Examination and clinical care of the patient with neuropathy.

Examination of a patient with peripheral neuropathy starts with careful questioning of the patient about the history of symptoms and signs and of a possible familial disorder. Several steps are required during examination of the patient with peripheral neuropathy: first the pattern of neuropathy and site of lesions should be determined: roots, nerve trunks, focal, multifocal, length-dependent generalized polyneuropathy, the type of nerve fibers predominantly affected, the association with trophic changes and autonomic dysfunction, the course of the disease ranging from acute inflammatory polyneuritis or fulminant multifocal neuropathy to an extremely slow progression as in Charcot-Marie-Tooth syndromes. At the end of this first contact with the patient, the neurologist must decide which investigations seem necessary and their timing including electrophysiological tests, imaging, CSF examination, blood tests, nerve and muscle biopsy, DNA testing, etc. In some cases, life-threatening manifestations, including weakness of respiratory muscles or swallowing difficulty, or autonomic dysfunction, require urgent therapeutic decisions.

Chronic inflammatory demyelinative polyneuropathy.

Chronic inflammatory demyelinative polyneuropathy (CIDP) is an acquired polyneuropathy presumably of immunological origin. It is characterized by a progressive or a relapsing course with predominant motor deficit. The diagnosis rests on the association of non-length-dependent predominantly motor deficit following a progressive or a relapsing course associated with increased CSF protein content. The demonstration of asymmetrical demyelinating features on nerve conduction studies is needed for diagnosis. The outcome depends on the amplitude of axon loss associated with demyelination. CIDP must be differentiated from acquired demyelinative neuropathies associated with monoclonal gammopathies. CIDP responds well to treatment with corticosteroids, intravenous immunoglobulins, and plasma exchanges, at least initially.

Vasculitic neuropathy.

Vasculitis is a primary phenomenon in autoimmune diseases such as polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, and essential mixed cryoglobulinemia. As a secondary feature vasculitis may complicate, for example, connective tissue diseases, infections, malignancies, and diabetes. Vasculitic neuropathy is a consequence of destruction of the vessel wall and occlusion of the vessel lumen of small epineurial arteries. Sometimes patients present with nonsystemic vasculitic neuropathy, i.e., vasculitis limited to peripheral nerves and muscles with no evidence of further systemic involvement. Treatment with corticosteroids, sometimes in combination with other immunosuppressants, is required to control the inflammatory process and prevent further ischemic nerve damage.

Sarcoidosis of the peripheral nervous system.

Neurological manifestations of sarcoidosis are relatively rare but constitute a treatable cause of central and peripheral neurological manifestations. Regarding the peripheral nervous system, cranial nerves are predominantly affected, and peripheral facial nerve palsy, often bilateral, is the most common neurological manifestation of sarcoidosis. Multifocal peripheral neuropathy is a rare event in sarcoidosis. In some cases, however, peripheral neuropathy is the presenting manifestation and seemingly the only organ affected. Definite diagnosis of sarcoidosis rests ideally on histological demonstration of sarcoid granulomas in tissue biopsy specimens.

Leprous neuropathy.

Leprous neuropathy, which is due to infection of nerve cells by Mycobacterium leprae, still affects millions of people in many developing countries. The clinical and pathological manifestations are determined by the natural resistance of the host to invasion of M. Leprae. Failure of early detection of leprosy often leads to severe disability in spite of eradication of mycobacterium at a later date. In the lepromatous type, bacilli are easily found in the skin and in nerve cells including Schwann cells, endothelial cells, and macrophages. In the tuberculoid type, a strong cell-mediated immune reaction leads to formation of granulomas and destruction of cells harboring bacilli and neighboring nerve fibers. In many cases, treatment of patients with the multibacillary leprosy is complicated by reversal reaction and further nerve damage. Nerve lesions lead to a symmetrical, pseudo-polyneuritic pattern in most cases of lepromatous leprosy, which is usually associated with typical skin lesions, but pure neuritic forms occur in up to 10% of patients with lepromatous leprosy. In the pure neuropathic cases, only nerve biopsy permits diagnosis. The multifocal pattern is more common in tuberculoid leprosy. Treatment is currently based on multidrug therapy with dapsone, rifampicin, and clofazimine. The use of corticosteroids can reduce or prevent nerve damage in reversal reactions. It is important to remember that sequelae, especially sensory loss, are extremely common, which can lead to secondary trophic changes due to repeated trauma in painless areas.

