How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?

Generalized myasthenia gravis (gMG) is a postsynaptic neuromuscular junction disorder that results in fatigable muscle weakness. The traditional treatment approach includes the use of acetylcholinesterase inhibitors, corticosteroids, and steroid-sparing immunosuppressant therapies (ISTs) for chronic management, whereas exacerbations and crises are managed with intravenous immunoglobulin (IVIg) and plasma exchange (PLEX). Over the past 6 years, four new therapeutic agents with novel immunological mechanisms of action-complement and neonatal Fc receptor (FcRn) inhibition-were approved as a result of clinically significant improvement in gMG symptoms of those treated with these newer agents in Phase 3 clinical trials. At present, it is unclear when and in whom to initiate these therapeutic agents and how to integrate them into the current treatment paradigm. When selecting a newer therapeutic agent, we use a simple equation: Value = Clinical Improvement/(Cost + Side Effects + Treatment Burden), which guides our decision-making. We consider using these novel therapeutic agents in two specific clinical situations. Firstly, the newer agents are fast-acting, suggesting they can be used in clinically unstable patients as "bridge therapy," and secondly, they provide additional options for those patients considered treatment-refractory. There are downsides, however, including treatment cost, unique side effect profiles, and intravenous and subcutaneous drug administration (though for some, this may be an advantage). As additional drugs enter the marketplace with unique mechanisms of action, routes of administration, and dosing schedules, the placement of the novel therapeutic agents in the gMG treatment algorithm will likely evolve.

Diagnostic delay in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease, and the time from symptom onset to diagnosis remains long. With the advent of disease-modifying treatments, the need to identify and diagnose ALS in a timely fashion has never been greater. METHODS: We reviewed the literature to define the severity of ALS diagnostic delay, the various factors that contribute to this delay (including patient and physician factors), and the role that site of symptom onset plays in a patient's diagnostic journey. RESULTS: Diagnostic delay is influenced by general practitioners' lack of recognition of ALS due to disease rarity and heterogenous presentations. As a result, patients are referred to non-neurologists, have unnecessary diagnostic testing, and may ultimately be misdiagnosed. Patient factors include their illness behavior-which impacts diagnostic delay-and their site of symptom onset. Limb-onset patients have the greatest diagnostic delay because they are frequently misdiagnosed with degenerative spine disease or peripheral neuropathy. CONCLUSION: Prompt ALS diagnosis results in more effective clinical management, with earlier access to disease-modifying therapies, multidisciplinary care, and, if desired, clinical trial involvement. Due to lack of commercially available ALS biomarkers, alternative strategies to identify and triage patients who likely have ALS must be employed. Several diagnostic tools have been developed to encourage general practitioners to consider ALS and make an urgent referral to ALS specialists, bypassing unnecessary referrals to non-neurologists and unnecessary diagnostic workup.

Neoplastic nerve lesions.

Though metastasis and malignant infiltration of the peripheral nervous system is relatively rare, physicians should have a familiarity with their presentations to allow for prompt diagnosis and initiation of treatment. This article will review the clinical presentations, diagnostic evaluation, and treatment of neoplastic involvement of the cranial nerves, nerve roots, peripheral nerves, and muscle. Due to the proximity of the neural structure traversing the skull base, metastasis to this region results in distinctive syndromes, most often associated with breast, lung, and prostate cancer. Metastatic involvement of the nerve roots is uncommon, apart from leptomeningeal carcinomatosis and bony metastasis with resultant nerve root damage, and is characterized by significant pain, weakness, and numbness of an extremity. Neoplasms may metastasize or infiltrate the brachial and lumbosacral plexuses resulting in progressive and painful sensory and motor deficits. Differentiating neoplastic involvement from radiation-induced injury is of paramount importance as it dictates treatment and prognosis. Neurolymphomatosis, due to malignant lymphocytic infiltration of the cranial nerves, nerve roots, plexuses, and peripheral nerves, deserves special attention given its myriad presentations, often mimicking acquired demyelinating neuropathies.

The neuromuscular fellowship portal and match.

