Amyotrophic Lateral Sclerosis Case File

Amyotrophic Lateral Sclerosis Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 41

A 64-year-old man comes to a neurologist with an 11-month history of progressive weakness. Initially, he noticed weakness of his right hand and difficulty grasping things. This progressed to right shoulder and upper arm weakness, with difficulty raising his arm above his head or buttoning his clothes. Over the past couple of months, he has also noted frequent tripping and stumbling while walking. Past medical history is significant for hypertension and arthritis in his bilateral knees. On examination, the patient is in no acute distress and cognitively intact. General examination reveals muscle atrophy and wasting of the intrinsic and small muscles of his right hand, right triceps, and right shoulder. There is visible muscle twitching of both arm muscles and paraspinal muscles of his back. The neurologic examination reveals significant weakness of the right upper extremity and moderate weakness of his left deltoid and biceps and bilateral hip flexors. Hyperreflexia is noted in both legs and left arm. His sensory and cerebellar examinations are normal. He denies pain to palpation of all muscle groups. Magnetic resonance imaging (MRI) of the brain and spine are normal. Laboratory studies are normal. Electrodiagnostic studies (electromyography [EMG]/nerve conduction velocity [NCV]) reveal diffuse muscle denervation in his arms, legs, and paraspinal muscles. There is no evidence of neuropathy or myopathy.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 41:

Amyotrophic Lateral Sclerosis                                                       

Summary: A 64-year-old relatively healthy man presents with progressive skeletal muscle weakness of both upper extremities and left lower extremity. His examination and diagnostic workup reveal pure motor weakness, without sensory and cerebellar involvement or spinal cord and brain abnormalities.

• Most likely diagnosis: Motor neuron disease—amyotrophic lateral sclerosis (ALS)
• Next diagnostic step: EMG of the skeletal muscle and nerve conduction study (NCS) of the peripheral nerve and nerve roots
• Next step in therapy: Supportive management of mobility and monitoring of respiratory and swallowing function

ANALYSIS

Objectives

1. Describe the diagnostic approach to motor neuron disease/ALS including neuroimaging, laboratory and pathologic studies, and electrodiagnostic tests.
2. Understand that ALS is a diagnosis based on the exclusion of other pure or predominantly motor syndromes.
3. Be familiar with the management of ALS.

Considerations

This 64-year-old man complains of progressive skeletal muscle weakness of his right upper extremity associated with muscle wasting (atrophy) along with recent gait abnormalities. His examination is also significant for weakness in the left upper and lower extremity. He reports no loss of sensation by history or examination; thus, this is a pure skeletal muscle (motor) process. The possible site(s) of pathology or disease for a pure motor process includes the motor cortex (voluntary motor control), motor neurons (voluntary movement), motor roots originating from the cord, or the muscle. These sites can be grouped into upper motor pathways and lower motor pathways.

Upper motor pathways include the upper motor neuron located in the motor cortex of the brain. Myelinated nerve fibers (corticospinal tract) originate from these neurons and travel to synapse on lower motor neurons located in the brainstem and spinal cord. It is at the level of the lower motor neuron that the lower motor neuron pathway originates. From the lower motor neuron, the motor nerve root originates and in combination with other nerve roots becomes a nerve, which synapses with the skeletal muscle and thus controls skeletal muscle movement of the face and body. Diseases that affect motor pathways can often be distinguished based on whether the upper or lower motor pathways are purely or predominantly effected. Patients with upper motor pathway disease will present with spastic muscle weakness associated with increased reflexes, whereas those with lower motor pathway disease will present with flaccid skeletal muscle weakness associated with muscle atrophy and decreased or absent reflexes. The latter presentation is caused by loss of direct innervation of the muscle and can also be accompanied by muscle twitching (fasciculations) and/or muscle cramping. Interestingly, oculomotor nuclei of the eye, and anal/bladder sphincter skeletal muscles are relatively spared in most patients.

