Review Article Address correspondence to Dr Ezgi Tiryaki, Hennepin ALS and Other Motor County Medical Center, Department of Neurology, 701 Park Avenue P5-200, Neuron Diseases Minneapolis, MN 55415, [email protected]. Ezgi Tiryaki, MD; Holli A. Horak, MD, FAAN Relationship Disclosure: Dr Tiryaki’s institution receives support from The ALS Association. Dr Horak’s ABSTRACT institution receives a grant from the Centers for Disease Purpose of Review: This review describes the most common motor neuron disease, Control and Prevention. ALS. It discusses the diagnosis and evaluation of ALS and the current understanding of its Unlabeled Use of pathophysiology, including new genetic underpinnings of the disease. This article also Products/Investigational covers other motor neuron diseases, reviews how to distinguish them from ALS, and Use Disclosure: Drs Tiryaki and Horak discuss discusses their pathophysiology. the unlabeled use of various Recent Findings: In this article, the spectrum of cognitive involvement in ALS, new concepts drugs for the symptomatic about protein synthesis pathology in the etiology of ALS, and new genetic associations will be management of ALS. * 2014, American Academy covered. This concept has changed over the past 3 to 4 years with the discovery of new of Neurology. genes and genetic processes that may trigger the disease. As of 2014, two-thirds of familial ALS and 10% of sporadic ALS can be explained by genetics. TAR DNA binding protein 43 kDa (TDP-43), for instance, has been shown to cause frontotemporal dementia as well as some cases of familial ALS, and is associated with frontotemporal dysfunction in ALS. Summary: The anterior horn cells control all voluntary movement: motor activity, res- piratory, speech, and swallowing functions are dependent upon signals from the anterior horn cells. Diseases that damage the anterior horn cells, therefore, have a profound impact. Symptoms of anterior horn cell loss (weakness, falling, choking) lead patients to seek medical attention. Neurologists are the most likely practitioners to recognize and diagnose damage or loss of anterior horn cells. ALS, the prototypical motor neuron disease, demonstrates the impact of this class of disorders. ALS and other motor neuron diseases can represent diagnostic challenges. Neurologists are often called upon to serve as a ‘‘medical home’’ for these patients: coordinating care, arranging for durable medical equipment, and leading discussions about end-of-life care with patients and caregivers. It is important for neurologists to be able to identify motor neuron diseases and to evaluate and treat patients affected by them. Continuum (Minneap Minn) 2014;20(5):1185–1207. INTRODUCTION motor neuron diseases affect only the The term motor neuron disease refers to lower motor neuron. various disease entities that result in The lower motor neurons are located progressive degeneration of motor neu- in the spinal cord anterior horn and in rons. The term motor neuron disease is the brainstem (motor nuclei of cranial also sometimes used interchangeably with nerves) and innervate the skeletal mus- amyotrophic lateral sclerosis (ALS), which cles. Since lower motor neurons of the is the most common disease in this category. spinal cord reside in the anterior horn, Motor neuron diseases can be hered- these diseases are also sometimes re- itary or acquired and vary in underlying ferred to as anterior horn cell diseases. pathology and clinical presentation. ALS The upper motor neurons are located in can affect both the lower motor neuron the motor cortex and give rise to the and the upper motor neuron, but most corticospinal and corticobulbar tracts. Continuum (Minneap Minn) 2014;20(5):1185–1207 www.ContinuumJournal.com 1185 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. ALS and Other Motor Neuron Diseases KEY POINT h motorneuronsymptomsismostlikely A motor unit is one motor TABLE 1-1 Motor Neuron neuron, its axon, and all Diseases to have ALS. the individual muscle The clinical hallmark of motor neu- fibers it innervates. b ALS ron disease is lower motor neuron dysfunction: atrophy, weakness, and b Multifocal motor neuropathy fasciculations of affected motor units. b Spinal muscular atrophy A motor unit is one motor neuron, its b Spinal bulbar muscular axon, the neuromuscular junction, and atrophy/Kennedy disease all the individual muscle fibers it in- b Monomelic amyotrophy nervates (Figure 1-11). b Poliomyelitis As the motor neuron undergoes b West Nile virus apoptosis, the motor nerve axon de- b Paraneoplastic motor generates, and the neuromuscular neuron diseasea junction is destroyed. Muscle fibers ALS = amyotrophic lateral sclerosis. innervated by that axon will be dener- a For