AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Amyotrophic lateral sclerosis (ALS) is the most common type of adult-onset motor neuron disease. Adult-onset motor neuron diseases are a group of neurologic disorders that present in adult life and are characterized primarily by progressive degeneration and loss of motor neurons. ALS involves both upper and lower motor neurons and presents as an idiopathic, progressive degeneration of anterior horn cells and their associated neurons resulting in progressive muscle weakness, atrophy, and fasciculations. The disease was first described in 1869 and is commonly called Lou Gehrig disease after the professional baseball player who died of ALS in 1941.

Other diseases classified as adult-onset motor neuron diseases have more restricted presentations and can evolve into idiopathic ALS if the patient is tracked for a long period. These diseases include the following:

• Progressive bulbar palsy - Pure bulbar involvement
• Progressive muscular atrophy - Pure lower motor neuron degeneration
• Primary lateral sclerosis - Pure upper motor neuron degeneration
• Adult-onset spinal muscular atrophy - Includes a broad range of primary motor neuron diseases classified by pattern of inheritance, distribution of weakness, or age of onset

Pathophysiology

ALS is named for its underlying pathophysiology. Amyotrophy refers to the atrophy of muscle fibers, which are denervated as their corresponding anterior horn cells degenerate. Lateral sclerosis refers to hardening of the anterior and lateral columns of the spinal cord as motor neurons in these areas degenerate and are replaced by fibrous astrocytes (gliosis).

Axonal Degeneration

Motor axons die by Wallerian degeneration, and large motor neurons are affected to a greater extent than smaller ones. This process occurs as a result of the death of the anterior horn cell body, leading to degeneration of the associated motor axon. As the axon breaks down, surrounding Schwann cells catabolize the axon's myelin sheath and engulf the axon, breaking it into fragments. This forms small ovoid compartments containing axonal debris and surrounding myelin, termed myelin ovoids. Ovoids then are phagocytized by macrophages recruited into the area to clean up debris.

This type of axonal degeneration can be seen in the brain on biopsy as atrophy and pallor of myelinated motor axons in the corticospinal tracts. In cases where the disease has been active for a long time, atrophy of the primary motor and premotor cortex may be seen as well. On biopsy of the spinal cord, degeneration of the myelinated motor axons with associated atrophy of the anterior motor roots of the spinal cord can be observed. Wallerian degeneration also occurs peripherally, and collateral branches of surviving axons in the surrounding area can be seen attempting to reinnervate denervated muscle fibers. On muscle biopsy, various stages of atrophy are noted from this pattern of denervation and subsequent reinnervation of muscle fibers.

In typical ALS, certain motor neurons are spared. In the brainstem, these include the oculomotor, trochlear, and abducens nerves. In the spinal cord, the posterior columns, spinocerebellar tracts, nucleus of Onuf (controls bowel and bladder function), and the Clarke column generally are spared, though the Clarke column can be affected in the familial form of the disease.

Frequency

United States

Currently, prevalence of ALS in the United States is estimated at 25,000-30,000 cases.

International

Annual incidence of ALS is 1-2 per 100,000 population with prevalence rate of 6 per 100,000 in the adult population. A geographic focus of the disease has been noted with increased incidence in the western Pacific where, in many cases, it is associated with Parkinsonism and dementia.

Mortality/Morbidity

Mean duration of ALS from onset to ventilator dependence or death is 2-4 years. Once ventilator use is initiated, mean survival generally is an additional 5 years, but frequently exceeds 10 years. Most patients who opt for ventilatory support die within 5 years of diagnosis, but a small percentage (8-22%) survive 10 years.

Sex

Male-to-female ratio is 1.5-2:1.

Age

ALS may occur from the teenage years to the late 80s, but peak age at onset occurs from 55-75 years with mean age of 62 years at diagnosis.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The clinical picture in all stages of ALS can vary and depends on the areas of the nervous system involved in each patient. Overall, the disease tends to be insidious and progressive with asymmetric weakness and atrophy. Fasciculations are seen from lower motor neuron involvement, and patients generally are hyperreflexic from upper motor neuron disease, though some reflexes may be diminished or absent because of excessive lower motor neuron degeneration.

