Phase 2 trial in acetylcholine receptor antibody-positive myasthenia gravis of transition from intravenous to subcutaneous immunoglobulin: The MGSCIg study.

BACKGROUND AND PURPOSE: Data on maintenance therapy with subcutaneous immunoglobulin (SCIg) in myasthenia gravis (MG) are limited. We report on transitioning acetylcholine receptor (AChR) antibody-positive (Ab+) MG patients on stable intravenous immunoglobulin (IVIg) regimens as part of routine clinical care to SCIg 1:1.2. METHODS: This multicenter North American open-label prospective investigator-initiated study had two components: the IVIg Stabilization Period (ISP) enrolling patients already on IVIg as part of routine clinical care (Weeks -10 to -1), followed by transition of stable MG subjects to SCIg in the Experimental Treatment Period (ETP; Weeks 0 to 12). We hypothesized that >65% of patients entering the ETP would have a stable Quantitative Myasthenia Gravis (QMG) score from Week 0 to Week 12. Secondary outcome measures included other efficacy measures, safety, tolerability, IgG levels, and treatment satisfaction. RESULTS: We recruited 23 patients in the ISP, and 22 entered the ETP. A total of 12 subjects (54.5%) were female, and 18 (81.8%) were White, with mean age 51.4 ± 17 years. We obtained Week 12 ETP QMG data on 19 of 22; one subject withdrew from ETP owing to clinical deterioration, and two subjects withdrew due to dislike of needles. On primary analysis, 19 of 22 participants (86.4%, 95% confidence interval = 0.72-1.00) were treatment successes using last observation carried forward (p = 0.018). Secondary efficacy measures supported MG stability. SCIg was safe and well tolerated, and IgG levels were stable. Treatment satisfaction was comparable between ISP and ETP. CONCLUSIONS: MG patients on IVIg as part of their routine clinical care remained stable on monthly IVIg dosage, and most maintained similar disease stability on SCIg.

Cryptogenic small-fiber neuropathies: Serum autoantibody binding to trisulfated heparan disaccharide and fibroblast growth factor receptor-3.

INTRODUCTION: Causes of small-fiber peripheral neuropathies (SFN) are often undefined. In this study we investigated associations of serum autoantibodies, immunoglobulin G (IgG) vs fibroblast growth factor receptor-3 (FGFR-3), and immunoglobulin M (IgM) vs trisulfated heparan disaccharide (TS-HDS) in cryptogenic SFN. METHODS: One hundred fifty-five patients with biopsy-proven SFN and no identified cause for their neuropathy were blindly tested for serum IgM vs TS-HDS and IgG vs FGFR-3. RESULTS: Forty-eight percent of SFN patients had serum antibodies, 37% with IgM vs TS-HDS and 15% with IgG vs FGFR-3. TS-HDS antibodies were more frequent in SFN patients than in controls (P = .0012). Both antibodies were more common in females, and with non-length-dependent nerve pathology. Nintey-two percent of patients with acute-onset SFN had serum IgM vs TS-HDS. DISCUSSION: Autoantibodies directed against TS-HDS and FGFR-3 suggest an immune disorder in otherwise idiopathic SFN. Serum IgM vs TS-HDS may be a marker for SFN with an acute onset.

Usefulness of skin biopsies in the evaluation and management of patients with suspected small fiber neuropathy.

OBJECTIVE: To assess the usefulness of skin biopsy in the assessment of patients with suspeted small fiber neuropathy (SFN). METHODS: Retrospective chart review of patients with sensory symptoms or findings restricted to small nerve fibers and normal nerve conduction studies (NCS) seen in a subspecialty neuromuscular private practice. RESULTS: Assessments were made on 145 patients. Skin biopsy was abnormal in at least one site in 86 patients (59%). There was no significant difference between patients with normal or abnormal skin biopsies with respect to age, gender, or duration of symptoms. Compared to patients with normal skin biopsies, patients with confirmed SFN were significantly more likely to have pain and were more than twice as likely to respond to standard neuropathic pain medications. CONCLUSIONS: Skin biopsy is useful in the diagnosis and management of patients with otherwise unexplained sensory symptoms or findings.

