Sci. Aging Knowl. Environ., 3 September 2003
Vol. 2003, Issue 35, p. dn2
[DOI: 10.1126/sageke.2003.35.dn2]

NEURODEGENERATIVE DISEASE CASE STUDIES

Amyotrophic Lateral Sclerosis

Paul H. Gordon, Hiroshi Mitsumoto, and Arthur P. Hays

The authors are at the Eleanor and Lou Gehrig Muscular Dystrophy Association/Amyotrophic Lateral Sclerosis Research Center, Department of Neurology (P.H.G. and H.M.), and Department of Pathology (A.P.H.), College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. E-mail: PGordon{at}neuro.columbia.edu (P.H.G.)

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/35/dn2

Key Words: amyotrophic lateral sclerosis • motor neuron disease • neurodegeneration

Abstract: In this case study, we describe the symptoms, neurological examination, and pathology of a woman with amyotrophic lateral sclerosis (ALS). ALS is a rare disorder leading to degeneration of the voluntary motor system and death in, on average, 3 to 4 years. The loss of motor neurons in the brain and spinal cord causes the progressive symptoms of muscular weakness, atrophy, fasciculation (muscle twitching), spasticity, and hyperreflexia. Signs of disease in both upper and lower motor neurons are required for a definitive clinical diagnosis. Pathology shows degeneration of the lateral corticospinal tracts, loss of motor neurons and astrogliosis in the brain and brain stem, and neuronal inclusions. This case was marked by the onset of weakness and muscle atrophy in the hand, which spread to involve contiguous muscle segments. Cognition, the extraocular muscles, and the urinary sphincters were spared. Respiratory muscle weakness was a late manifestation.

Introduction Back to Top

K.G. was 55 when she first noticed difficulty in turning keys and buttoning collar buttons with her left hand. She did not experience pain or numbness. After several months, the left arm muscles atrophied and there was twitching of muscles in the left arm and torso. She occasionally experienced cramps in her hand and arm muscles during periods of muscle contraction, and then later during periods of rest. The symptoms progressed. At first she struggled only with buttons and keys, but after several months the weakness became more marked, and she also had trouble lifting objects with her left arm, carrying grocery bags, and holding her arm over her head while she shampooed her hair in the shower. After 6 months, she began to trip on her left foot as she stepped over curbs. She was evaluated by a neurologist who performed an examination, and ordered magnetic resonance imaging of the cervical spine and electromyography (EMG) of three limbs. The diagnosis was amyotrophic lateral sclerosis (ALS), and riluzole was prescribed to slow its progression.

One year after her symptoms began, K.G. developed slurred speech and problems chewing. She laughed and cried easily and was prescribed paroxetine for emotional lability (pseudobulbar affect). She had severe weakness in her left arm and needed a brace on her left ankle to prevent falls. She also experienced mild weakness in the right hand, although she still walked, dressed, and bathed independently. Her neurological examination at this stage is outlined below. Eighteen months after the onset of symptoms, she was frequently asked to repeat sentences because of unintelligible words, and she began to drool and choke on some foods. She required assistance with cutting meat and intermittent assistance with dressing and hygiene. She began to walk with a cane. She received consultation with physical and occupational therapists specially trained in the care of ALS patients, who provided assistance with methods to maintain independence.

At 24 months after onset, her left side was severely weak, and her right arm and leg became weaker. She was unable to grip a pen and needed to have her food cut by her spouse. She was able to walk short distances with a walker. She had shortness of breath while eating and dressing, and, occasionally, while sleeping flat at night. Pulmonary function testing showed reduced forced vital capacity as a result of weakness of respiratory muscles. She began eating soft food to prevent choking. She lost 15 pounds over the next 6 months. There was no incontinence of bowel or bladder, no change in vision, and no cognitive symptoms.

After 30 months from the time of her first symptoms, her shortness of breath was more marked, and she was prescribed noninvasive positive pressure ventilation. Her bulbar muscles (muscles of the tongue and throat that are supplied by nerves emanating from the brain stem) became weaker, and she lost the ability to swallow adequate nutrition safely. Consequently, she underwent placement of a percutaneous gastrostomy. She needed assistance with all of her activities of daily living, including dressing, bathing, and eating, and was unable to walk. During the next few months, her condition continued to deteriorate. Nearly all of her activities had to be performed by her spouse. She expressed wishes not to be placed on life support for progressive respiratory failure. She was given hospice care, and she died of progressive respiratory failure, peacefully at home with her family, 3 years after she first noticed weakness in her hand.

