Updated consensus statement: Intravenous immunoglobulin in the treatment of neuromuscular disorders report of the AANEM ad hoc committee.

Intravenous immune globulin (IVIG) is an immune-modulating biologic therapy that is increasingly being used in neuromuscular disorders despite the paucity of high-quality evidence for various specific diseases. To address this, the AANEM created the 2009 consensus statement to provide guidance on the use of IVIG in neuromuscular disorders. Since then, there have been several randomized controlled trials for IVIG, a new FDA-approved indication for dermatomyositis and a revised classification system for myositis, prompting the AANEM to convene an ad hoc panel to update the existing guidelines.New recommendations based on an updated systemic review of the literature were categorized as Class I-IV. Based on Class I evidence, IVIG is recommended in the treatment of chronic inflammatory demyelinating polyneuropathy, Guillain-Barré Syndrome (GBS) in adults, multifocal motor neuropathy, dermatomyositis, stiff-person syndrome and myasthenia gravis exacerbations but not stable disease. Based on Class II evidence, IVIG is also recommended for Lambert-Eaton myasthenic syndrome and pediatric GBS. In contrast, based on Class I evidence, IVIG is not recommended for inclusion body myositis, post-polio syndrome, IgM paraproteinemic neuropathy and small fiber neuropathy that is idiopathic or associated with tri-sulfated heparin disaccharide or fibroblast growth factor receptor-3 autoantibodies. Although only Class IV evidence exists for IVIG use in necrotizing autoimmune myopathy, it should be considered for anti-hydroxy-3-methyl-glutaryl-coenzyme A reductase myositis given the risk of long-term disability. Insufficient evidence exists for the use of IVIG in Miller-Fisher syndrome, IgG and IgA paraproteinemic neuropathy, autonomic neuropathy, chronic autoimmune neuropathy, polymyositis, idiopathic brachial plexopathy and diabetic lumbosacral radiculoplexopathy.

The distribution of acquired peripheral nerve injuries associated with severe COVID-19 implicate a mechanism of entrapment neuropathy: a multicenter case series and clinical feasibility study of a wearable, wireless pressure sensor.

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting.

Combination rituximab and intravenous immunoglobulin for treatment of refractory vasculitic neuropathy: a case series.

OBJECTIVE: Limited evidence exists to guide treatment of refractory vasculitic neuropathy. While rituximab (RTX) and IVIG have both been proposed as individual treatment options for these patients, combination therapy has never been reported. METHODS: Written informed consent was obtained from three patients with refractory vasculitic neuropathy who were treated with combination RTX and IVIG. Their electronic medical records were reviewed and clinical and functional outcomes were reported. RESULTS: Two male patients with non-systemic vasculitic neuropathy and one male patient with granulomatosis with polyangiitis were treated with combination RTX and IVIG therapy. All three patients demonstrated clinical improvement with at least partial functional recovery and a reduction in corticosteroid dose. This combination was generally well tolerated. CONCLUSIONS: Combination RTX and IVIG therapy may be a safe and effective treatment option for patients with refractory vasculitic neuropathy. Further studies are needed to better characterize the risks and benefits of this combination.

Differentiation between neurosarcoidosis and primary central nervous system vasculitis based on demographic, cerebrospinal and imaging features.

OBJECTIVES: Neurosarcoidosis (NS) and primary angiitis of central nervous system (PACNS) are inflammatory diseases affecting central nervous system, with overlapping clinical and pathological characteristics. Distinguishing these diseases is important given distinct therapeutic implications. In this study, we aimed to compare demographic, CSF and MRI characteristics between these two conditions. METHODS: All the clinical, CSF and laboratory characteristics at the time of presentation were retrieved from electronic medical records. Brain and/or spinal cord MRI performed near the time of presentation were blindly evaluated by two neuroradiologists. Data regarding involvement of pachy- and leptomeninges, basal meninges, cranial nerves, cerebral grey and white matter, and spinal cord were recorded for each patient. RESULTS: 78 patients with PACNS and 25 patients with NS were included in the study. Mean age of patients was 43.7 (±16.7) and 43.6 (±12.5) in PACNS and NS, respectively. African-American race was found to be associated with the diagnosis of NS rather than PACNS. Patients with PACNS had higher frequency of cerebral involvement, while patients with NS demonstrated more frequent spinal cord, basal meningeal and cranial nerve involvements. CONCLUSIONS: These findings suggest that MRI can be an efficient tool in distinguishing PACNS from NS. A follow-up study with a larger sample size would be required to validate our results.