Diagnoses to consider when the presentation is predominantly a lower motor pathway syndrome include processes that affect lower motor neurons, motor roots, nerves, or muscle, including spinal cord and root compression, motor neuropathies (Guillain-Barré syndrome, multifocal motor neuropathy), and myopathies (polymyositis). Diagnoses to consider when the presentation is predominantly an upper motor pathway syndrome include processes that affect upper motor neurons, motor cortex, and associated pathways, such as stroke, tumors, and demyelinating disease, such as multiple sclerosis. Of note, spinal cord compression can cause signs and symptoms of both upper and lower motor syndromes when compression involves descending motor pathways and contiguous motor nerve roots at that level of the cord.

In this case, the man presents with signs and symptoms of both upper and lower motor dysfunction. Neuroimaging of his brain and spinal cord rules out a brain, cord, or root process. Electrodiagnostic studies of his muscles and nerves rule out a neuropathy or myopathy. Thus, his presentation is consistent with a motor neuron process affecting both upper and lower motor neurons, such as ALS.

It is important to note that there is no cure for ALS. Therefore, other reversible processes that may cause mixed upper and lower motor neuron deficits need to be first ruled out before a diagnosis of ALS is given.

APPROACH TO:

Pure Motor Weakness                                                     

DEFINITIONS

UPPER MOTOR NEURON DISEASE: Pathologic process resulting in skeletal muscle weakness, spasticity, and increased reflexes with normal sensation.

LOWER MOTOR NEURON DISEASE: Pathologic process resulting in skeletal muscle weakness, flaccidity, decreased or absent reflexes, muscle atrophy, and fasciculations with normal sensation.

MYELOPATHY: Pathologic process that is extrinsic or intrinsic to the spinal cord, which can result in muscle weakness, spasticity, and sensory abnormalities at and below the level of the cord pathology.

RADICULOPATHY: Pathologic process affecting the motor and/or sensory nerve roots, which originate from or enter into the spinal cord; it is usually caused by compression or narrowing of nerve root foramen (nerve/root canal) associated with degenerative spine or disc disease (spondylosis or spondylolisthesis).

CLINICAL APPROACH

Clinical Features and Epidemiology

ALS is caused by the degeneration of both upper (corticospinal) and lower (spinal) motor neurons, resulting in skeletal muscle atrophy and weakness and culminating in respiratory insufficiency. Onset is usually insidious over months with limb onset occurring in 56% to 75% of patients. Involvement of speech (dysarthria) and/or swallowing (dysphagia) is defined as bulbar dysfunction and occurs as the primary symptom in 25% to 44% of patients. Bulbar dysfunction is uncommon when ALS presents in the third and fourth decade but represents more than 50% of patients when ALS presents in the sixth and seventh decades, especially in women.

The incidence (number of new cases per 100,000 per year) and prevalence (the number of existing cases per 100,000 per year) are one to two cases and four to six cases, respectively. There is an overall male predominance of 1.5:1 in sporadic cases, with a ratio of 3-4 to 1 when ALS presents in the third and fourth decades, and 1 to 1 when ALS presents in the sixth and seventh decades. The time interval between first symptom and diagnosis ranges from 9 to 20 months, with an average time interval of 13 months. The overall survival is 3 to 5 years for over 50% of patients, although this can vary between 1 and 20 years. Age of onset is clearly a prognostic factor for survival. Improved survival is also associated with limb onset and slow rate of progression, whereas a poorer prognosis is associated with bulbar (speech and swallowing dysfunction) onset and a faster rate of progression.

Etiology and Pathogenesis

The etiology of ALS is unknown, but 10% of cases are transmitted as a dominant, recessive, X-linked dominant, or indeterminate trait, whereas 90% of cases are sporadic. Of the familial cases, up to 50% are caused by repeat expansions of the C9ORF72 gene located on chromosome 9 and 25% are caused by mutations of the copper-zinc (Cu/Zn) superoxide dismutase gene (SOD1) located on chromosome 21, making mutations in these genes the most common causes of familial ALS. Inheritance is autosomal dominant in these common cases.