Medical History Back to Top

Her prior medical history, which included gastroesophageal reflux and kidney stones, was unrelated to her current symptoms. She had stopped smoking cigarettes 20 years prior and drank 1 to 2 glasses of wine with dinner each day. There was no family history of any neurological disease.

Neurological Examination Back to Top

This examination was performed 1 year after the onset of symptoms. She laughed loudly several times during the assessment without obvious stimulus, once quickly followed by tearfulness (pseudobulbar affect). The mental status testing was otherwise normal.

Olfactory sense, vision, and extraocular muscle function, which provide an assessment of whether cranial nerves (CNs) I to VI are functional, were normal. Facial strength, sensation, and hearing were also normal, signifying that there were no abnormalities in CN V or VII to VIII function. The palate elevated weakly, then more briskly after touching of the back of the throat to elicit a gag reflex, signifying CN IX to X dysfunction. Tongue atrophy and fasciculation were observed, indicating degeneration of CN XII (video clip 1). Neck flexion and extension were slightly weak against resistance testing (demonstrating some malfunction of CN XI). The jaw jerk reflex was hyperactive (video clip 2), which can be a symptom of upper motor neuron dysfunction. The speech was slow and spastic (also typical of upper motor neuron dysfunction), and there was mild dysarthria as a result of deficient tongue coordination and strength.

Upon muscle examination, the left hand, forearm, shoulder, and distal left leg muscles were found to be atrophied (for example, see video clip 3). Muscles on the right side of the body had normal bulk, but there were fasciculation in all four limbs and across the chest and back. There was moderate spasticity of the left arm and leg and more mild spasticity on the right side. There was moderate weakness of muscles supplying the left foot and ankle, and of the biceps, triceps, and deltoid muscles in the left arm. The patient could not move her left toe and left hand muscles against gravity. There was slight weakness of right great toe extension and right hand muscles.

Deep tendon reflexes were briskly hyperactive at all joints tested, but hyperactivity was more prominent in joints on the left side of the body. A Hoffmann sign was observed in the left hand (video clip 4). Left forearm, arm, and knee reflexes were hyperactive and resulted in the spread of contraction across adjacent joints (a response that is probably abnormal in this context). Ankle clonus and a Babinski sign were elicited on the left side.

K.G. was unable to elevate her left foot when she walked and could not stand on either heel. Finally, her ability to perceive sensation was normal.

Laboratory Testing and Diagnostic Imaging Back to Top

Routine blood tests to examine electrolyte levels, glucose levels, renal function, and thyroid function were performed, and the results were normal. A test was also done to determine whether antibodies to ganglioside were present (which would be indicative of an autoimmune disorder; see below), and none were found. Results from magnetic resonance imaging of the spinal cord and brain were also normal.

Electrophysiology Back to Top

Nerve conduction studies gave normal results, but needle electromyography demonstrated fibrillation potentials consistent with acute denervation, fasciculation potentials consistent with anterior horn cell (lower motor neuron) excitability, and large motor unit size consistent with chronic denervation and reinnervation of muscle by surviving lower motor neurons. The findings were seen in three limbs, as well as in thoracic paraspinal and bulbar muscles, and were considered to be consistent with an acute and chronic disorder of the lower motor neurons.