Diagnosis of mast cell activation syndrome: a global "consensus-2".

The concept that disease rooted principally in chronic aberrant constitutive and reactive activation of mast cells (MCs), without the gross MC neoplasia in mastocytosis, first emerged in the 1980s, but only in the last decade has recognition of "mast cell activation syndrome" (MCAS) grown significantly. Two principal proposals for diagnostic criteria have emerged. One, originally published in 2012, is labeled by its authors as a "consensus" (re-termed here as "consensus-1"). Another sizable contingent of investigators and practitioners favor a different approach (originally published in 2011, newly termed here as "consensus-2"), resembling "consensus-1" in some respects but differing in others, leading to substantial differences between these proposals in the numbers of patients qualifying for diagnosis (and thus treatment). Overdiagnosis by "consensus-2" criteria has potential to be problematic, but underdiagnosis by "consensus-1" criteria seems the far larger problem given (1) increasing appreciation that MCAS is prevalent (up to 17% of the general population), and (2) most MCAS patients, regardless of illness duration prior to diagnosis, can eventually identify treatment yielding sustained improvement. We analyze these proposals (and others) and suggest that, until careful research provides more definitive answers, diagnosis by either proposal is valid, reasonable, and helpful.

Small Fiber Neuropathy.

Small fiber neuropathy has a broad array of presentations. Length-dependent symptoms and findings present little diagnostic difficulty, but non-length-dependent or multifocal symptoms can be challenging. Intraepidermal nerve fiber density (IENFD) testing in apparent fibromyalgia warrants further study, but skin biopsy testing of this patient population is reasonable. Avoidance of IENFD testing in situations where diagnosis of neuropathy is already clear or where neuropathy is not the cause of symptoms helps to prevent incorrect conclusions. Careful history and physical examination plus pretest probability are important factors to consider when assessing the results of an IENFD test report.

Review process for IVIg treatment: Lessons learned from INSIGHTS neuropathy study.

BACKGROUND: This project is an effort to understand how orders for IV immunoglobulin (IVIg) are documented and prescribed by physicians, and subsequently, how they are reviewed by insurance companies for the treatment of immune neuropathies. METHODS: A panel of neuromuscular specialists reviewed case records from 248 IVIg-naive patients whose in-home IVIg infusion treatment was submitted to insurance for authorization. After reviewing a case record, 1 panelist was asked to make a diagnosis and to answer several questions about the treatment. A second panelist reviewed the original record and follow-up records that were obtained for reauthorization of additional treatments and was asked to determine whether the patient had responded to the treatment. RESULTS: Our specialists believed that only 32.2% of 248 patients had an immune neuropathy and were appropriate candidates for IVIg therapy, whereas 46.4% had neuropathies that were not immune mediated. Only 15.3% of cases met electrodiagnostic criteria for a demyelinating neuropathy. Our specialists believed that 36.7% of 128 cases with follow-up records had responded to therapy. In cases in which the initial reviewer had predicted that there would be a response to IVIg, the second reviewer found that 54% had responded. This is compared with a 27% response rate when the first reviewer predicted that there would be no response (p = 0.019). CONCLUSIONS: Our expert review finds that the diagnosis of immune neuropathies made by providers, and subsequently approved for IVIg therapy by payers, is incorrect in a large percentage of cases. If payers include an expert in their review process, it would improve patient selection, appropriate use, and continuation of treatment with this expensive therapeutic agent.

Phase I clinical trial of safety of L-serine for ALS patients.

