Mark B. Bromberg

In 2011, a pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was discovered to be the leading genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Before this, the C9ORF72 gene and its protein were unknown. The repeat expansion was found to cause both haploinsufficiency and gain of toxicity through aggregating RNA products and dipeptide repeat proteins. A worldwide effort was then initiated to define C9ORF72 ALS/FTD and unravel the pathogenic mechanism for the development of therapeutic options. A decade later, C9ORF72 genetic testing is readily available. There is now an increasing appreciation that C9ORF72 not only is the leading genetic cause of ALS/FTD but may contribute to a spectrum of disorders. This article reviews what is currently known about the C9ORF72 expansion and how C9ORF72 expansion manifests in ALS, FTD, psychiatric disorders, and movement disorders. With therapeutic strategies fast approaching the clinic, earlier recognition of possible C9ORF72 expansion related disorders is even more paramount to improve patient care.

We describe an individual with slowly progressive amyotrophic lateral sclerosis who decided to enter the Talisker Whisky Atlantic Challenge, a rowing event across the Atlantic Ocean, and completes it in 51 days in a 5-man boat.

This edition of “What is in the Literature?” will focus on motor neuron disease (MND), including adult forms [amyotrophic lateral sclerosis (ALS), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), progressive bulbar palsy (PBA), and monomelic mononeuropathy (MMND)], and childhood forms [spinal muscle atrophy (SMA)].

Chronic inflammatory demyelinating polyradicoloneuropathy (CIDP) is a treatable form of neuropathy. Efforts to devise sets of electrodiagnostic (nerve conduction) criteria to distinguish primary demyelination from primary axonal neuropathies have been elusive, and at least 16 criteria have been proposed. Modifications to criteria frequently represent minor changes based on applying a set to a small number of patients with the clinical diagnosis of CIDP, whereas others are based on physiological changes related to demyelination and other pathophysiological features. The various modifications continue to result in limited sensitivity, likely related to the wide range of nerve conduction abnormalities among CIDP patients. Although some sets are appropriate for formal clinical drug trials, their complexity makes them difficult to apply in the clinic or electromyography laboratory. This study considers the evolution of the criteria, discusses their limitations, and ends with a simplified set of guidelines that can be applied in the clinic or laboratory. Muscle Nerve, 2011

Amyotrophic lateral sclerosis (ALS) is a uniformly fatal disease. In the US, care is concentrated in specialized clinics. ALS health care providers likely experience stress, but levels and associated factors and methods to manage them are not known. A questionnaire was designed to assess levels of emotional stress among ALS clinic providers (neurologists and clinic managers) at time of diagnosis, during care of the patient, and at time of the patient's death. Also included were questions about diagnostic practice patterns. Sixty-eight Muscular Dystrophy Association and ALS Association certified clinics were surveyed with a 47% response rate. Stress levels ranged from very severe to none at the various clinical stages but did not differ significantly between neurologists and managers. Stress tended to be lower in more experienced providers, although not uniformly so for all situations and time-points. Stress reduction techniques were rated as more effective for managers than for neurologists. Providers reported high levels of job satisfaction but a significant number gave consideration to leaving their positions due to stress and operational issues. In conclusion, stress is experienced by ALS clinic providers and managed by a variety of methods but with limited success.

The authors discuss the techniques and use of electrodiagnosis to help fully characterize peripheral neuropathies, including electrodiagnostic principles, normal findings, correlations between underlying nerve pathology that leads to abnormal electrodiagnostic findings, and how to detect and interpret electrodiagnostic findings.

Requests for an evaluation for a peripheral neuropathy are common in the clinic and electrodiagnostic laboratory. Lists of types of neuropathies are long as are diagnostic tests. An approach to the evaluation of peripheral neuropathies is valuable as it permits full characterization of the neuropathy after which the lists of possible types and tests becomes much shorter and manageable. In this article, the author presents such an approach, focusing on the clinical aspects.

This issue of Seminars in Neurology is devoted to peripheral neuropathies. The subject of peripheral neuropathies is large and a single issue cannot cover the full spectrum. The articles selected for this issue are based on common problems and clinical issues encountered in practice. Articles include an approach to the clinical evaluation; an approach to electrodiagnosis with commentary on technical and interpretative errors; clinical and diagnostic features of inflammatory, bariatric, hereditary, and unusual neuropathies; and a review of diagnostic testsas well as treatment of inflammatory neuropathies and neuropathic pain. Several topics are not included, such as diabetic neuropathy (because features are well described in the literature) and nerve biopsies (because they are seldom performed and are rarely diagnostic). It is worthwhile to briefly discuss the spectrum of peripheral neuropathies as the term “peripheral neuropathy” is very broad. The anatomic entity of axons wrapped by peripheral myelin is simple in concept but histologically and metabolically complex, and hence subjected to a wide variety of disturbances. The boundaries of the peripheral nervous system cannot be precisely defined to include all disorders clinically considered to be “peripheral neuropathies.” Histologically, the peripheral nervous system can be considered to be the neurons ensheathed by Schwann cells, and this would include cranial nerves and spinal nerves. There are difficulties in classifying some types of peripheral neuropathies. Disorders that damage peripheral processes of motor nerves are easily categorized as peripheral neuropathies, whereas disorders that affect anterior horn cells (neuronopathies) are generally categorized as motor neuron diseases even though there may be a significant component of a dying-back process in the peripheral system. Many disorders of sensory nerves, especially those affecting cell bodies in the dorsal root ganglia, will also include involvement of the branch extending into the central nervous system. Some disorders may be predominantly peripheral but include pathology of both central and peripheral axons or myelin. Some immune-mediated neuropathies may include functional alteration of conduction and not structural damage to myelin or axons. Painful neuropathies may affect only intraepidermal nerves. Peripheral neuropathies can be categorized by different schemas (Table [ 1 ]). There will be overlap or combinations among the schemas for a given clinical entity. Table 1 Classification of Peripheral Neuropathies Based on Different Schemas By anatomic distribution Mononeuropathy, mononeuropathy multiplex, diffuse-polyneuropathy, symmetric, asymmetric, distal, distal and proximal, cranial, peripheral and central, intraepidermal By modality Sensory, motor, autonomic By time course Acute (weeks), chronic, relapsing–remitting, insidious By symptoms Pain, sensory loss, weakness, dystaxic By basic pathology Primary axonal, primary demyelination, primary conduction block (mechanical, demyelinating, functional) By basic disease process Acquired, hereditary, compressive, traumatic By pathophysiology Metabolic, toxic, hereditary, immune-mediated, to cell body, to axon, to myelin, ischemic, mechanical, idiopathic By association with Systemic diseases, cancer (direct, paraneoplastic), infections By test features Subclinical, primary axonal, primary demyelination, primary conduction block, nerve or skin biopsy, associated laboratory findings Many neuropathies will be characterized by one or more features from several of the above categories. Despite complexity, the evaluation process described in this issue of Seminars in Neurology argues for an orderly approach. Table 1 becomes simplified as the neuropathy is fully characterized, first by the history and examination, and second by the electrodiagnostic testing. At that point informative laboratory testing can be ordered. It is hoped that this issue will help organize the evaluation process.