Neuropathology Back to Top

After the death of K.G., an autopsy (limited to the nervous system and muscles) was performed. The brain weight was 1300 g, which is within the normal range. The brain seemed grossly normal, but the spinal cord showed marked atrophy of the anterior roots (versus the posterior roots) and mild degeneration of each lateral corticospinal tract. Microscopic examination demonstrated marked loss of neurons and astrogliosis in the ventral horns bilaterally throughout the cord (Fig. 1). Loss of neurons and astrogliosis was also prominent in the hypoglossal nucleus (CN XII), which innervates the tongue. Small intracytoplasmic inclusion bodies known as Bunina bodies (Fig. 2) and Lewy body-like inclusions (Fig. 3, A and B) were seen in occasional residual anterior horn cells. Immunocytochemistry using antibodies that recognize ubiquitin revealed the presence of intracytoplasmic inclusions within the motor neurons. These inclusions consisted of loosely arranged fibrils (Fig. 4A) or more compact skein-like structures (Fig. 4B). Examination of the primary motor cortex revealed loss of Betz cells and a small group of macrophages laden with lipofuscin (a product of fatty acid oxidation), indicating that these macrophages had phagocytosed components of nerve cells (neuronophagia). Pyramidal tract degeneration was evident in the spinal cord as indicated by pallor (loss of normal coloring) (Fig. 5A) and the presence of numerous microglia and macrophages (Fig. 5B). Neurons of the oculomotor nucleus, trochlear nucleus, dentate nucleus, and dorsal vagal nucleus (brain stem nuclei usually unaffected by ALS) were preserved. Purkinje cells (a prominent class of neurons in the cerebellum) were also preserved.



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Fig. 1. Ventral horn of the spinal cord from an ALS patient. The loss of motor nerve cells is evident, but a few surviving neurons are observed (arrow). One large axonal swelling or spheroid (arrowhead) is present and is typical of ALS. The myelin in the lower part of the field (anterior column) is blue. Luxol fast blue-periodic acid Schiff reagent was used to prepare this specimen; objective magnification x4.

 


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Fig. 2. A Bunina body (BB). A surviving motor neuron exhibits a BB (arrow). This inclusion is eosinophilic, hyaline (glasslike), and fish-shaped, but others may be round or irregular in contour. They contain little or no detectable ubiquitin. The inclusions occur in most patients with ALS and are nearly specific for the disorder. Hematoxylin and eosin were used to stain the BB; objective magnification, x100.

 


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Fig. 3. A Lewy body-like inclusion (LBLI). The cytoplasm of a surviving motor neuron exhibits a round, eosinophilic inclusion (arrow) that is surrounded by a halo (A). The inclusion (arrow) includes strongly immunoreactive ubiquitin (B). Although these inclusions resemble the Lewy bodies of Parkinson's disease, they are not very hyaline (glasslike) and do not contain alpha-synuclein. LBLIs are nearly specific for ALS but are present in only about one-quarter of the patients. Objective magnification, x100.

 


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Fig. 4. Skein-like inclusions. These intracytoplasmic inclusions are located in surviving motor nerve cells. They are ubiquinated and consist of loosely arranged fibrils (A) or more compact bodies (B) that resemble a skein of yarn. Ubiquitin is presumably linked covalently to one or more proteins, although the identity of these macromolecules is not known. Such inclusions are found in nearly 100% of patients with ALS and are nearly specific for this disorder. Immunoperoxidase stains for ubiquitin were used; objective magnification, x100.

 


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Fig. 5. Crossed pyramidal tract of the spinal cord. (A) Myelin pallor is displayed in the pyramidal tract region of a lateral column. Luxol fast blue-periodic acid Schiff reagent was used; objective magnification, x4. (B) A microglial/macrophage marker (CD68) demonstrates numerous positive cells in the pyramidal tract (arrow). Fewer microglial cells or macrophages are present elsewhere in the lateral column and the anterior column. By contrast, only rare CD68 cells are detected in the posterior column. Immunoperoxidase stain for CD68 was used; objective magnification, x2.

 

Discussion Back to Top

ALS (or Lou Gehrig's disease) is a progressive disorder that results in degeneration of the voluntary motor system. It affects both upper and lower motor neurons, which are located in the brain and spinal cord, respectively. Charcot first described the pathological and clinical features of the disease in 1874, detailing the correlations between upper motor neuron symptoms (see below) and lateral sclerosis of the spinal cord (scarring of the lateral spinal cord that contains the corticospinal tracts), and lower motor neuron symptoms and amyotrophy or loss of anterior horn cells. He termed the combination of upper and lower motor neuron signs amyotrophic lateral sclerosis. Additional pathological indications of ALS include neuronal inclusions and astrogliosis.

