Alexander F. J. E. Vrancken

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.

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Incidence of polyneuropathy in Utrecht, the Netherlands

Objective: Ascertain the incidence of cryptogenic axonal polyneuropathy (CAP) and how this relates to the overall incidence of polyneuropathy. Methods: Electronic diagnostic registries of all hospital-based neurologic practices in the province of Utrecht (population 1,224,852 = 7.4% of the Dutch population) were consulted in 2010 to identify incident cases with polyneuropathy. Medical files were reviewed to specify the final diagnosis. Age-adjusted incidence rates for the Netherlands were calculated using national age-specific population figures. Results: The overall incidence of polyneuropathy was 77.0/100,000 person-years (95% confidence interval 71.1–82.8) in persons aged 18 years and older. Diabetic polyneuropathy (32%), CAP (26%), toxic polyneuropathy (14%), and immune-mediated polyneuropathy (9%) were the most frequent diagnoses. The incidence of CAP was 31.6/100,000 person-years (95% confidence interval 27.0–36.3) in persons aged 40 years and older. The incidence of polyneuropathy increased with age, as well as the proportion of patients diagnosed with CAP: 12% (40–49 years), 20% (50–59 years), 28% (60–69 years), 32% (70–79 years), and 35% (≥80 years) (χ2 test, p = 0.005). Conclusions: The chance of establishing an etiologic diagnosis in patients presenting with a polyneuropathy decreases with age. Given the aging population, polyneuropathy in general and CAP in particular will pose a growing health care problem.

Dysfunction of the neuromuscular junction in spinal muscular atrophy types 2 and 3

ABSTRACT Objective: Spinal muscular atrophy (SMA) is pathologically characterized by degeneration of anterior horn cells. Recent observations in animal models of SMA and muscle tissue from patients with SMA suggest additional abnormalities in the development and maturation of the neuromuscular junction. We therefore evaluated neuromuscular junction function in SMA with repetitive nerve stimulation. Methods: In this case-control study, repetitive nerve stimulation was performed in 35 patients with SMA types 2, 3, and 4, 20 healthy controls, and 5 controls with motor neuron disease. Results: Pathologic decremental responses (>10%) during 3-Hz repetitive nerve stimulation were observed in 17 of 35 patients (49%) with SMA types 2 and 3, but not in healthy controls or controls with motor neuron disease. None of the patients or controls had an abnormal incremental response of >60%. The presence of an abnormal decremental response was not specific for the type of SMA, nor was it associated with compound muscle action potential amplitude, clinical scores, or disease duration. Two of 4 patients with SMA type 3 who tried pyridostigmine reported increased stamina. Conclusions: These data suggest dysfunction of the neuromuscular junction in patients with SMA types 2 and 3. Therefore, drugs that facilitate neuromuscular transmission are candidate drugs for evaluation in carefully designed, placebo-controlled, clinical trials.

The meaning of distal sensory loss and absent ankle reflexes in relation to age

ContextPolyneuropathy is a common disease and is more prevalent (at least 3 %) in elderly people. However, routine neurological examination of healthy elderly people may show distal sensory loss and absent tendon reflexes, which can obscure the distinction from polyneuropathy.ObjectiveTo investigate the relation between age and the prevalence of distal sensory loss, absent tendon reflexes, or muscle weakness, and to ascertain above which age these neurological signs could be considered as normal in ageing.Data sourcesPubMed, Embase, the Cochrane Library, and Current Contents from 1960 until 2004. Reference lists of relevant studies were searched for additional studies, reviews or textbooks.Study selectionStudies reporting on neurological signs upon routine neurological examination in generally healthy adult persons were considered for inclusion. Two reviewers independently assessed study eligibility and performed study inclusion. Of 629 studies initially identified, 50 (8 %) met the inclusion criteria.Data extractionTwo reviewers independently performed data extraction and assessed study quality based on study design and the rigour by which confounding co–morbidity was excluded.Data synthesisThe 50 included studies comprised a total of 9,996 adult persons. Assuming heterogeneity between studies, the prevalence data from different studies were pooled for separate age groups with a random–effects model. In healthy persons older than 60 years the prevalence of absent vibration sense at the big toes (29 % [95 % CI 18 % to 38%]) or ankles (15 % [95 % CI 11 % to 20%]), and absent ankle reflexes (23 % [95 % CI 16 % to 30 %]) was increased.ConclusionsSelfdeclared healthy adult persons younger than 60 years do not have neurological signs. After the age of 60 absent vibration sense at the big toes or ankles, and absent ankle reflexes are more prevalent, although the majority does not have these neurological signs. It seems more appropriate to apply different diagnostic criteria for polyneuropathy in adult persons younger and older than 60 years.