C9ORF72 encodes an uncharacterized protein that is highly conserved across species. It has been linked to frontotemporal dementia (FTD) as well as ALS, with some patients developing FTD alone, ALS alone, or both ALS and FTD. Because of the disease spectrum involving FTD, we now know that, contrary to previous dogma that ALS only affects the motor neurons, ALS patients may also exhibit cognitive symptoms.

More than 100 mutations of the SOD1 gene have been linked to familial ALS. For many of these mutations, enzyme activity is actually normal or elevated. Therefore, the mutation of SOD1 gene causes disease by a gain of a toxic, injurious property rather than a loss of enzyme function.

Other genes involved in familial ALS include TAR DNA-binding protein 43 (TDP-43), also found in FTD, and fused in sarcoma (FUS)/translocated in sarcoma, which have roles in DNA/RNA metabolism.

Sporadic cases are likely caused by environmental factors on a susceptible genetic background. This may explain the known increased incidence of ALS in army veterans. In addition, C9ORF72 mutant gene expansions are found in 4% to 20% of sporadic cases, supporting this multifactorial etiopathogenesis.

Several disease processes (pathogenic mechanisms) are implicated in motor neuron degeneration, including overactivation of excitatory neural synapses (excitotoxicity), immune activation and inflammation, mitochondrial dysfunction or altered energy metabolism, impaired clearing of aggregated proteins, and premature cell death (apoptosis). Although disturbances in each of these pathways can contribute to amplification or even initiation of motor neuron injury, the temporal relationship of these pathways and their primacy in dictating disease onset and progression is unclear.

DIAGNOSIS

No one test can provide a definitive diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive of the disorder. The diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. A full medical history and neurologic examination at regular intervals can assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.

Because symptoms of ALS can be similar to those of a wide variety of other more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. These tests include EMG, NCV, and MRI, which can diagnose conditions such as a spinal cord tumor, a herniated disc in the neck, fluid-filled spaces within the cord (syringomyelia), or cervical spine degenerative diseases (spondylosis or spondylolisthesis). A lumbar puncture can evaluate for blood-brain barrier disruption, intrinsic inflammation, or malignant cells.

Based on the patient’s symptoms and findings from the examination and from these tests, the physician can order routine laboratory tests as well as tests on blood and urine samples to eliminate the possibility of other diseases. In some cases, for example, if a physician suspects that the patient has a myopathy rather than ALS, a muscle biopsy can be performed. Infectious diseases such as human immunodeficiency virus (HIV), syphilis, human T-cell leukemia virus (HTLV), and Lyme disease caused by Borrelia burgdorferi infection can in some cases cause ALS-like symptoms since they can cause mixed upper and lower motor neuron signs. Metabolic disorders such as B12 and folate deficiencies, which can cause subacute degeneration of the spinal cord, should be ruled out. Neurologic disorders such as multiple sclerosis, postpolio syndrome, multifocal motor neuropathy, and spinal muscular atrophy (lower motor neuron disease), myasthenia gravis, and Lambert-Eaton syndrome also can mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis.

Because of the prognosis of this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, patients may wish to obtain a second neurologic opinion. Based on El Escorial diagnostic criteria determined by World Federation of Neurology Research Group on Motor Neuron

Diseases, a definite diagnosis of ALS requires the presence of both upper and lower motor neuron signs in at least three separate regions, including upper and/or lower extremities, tongue/speech, and paraspinal muscles using clinical, laboratory, radiographic, and pathologic results.

TREATMENT

The only first Food and Drug Administration (FDA)-approved drug for the disease is riluzole (Rilutek). Riluzole is believed to reduce damage to motor neurons by acting on voltage-gated sodium channels and decreasing the release of glutamate, a neurotransmitter involved in excitotoxicity; one of the disease mechanism implicated in ALS. Clinical trials with ALS patients showed that riluzole prolongs survival by several months, mainly in those with difficulty swallowing. The drug also extends the time before a patient needs ventilation support. Riluzole does not reverse the damage already done to motor neurons, and patients taking the drug must be monitored for liver damage and other possible side effects. However, this drug offers hope that the progression of ALS may one day be slowed by new medications or combinations of drugs. Recently, the FDA approved edavarone (Radicava), a free radical scavenger, for the treatment of ALS based upon a Phase III study completed in Japan. The study showed that patients in the early stage of disease who were randomized to receive endavarone had 33% less disability at 6 months than those receiving placebo. It is unclear whether other populations, including patients with more advanced disease, will experience benefit.

