Case Records of the Massachusetts General Hospital. Case 30-2015: A 50-Year-Old Man with Cardiogenic Shock.

A 50-year-old man with a history of cardiomyopathy and progressive muscle weakness was admitted with cardiogenic shock. Electroencephalography showed total suppression of cerebral activity; ventilator support was withdrawn, and he died. An autopsy was performed.

Clinical neurophysiology of demyelinating polyneuropathy.

Demyelinating neuropathies are remarkably varied in their clinical characteristics: In etiology they may be inherited or acquired, in their time course, acute or chronic, and in their distribution, multifocal or generalized. They present with phenotypes that range from an indolent disorder that begins in childhood and progresses slowly over decades (as might be seen in an inherited form) and leads to weakness but preserved ambulation, to a neuropathy with fulminant onset and rapid progression culminating in tetraparesis and respiratory failure (as seen in the Guillain-Barre syndrome). Often demyelinating neuropathies are amenable to treatment that greatly reduces the burden of disease and extent of disability. Thus, electrophysiologic studies are critically important as an investigatory tool in the evaluation of patients with suspected demyelinating neuropathies. In this chapter, we focus our discussion on the manifold electrophysiologic details regarding the demyelinating neuropathies and provide the reader with the clinical context and pathophysiological underpinnings to help appreciate the complex character of these disorders, including the Guillain-Barré syndrome; chronic inflammatory demyelinating polyneuropathy and its variants; the dysimmune demyelinating neuropathies that accompany systemic disease such as paraproteinemia, POEMS syndrome, and multifocal motor neuropathy; diabetic neuropathy; the demyelinating inherited polyneuropathies, and the demyelinating neuropathy from toxic exposures.

Lumbar spinal stenosis.

Lumbar spinal stenosis may be congenital or acquired. A classic clinical presentation is described as neurogenic claudication. Physical signs of sensory loss, weakness, and attenuation of reflexes often are mild and limited in distribution. Neuroimaging of the lumbosacral spine with MRI and electrodiagnostic (electromyographic [EMG]) tests are the most informative diagnostic modalities. Conservative management often is successful, but surgical decompression may be indicated in refractory cases.

A standardized clinical evaluation of phenotypic diversity in diabetic polyneuropathy.

Diabetic polyneuropathy (DPN) is a major cause of neuropathic pain and a frequent target condition in analgesic treatment trials. Differences in the clinical symptoms and signs associated with DPN suggest distinct pathophysiological mechanisms underlying nerve damage and dysfunction that are likely to have therapeutic relevance. The aim of this study was to develop a tool for the bedside assessment of painful neuropathies such as DPN that captures the diversity of phenotypes. Sixty-one patients with type 2 diabetes and painful neuropathy, 19 patients with painless DPN, 25 patients with type 2 diabetes but no clinical evidence of neuropathy, and 20 healthy control subjects completed a structured interview (47 items) and a standardized physical examination (39 items). After analyzing critical features of pain and painless symptoms and examining the outcome of physical tests of sensory function, we determined principal components of the phenotypic variance among patients. Increased sensitivity to mechanical or thermal stimuli and, to a lesser extent, the sensory quality of pain or paresthesia were the most discriminating elements of DPN phenotypes. Correlation patterns of symptoms and signs indicated the involvement of functionally distinct nerve fiber populations. We combined interview questions and physical tests identifying these differences in a shortened assessment protocol that we named Standardized Evaluation of Pain and Somatosensory Function (StEPS). The protocol StEPS generates a phenotypic profile of patients with neuropathy. Separate intensity ratings for spontaneous painful symptoms and pain evoked by standard stimuli support a detailed documentation of neuropathic pain and its response to analgesic treatment.

Acute lower motor neuron syndrome and spinal cord gray matter hyperintensities in HIV infection.

OBJECTIVE: To describe a novel manifestation of lower motor neuron disease in patients with well-controlled HIV infection. METHODS: A retrospective study was performed to identify HIV-positive individuals with acute, painful lower motor neuron diseases. RESULTS: Six patients were identified with HIV and lower motor neuron disease. Two patients met the inclusion criteria of well-controlled, chronic HIV infection and an acute, painful, unilateral lower motor neuron paralytic syndrome affecting the distal portion of the upper limb. These patients had segmental T2-hyperintense lesions in the central gray matter of the cervical spinal cord on MRI. One patient stabilized and the second patient improved with immunomodulatory therapy. CONCLUSIONS: This newly described syndrome expands the clinical spectrum of lower motor neuron diseases in HIV.

