunosuppressive or immunomodulatory drugs would be expected to be beneficial. OBJECTIVES: We aimed to review systematically the evidence from randomised trials of cytotoxic drugs and interferons other than corticosteroids, immunoglobulin and plasma exchange for chronic inflammatory demyelinating polyradiculoneuropathy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Specialised Register (May 2010), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 2), MEDLINE (January 1977 to May 2010), EMBASE (January 1980 to May 2010), CINAHL (January 1982 to May 2010) and LILACS (January 1982 to May 2010). We contacted the authors of the trials identified and other disease experts seeking other published and unpublished trials. SELECTION CRITERIA: We sought randomised and quasi-randomised trials of all immunosuppressive agents such as azathioprine, cyclophosphamide, methotrexate, ciclosporin A, mycophenolate mofetil, and rituximab and all immunomodulatory agents such as interferon alfa and interferon beta in participants fulfilling standard diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged their methodological quality and extracted data. We wanted to measure the change in disability after one year as our primary outcome. Our secondary outcomes were change in disability after four or more weeks (from randomisation), change in impairment after at least one year, change in maximum motor nerve conduction velocity and compound muscle action potential amplitude after one year and for those participants who were receiving corticosteroids or intravenous immunoglobulin, the amount of this medication given during at least one year after randomisation. Participants with one or more serious adverse events during the first year was also a secondary outcome. MAIN RESULTS: Four trials fulfilled the selection criteria, one of azathioprine (27 participants), two of interferon beta-1a (77 participants in total) and one of methotrexate (60 participants). None of these trials showed significant benefit in the primary outcome or secondary outcomes selected for this review. AUTHORS' CONCLUSIONS: The evidence from randomised trials does not show significant benefit from azathioprine, interferon beta-1a or methotrexate but none of the trials was large enough to rule out small or moderate benefit. The evidence from observational studies is insufficient to avoid the need for randomised controlled trials to discover whether these drugs are beneficial. Future trials should have improved designs, more sensitive outcome measures and longer durations.

Autologous peripheral blood stem cell transplantation for chronic acquired demyelinating neuropathy.

Six patients with chronic acquired demyelinating neuropathy (CADP) were treated with autologous peripheral blood stem cell transplantation (PBSCT). Two with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome improved-improvement was sustained in one but relapsed and required repeat transplant in the other. Two of the three with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and one with an IgM paraprotein and antibodies to nerve improved--of the responders, one relapsed after 18 months and the other was in remission after 6 months. Four developed neutropenic septicemia and pneumonia. The role of PBSCT in CADP refractory to other treatment deserves further investigation but the serious adverse events and lack of sustained response in some patients emphasize the need for caution.

Overview of the pathogenesis and treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulins.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired heterogeneous disorder of immune origin affecting the peripheral nerves, causing motor weakness and sensory symptoms and signs. The precise pathophysiology of CIDP remains uncertain although B and T cell mechanisms are believed to be implicated. Intravenous immunoglobulins (IVIg) have been shown in a number of trials to be an effective treatment for CIDP. IVIg is thought to exert its immunomodulatory effects by affecting several components of the immune system including B-cells, T-cells, macrophages and complement. This article provides an overview of the pathogenesis of CIDP and of its treatment with IVIg.