Symptoms of weakness and muscle atrophy usually begin asymmetrically and distally in one limb, and then spread to involve each contiguous myotome, but symptoms can begin either in bulbar or limb muscles. Extraocular muscles and the urinary sphincters are usually spared. Respiration is usually affected late in those patients whose symptoms are first noticed in the limb (limb-onset patients) but occasionally can be an early manifestation. Clinical signs of both upper and lower motor neuron disease are required for a definitive diagnosis. The clinical features resulting from dysfunction of upper motor neurons include limb spasticity, hyperreflexia, Babinski sign, Hoffmann sign, clonus, and emotional lability; whereas symptoms resulting from dysfunction of lower motor neurons include focal or multifocal limb muscle weakness and atrophy, cramps, fasciculation, dysarthria, and dysphagia (difficulty swallowing). If lower motor neuron signs alone are evident, the condition is referred to as progressive muscular atrophy, whereas if upper motor neuron signs are present exclusively, the label primary lateral sclerosis is used. These two disorders represent about 10% and less than 5% of motor neuron disease cases, respectively.

The clinical diagnosis is confirmed by demonstrating electromyographic evidence of active and chronic denervation in at least three limbs. Nerve conduction studies, the results of which are usually normal, may reveal reduced motor conduction amplitudes as a result of the death of motor neurons. Electromyography tests only the lower motor neurons. Cortical magnetic stimulation and magnetic resonance spectroscopy are nonspecific methods of testing the upper motor neurons and are not required for diagnosis. Results from cerebrospinal fluid testing are usually normal, although protein content might be elevated. One of the most important differential diagnoses is multifocal motor neuropathy with conduction block, an autoimmune disorder that is responsive to immunosuppressive therapy. In this condition, conduction block may be detected by nerve conduction studies, and serum analysis might reveal antibodies to ganglioside. Myasthenia gravis may be considered in patients with bulbar-onset symptoms.

ALS is a rare disorder. The prevalence is 4 to 6 cases per 100,000 individuals, with an incidence of 0.4 to 1.8 new cases per 100,000 per year. In sporadic ALS, the median age of onset is 55 years. Patients with ALS have a mean survival time of approximately 3 years after the onset of symptoms. Patients with older age at onset, bulbar onset, and greater severity of clinical disability or respiratory function have shorter survival times. There is a slight predominance of the disease in males; age and gender are the only recurrent risk factors documented in epidemiological studies. No increased risk based on race or geographic location has been observed, with one exception. ALS occurs with higher than expected frequency on the Marianas Islands of Guam, where this disorder is often associated with parkinsonism and dementia.

The etiology of ALS is not known, and the majority of ALS cases are sporadic. However, ALS is inherited as an autosomal dominant trait known as familial ALS (FALS) in 10 to 15% of cases. Of these, 25% are associated with a defect in the gene encoding the enzyme copper-zinc superoxide dismutase (SOD1). SOD1 catalyzes the conversion of the toxic superoxide anion into hydrogen peroxide and oxygen. After the discovery that mutations in SOD1 were associated with FALS, a transgenic mouse model was developed in which a mutant form of human SOD1 is overexpressed. The SOD1 FALS rodent model has become an important method of pathological study and therapeutic drug screening in ALS-associated research (see "A Game of Cellular Clue", "Nerve Verve", "A Greasy Way to Die", and "A Keen I"). The sporadic and familial forms of human ALS are clinically and pathologically similar to each other and to the rodent model.

Four other types of inherited ALS have been identified. ALS 2, an autosomal recessive juvenile-onset form, maps to a gene that encodes a guanine exchange factor on chromosome 22. Linkages to chromosome 23, 15, and 9 have also been identified. The form linked to chromosome 9 is associated with dementia.

Once the motor neurons have been damaged, be it from genetic or environmental causes, a cascade of intracellular events, including increased levels of the excitatory neurotransmitter glutamate (which can be toxic to neurons), mitochondrial dysfunction, neurofilament aggregation, and free radical production is set in motion, which may lead to cell death via apoptosis and inflammation. Caspase enzymes (which regulate apoptosis) and pro-inflammatory mediators are activated in human and mouse-model ALS. Caspase enzyme inhibitors and anti-inflammatory agents slow disease progression in the SOD1 FALS mouse model but have not yet translated into medications with meaningful impact for humans.