Diabetic neuropathy.

Diabetes is the most common cause of peripheral neuropathy in the world. Both type 1 (insulin-dependent) and type 2 diabetes are commonly complicated by peripheral nerve disorders. Two main types of neuropathy are observed: the most common is a nerve fiber length-dependent, distal symmetrical sensory polyneuropathy with little motor involvement but frequent, and potentially life threatening, autonomic dysfunction. Alteration of temperature and pain sensations in the feet is an early manifestation of diabetic polyneuropathy. The second pattern is a focal neuropathy, which more commonly complicates or reveals type 2 diabetes. Poor diabetic control increases the risk of neuropathy with subsequent neuropathic pains and trophic changes in the feet, which can be prevented by education of patients.

Uremic neuropathy.

Polyneuropathy is a common complication of end-stage renal failure especially when treatment with periodic hemodialysis is started too late. Large myelinated fibers bear the brunt of the many biological changes associated with renal failure. Nerve conduction slowing is common in this setting. Compression of the median nerve in the carpal tunnel commonly occurs in these patients, as a result of amyloid deposits at this site. End-stage renal failure in diabetic patients is often associated with severe distal motor and sensory deficits. Improved quality of periodic hemodialysis and renal transplantation have dramatically reduced the prevalence and severity of peripheral neuropathy in these patients.

PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetically heterogeneous group of peripheral neuropathies characterized by progressive distal muscle weakness and atrophy, foot deformities and distal sensory loss. Following the analysis of two consanguineous families affected by a medium to late-onset recessive form of intermediate CMT, we identified overlapping regions of homozygosity on chromosome 1p36 with a combined maximum LOD score of 5.4. Molecular investigation of the genes from this region allowed identification of two homozygous mutations in PLEKHG5 that produce premature stop codons and are predicted to result in functional null alleles. Analysis of Plekhg5 in the mouse revealed that this gene is expressed in neurons and glial cells of the peripheral nervous system, and that knockout mice display reduced nerve conduction velocities that are comparable with those of affected individuals from both families. Interestingly, a homozygous PLEKHG5 missense mutation was previously reported in a recessive form of severe childhood onset lower motor neuron disease (LMND) leading to loss of the ability to walk and need for respiratory assistance. Together, these observations indicate that different mutations in PLEKHG5 lead to clinically diverse outcomes (intermediate CMT or LMND) affecting the function of neurons and glial cells.

Guideline of transthyretin-related hereditary amyloidosis for clinicians.

Transthyretin amyloidosis is a progressive and eventually fatal disease primarily characterized by sensory, motor, and autonomic neuropathy and/or cardiomyopathy. Given its phenotypic unpredictability and variability, transthyretin amyloidosis can be difficult to recognize and manage. Misdiagnosis is common, and patients may wait several years before accurate diagnosis, risking additional significant irreversible deterioration. This article aims to help physicians better understand transthyretin amyloidosis--and, specifically, familial amyloidotic polyneuropathy--so they can recognize and manage the disease more easily and discuss it with their patients. We provide guidance on making a definitive diagnosis, explain methods for disease staging and evaluation of disease progression, and discuss symptom mitigation and treatment strategies, including liver transplant and several pharmacotherapies that have shown promise in clinical trials.

Krabbe disease in adults: phenotypic and genotypic update from a series of 11 cases and a review.