Electrodiagnostic approach to the patient with suspected motor neuron disease.

The diagnosis of amyotrophic lateral sclerosis (ALS) per se may be challenging since there is no single diagnostic test for ALS (with the exception of finding a mutation in the SOD1 gene). Additionally, the disease may begin focally and resemble a variety of other neurologic disorders that share clinical features with ALS. This latter point emphasizes an important imperative for the clinician--the need to consider a broad range of peripheral and central nervous system disorders in the process of differential diagnosis of ALS, especially when the disease is in its early stages. The authors review the diagnostic criteria for ALS and discuss which features to consider in determining the degree of certainty or level of confidence in the diagnosis. The authors then enumerate the important differential diagnostic possibilities that emerge from a careful consideration of the clinical features and comment on neuroimaging studies and laboratory tests employed in the diagnostic process. Next, the authors turn their attention to the important role played by electrophysiologic studies in the diagnostic evaluation of the patient with suspected ALS. The authors then return to a focused consideration of selected disorders in the differential diagnosis of ALS and conclude with a summary of their diagnostic approach for this disease.

Expanding the phenotype associated with the NEFL mutation: neuromuscular disease in a family with overlapping myopathic and neurogenic findings.

IMPORTANCE: Newer sequencing technologies in combination with traditional gene mapping techniques, such as linkage analysis, can help identify the genetic basis of disease for patients with rare disorders of uncertain etiology. This approach may expand the phenotypic spectrum of disease associated with those genetic mutations. OBJECTIVE: To elucidate the molecular cause of a neuromuscular disease among a family in which 4 members, a mother and her 3 sons, were affected. DESIGN, SETTING, AND PARTICIPANTS: Two of 4 affected members manifested nemaline myopathy, a common subtype of congenital myopathy, while the other 2 had a nonspecific myopathy. Single-nucleotide polymorphism-based linkage analysis was performed on DNA samples from the 4 affected family members, and whole-genome sequencing was performed in the proband. Real-time quantitative reverse transcription-polymerase chain reaction, immunofluorescence, and Western blot analysis were performed on muscle biopsy specimens. MAIN OUTCOMES AND MEASURES: Whole-genome sequencing and linkage analysis identified a variant in a gene that explains the phenotype. RESULTS: We identified a novel neurofilament light polypeptide (NEFL) nonsense mutation in all affected members. NEFL mutations have been previously linked to Charcot-Marie-Tooth disease in humans. This led us to reevaluate the diagnosis, and we recognized that several of the findings, especially those related to the muscle biopsy specimens and electromyography, were consistent with a neurogenic disease. CONCLUSIONS AND RELEVANCE: NEFL mutations are known to cause Charcot-Marie-Tooth disease in humans and motor neuron disease in mice. We report the identification of an NEFL mutation in a family clinically manifesting congenital myopathy. We also describe potential overlap between myopathic and neurogenic findings in this family. These findings expand the phenotypic spectrum of diseases associated with NEFL mutations. This study is an example of the power of genomic approaches to identify potentially pathogenic mutations in unsuspected genes responsible for heterogeneous neuromuscular diseases.

Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research.

Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups. The Foundation supports innovative projects, including stem-cell research, and Patient Advocacy is committed to supporting excellence in ALS research and patient care, and believes strongly in enhancing communication between patients and members of the research community.

Peer recommendations on how to improve clinical research, and Conference wrap-up.

To promote clinical and patient oriented research, as part of the Second International ALS Conference in Tarrytown, NY, USA, seven pairs of clinicians and scientists were asked to lead discussions with meeting attendees on six major topics (one of which was discussed by two groups); each one the focus of a 90-min Breakout Session. Approximately 25 meeting attendees participated in each session. The Breakout Sessions considered six major themes: 1) Approaches to encourage clinicians to engage in more clinical research to discover the pathogenesis and cause of ALS; 2) Exploring avenues to build more effective partnerships between basic scientists and ALS physicians; 3) Increasing patient interest and commitment to participating in non-trial clinical research; 4) Brainstorming about factors that are most critical to the discovery of the pathogenesis and cause of ALS; 5) Finding ways to incorporate clinical research projects into clinical trials; and 6) Developing state-of-the-art epidemiological studies to solve the mystery of ALS. In this paper, we present the reports from each of the Breakout Sessions; and we provide a wrap-up of the entire conference.