Nonorgan manifestations of sarcoidosis.

PURPOSE OF REVIEW: The current review discusses the diagnosis and management of nonorgan-related symptoms that commonly arise in the setting of systemic sarcoidosis. Fatigue, small fiber neuropathy (SFN) and neuropsychological symptoms are highlighted. RECENT FINDINGS: The debilitating effects of chronic nonorgan-based symptoms in sarcoidosis have led to recent studies focusing on incidence rates, contributing factors and potential therapeutic strategies. In a web-based survey of over 1000 sarcoidosis patients, the most common symptom was fatigue, which was reported by over 90% of participants, whereas memory loss and concentration problems were reported in 50%. SFN was also common, and may be diagnosed with tools such as skin biopsy measurement of intraepidermal nerve fibers and corneal confocal microscopy. In a recent cohort study of SFN patients, serologic evaluation demonstrated other contributing causes such as diabetes and vitamin B12 deficiency, which warrant-specific treatment. Finally, physical inactivity in patients with sarcoidosis correlated with lower quality-of-life (QOL) scores and possibly fatigue. Multidisciplinary programs that include physical therapy, patient education and psychological support were found to improve fatigue and mood disorders. SUMMARY: Recognition of nonorgan-related symptoms and their impact on patient QOL is essential to optimal treatment of the sarcoidosis patient.

Sural sensory nerve action potential, epidermal nerve fiber density, and quantitative sudomotor axon reflex in the healthy elderly.

INTRODUCTION: Polyneuropathy evaluation in older patients is often challenging due to conflicting data regarding normative values for peripheral nerve testing. METHODS: We characterized the results of sural nerve conduction studies, intraepidermal nerve fiber density (IENFD), and quantitative sudomotor axon reflex testing (QSART) in a prospective study of 50 healthy subjects aged ≥60 years. RESULTS: Of the 50 subjects, 48 (96%) had an obtainable sural sensory nerve action potential (SNAP). Using quantile regression, we estimated the lower limit of normal (LLN) for sural amplitudes to be 3 µV for patients 60-70 years, 1 µV for those 70-74 years, and <1 µV (absent) for those ≥75 years of age. IENFD and QSART volume were reduced with advancing age, although IENFD was lower in men and QSART volume was lower in women. CONCLUSIONS: We propose that an absent sural SNAP in patients up to 75 years of age should be considered abnormal. Our findings also support age- and gender-stratified normative data for IENFD and QSART.

Peripheral neuropathy in sarcoidosis.

Peripheral nerve disorders in sarcoidosis consist of granulomatous neuropathy and non-granulomatous small fiber neuropathy (SFN), which differ in their underlying pathology, diagnostic methods and treatment. While granulomatous nerve involvement is rare in sarcoidosis, SFN is reported in over 40% of systemic cases. Distal symmetric polyneuropathy and asymmetric polyradiculoneuropathy are the most common presentations of granulomatous neuropathy, which typically responds to corticosteroids. In contrast, SFN is often manifested as non-length dependent pain and paresthesias that may improve with intravenous immune globulin or infliximab. Early recognition and treatment of sarcoidosis neuropathy can lead to improved outcomes and patient quality of life.

Sarcoidosis and small-fiber neuropathy.

Chronic pain is one of the most commonly reported symptoms among sarcoidosis patients. Not only does it significantly affect quality of life, but it also is a source of frustration for both the patient and physician because the etiology for pain often is unknown. Although patients typically complain of neuropathic-type pain, nerve conduction studies and other conventional diagnostic procedures frequently fail to reveal objective evidence of neurologic disease. However, in recent years, the growing use of specialized tests such as skin biopsy and sudomotor testing has helped to establish the diagnosis of small-fiber neuropathy as the cause of pain in these patients via objective and quantifiable means. Management of sarcoidosis small-fiber neuropathy should consist of target-directed treatment of the underlying disease and appropriate symptomatic therapy.