Krabbe disease usually presents as a severe leukodystrophy in early infancy and childhood. From a series of 11 patients and 30 cases previously reported in the literature we describe the clinical, radiological, electrophysiological and genetic features of adult Krabbe disease. Patients diagnosed after the age of 16 years were included in this study. They were further divided into three groups depending on age at symptoms onset: (1) childhood onset cases (n = 7); (2) adolescence onset cases (n = 6) and adult onset cases (n = 28). Overall, 96 % of patients in the adult-onset group presented with signs of pyramidal tracts dysfunction. Spastic paraparesis or tetraparesis became prominent in all cases. A peripheral neuropathy was present in 59 % of cases and was most often demyelinating (80 %). Other clinical signs encompassed dysarthria (31 %), cerebellar ataxia (27 %), pes cavus (27 %), deep sensory signs (23 %), tongue atrophy (15 %), optic neuropathy (12 %), cognitive decline (12 %). Cerebrospinal fluid protein concentration was moderately increased in 54 % of patients. Patients in the adolescent- and childhood-onset groups had similar presentations but were more likely to display optic neuropathy (33 % and 57 %) and cerebellar ataxia (50 % and 57 %). In the adult-onset group, the disease progressed slowly over more than 10 years, but a rapid course was observed in two patients. Abnormalities of brain MRI was similar in the three groups and included high signals of cortico-spinal tracts (94 % of cases), hyper-intensities of optic radiations (89 %) and hyper-intensities or atrophy of the posterior part of the corpus callosum (60 %). No clear genotype-phenotype relationship could be demonstrated.

TTR-familial amyloid polyneuropathy--neurological aspects.

Transthyretin familial amyloid polyneuropathy is characterized by a devastating sensory-motor polyneuropathy associated with life-threatening autonomic disturbance. An early diagnosis is mandatory to increase the chance to modify the course of the disease. This paper underlines the diagnostic problems encountered in this condition.

Tafamidis.

In November 2011, tafamidis (Vyndaqel; Pfizer), a small molecule that inhibits the dissociation of transthyretin tetramers, was granted marketing authorization by the European Commission for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurological impairment.

Familial amyloid polyneuropathy.

Familial amyloid polyneuropathies (FAPs) are a group of life-threatening multisystem disorders transmitted as an autosomal dominant trait. Nerve lesions are induced by deposits of amyloid fibrils, most commonly due to mutated transthyretin (TTR). Less often the precursor of amyloidosis is mutant apolipoprotein A-1 or gelsolin. The first identified cause of FAP-the TTR Val30Met mutation-is still the most common of more than 100 amyloidogenic point mutations identified worldwide. The penetrance and age at onset of FAP among people carrying the same mutation vary between countries. The symptomatology and clinical course of FAP can be highly variable. TTR FAP typically causes a nerve length-dependent polyneuropathy that starts in the feet with loss of temperature and pain sensations, along with life-threatening autonomic dysfunction leading to cachexia and death within 10 years on average. TTR is synthesised mainly in the liver, and liver transplantation seems to have a favourable effect on the course of neuropathy, but not on cardiac or eye lesions. Oral administration of tafamidis meglumine, which prevents misfolding and deposition of mutated TTR, is under evaluation in patients with TTR FAP. In future, patients with FAP might benefit from gene therapy; however, genetic counselling is recommended for the prevention of all types of FAP.

Professor P. K. Thomas: clinician, investigator, editor and leader--a retrospective appreciation.

P. K. Thomas (1926-2008) occupied a prominent place in British and world neurology during the second half of the 20th century. Here, his lasting achievements as clinical neurologist, clinician scientist and experimentalist, editor of monographs and journals and leader of professional developments in the UK and elsewhere are assessed.

Peripheral Nerve Society Guideline on the classification, diagnosis, investigation, and immunosuppressive therapy of non-systemic vasculitic neuropathy: executive summary.