For many years, Neuromuscular Medicine programs lacked a standardized means of handling fellowship applications and offering positions. Programs interviewed applicants and made offers as early as the first half of Post Graduate Year 3 (PGY3), a suboptimal timeline for applicants who may have had little prior exposure to neuromuscular or electrodiagnostic medicine. In 2021, the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) developed the Neuromuscular Fellowship Portal to standardize a later timeline and establish a process for fellowship applications and offers. In its first year, the Neuromuscular Fellowship Portal used a unique one-way match, in which the portal released serial offers to applicants based on rank order lists submitted by programs. Fifty-two Neuromuscular Medicine programs and seven electromyography (EMG)-focused Clinical Neurophysiology programs participated. Sixty-eight positions were filled, a similar number to previous years. A survey of fellowship directors and applicants following this process showed overwhelming support for the standardized timeline and application portal, but all program directors and most applicants favored moving to a traditional match. To maintain the existing application timeline and minimize costs for all parties, the AANEM Neuromuscular Fellowship Portal will host a two-way match, based on existing commercial match algorithms, in 2022. A match will afford a fair and efficient process for all involved. Both Neuromuscular Medicine and EMG-focused Clinical Neurophysiology programs will be encouraged to participate. The process undertaken by the AANEM can stand as an example for other neurologic subspecialties who are interested in standardizing their application timeline.

Disease-Modifying Treatments for Transthyretin Amyloidosis.

ABSTRACT: The transthyretin (TTR) amyloidoses result from misfolding of the protein leading to fibril formation and aggregation as amyloid deposits in predominantly the cardiovascular and nervous systems. Cardiac involvement can manifest as heart failure, arrhythmias, and valvular disease. Neurologic involvement can cause sensorimotor polyneuropathies, mononeuropathies, and dysautonomia. Previously, treatment has focused on management of these symptoms and disease sequelae, with a high rate of mortality due to the absence of disease-modifying therapies. In this article, we review novel treatments focusing on 3 mechanistic pathways: (1) silencing of the TTR gene to suppress production, (2) stabilizing of TTR tetramers to prevent misfolding, or (3) disrupting of existing TTR amyloid fibrils to promote reabsorption.

Chronic Immune-Mediated Polyneuropathies.

This article discusses the chronic immune-mediated polyneuropathies, a broad category of acquired polyneuropathies that encompasses chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the most common immune-mediated neuropathy, the CIDP variants, and the vasculitic neuropathies. Polyneuropathies associated with rheumatological diseases and systemic inflammatory diseases, such as sarcoidosis, will also be briefly covered. These patients' history, examination, serum studies, and electrodiagnostic studies, as well as histopathological findings in the case of vasculitis, confirm the diagnosis and differentiate them from the more common length-dependent polyneuropathies. Prompt identification and initiation of treatment is imperative for these chronic immune-mediated polyneuropathies to prevent disability and even death.

Peripheral nervous system manifestations of rheumatological diseases.

Rheumatological diseases result in immune-mediated injury to not only connective tissue, but often components of the peripheral nervous system. These overlap conditions can be broadly categorized as peripheral neuropathies and overlap myositis. The peripheral neuropathies are distinctive as many have unusual presentations such as non-length-dependent, small fiber neuropathies and sensory neuronopathies (both due to dorsal root ganglia dysfunction), multiple mononeuropathies (e.g. vasculitic neuropathies), and even cranial neuropathies. Overlap myositis is increasingly recognized and is often associated with specific autoantibodies. Sarcoidosis also has widespread neurological manifestations and impacts both the peripheral nerves and muscle. Much work is needed to fully characterize the vast presentations of these overlap diseases. Given the rarity of these disorders, they are understudied, resulting in significant knowledge gaps with regards to their underlying pathophysiology and the best treatment approach. A basic knowledge of these disorders is mandatory for both practicing rheumatologists and neurologists as prompt recognition and early initiation of immunotherapy may prevent significant morbidity and permanent disability.

Immune-Mediated Neuropathies.

The immune-mediated neuropathies are a broad category of diseases differentiated by time course, affected nerve fibers, and disease associations. This article spans the common, well-defined inflammatory demyelinating polyradiculoneuropathies (Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy) to the rarer, acquired demyelinating neuropathy variants (Miller-Fisher syndrome and multifocal motor neuropathy), vasculitic neuropathies, and sensory neuronopathies (dorsal root ganglionopathies). These case studies illustrate the characteristic clinical patterns of the immune-mediated neuropathies encountered in neurologic practice. Recommendations for diagnostic evaluation and treatment approach accompany each case. Prompt recognition of these disorders is imperative; delays in treatment may result in prolonged morbidity and permanent disability.

Nutritional neuropathies.