Health-Related Quality of Life (HRQoL) in Sarcoidosis: Diagnosis, Management, and Health Outcomes.

Health-related quality of life (HRQoL), though rarely considered as a primary endpoint in clinical trials, may be the single outcome reflective of patient priorities when living with a health condition. HRQoL is a multi-dimensional concept that reflects the degree to which a health condition interferes with participation in and fulfillment of important life areas. HRQoL is intended to capture the composite degree of physical, physiologic, psychological, and social impairment resulting from symptom burden, patient-perceived disease severity, and treatment side effects. Diminished HRQoL expectedly correlates to worsening disability and death; but interventions addressing HRQoL are linked to increased survival. Sarcoidosis, being a multi-organ system disease, is associated with a diffuse array of manifestations resulting in multiple symptoms, complications, and medication-related side effects that are linked to reduced HRQoL. Diminished HRQoL in sarcoidosis is related to decreased physical function, pain, significant loss of income, absence from work, and strain on personal relationships. Symptom distress can result clearly from a sarcoidosis manifestation (e.g., ocular pain, breathlessness, cough) but may also be non-specific, such as pain or fatigue. More complex, a single non-specific symptom, e.g., fatigue may be directly sarcoidosis-derived (e.g., inflammatory state, neurologic, hormonal, cardiopulmonary), medication-related (e.g., anemia, sleeplessness, weight gain, sub-clinical infection), or an indirect complication (e.g., sleep apnea, physical deconditioning, depression). Identifying and distinguishing underlying causes of impaired HRQoL provides opportunity for treatment strategies that can greatly impact a patient's function, well-being, and disease outcomes. Herein, we present a reference manual that describes the current state of knowledge in sarcoidosis-related HRQoL and distinguish between diverse causes of symptom distress and other influences on sarcoidosis-related HRQoL. We provide tools to assess, investigate, and diagnose compromised HRQoL and its influencers. Strategies to address modifiable HRQoL factors through palliation of symptoms and methods to improve the sarcoidosis health profile are outlined; as well as a proposed research agenda in sarcoidosis-related HRQoL.

Hematopoietic stem cell transplantation for chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: Determine toxicity and efficacy of autologous hematopoietic stem cell transplantation (HSCT) for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are dependent on intravenous immunoglobulins or plasmapheresis. METHODS: Unselected peripheral blood stem cells were re-infused on day 0 after conditioning with cyclophosphamide 200 mg/kg/intravenously (IV), rATG (thymoglobulin) 5.5 mg/kg/IV, and rituximab 1000 mg/IV. RESULTS: Sixty-six patients underwent HSCT for CIDP. Data on sixty patients with a mean follow-up of 4.5 years (range 2-5 years) were available for analysis. There were no treatment-related deaths, and overall survival was 97%. Post-transplant immune medication-free remission was 80%, 78%, 76% 78%, and 83% at 1, 2, 3, 4, and 5 years. Ambulation without assistance improved from 33% pre-HSCT to 82% 82%, 81%, 86%, and 83% at 1, 2, 3, 4, and 5 years, respectively. Mean right/left hand grip strength (kg) improved significantly (all p values < 0.01) from 18.1/16.5 pre-HSCT to 26.3/25.4, 29.2/28.2, 28.8/28.6, 30.3/25.5, and 30.8/29.1 at 1, 2, 3, 4, and 5 years, respectively. Average nerve conduction velocity (NCV) (m/s) improved significantly (all p values ≤ 0.001) from a mean of 27.2 pre-HSCT to 33.5, 33.8, 37.7, 38.2, and 38.3 at 1, 2, 3, 4, and 5 years, respectively. Average compound motor action potential (CMAP) (mv) improved significantly (p values ≤ 0.001) from a mean of 3.6 pre-HSCT to 4.6, 4.6, 5.0, 5.1, and 4.1 at 1, 2, 3, 4, and 5 years, respectively. CONCLUSION: A randomized trial is indicated to verify these results and confirm that HSCT reverses disability and offers long-term immune therapy independence.

Nerve conduction studies: Basic concepts.