We performed a randomized, double-blind phase I clinical trial for six months on the effects of oral L-serine in patients with ALS. The protocol called for enrollment of patients with a diagnosis of probable or definite ALS, age 18-85 years, disease duration of less than three years and forced vital capacity (FVC) ≥ 60%. Patients were randomly assigned to four different oral twice-daily dose regimens (0.5, 2.5, 7.5, or 15 g/dose). Blood, urine and CSF samples, ALS Functional Rating Scale-Revised (ALSFRS-R) scores and forced vital capacity (FVC) were obtained throughout the trial. Disease progression was compared with matched historical placebo controls from five previous ALS therapeutic trials. Of 20 patients enrolled, one withdrew before receiving study drug and two withdrew with gastro-intestinal problems. Three patients died during the trial. L-serine was generally well tolerated by the patients and L-serine did not appear to accelerate functional decline of patients as measured by slope of their ALSFRS-R scores. Based on this small study, L-serine appears to be generally safe for patients with ALS.

Progressive Muscular Atrophy.

Progressive muscular atrophy (PMA) is a rare, sporadic, adult-onset motor neuron disease, clinically characterized by isolated lower motor neuron features; however, clinically evident upper motor neuron signs may emerge in some patients. Subclinical upper motor neuron involvement is identified pathologically, radiologically, and neurophysiologically in a substantial number of patients with PMA. Patients with subclinical upper motor neuron involvement do not fulfill the revised El Escorial criteria to participate in amyotrophic lateral sclerosis clinical trials. Intravenous immunoglobulin therapy is only marginally beneficial in a small subgroup of patients with lower motor neuron syndrome without conduction block.

Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients.

Fibromyalgia is a clinical syndrome that currently does not have any specific pathological finding to aid in diagnosis. Therefore, fibromyalgia is most likely a heterogeneous group of diseases with similar symptoms. Identifying and understanding the pathological basis of fibromyalgia will allow physicians to better categorize patients, increasing prospective treatment options, and improving potential therapeutic endeavors. Recent work has demonstrated that approximately 50% of patients diagnosed with fibromyalgia have damage to their small unmyelinated nerve fibers. A skin punch biopsy is a sensitive and specific diagnostic test for this damage as a reduction in nerve fiber density allows for the diagnosis of small fiber neuropathy. Small fiber neuropathy is a disease with symptoms similar to fibromyalgia, but it often has a definable etiology. Identifying small fiber neuropathy and its underlying cause in fibromyalgia patients provides them with a succinct diagnosis, increases treatment options, and facilitates more specific studies for future therapeutics.

Challenges in the identification of cobalamin-deficiency polyneuropathy.

BACKGROUND: Diagnosing cobalamin (Cbl) deficiency as a cause of polyneuropathy (PN) is problematic, as the frequency of both disorders increases with age, and serum Cbl levels can be difficult to interpret. OBJECTIVES: To identify unique clinical or laboratory features among PN patients with Cbl deficiency and to examine the role of testing of serum metabolite levels in the identification of Cbl deficiency. DESIGN: Cohort survey comparing patients with Cbl deficiency and cryptogenic PN identified during a 2-year period. Cobalamin deficiency was diagnosed using low serum Cbl levels or elevated serum methylmalonic acid or homocysteine levels. SETTING: Academic neuromuscular clinic. RESULTS: Of 324 PN patients, 27 were diagnosed as having Cbl deficiency. Twelve had Cbl levels within the normal range, but elevated serum metabolite levels. Compared with patients with cryptogenic sensory/sensorimotor PN, those with Cbl deficiency were more likely to have concomitant involvement of the upper and lower extremities and experience symptom onset in the hands and a sudden onset of symptoms (P<.005). These differences were seen regardless of whether Cbl deficiency was defined using low Cbl levels or elevated serum metabolite levels. Autoimmune pernicious anemia was identified in 6 (50%) of 12 Cbl-deficient patients with normal serum Cbl levels. The patients with PN and Cbl deficiency showed little objective improvement after parenteral replacement therapy; however, progression occurred less often in these patients compared with those with cryptogenic sensory/sensorimotor PN (P =.02). CONCLUSIONS: This study highlights the challenges of proving that Cbl deficiency is the cause for PN and identifies clinical features that suggest Cbl-deficiency PN. Testing of serum metabolite levels may identify Cbl deficiency in some patients with normal serum Cbl levels.