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.

Chronic Idiopathic Axonal Polyneuropathy Is Associated With the Metabolic Syndrome

OBJECTIVE This study aims to investigate the association between chronic idiopathic axonal polyneuropathy (CIAP) and the metabolic syndrome or its individual components. RESEARCH DESIGN AND METHODS A total of 249 patients with CIAP and 709 controls underwent fasting laboratory studies, and blood pressure and waist circumference were measured. The metabolic syndrome was diagnosed if three or more of the following Adult Treatment Panel III criteria were present: impaired fasting glucose, hypertension, abdominal obesity, reduced HDL cholesterol, and hypertriglyceridemia. Subgroup analysis was performed for patients with a painful predominantly sensory CIAP, because this phenotype is most similar to diabetic polyneuropathy. Statistical analysis was performed with adjustment for age and gender. RESULTS Fifty-five percent of all patients fulfilled the metabolic syndrome criteria compared with 34% of controls (odds ratio 2.2 [95% CI 1.7–3.0]). Multivariate analysis shows hypertension (2.9 [1.7–4.9]) and abdominal obesity (3.3 [2.4–4.6]) to be significantly more prevalent in patients than in controls. Of the patients classified as having a painful predominantly sensory CIAP, 62% fulfilled the metabolic syndrome criteria (3.1 [2.0–4.8]). In this subgroup, hypertension and abdominal obesity also were significantly more prevalent compared with controls. CONCLUSIONS Abdominal obesity and hypertension seem to be the most consistent contributing components of the metabolic syndrome in patients with CIAP. Evaluation and appropriate treatment of these risk factors in patients with CIAP would be advocated.

Rapid worsening of IgM anti-MAG demyelinating polyneuropathy during rituximab treatment

Dear Editor, There are no proven treatments for polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (anti-MAG) antibodies (Lunn and Nobile-Orazio, 2012). Two recent randomized trials (RCTs) comparing rituximab to placebo failed to demonstrate improvement on the primary endpoints (Dalakas et al., 2009; Leger et al., 2011). In these trials, treatment with rituximab was safe and well tolerated. The total published experience with rituximab in anti-MAG polyneuropathy encompasses fewer than 100 patients (Renaud et al., 2003; RojasGarcia et al., 2003; Niermeijer et al., 2009). Because rituximab is at best effective only in a small subgroup of patients, even fairly rare side effects would be relevant to the decision to prescribe it for antiMAG neuropathy. Some side effects could have been missed because of the low numbers of patients in published series. We report three patients with IgM monoclonal gammopathy-associated polyneuropathy and anti-MAG antibodies who rapidly worsened within weeks after the start of rituximab treatment. One patient presented with mild weakness of the dorsiflexors of foot and toes (Medical Research Council [MRC] grade 4), glove and sock-patterned hypoesthesia, and sensory ataxia, which had developed slowly over the previous 2 years. His anti-MAG titer before treatment was 7,180 BTU (Buehlmann Titer Units, normal values below 2,000 BTU), total serum IgM was 13 g/l, and the M protein was 9 g/l. Nerve conduction studies showed demyelination in nerves of both arms and legs, distally more than proximally, as well as axonal loss, more pronounced in the nerves of the legs than in those of the arms (Table 1). After the second of a planned four weekly rituximab infusions (375 mg/m2), he developed proximal weakness and severe progression of the distal weakness in the legs

Increase of sural nerve T cells in progressive axonal polyneuropathy and monoclonal gammopathy

The authors investigated whether T cells have a role in the pathogenesis of axonal polyneuropathy and monoclonal gammopathy by comparing the presence of T cells in sural nerves of 23 patients with axonal polyneuropathy and monoclonal gammopathy (12 IgM, 11 IgG), of 15 patients with chronic idiopathic axonal polyneuropathy, and of 10 autopsy cases. Seven patients with an increased T-cell density had a progressive disease course, and four of these patients were treated with prednisone with a good response, suggesting that vasculitis plays a role in the pathogenesis.

Chapter 26 - Vasculitic neuropathy

Vasculitis is a primary phenomenon in autoimmune diseases such as polyarteritis nodosa, Wegeners 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.