more information on paraneoplastic vated and, subsequently, atrophy. motor neuron disease, please see the article ‘‘Paraneoplastic Neuropathies’’ by Srikanth Electrically, the individual fiber will Muppidi, MD, and Steven Vernino, MD, show fibrillations and positive waves, a PhD, FAAN, in this issue of Continuum. marker of the instability of the dener- vated muscle membrane. When con- tracting as a group, the fibers of an See Table 1-1 for a list of the most affected motor unit will fasciculate, common motor neuron diseases, which which can be seen clinically and electri- are discussed in this article. Of these, cally on EMG. Initially, with an acquired ALS is more common than all the motor neuron disease, adjacent motor others, so an adult presenting with nerve axons will reinnervate the muscle FIGURE 1-1 Motor unit. A motor unit consists of the anterior horn cell or lower motor neuron and all the skeletal muscle fibers it innervates. The number of muscle fibers in a motor unit may vary depending on the muscle. Depicted are two motor neurons that each innervate four fibers. Reprinted with permission from Saladin K, McGraw-Hill.1 B 2009 McGraw-Hill Education. 1186 www.ContinuumJournal.com October 2014 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT fibers (causing a reinnervation pattern A pattern of (1) low-amplitude compound h EMG performed for on EMG). However, as these motor muscle action potentials with preserved suspected ALS must neurons die too, eventually there are sensory responses on nerve conduction include at least three not enough motor neurons left for studies; (2) denervation changes (fibrilla- regions of the reinnervation and the predominating tions, positive waves); and (3) and neuraxis to confirm a processthatoccursisdenervation. reinnervation changes (reduced numbers widespread pattern Motor neurons of cranial nerve nuclei of large-amplitude, long-duration, poly- beyond regional are variably affected, depending upon phasic motor unit potentials) will be damage from the disease and phenotype. Cranial documented by the electromyographer. radiculopathies. nerves XI and XII are most often If a polyradicular pattern of denervation/ affected, especially with ALS and spinal reinnervationisseen(ie,morethanone bulbar muscular atrophy/Kennedy dis- or two radicular levels), then the electro- ease. Cranial nerves III, IV, and VI myographer must consider a motor (extraocular muscle nuclei) are affected neuron disease as the etiology of the late, or never, in these diseases. pattern. EMG performed for suspected ALS must include at least three regions of DIAGNOSIS the neuraxis to confirm a widespread Motor neuron diseases are diagnosed pattern of denervation/reinnervation be- clinically. Supportive testing, such as yond regional damage from radiculopathies. nerve conduction studies and EMG can confirm active denervation, which in- CLINICAL DISEASES dicates loss of the motor neuron. For ALS specific differential diagnoses, genetic ALS is the most common acquired testing or infectious disease titers can motor neuron disease. ALS affects more confirm the underlying pathology. These than the motor neurons and is often tests will be discussed in detail for each associated with cognitive abnormalities pertinent disease. Imaging does not play (frontotemporal dysfunction) and pseu- a role in the diagnosis of motor neuron dobulbar affect. disease, other than to exclude mimics. About 5000 people in the United States are diagnosed with ALS each year. Electrical Studies in Motor The incidence worldwide is estimated to Neuron Disease be 4 to 8 per 100,000 individuals. The Nerve conduction studies and EMG can mean age of onset is 56 years in be very useful in the diagnosis of motor individuals without a known family his- neuron disease. Electrodiagnostic stud- tory and 46 years in individuals with ies reflect that sensory function is pre- familial ALS. The male to female ratio is served while motor function is affected. 1.6 to 1. Average disease duration from Specifically, in the setting of advanced onset of symptoms is about 3 years, but motor axon loss, nerve conduction it can vary significantly. Patients usually studies may show low compound die of respiratory failure.2 muscle action potential amplitudes with The primary feature of ALS is motor normal sensory nerve amplitudes. This neuron dysfunction, which typically be- may not apply to spinal bulbar muscular gins in one limb or one region of the atrophy/Kennedy disease, which often spinal cord, but may also begin in cranial has some sensory involvement on nerve nerve nuclei, which is termed ‘‘bulbar’’ conduction studies. onset (‘‘bulb’’ being an antiquated term EMG in motor neuron disease will for the brainstem).