Other treatments for ALS are designed to relieve symptoms and improve the quality of life for patients. This supportive care is best provided by multidisciplinary teams of health care professionals such as physicians; pharmacists; physical, occupational, and speech therapists; nutritionists; social workers; and home care and hospice nurses. Working with patients and caregivers, these teams can design an individualized plan of medical and physical therapy and provide special equipment aimed at keeping patients mobile and comfortable. In addition, multidisciplinary team care of ALS patients is associated with improved survival and quality of life. The most important facets of supportive care in ALS include maintenance of respiratory function, nutrition and prevention of weight loss, and prevention of trauma and falls.

All patients with ALS should have serial assessment of their pulmonary function. When the muscles that assist in breathing weaken, use of noninvasive ventilatory assistance can be used to aid breathing during sleep. Such devices artificially inflate the patient’s lungs from various external sources that are applied directly to the airway. When muscles are no longer able to maintain oxygen and carbon dioxide levels, patients can consider more invasive and permanent forms of mechanical ventilation (respirators) in which a machine inflates and deflates the lungs. This requires a tracheostomy, in which the breathing tube is inserted directly in the patient’s trachea. Patients and their families should consider several factors when deciding whether and when to use one of these options. Ventilation devices differ in their effect on the patient’s quality of life and in cost. Although ventilation support can ease problems with breathing and prolong survival, it does not affect the progression of ALS. Patients need to be fully informed about these considerations and the long-term effects of life without movement before they make decisions about ventilation support.

Patients and caregivers can learn from speech therapists and nutritionists how to plan and prepare numerous small meals throughout the day that provide enough calories, fiber, and fluid and how to avoid foods that are difficult to swallow. Patients may begin using suction devices to remove excess fluids or saliva and prevent choking. When patients can no longer get enough nourishment from eating, doctors may advise inserting a feeding tube into the stomach. The use of a feeding tube also reduces the risk of choking and pneumonia that can result from inhaling liquids into the lungs. The tube, once placed, is not painful and does not prevent patients from eating food orally if they wish. Physicians can prescribe medications to help reduce emotional labiality (pseudobulbar affect) and fatigue, ease muscle cramps, control spasticity, and reduce excess saliva and phlegm. In particular, Nuedexta has been shown to be effective in treating pseudobulbar affect. Drugs also are available to help patients with pain, depression, sleep disturbances, and constipation. Physical therapy and special equipment can improve and maintain the patient’s independence and safety throughout the course of the disease. Low-impact aerobic exercises such as walking, swimming, and stationary bicycling can strengthen unaffected muscles, improve cardiovascular health, and help patients fight fatigue and depression. Range-of-motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles. Physical therapists can recommend exercises that provide these benefits without overworking muscles. Occupational therapists can suggest devices such as ramps, braces, walkers, and wheelchairs that help patients conserve energy and remain mobile.

ALS patients who have difficulty speaking can benefit from working with a speech therapist. These health professionals can teach patients adaptive strategies, such as techniques to help them speak louder and more clearly. As ALS progresses, speech therapists can help patients develop ways for responding to yes-or-no questions with their eyes or by other nonverbal means and can recommend aids such as speech synthesizers and computer-based communication systems. These methods and devices help patients communicate when they can no longer speak or produce vocal sounds.

Social workers and home care and hospice nurses help patients, families, and caregivers with the medical, emotional, and financial challenges of coping with ALS, particularly during the final stages of the disease. Social workers provide support such as assistance in obtaining financial aid, arranging durable power of attorney, preparing a living will, and finding support groups for patients and caregivers. Respiratory therapists can help caregivers with tasks such as operating and maintaining respirators, and home care nurses are available not only to provide medical care but also to teach caregivers about giving tube feedings and moving patients to avoid painful skin problems and contractures. Home hospice nurses work in consultation with physicians to ensure proper medication, pain control, and other care affecting the quality of life of patients who wish to remain at home. The home hospice team can also counsel patients and caregivers about end-of-life issues.