In 75-80% of patients, symptoms begin with limb involvement, while 19-25% of patients present with bulbar symptoms. For those with limb involvement at presentation, incidence of upper limb versus lower limb involvement is approximately equal. Patients who have lower limb onset initially may complain of tripping, stumbling, or awkwardness when running. Those with upper limb onset may have difficulty with actions such as buttoning clothes, picking up small objects, or turning a key. With bulbar onset, patients note problems such as slurred speech, hoarseness, or decreased volume of speech.

Disease progression

As the disease progresses, muscle atrophy becomes more apparent, and spasticity may complicate gait and manual dexterity. Physicians usually recognize fasciculations first, but as patients become more aware of the involuntary twitchings, they may become embarrassed by them. Immobility predisposes the patient to development of painful joint contractures. Muscle cramps are common, and, in some patients, persistent cramping of muscles and related joint stresses can cause diffuse and continuous aching of the limbs and back.

In patients with bulbar involvement, a mixture of spastic and flaccid components may characterize speech, resulting in a dysarthria with severe disintegration and slowness of articulation. Hypernasality occurs from palatal weakness, and patients eventually develop a strained, strangled vocal quality. With time, speech may be lost, and patients need to depend on other forms of communication such as writing, communication boards, or other assistive devices.

Patients with bulbar involvement also can develop swallowing difficulties (dysphagia) from progressive motor weakness. Swallowing liquids requires the greatest oropharyngeal muscle control; therefore, patients usually complain of more difficulty with liquids than with solids. Drooling is common and results from a combination of excessive salivation and poor labial control.

Some individuals may have pseudobulbar symptoms associated with their disease. These patients have an exaggerated emotional response, resulting in frequent and rapid alterations in emotions. Episodes of intense laughter may be followed immediately by tears, but the patient's response usually does not correspond to apparent social stimulus or the current psychosocial situation.

Preserved functions

Certain motor neurons usually are spared, and, as a result, patients have some functions that are preserved. Most retain extraocular movements and bowel and bladder control. Once patients become more affected, they may develop problems with urge incontinence and severe constipation because of weak abdominal musculature, but sphincter control generally is unaffected.

Since the disease primarily involves motor neurons, sensory function typically is preserved. Patients may complain of some numbness and paresthesias, but most do not have sensory symptoms. Sensory nerve conduction studies can be performed if indicated, but results generally are normal unless there is another identifiable condition to account for the patient's symptoms. Abnormalities have been reported on sensory nerve conduction studies in a small number of ALS patients. These findings, however, are varied, as they can be difficult to identify on routine nerve conduction studies.

In most patients, cognitive functioning is preserved. However, 3.5% of patients do exhibit clinical signs of dementia. These patients are usually found in the western Pacific, and may have associated symptoms of Parkinsonism.

Skin integrity usually is maintained, primarily from the combination of preserved sensory function along with continued control of bowel and bladder function. Some studies on these patients also have found morphologic changes in the skin that are complex and poorly understood but that may contribute to preservation of skin integrity.

Physical

Examination should correlate with the patient's clinical history and disease progression.

• Muscle weakness usually is asymmetric, and signs of both upper and lower motor neuron involvement should be observed.
• In the initial stages, reflexes should be normal to increased, but as the disease becomes more advanced, reflexes may be diminished or absent. Pathologic long-tract signs of upper motor neuron involvement, such as the extensor plantar response and/or Hoffmann sign, may be present in patients with hyporeflexia or areflexia, depending upon the extent of the upper motor neuron involvement.
• In patients with bulbar involvement, speech may be impaired.
• Initially, a gag reflex should be present, and, if elicited, the physician should observe swallowing to check for signs of dysphagia. In advanced stages, the gag reflex may be absent; these patients probably have severe dysphagia and are at high risk for aspiration.