Nerve conduction studies (NCSs) are an essential tool in the evaluation of the peripheral nervous system. The sensory nerve action potential (SNAP) provides information on the sensory nerve axon and its pathway from the distal receptors in the skin to the dorsal root ganglia, while the compound muscle action potential (CMAP) is an assessment of the motor nerve fibers from their origins in the anterior horn cell to their termination along muscle fibers. Various parameters of the SNAP and CMAP waveforms are used to determine the number of functioning nerve fibers and the speed of conduction. Similarly, specific electrodiagnostic patterns involving SNAP and CMAP amplitudes, latencies and other measurements can help discern the underlying nerve pathophysiology as either axon loss or demyelinating in nature. Numerous technical and environmental factors can affect the NCS and should be recognized and corrected if possible. Finally, while basic NCSs are a noninvasive and low-risk procedure, safety issues for patients with implanted electrical devices should be considered.

Electrodiagnosis of radiculopathy.

While nerve conduction studies are an important part of the electrodiagnostic examination (EDX), the diagnosis of a radiculopathy rests mainly on the needle electrode examination (NEE) findings. Myotomal spontaneous activity and neurogenic motor unit potential (MUP) changes are the key abnormalities seen. To optimize the rate of identifying a radiculopathy, selection of appropriate muscles for the NEE is paramount. Myotomal charts derived from anatomic, radiographic, and EDX studies may help guide development of the NEE protocol for radiculopathy and increase the diagnostic yield. As recommended by a number of studies, the suggested minimum NEE protocol should consist of at least five proximal and distal limb muscles. NEE of paraspinal muscles should also be included routinely, but several limitations preclude reliance on isolated findings for establishing a diagnosis of radiculopathy. In addition to the NEE, the preservation of sensory nerve action potentials is also important in localizing the lesion to the nerve root. In some cases, they may be absent due to age or technical factors, confounding the diagnosis. Finally, various patterns of EDX findings may be seen in specific nerve root disorders that can help expedite diagnosis and clinical management.

Severe postictal laryngospasm as a potential mechanism for sudden unexpected death in epilepsy: a near-miss in an EMU.

A 42-year-old man with refractory epilepsy experienced a 1-min generalized tonic-clonic seizure followed by persistent inspiratory stridor and cyanosis while being monitored in our epilepsy monitoring unit (EMU). Although his cardiac parameters remained stable throughout the event, the patient's respiratory status rapidly declined, despite the urgent administration of oxygen via bag-valve-mask. He was subsequently intubated by the emergency code team, who noted severe laryngospasm while trying to insert the endotracheal tube. The patient was successfully resuscitated. This monitored case demonstrates that postictal laryngospasm may represent another potential cause of sudden unexpected death in epilepsy (SUDEP).

Vasospasm and stroke attributable to ephedra-free xenadrine: case report.

Following the 2004 ban of ephedra, which was linked to several cases of stroke and myocardial infarction, manufacturers have marketed "ephedra-free" weight loss products that include the active ingredient synephrine. Despite the lack of data on safety and efficacy, synephrine is touted by its promoters as a "safe" alternative to ephedra and is often combined with caffeine, as in the supplement Xenadrine-EFX. We report a case of left middle cerebral artery vasopasm and stroke in a young healthy patient in the setting of Xenadrine-EFX use.

Office approach to small fiber neuropathy.

Small fiber neuropathy is often characterized by neuropathic pain in the feet with normal nerve conduction studies and neurologic examination. Diagnosis requires specialized nerve tests, including autonomic studies and a skin biopsy study showing reduced intraepidermal nerve fiber density. Small fiber neuropathy has numerous causes but is often idiopathic. A practical approach to identifying an underlying cause is to first screen for common ones and then proceed with further testing as needed. Treatment consists of correcting the underlying cause, managing pain, and modifying lifestyle.

Intra cranial granulomatous disease in common variable immunodeficiency: Case series and review of the literature.