CASE CORRELATION

• See also Case 38 (Chronic Inflammatory Demyelinating Polyneuropathy), Case 39 (Guillain-Barré Syndrome), and Case 40 (Dermatomyositis)

COMPREHENSION QUESTIONS

41.1 A 65-year-old man is being seen by his physician for progressive weakness. The physician is suspecting ALS. Which of the following diagnostic studies is critical to the diagnosis?

A. Cerebrospinal fluid (CSF) analysis

B. Electroencephalograph (EEG)

C. EMG/NCV

D. Genetic testing

41.2 What percentage of ALS cases is familial?

A. 10%

B. 25%

C. 50%

D. 100%

41.3 A 62-year-old woman is being evaluated for weakness and suspected ALS. Which of the following clinical features would be expected in this patient?

A. Sensory loss on face

B. Resting tremor of the hands

C. Slurred speech

D. Loss of position sense of the toes

ANSWERS

41.1 C. ALS is diagnosed based on the presence of upper and lower motor neuron weakness and physical examination findings. It is confirmed by EMG/NCV findings showing normal sensory NCSs, abnormal motor nerve conduction, and reduced motor compound muscle action potentials along the muscles of the concern. Some of the other answer choices may help to support the diagnosis or rule out other causes.

41.2 A. Ten percent of all ALS cases show an autosomal dominant inheritance pattern. Most (90%) of ALS is sporadic, and the affected person is the only one in his/her family with the disease. Individuals with familial ALS usually have an onset earlier than those with sporadic disease.

41.3 C. ALS is motor neuron disorder and is not associated with sensory symptoms. Early symptoms include difficulty with manual dexterity (buttoning shirt, writing with pen), difficulty walking, slurred speech, and then over time, the weakness progresses to involve swallowing and breathing. Twitching of the muscles can be seen, but not tremor. Some ALS patients will also have a dementia.

    CLINICAL PEARLS    

▶ ALS is a progressive neurodegenerative disease, which is sporadic in 90% to 95% of cases. ▶ Cervical myelopathy is a common mimic of ALS and must be ruled out by appropriate imaging studies. ▶ ALS is a diagnosis of exclusion and requires evaluation for metabolic, structural, and infectious or inflammatory disorders that can produce an ALS-like presentation. ▶ Riluzole is the first FDA-approved drug for ALS and has been shown to prolong survival by 10%, as defined by a delay in initiating invasive ventilatory support by 3 months. ▶ Radicava is the second FDA-approved drug for ALS and has been shown to delay disability in ALS patients treated at earlier stage of disease. ▶ Nuedexta is effective in treating pseudobulbar affect, which can affect up to 50% of ALS patients.

REFERENCES

Boylan K. Familial amyotrophic lateral sclerosis. Neurol Clin. 2015;33(4):807-830. 

Miller RG, Jackson CE, Kasarskis EJ, et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-1233. 

Pioro EP. Review of dextromethorphan 20 mg/quinidine 10 mg (NUEDEXTA®) for pseudobulbar affect. Neurol Ther. 2014;3(1):15-28. 

Simpson EP, Yen AA, Appel SH. Oxidative stress: a common denominator in the pathogenesis of amyotrophic lateral sclerosis. Curr Opin Rheumatol. 2003;15(6):730-736. 

Traynor BJ, Codd MB, Corr B, et al. Clinical features of amyotrophic lateral sclerosis according to the El Escorial and Airlie House diagnostic criteria: a population-based study. Arch Neurol. 2000;57(8):1171-1176. 

Van den Berg JP, Kalmijn S, Lindeman E, et al. Multidisciplinary ALS care improves quality of life in patients with ALS. Neurology. 2005;65(8):1264-1267. 

Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. The Lancet. Neurology. 2017;16(7):505-512.

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