Causes

ALS can be divided into familial and sporadic forms. Most are sporadic, accounting for 90-95% of cases. Remaining cases are familial. The clinical picture in the familial type of ALS is the same as in the sporadic form of the disease. Familial ALS nearly always is transmitted in an autosomal dominant pattern, and, in a subset of patients, a mutation for the gene Cu/Zn superoxide dismutase on chromosome 21 has been identified. Recent research points to involvement of deregulated cdk5 activity in the pathogenesis of the disease in individuals with this mutation. A second gene, ALS2, has also been found to be associated with the familial form of the disease. The role of these genes needs to be studied further.

Current research into the mechanisms resulting in both sporadic and familial types of ALS has focused on excitotoxicity. This may occur secondary to overactivation of glutamate receptors, autoimmunity to calcium ion channels, oxidative stressors linked to free radical formation, or even cytoskeletal abnormalities such as intracellular accumulation of neurofilaments. Apoptosis has emerged as a significant pathogenic factor, and recent evidence suggests that insufficient vascular endothelial growth factor may also be a risk factor for ALS in humans. However, no direct mechanism has been identified and most researchers and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of ALS. Current goals for therapies aim at studying combinations of agents that act by various mechanisms and evaluating stem cell therapy in combination with some of these agents.

Informing the patient

The American Academy of Neurology has established guidelines for breaking the news of a diagnosis of ALS to a patient. They include the following recommendations:

• Give the diagnosis to the patient and discuss its implications. Respect the cultural and social background of the patient in the communication process by asking whether the patient wishes to receive information or prefers the information be communicated to a family member.
• Always give the diagnosis in person, never by telephone.
• Provide printed materials about the disease, contact information for advocacy associations, as well as a letter or audiotape summarizing what has been discussed.
• Avoid withholding the diagnosis, providing insufficient information, delivering information callously, or taking away or failing to provide hope.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Central nervous system tumors
Lead intoxication
Mercury poisoning
Motor neuropathies
Multifocal acquired demyelinating neuropathy
Myasthenia gravis
Myopathies
Polymyositis
Spinal cord AV malformation, monoclonal and disimmune gammopathies
Acute viral infections involving motor neurons—polio, Coxsackie, and herpes zoster viruses
Lymphoma
Vasculitis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Lab test results generally are normal and are performed primarily to rule out other disease processes. Biochemical markers in blood or cerebrospinal fluid (CSF) are used almost routinely to identify diseases that could mimic ALS. Genetic testing may be performed to identify gene defects in some familial types of ALS as well as other inherited motor neuron diseases.
• Diagnosis of ALS should be made according to established and well-accepted criteria after a thorough history, physical examination, and diagnostic workup. This ensures that no treatable or nonfatal disorder accounting for the patient's symptoms is overlooked. El Escorial Criteria for the Diagnosis of ALS were established by the World Federation of Neurology (WFN) in 1994 and revised by the WFN Research Committee on Motor Neuron Diseases in 1998 in an effort to increase sensitivity. Revised criteria for diagnosis of ALS require the following:
• • Presence of signs of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic examination
  • Presence of signs of upper motor neuron degeneration by clinical examination
  • Presence of progressive spread of signs within a region or to other regions (bulbar, cervical, thoracic, lumbosacral)
  • Absence of electrophysiologic evidence of other disease processes that might explain the signs of lower and/or upper motor neuron degeneration
  • Absence of neuroimaging evidence of other disease processes that might explain observed clinical and electrophysiologic signs

Imaging Studies

• Neuroimaging may include computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain and spinal cord. These studies may be helpful to rule out structural lesions or neurologic conditions that may mimic ALS. Results of these studies, however, generally are normal in patients with ALS. The value of positron emission tomography scanning, functional MRI, and magnetic resonance spectroscopy in ALS is being studied.