Acquired immune demyelinating neuropathies.

PURPOSE OF REVIEW: Acquired immune demyelinating neuropathies refer to a group of disorders that share overlapping sensory, motor, and autonomic clinical, laboratory, and electrodiagnostic features. It is important to recognize acquired immune demyelinating neuropathies as they are generally responsive to immunosuppressive or immunomodulatory therapies. RECENT FINDINGS: This article reviews recently developed early prognostic tools in Guillain-Barré syndrome and discusses the evolving understanding of chronic demyelinating phenotypes with differing treatment responsiveness. SUMMARY: While weakness and numbness progress over 2 to 4 weeks in Guillain-Barré syndrome, they continue to evolve beyond 8 weeks in chronic inflammatory demyelinating polyradiculoneuropathy and over 4 to 8 weeks in subacute inflammatory demyelinating polyradiculoneuropathy. Acquired immune demyelinating neuropathies present uncommonly as variants with predominance of ocular, bulbar, sensory, autonomic, or motor manifestations in addition to regional variants, such as paraparetic acquired immune demyelinating neuropathies. Establishing the correct diagnosis is important as these immune disorders differ in response to corticosteroids and other immunosuppressive therapies.

Laboratory evaluation of peripheral neuropathy.

The question of how to evaluate peripheral neuropathies is complicated by there being hundreds of potential causes, both acquired and inherited. This article focuses on a targeted and thoughtful approach to the laboratory evaluation of patients with peripheral neuropathy, designed to allow the identification of treatable neuropathies without undue expense and risk to patients. After determining which clinical patterns are present, the patterns are used to define a discrete manageable subset of diseases underlying these neuropathies. Thinking in terms of such patterns is often more helpful than relying on electrodiagnostic studies, leading to a more accurate, cost-effective laboratory evaluation.

A Pilot Trial of Pioglitazone HCl and Tretinoin in ALS: Cerebrospinal Fluid Biomarkers to Monitor Drug Efficacy and Predict Rate of Disease Progression.

Objectives. To determine if therapy with pioglitazone HCl and tretinoin could slow disease progression in patients with ALS. Levels of tau and pNFH in the cerebrospinal fluid were measured to see if they could serve as prognostic indicators. Methods. 27 subjects on stable doses of riluzole were enrolled. Subjects were randomized to receive pioglitazone 30 mg/d and tretinoin 10 mg/BID for six months or two matching placebos. ALSFRS-R scores were followed monthly. At baseline and at the final visit, lumbar punctures (LPs) were performed to measure cerebrospinal fluid (CSF) biomarker levels. Results. Subjects treated with tretinoin, pioglitazone, and riluzole had an average rate of decline on the ALSFRS-R scale of -1.02 points per month; subjects treated with placebo and riluzole had a rate of decline of -.86 (P = .18). Over six months of therapy, CSF tau levels decreased in subjects randomized to active treatment and increased in subjects on placebo. Further higher levels of pNF-H at baseline correlated with a faster rate of progression. Conclusion. ALS patients who were treated with tretinoin and pioglitazone demonstrated no slowing on their disease progression. Interestingly, the rate of disease progression was strongly correlated with levels of pNFH in the CSF at baseline.

Isolated neck extensor myopathy: is it responsive to immunotherapy?