Non-systemic vasculitic neuropathy (NSVN) is routinely considered in the differential diagnosis of progressive axonal neuropathies, especially those with asymmetric or multifocal features. Diagnostic criteria for vasculitic neuropathy, classification criteria for NSVN, and therapeutic approaches to NSVN are not standardized. The aim of this guideline was to derive recommendations on the classification, diagnosis, investigation, and treatment of NSVN based on the available evidence and, where evidence was not available, expert consensus. Experts on vasculitis, vasculitic neuropathy, and methodology systematically reviewed the literature for articles addressing diagnostic issues concerning vasculitic neuropathy and NSVN as well as treatment of NSVN and the small-to-medium vessel primary systemic vasculitides using MEDLINE, EMBASE, and the Cochrane Library. The selected articles were analyzed and classified. The group initially reached consensus on a classification of vasculitides associated with neuropathy. Non-diabetic radiculoplexus neuropathy was incorporated within NSVN. The consensus definition of pathologically definite vasculitic neuropathy required that vessel wall inflammation be accompanied by vascular damage. Diagnostic criteria for pathologically probable vasculitic neuropathy included five predictors of definite vasculitic neuropathy: vascular deposits of IgM, C3, or fibrinogen by direct immunofluorescence; hemosiderin deposits; asymmetric nerve fiber loss; prominent active axonal degeneration; and myofiber necrosis, regeneration, or infarcts in peroneus brevis muscle biopsy (Good Practice Points from class II/III evidence). A case definition of clinically probable vasculitic neuropathy in patients lacking biopsy proof incorporated clinical features typical of vasculitic neuropathy: sensory or sensory-motor involvement, asymmetric/multifocal pattern, lower-limb predominance, distal-predominance, pain, acute relapsing course, and non-demyelinating electrodiagnostic features (Good Practice Points from class II/III evidence). Proposed exclusionary criteria for NSVN--favoring the alternate diagnosis of systemic vasculitic neuropathy--were clinicopathologic evidence of other-organ involvement; anti-neutrophil cytoplasmic antibody (ANCAs); cryoglobulins; sedimentation rate ≥100 mm/h; and medical condition/drug predisposing to systemic vasculitis (Good Practice Points supported by class III evidence). Three class III studies on treatment of NSVN were identified, which were insufficient to permit a level C recommendation. Therefore, the group reviewed the literature on treatment of primary small-to-medium vessel systemic vasculitides prior to deriving Good Practice Points on treatment of NSVN. Principal treatment recommendations were: (1) corticosteroid (CS) monotherapy for at least 6 months is considered first-line; (2) combination therapy should be used for rapidly progressive NSVN and patients who progress on CS monotherapy; (3) immunosuppressive options include cyclophosphamide, azathioprine, and methotrexate; (4) cyclophosphamide is indicated for severe neuropathies, generally administered in IV pulses to reduce cumulative dose and side effects; (5) in patients achieving clinical remission with combination therapy, maintenance therapy should be continued for 18-24 months with azathioprine or methotrexate; and (6) clinical trials to address all aspects of treatment are needed.

Familial amyloid polyneuropathy: a clinico-pathologic study.

UNLABELLED: In familial amyloid polyneuropathy (FAP), destruction of nerve fibres is related to accumulation of mutated transthyretin (mTTR) derived amyloid deposits (AD) in the endoneurium. Liver transplantation (LT), which removes the main source of mTTR, does not prevent deterioration of the clinical condition in all recipients. MATERIAL AND METHODS: We evaluated the distribution of AD in the central and peripheral nervous system in order to better understand the pathophysiology of FAP and the potential role of lesions of nerve blood vessels and of mTTR released by choroid plexuses (CP). Forty nerve biopsy specimens and 3 autopsy cases, including 7 patients who underwent liver transplantation, all from patients with symptomatic FAP and DNA mutation of the TTR gene, were included. RESULTS: Patients were ranged into three categories: MORPHOLOGICAL CHANGES: Amyloid predominated around endoneurial capillaries in 37 patients, with occlusion/destruction of endoneurial capillaries in 15 nerves at late stages of the disease. Post-mortem examination showed amyloid in choroid plexuses and perivascular spaces in the brain and around blood vessels penetrating the endoneurium, following arachnoid and connective tissue septae. Destruction of endoneurial blood vessels is a late event in the natural course of FAP. Morphological findings were similar in patients who underwent liver transplantation and in those who did not. The distribution of amyloid in areas communicating with the subarachnoid space suggests that mutated TTR released in the CSF may move to the endoneurial fluid and accumulate in peripheral nerves, accounting for lack of efficacy of liver transplantation in some individuals.