Procedures

• Electromyography
• • Needle EMG recruitment abnormality is due to a loss of anterior horn cells and a reduction in the number of viable motor axons to activate the muscle(s) involved. This loss results in increased recruitment frequency because a decreased number of anterior horn cells (motor axons) is available to be activated as the amount of effort increases. As this process of anterior horn cell loss progresses, fewer and fewer motor axons are viable, causing a higher recruitment frequency with a decreased number of voluntary motor unit action potentials. This must be distinguished from poor activation—slow firing of a few voluntary motor unit action potentials due to upper motor neuron disease, pain inhibition, or poor cooperation.
  • Recently reinnervated muscles demonstrate variability of morphology on needle EMG examination. This is due to sprouting nerve terminals that are unmyelinated, have slower conduction, and may cause intermittent conduction block. Increased polyphagia of voluntary motor unit action potentials is a result of asynchronous firing of reinnervated unmyelinated muscle fibers due to slowed terminal nerve conduction. Over time, the voluntary motor unit action potentials increase in size and duration because of collateral sprouting, bringing more muscle fibers into the motor unit. With maturation of the terminal sprouting, voluntary motor unit action potentials increase in size with reinnervating muscle fibers, restoring their size and a greater degree of motor firing synchrony due to myelinization of terminal nerve fibers and more rapid terminal nerve conduction.
• Signs of both active and chronic denervation are likely to be observed.
• Fibrillation potentials and positive sharp waves represent active denervation.
• Chronic denervation is demonstrated by evidence of large motor unit potentials with increased duration and amplitude, as well as polyphasic potentials, a reduced interference pattern with firing rates higher than 10 Hz, and unstable motor unit potentials.
• Complex repetitive discharges occur in ALS of long duration and other chronic neurogenic atrophic conditions. These are regularly discharging multispike potentials that are time-locked. Other than an EMG finding associated with a chronic neurogenic atrophic condition, this finding has no other unique significance.
• Fasciculation potentials are characteristic of the disease, but their presence is not specific.
• Conversely, clinical presence of fasciculations is very sensitive for the disease and should be present in a patient with ALS.
• Examine at least 3 levels—cervical/thoracic/lumbar paraspinal muscles and bulbar muscles.
• • Most involved limb first—2 or more weak muscles with different innervation
  • Distal muscles of other possibly abnormal extremities
  • If other levels are not abnormal then check bulbar muscles
  • If necessary, for respiratory involvement, check intercostal and respiratory diaphragm
  • Somatosensory evoked potentials to rule out a demyelinating process or primary spinal cord disease

• Nerve conduction studies
• • Motor and sensory nerve conduction studies (NCS) are performed primarily to rule out other disorders. In patients with predominantly lower motor neuron findings, determine if there is conduction block to exclude treatable diseases such as multifocal motor neuropathy.
  • Sensory nerve conduction studies are usually normal, and less than 10% of patients with ALS have abnormal sural sensory nerve conduction studies. If sural nerve conduction studies are abnormal, controlling for temperature and age, some other diagnosis should be strongly considered.
  • In late stages of the disease, lower motor neuron involvement may be extensive, and, in such cases, compound muscle action potentials may be reduced. Hallmark findings in the electrodiagnosis of ALS are normal sensory NCS and abnormal motor NCS, with reduced motor compound muscle action potentials.
  • Repetitive stimulation: Neuromuscular transmission instability of collateral nerve terminal sprouts in ALS patients presents as decrement with slow repetitive stimulation. This instability is present in over 50% of patients with ALS. The decrement is usually less than 10%, and may appear identical to myasthenia gravis. Determining whether myasthenia gravis is a comorbid condition to ALS is not possible by electrodiagnosis alone.
• Biopsy: Muscle or nerve biopsy can be performed to confirm neurogenic abnormalities in ALS and exclude other neuromuscular diseases, but these studies generally are not needed.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Rehabilitation Program