Riluzole, a glutamate antagonist, is the only drug currently approved by the Food and Drug Administration for the treatment of ALS. It slows the progression of the disease and prolongs survival by approximately 11%. Other treatments, which are designed to maintain function as long as possible, include appropriate physical and occupational therapy, maintenance of adequate and safe caloric intake using speech and nutrition therapy and gastrostomy placement if needed, management of respiratory failure with ventilatory assistance, and palliative care in the latter stages to maintain patient comfort. Current clinical research is aimed at identifying and testing medications that counteract the cellular pathophysiologic events that contribute to motor neuron death.


September 3, 2003

Abbreviations: Activities of daily living. Daily tasks such as bathing, eating, and dressing. Clinicians often assess activities of daily living to determine what kind of care a patient needs and to measure the rate of disease progression over time. • Anterior roots. The component of the peripheral process of a lower motor neuron just after it exits the spinal cord and before it has united with the posterior roots to form the peripheral nerve. This component is reduced in size in ALS as a result of the loss of lower motor neurons. • Apoptosis. Programmed cell death, signaled by the nuclei in normally functioning cells when age or the state of cell health dictates. It is an active process requiring metabolic activity by the dying cell, often characterized by cleavage of the DNA into fragments. Cancerous cells lose the normal apoptosis-driven cell death process. In neurodegenerative disorders, cells may undergo apoptosis prematurely. • Astrogliosis. The process of structural repair within the central nervous system whereby astrocytes aggregate and secrete substances in response to local tissue destruction. Glial cells release substances that themselves may damage nearby normal tissue and are designed to facilitate repair and attract other repair cells to the area. • Babinski sign. A reflex movement in which the big toe extends upward when the outer edge of the sole of the foot is scratched. This sign indicates damage to or disease of the upper motor neuron or pyramidal tracts. • Betz cells. The largest motor pyramidal cells of the fifth cerebral cortical layer. This term is synonymous with upper motor neurons. • Bunina bodies. Eosinophilic, rounded or elongated intracytoplasmic inclusion bodies found in the motor neurons of the spinal cord, brain stem, and motor cortex in ALS. • Cerebellum. Portion of the brain that lies just below the posterior part of the cerebrum and behind the brain stem. Integrating information from the cerebrum and peripheral parts of the body, the cerebellum plays an essential role in coordinating voluntary movement, controlling muscle tone, and maintaining balance. • Cerebrospinal fluid. The fluid that bathes and cushions the brain and spinal cord. If the brain shrinks, cerebrospinal fluid fills up the space. This is often seen as an enlargement of the cerebrospinal fluid-filled ventricles. • Charcot, Jean Martin (1825-1893). French neurologist, one of the fathers of modern neurology. An eminent clinician and pathologist as well as a neurologist, he created the method that correlates the patient's symptoms with the lesions discovered at autopsy. He was the first to describe the disintegration of joints (the condition now known as Charcot's joint) caused by syphilis. He did pioneering work on the determination of the brain centers responsible for specific nervous functions. He demonstrated the clear relationship between psychology and physiology, and his work on hysteria and hypnosis stimulated Sigmund Freud, one of his students, to pursue the psychological origins of neurosis. He defined motor neuron disease as an entity and formulated the term "amyotrophic lateral sclerosis," still called Charcot's disease in Europe. • Clonus. The term used to describe a hyperactive response to tapping of a muscle tendon (deep tendon reflex). It is characterized by rapid, repetitive, alternating muscular contraction and relaxation. On rare occasions it occurs spontaneously. Clonus may be a sign of damage to the upper motor neurons. A typical example of clonus is called ankle clonus. A physician may demonstrate this type by forcibly jerking the front of the foot upward, stretching the muscles of the calf, which are then triggered into a series of rhythmic contractions. • Corticospinal tract. A column of motor fibers that run on each side of the brain stem and spinal cord and are continuations of the pyramids of the medulla oblongata. The tracts contain fibers of the upper motor neurons that originate in the cerebral cortex and descend to synapse on the lower motor neurons in the brain stem and spinal cord. Degeneration of these tracts is termed lateral sclerosis. • Cramps. Sudden, severe, painful, involuntary contractions of muscles, most commonly experienced in the calves by elderly people during the night but may occur with increased frequency in denervated muscles. This condition can be relieved by passive stretching. • Dementia. The loss of cognitive and intellectual capacities characterized by deficits in memory, attention, orientation, language, judgment, and motor and spatial skills and in altered emotional behavior and personality. Dementia is most commonly caused by conditions that injure the brain at tissue or cellular levels, notably by Alzheimer's disease, but may be caused by many conditions, including other neurodegenerative disorders such as Parkinson's disease or ALS. • Denervation. The separation of muscle from its nerve supply. Clinically, the resulting changes in muscle include atrophy and weakness. Electromyographically, spontaneous activity, such as fibrillation potentials, are seen, as well as abnormalities of the remaining motor unit potentials with increased amplitude, abnormally long duration, polyphasia, and a high firing rate. • Dysarthria. The indistinct pronunciation of words, resulting from disturbance in the muscular control of the speech mechanisms, including tongue, lips, and throat. A frequent component of most neuromuscular disorders. Can progress to complete loss of intelligible speech in ALS. • Electromyography (EMG). A test in which the electrical activity in muscle, as detected by a small needle electrode, is analyzed after being amplified, displayed, and recorded. It is used to diagnose neuromuscular disorders. • Fasciculation. Clinically, the spontaneous contractions of all of the muscle cells supplied by a lower motor neuron (defined below).The twitches do not usually move joints but can be seen and felt by the subject or by an observer. • Fibrillation potentials. Action potentials of