Neurolymphomatosis associated with Sézary syndrome.

BACKGROUND: Mycosis fungoides and Sézary syndrome are cutaneous T-cell lymphomas characterized by the epidermotropism of tumor cells. Neuropathic disease is rare during mycosis fungoides and Sézary syndrome and usually results from a central nervous system involvement in late stages. Neurolymphomatosis is defined as the infiltration of the peripheral nerves by tumor lymphocytes. It has been described in patients with aggressive systemic lymphomas but, to our knowledge, not in patients with mycosis fungoides or Sézary syndrome. We report the first case of neurolymphomatosis in a patient with Sézary syndrome and the partial efficacy of high-dose methotrexate sodium in treating this usually refractory complication. OBSERVATION: A 73-year-old woman with newly diagnosed Sézary syndrome rapidly developed severe peripheral neuropathic disease with multiple paralyses. Biopsy specimens were taken from a clinically affected nerve and the adjacent muscle; they revealed a neural infiltration by Sézary cells with secondary muscular atrophy. Partial response and major neurologic recovery occurred and persisted under high doses of intravenous methotrexate until the patient died 14 months after the Sézary syndrome diagnosis from a pericarditis of uncertain origin. CONCLUSION: This unusual and demonstrative case report highlights the possible neurotropism of malignant cells in Sézary syndrome and suggests the effectiveness of high doses of intravenous methotrexate in this rare and fatal disorder.

Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain.

BACKGROUND: Few direct head-to-head comparisons have been conducted between drugs for the treatment of diabetic peripheral neuropathic pain (DPNP). Approved or recommended drugs in this indication include duloxetine (DLX), pregabalin (PGB), gabapentin (GBP) and amitriptyline (AMT). We conducted an indirect meta-analysis to compare the efficacy and tolerability of DLX with PGB and GBP in DPNP, using placebo as a common comparator. METHODS: We searched PubMed, EMBASE, CENTRAL databases and regulatory websites for randomized, double-blind, placebo-controlled, parallel group or crossover clinical trials (RCTs) assessing DLX, PGB, GBP and AMT in DPNP. Study arms using approved dosages with assessments after 5-13 weeks were eligible. Efficacy criteria were: reduction in 24-hour pain severity (24 h PS) for all three drugs, and response rate (>or= 50% pain reduction) and Patient Global Impression of Improvement/Change (PGI-I/C) for DLX and PGB only. Tolerability criteria included: discontinuation, diarrhoea, dizziness, headache, nausea and somnolence. Direct comparisons versus placebo were conducted with pooled fixed - and random-effects analyses on endpoints reported in at least two studies of each drug. Indirect comparisons were performed between DLX and each of PGB and GBP using Bayesian simulation. RESULTS: Three studies of DLX, six of PGB, two of GBP and none of AMT met the inclusion criteria. In random-effects and fixed-effects analyses of DLX, PGB and GBP, all were superior to placebo for all efficacy parameters, with some tolerability trade-offs. Indirect comparison of DLX with PGB found no differences in 24 h PS, but significant differences in PGI-I/C, favouring PGB, and in dizziness, favouring DLX were apparent. Comparing DLX and GBP, there were no statistically significant differences. CONCLUSION: From the few available studies suitable for indirect comparison, DLX shows comparable efficacy and tolerability to GBP and PGB in DPNP. Duloxetine provides an important treatment option for this disabling condition.