BACKGROUND/PURPOSE: Common variable immunodeficiency (CVID) is typically characterized by hypogammaglobulinemia and often but not always recurrent infections. Paradoxically, 8-22% of patients with CVID develop granulomatous disease. Granulomata have been described in many organs including the lungs, skin, liver, spleen, kidneys, eyes, lymph nodes, and intestines. Data about central nervous system (CNS) involvement in CVID are extremely rare. We aim to describe a case series and include an extensive literature review of CNS involvement in CVID to understand the different features and patterns of the disease. METHODS: We searched the English Pubmed database for relevant articles between 1950 and 2014 using the Key Words "common variable immunodeficiency", "granulomatous disease", "brain", "sarcoidosis", and "sarcoid-like syndrome". Data from all case series, surveys, systematic reviews, and individual case reports, as well as retrospective studies were extracted. A total of 15 patients were reported in the literature. We combined our experience with four additional patients from The Cleveland Clinic between 2009 and 2014. Demographics, clinical features, laboratory and imaging findings, treatment and follow-up were extracted for the 19 patients and summarized descriptively. RESULTS: Female sex and Caucasian race represented 63.2% (12/19), and 80% of the patients, respectively. The mean age of CVID diagnosis was 24 years; mean age when the CNS disease was diagnosed was 21.5 years. 68.4% of the patients (13/19) had granulomas involving ≥2 organs including the central nervous system, 31.6% (6/19) had CNS granulomas only. Associated granulomatous diseases occurred in lungs (72.7%), lymph nodes (27.2%), spleen (27.2%), eyes (18.1%), liver (18.1%), parotid glands (9%), and skin (9%). Fifty-three percent (10/19) of the patients had documented recurrent infections, all of them being upper respiratory tract infections. CNS manifestations included seizures (31.6%), headaches (21%), vision loss (15.7%), decreased cognition (10.5%), focal weakness (5.2%), nystagmus (5.2%), ataxia (5.2%), coma (5.2%), polyuria, and polydipsia (5.2%). Brain mass was the most common radiologic finding (70%) followed by leptomeningeal enhancement (10%), non-specific white matter lesions (10%) and absence of normal signal of the neurohypophysis (10%). Brain pathology was available in 12 patients: findings included granulomatous disease in 83.3%, angiocentric granulomas in 50%, vasculitis without granulomas in 8.3%, and lymphocytic infiltrate of the meninges with diffuse non-caseating granulomas in 8.3%. Cerebrospinal fluid analysis revealed elevated total proteins with/or without lymphocytic pleocytosis in 80%. CONCLUSION: CNS disease is a rare challenging complication of CVID. Patients with brain involvement are generally female, Caucasian, and likely have lung involvement. Although immunoglobulin and steroids remain the first line of treatment, other immunosuppressive agents have shown some promise with regards to recurrent relapsing presentations.

Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group.

Importance: The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations: The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance: Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

Immune Axonal Polyneuropathy.

PURPOSE OF REVIEW: Immune axonal polyneuropathy is caused by a diverse group of disorders that share similar presentations and treatment regimens. This article focuses on the clinical findings, evaluation, and management of immune-mediated causes of axonal polyneuropathy, focusing primarily on large fiber sensorimotor polyneuropathy. RECENT FINDINGS: Specific characteristics of an immune-mediated polyneuropathy have been incorporated in a new diagnostic screening tool that is highly sensitive and can easily be used in the outpatient clinic setting. New insights into autoantibodies may help identify the presence of an underlying autoimmune or paraneoplastic disease as the cause of a polyneuropathy. SUMMARY: This article provides readers with further understanding into the autoimmune causes of axonal polyneuropathy and will help the clinician recognize key clinical features that may lead to timely diagnosis and treatment.

Low Back Pain.

PURPOSE OF REVIEW: This article provides an overview of evaluating and treating low back pain in the outpatient setting. RECENT FINDINGS: As most cases of acute low back pain have a favorable prognosis, current guidelines on imaging studies recommend conservative treatment for 6 weeks prior to obtaining an MRI if no red flags are present. Of these red flags, a prior history of cancer is the strongest risk factor for a malignant etiology and requires urgent evaluation with MRI. Management of acute low back pain is mainly conservative with oral non-narcotic analgesics and mobilization as the initial recommendations. For patients with radiculopathy, epidural steroids may result in short-term pain relief, but long-term effects are still unclear. SUMMARY: A systematic, evidence-based approach to the patient with low back pain is key to providing safe and cost-efficient care.