spontaneously contracting individual muscle fibers. The action potentials occur spontaneously after denervation. In contrast to fasciculation, which can be seen clinically or measured with electromyography, fibrillation potentials can only be measured with EMG. • Forced vital capacity. A pulmonary function test used to assess diaphragm strength in which the patient inhales completely and then the volume of the forced exhalation is determined. The forced vital capacity is expressed as a percentage of the normal mean for the patient's height and weight. • Gastrostomy. The surgical formation of an opening through the abdominal wall into the stomach. In ALS, a semipermanent feeding tube is placed through the opening so that ALS patients with severe swallowing weakness can maintain adequate hydration and nutrition. • Hoffmann sign. Flexion of the terminal phalanx of the thumb in response to the sudden release of the flexed distal phalanx of the second, third, or fourth digits. This response is a sign of hyperreflexia and in the proper setting may indicate disease of the upper motor neurons (defined below). • Hospice. A service that provides a program of palliative and supportive care to dying persons and their families in the form of physical, psychological, social, and spiritual care. Such services are provided by an interdisciplinary team of professionals and volunteers who are available at home and in specialized inpatient settings. • Hyperreflexia. Abnormally exaggerated reflex strength associated with a lack of corticospinal inhibition, suggesting upper motor tract disease. • Lewy body. A type of eosinophilic inclusion body found in the cytoplasm of neurons of the cortex and brain stem in Parkinson's disease, some forms of dementia, and occasionally ALS. Lewy bodies contain many proteins, but three proteins are particularly abundant: alpha-synuclein, neurofilament, and ubiquitin. • Lower motor neuron. A motor neuron in which the cell body resides in the ventral horn of the spinal cord, or in the brain stem. This structure receives input from the upper motor neuron and synapses directly on muscle. Diseases of the lower motor neuron (amyotrophy) may cause wasting, weakness, and depressed deep tendon reflexes. • Magnetic resonance imaging (MRI). MRI is a diagnostic technique in which the body to be imaged is inserted into a magnetic field, causing the magnetic spin of the hydrogen nuclei to align with the magnet. Radio signals are used to transiently perturb this alignment. As the nuclei snap back into alignment, weak electromagnetic signals are produced. Multiple signals are integrated by computer to construct an image of the tissue. MRI provides excellent resolution for detecting and localizing brain pathologies. MRI is also referred to as nuclear magnetic resonance imaging. • Magnetic resonance spectroscopy. A technique based on the principles of MRI but which also examines the concentration and distribution of elements other than the hydrogen proton, thus providing information on the metabolism of tissues without direct intervention such as biopsy. • Motor neuron disease. A group of rare disorders in which the nerves that control muscular activity degenerate within the brain and spinal cord. • Multifocal motor neuropathy with conduction block. An autoimmune condition in which autoantibodies are produced that recognize the peripheral components of lower motor neurons. These antibodies cause demyelination (and conduction block as assayed by nerve conduction studies) and symptoms that can be similar to those of ALS. The condition is treated by immunosuppressive therapy. • Myotome. The muscles supplied by a specific spinal cord segment. • Nerve conduction studies. The recording and analysis of electrical waveforms generated by peripheral nerves in response to electrical or physiological stimuli. These studies give a measure of the integrity of the peripheral nerve and are usually performed in conjunction with an electromyogram. • Noninvasive positive pressure ventilation. A form of noninvasive respiratory support for patients with respiratory muscle weakness, in which a device connected to a face mask worn by the patient forces small volumes of air into the airway at a specified frequency to assist the patient's own respiration. • Parkinsonism. Symptoms of the type seen in Parkinson's disease, such as rigidity, loss of balance, certain tremors, or bent posture. • Primary lateral sclerosis. A rare form of motor neuron disease affecting only the upper motor neurons. Symptoms include progressive spasticity, hyperreflexia, and Babinski signs. • Progressive muscular atrophy. A form of motor neuron disease in which the upper motor neurons are largely unaffected, with the principal disease being within the lower motor neurons. Symptoms include progressive muscle weakness and wasting, fasciculation, and loss of deep tendon reflexes. • Pseudobulbar affect. Emotional lability. This phenomenon involves involuntary crying or laughing and the expression of emotion without experiencing it, usually in the context of brain disease affecting the descending motor pathways bilaterally. • Pyramidal tract. Corticospinal tract. A fiber pathway comprising a bundle of about a million descending fibers that arise from the Betz cells of the motor cortex and traverse the medullary pyramids en route to the anterior horn cells in the spinal cord. • Riluzole. A medication used to treat patients with ALS. Riluzole is not a cure for ALS, but it may extend survival in the early stages of the disease and/or may extend the time until a tracheostomy may be needed. Originally designed as an antiepileptic medication because of its glutamate antagonism properties, it was tested as a treatment for ALS after identification of excess glutamate in the ALS mouse model and in some patients with ALS. • Spasticity. A motor disorder characterized by a velocity-dependent increase in muscle tone and often associated with exaggerated tendon jerks. This disorder results from a loss of supraspinal control, which leads to reduced descending inhibition and excessive activity of motor neurons. Spasticity is one component of upper motor neuron syndrome. • Ubiquitin. A cellular protein that is one component of neuronal inclusions seen in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and ALS. • Upper motor neuron. Motor neurons residing withing the cerebral cortex. These structures descend in the pyramidal tract or corticospinal tract between the cortex and the brain stem or spinal cord to synapse on the lower motor neurons. A lesion will produce a syndrome of increased tone (spasticity), decreased power, hyperreflexia, and Babinski signs. • Ventral horns. The anteriormost component of the spinal cord that contains the cell bodies for the lower motor neurons.