OBJECTIVE: To determine if isolated neck extensor myopathy (INEM) is responsive to immunosuppressive treatment. METHODS: We retrospectively reviewed charts of patients with INEM from 2002 to 2008 to identify patients and determine the response to immunomodulatory therapy. Clinical, electrodiagnostic, histologic, and radiographic data were reviewed. RESULTS: Four patients were identified during the study period. Three were women. The age of onset of neck extensor weakness ranged from 58 to 78 years. Serum creatine kinase levels were within normal limits in all patients. None had clinical, laboratory, or electrophysiological findings to suggest a generalized neuromuscular disorder. On electrodiagnostic studies, all patients had myopathic changes with or without irritative features in cervical paraspinal muscles. No inflammation was present on muscle biopsy from three of the patients. All patients received one or more immunosuppressive agents. Neck strength improved by 1 point or greater on the Medical Research Council scale in all subjects with a peak response observed between 3 and 6 months after treatment initiation. CONCLUSIONS: A trial of immunosuppressive agents should be offered to patients with INEM because a subset will improve. Rigorously defined, INEM is a noninflammatory myopathy. However, a focal myositis could be missed on muscle biopsy and may explain the favorable response to treatment.

Chronic acquired demyelinating polyneuropathies.

Several entities can be put under the heading of chronic acquired demyelinating polyneuropathy. Future research will hopefully provide a greater understanding of pathophysiology, which may suggest the ideal way to classify and manage these patients. In the meantime, it is reasonable and useful to use clinical, laboratory, and electrodiagnostic data to classify patients in ways that facilitate identification and treatment. This article outlines an approach to the diagnosis and management of chronic acquired demyelinating polyneuropathies.

Muscle channelopathies.

In recent years the term CHANNELOPATHY has been adopted to describe neurological disorders caused by mutations in different ion channel genes. Myopathic channelopathies include two main groups: nondystrophic myotonias and periodic paralyses. This article reviews the clinical features, diagnostic approach, molecular causes, and management of patients with nondystrophic myotonias and periodic paralyses.

Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis.

Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.

Asymmetric Acquired Demyelinating Polyneuropathies: MMN and MADSAM.

More than a half a century after Austin's initial description of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the clinical spectrum of chronic acquired demyelinating polyneuropathies has expanded. Currently there are a number of entities that can be put under the heading of chronic acquired demyelinating neuropathy (CADP) based on differing clinical presentations. In this scheme, CIDP is used only to refer to patients with demyelinating neuropathies and generalized symmetric weakness. In contrast, multifocal motor neuropathy (MMN) and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) fall into the category of asymmetrical, multifocal forms of CADP. These are distinguished from each other only by the presence of sensory involvement. In our opinion, there are pragmatic reasons for splitting these clinical presentations into distinct entities. Although each of these clinical subtypes shares some basic similarities, there are important differences. MMN is usually considered resistant to corticosteroid therapy and the first line agent in this disorder is intravenous immunoglobulin (IVIg). MADSAM neuropathy can be responsive to prednisone or IVIg, and has a profile more analogous to classic CIDP with regards to its laboratory features and treatment response.

Peripheral Neuropathy Due to Cobalamin Deficiency.

Vitamin B12, or cobalamin (Cbl), deficiency can produce a number of neurologic complications, including myelopathy, peripheral neuropathy, optic neuropathy, and dementia. The myelopathy, combined systems disease, is probably the most well known manifestation, and is usually readily recognized. The frequency with which peripheral neuropathy is the sole presenting feature of Cbl deficiency is a point of controversy. The prevalence and the clinical and electrophysiologic features of Cbl deficiency peripheral neuropathy have not been well characterized. In addition, there is evidence that the commonly used assays of serum Cbl are not adequately sensitive. Testing the serum metabolites methylmalonic acid and homocysteine can increase the identification of Cbl deficient patients. Treatment with parenteral Cbl injections may not produce improvement of neurologic deficits, but might prevent worsening. In some patients with Cbl deficiency, oral Cbl may be an effective therapy.

Management of myasthenia gravis.

Although once a severe and often fatal illness, myasthenia gravis can now be well managed with several relatively safe and effective therapies. Management involves a graded approach, beginning with cholinesterase inhibitors for mild symptoms and advancing to immunomodulating medications for more severe weakness. There are several immunomodulating agents from which to choose; selection is based largely on time to clinical effect and adverse effects. This review will discuss the selection and use of therapies for patients with myasthenia gravis.