Neuropathies associated with nutritional deficiencies are routinely encountered by the practicing neurologist. Although these neuropathies assume different patterns, most are length-dependent, sensory axonopathies. Cobalamin deficiency neuropathy is the exception, often presenting with a non-length-dependent sensory neuropathy. Patients with cobalamin and copper deficiency neuropathy characteristically have concomitant myelopathy, whereas vitamin E deficiency is uniquely associated with a spinocerebellar syndrome. In contrast to those nutrients for which deficiencies produce neuropathies, pyridoxine toxicity results in a non-length-dependent sensory neuronopathy. Deficiencies occur in the context of malnutrition, malabsorption, increased nutrient loss (such as with dialysis), autoimmune conditions such as pernicious anemia, and with certain drugs that inhibit nutrient absorption. When promptly identified, therapeutic nutrient supplementation may result in stabilization or improvement of these neuropathies.

Peripheral Nerve Vasculitis: Classification and Disease Associations.

"The vasculitic neuropathies encompass a wide range of disorders characterized by ischemic injury to the vasa nervorum. Patients with vasculitic neuropathies develop progressive, painful sensory or sensorimotor deficits that are typically multifocal or asymmetric. Depending on the underlying etiology, the vasculitis may be confined to the peripheral nervous system; may be one manifestation of a primary systemic vasculitis; or one manifestation of a systemic vasculitis that is secondary to underlying connective tissue disease, drug exposure, viral infection, or paraneoplastic syndrome. This article reviews the classification, clinical presentation, diagnostic approach, etiologies, and treatment of the vasculitic neuropathies."

Validation of a simple disease-specific, quality-of-life measure for diabetic polyneuropathy: CAPPRI.

OBJECTIVE: We studied the performance of a 15-item, health-related quality-of-life polyneuropathy scale in the clinic setting in patients with diabetic distal sensorimotor polyneuropathy (DSPN). METHODS: Patients with DSPN from 11 academic sites completed a total of 231 Chronic Acquired Polyneuropathy Patient-Reported Index (CAPPRI) scales during their clinic visits. Conventional and modern psychometric analyses were performed on the completed forms. RESULTS: Conventional and modern analyses generally indicated excellent psychometric properties of the CAPPRI in patients with DSPN. For example, the CAPPRI demonstrated unidimensionality and performed like an interval-level scale. CONCLUSION: Attributes of the CAPPRI for DSPN include ease of use and interpretation; unidimensionality, allowing scores to be summed; adequate coverage of disease severity; and the scale's ability to address relevant life domains. Furthermore, the CAPPRI is free and in the public domain. The CAPPRI may assist the clinician and patient with DSPN in estimating disease-specific quality of life, especially in terms of pain, sleep, psychological well-being, and everyday function. The CAPPRI may be most useful in the everyday clinical setting but merits further study in this setting, as well as the clinical trial setting.

Plexus and peripheral nerve metastasis.

Cancer in the form of solid tumors, leukemia, and lymphoma can infiltrate and metastasize to the peripheral nervous system, including the cranial nerves, nerve roots, cervical, brachial and lumbosacral plexuses, and, rarely, the peripheral nerves. This review discusses the presentation, diagnostic evaluation, and treatment options for metastatic lesions to these components of the peripheral nervous system and is organized based on the anatomic distribution. As skull base metastases (also discussed in Chapter 14) result in cranial neuropathies, these will be covered in detail, as well as cancers that directly infiltrate the cranial nerves. Particular emphasis is placed on the clinical, imaging, and electrodiagnostic features that differentiate neoplastic plexopathies from radiation-induced plexopathies. Neurolymphomatosis, in which malignant lymphocytes invade the cranial nerves, nerve roots, brachial and lumbosacral plexuses, and peripheral nerves, is a rare manifestation of lymphoma and leukemia. Diagnoses of neurolymphomatosis are often missed or delayed given its varied presentations, resulting in poorer outcomes. Thus this disease will also be discussed in depth.

Gluteal compartment syndrome with neurologic impairment: Report of 2 cases and review of the literature.

INTRODUCTION: We describe two patients who developed gluteal compartment syndrome (GCS) in the context of drug overdose. One patient developed a sciatic neuropathy, and one patient developed a lumbosacral plexopathy. METHODS: We reviewed the literature of atraumatic GCS and resultant neurological impairment. RESULTS: We reviewed 26 cases (our two cases and 24 previously published cases) of GCS and neurological impairment. All patients developed GCS in the context of drug or alcohol overdose. Creatine kinase was markedly elevated in all patients in which it was tested, and most patients developed renal failure. Seventeen patients had a fasciotomy, and 9 patients were managed conservatively. There appeared to be a trend toward worse prognosis in the conservatively managed group. DISCUSSION: Neurologists should be aware of GCS. Immediate recognition facilitates consideration of further diagnostic testing, including intracompartmental pressure measurement and consideration of surgical decompression, which may influence outcome. Muscle Nerve, 57: 325-330, 2018.