Suggested ReadingBack to Top

  • J. Andersen, Defects in dynein linked to motor neuron degeneration in mice. Sci. SAGE KE 2003, pe10 (2003). [Abstract] [Full Text]
  • M. Mitsumoto, D. A. Chad, E. P. Pioro, Amyotrophic Lateral Sclerosis (Davis, Philadelphia, PA, 1998).
  • H. Mitsumoto, Clinical trials: present and future. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 2 (suppl. 1), S10-S14 (2001). [Abstract]
  • T. L. Munsat, P. L. Andres, L. Finison, T. Conlon, L. Thibodeau, The natural history of motor neuron loss in amyotrophic lateral sclerosis. Neurology 38, 409-413 (1988). [Abstract]
  • S. Przedborski, H. Mitsumoto, L. P. Rowland, Recent advances in amyotrophic lateral sclerosis research. Curr. Neurol. Neurosci. Rep. 3, 70-77 (2003). [Abstract]
  • L. P. Rowland, Merritt's Textbook of Neurology, L. P. Rowland, Ed. (Williams and Wilkins, Philadelphia, PA, ed. 9, 1995), pp. 742-749.
  • L. P. Rowland, N. A. Shneider, Amyotrophic lateral sclerosis. N. Engl. J. Med. 344, 1688-1700 (2001). [Abstract]
Citation: P. H. Gordon, H. Mitsumoto, A. P. Hays, Amyotrophic Lateral Sclerosis. Sci. SAGE KE 2003 (35), dn2 (2003).








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