Sensory Neuronopathies.

PURPOSE OF REVIEW: The sensory neuronopathies are sensory-predominant polyneuropathies that result from damage to the dorsal root and trigeminal sensory ganglia. This review explores the various causes of acquired sensory neuronopathies, the approach to diagnosis, and treatment. RECENT FINDINGS: Diagnostic criteria have recently been published and validated to allow differentiation of sensory neuronopathies from other polyneuropathies. On the basis of serial electrodiagnostic studies, the treatment window for the acquired sensory neuronopathies has been identified as approximately 8 months. If treatment is initiated within 2 months of symptom onset, there is a better opportunity for improvement of the patient's condition. Even though sensory neuronopathies are rare, significant progress has been made regarding characterization of their clinical, electrophysiologic, and imaging features. This does not hold true, however, for treatment. There have been no randomized controlled clinical trials to guide management of these diseases, and a standard treatment approach remains undetermined.

Splenic marginal zone lymphoma: An indolent malignancy leading to the development of neurolymphomatosis.

INTRODUCTION: Acute neuropathic pain and weakness with a sensory level in a patient with a history of lymphoma has a broad differential diagnosis. Evaluation of such a presentation often includes MRI, neurophysiologic studies, and cerebrospinal fluid evaluation. We report a patient with splenic marginal zone lymphoma who developed acute weakness, sensory loss, and neuropathic pain due to neurolymphomatosis. METHODS: Clinical evaluation, MRI of the lumbar spine, cerebrospinal fluid evaluation, electrodiagnostic (EDx) studies, and biopsy of a dorsal nerve root were undertaken. RESULTS: EDx studies were consistent with an acute, acquired demyelinating sensorimotor polyradiculoneuropathy. Treatment with intravenous immunoglobulin and plasma exchange did not lead to clinical improvement. Ultimately, biopsy of a dorsal nerve root was performed and revealed neurolymphomatosis. CONCLUSION: This case emphasizes that, when it can be performed safely, biopsy for suspected neurolymphomatosis is imperative for appropriate diagnosis and treatment. Muscle Nerve 55: 440-444, 2017.

International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r.

INTRODUCTION: The MG-QOL15 is a validated, health-related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties. METHODS: We first performed Rasch analysis on >1,300 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG-QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on >1,300 MG-QOL15r scales. RESULTS: The MGQOL15r performed slightly better than the MG-QOL15. The 3-response option MG-QOL15r demonstrated better clinimetric properties than the 4- or 5-option scales. Relative distributions of item and person location estimates showed good coverage of disease severity. CONCLUSIONS: The MG-QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG-QOL15. Muscle Nerve 54: 1015-1022, 2016.

Construction and validation of the chronic acquired polyneuropathy patient-reported index (CAP-PRI): A disease-specific, health-related quality-of-life instrument.

INTRODUCTION: Generic health-related quality-of-life (HRQOL) patient-reported outcome measures have been used in patients with chronic immune-mediated polyneuropathies. We have created a disease-specific HRQOL instrument. METHODS: The chronic acquired polyneuropathy patient-reported index (CAP-PRI) was developed and validated in multiple steps. Items were initially generated through patient and specialist input. The performance of the preliminary 20 items was analyzed via a prospective, 5-center study involving chronic immune-mediated polyneuropathy patients. RESULTS: Data analysis suggested modification to a 15-item scale with 3 response categories rather than 5. The final CAP-PRI was validated in another prospective, 5-center study. The CAP-PRI appeared to be a unidimensional outcome measure that fit the Rasch model in our multicenter cohort. It correlated appropriately with outcome measures commonly used in this patient population. CONCLUSIONS: The CAP-PRI is a simple disease-specific HRQOL measure that appears to be useful for clinical care and possibly also for clinical trials. Muscle Nerve 54: 9-17, 2016.

Myasthenia Gravis.

Myasthenia gravis is an autoimmune neuromuscular disease caused by antibodies directed against the postsynaptic muscle membrane. The clinical hallmark of the disease is fluctuating and fatigable weakness that affects the ocular muscles (resulting in diplopia and ptosis), the bulbar muscles (causing dysphagia, dysarthria, and dyspnea), and extremity muscles. The diagnosis is most often made with serological testing that identifies either acetylcholine receptor antibodies or muscle-specific tyrosine kinase antibodies. Electrodiagnostic testing has a role in supporting the diagnosis. There are many available treatments that result in improvement of function and quality of life. Treatment should be individualized after consideration of many factors, including disease distribution and severity, patient comorbidities, age, serological status, and what is known about the efficacy and safety of the various treatments.