Physical Therapy

Physical therapists should instruct proper stretching and daily range of motion (ROM) exercises to the patient and caregivers. Therapists should try to anticipate the patient's future needs and introduce assistive devices in a timely manner. Lightweight ankle foot orthoses can be provided to minimize foot drop and stabilize weak quadriceps muscles to prevent falls. The physical therapist should also emphasize energy conservation and teach patients and caregivers methods for performing safe, efficient transfers. Therapists also can provide instruction for strengthening exercise programs, but exercises should be performed at submaximal levels in muscles without marked weakness and should be prescribed only for patients with slowly progressive disease. In a recent study, individualized, moderate-intensity, endurance-type exercises for the trunk and limbs performed 15 minutes twice daily was shown to significantly reduce spasticity as measured by the Ashworth scale.

When making wheelchair recommendations, the therapist should try to anticipate the patient's future needs. Wheelchairs should be introduced while the patient is still ambulatory in order to enhance energy conservation. Initially, a lightweight wheelchair should be rented with plans to purchase a heavier, more expensive chair when the patient is no longer able to ambulate. Recommend modifications to the patient's wheelchair in a timely manner and in accordance with the patient's tolerance for gadgets.

Occupational Therapy

Occupational therapists should focus on teaching energy conservation techniques to the patient and caregivers. Adaptive equipment should be introduced early and in synchronization with the patient's progressing needs.

Upper extremity bracing can be used in cases where weakness may alter joint biomechanics. Patients with poor grasp can be provided with a universal cuff, and patients with hand weakness can be braced in 20-25° of extension to improve grip strength. For patients with proximal upper extremity weakness, a balanced forearm orthosis (ie, deltoid aid) may be beneficial to enhance upper extremity movement by eliminating the effects of gravity. When shoulder girdle weakness progresses to advanced stages, slings can be used to decrease pain by limiting traction on the associated ligaments, nerves, and vessels.

For patients with severe limb involvement, introduce environmental control units (ECUs) that utilize oral-motor movements. In patients with severe bulbar involvement, extraocular movements are usually preserved so ECUs incorporating eye gaze technology can be used.

Speech Therapy

Speech therapists can teach patients with bulbar involvement to slow down their speech and exaggerate articulation to improve comprehension for caregivers. For patients with respiratory insufficiency, the therapist can teach phrasing to promote energy conservation. Submaximal tongue strengthening exercises and diaphragmatic exercises also should be taught to help improve articulation and voice projection.

As the patient's voice becomes more strained, the caregiver can be fitted with a hearing aid to promote communication with the patient. This also provides the patient with an "interpreter" who can assist in communicating with others. If the patient and caregiver already have their own form of communication (ie, gestures) that works well for them, encourage them to continue using their existing system as long as it is effective.

Monitor patients, and, as their speech declines, introduce augmentative communication devices, such as writing implements, communication boards, or computer-assistive technology. For those with severe bulbar and limb involvement, eye gaze and blink generally are preserved. Therefore, the speech therapist can take advantage of these preserved functions by introducing blink controlled voice synthesizers, communication boards, and computer assistive devices that utilize eye gaze techniques.

In patients with bulbar involvement, the speech therapist can perform an oropharyngeal assessment to evaluate for clinical signs of dysphagia. In many cases, a videofluoroscopic swallowing evaluation is necessary to identify specific problems during the various phases of swallowing. Speech therapists can provide interventions, such as alterations in the consistency, taste, or temperatures of foods, to improve oral intake and prevent aspiration. Straws may be used to encourage the recommended chin-tuck position for swallowing thin liquids. Enforce upright positioning at all meals, and, in patients with neck extensor weakness, recommend a soft cervical collar to improve positioning during meals.

Respiratory Therapy: Patients with ALS with predominantly limb and respiratory weakness, accompanied by limited bulbar involvement, may prevent respiratory complications and placement of permanent tracheostomy through aggressive pulmonary care. Respiratory therapists can play a critical role in management of these patients.

Recommend that patients perform routine measures of assisted peak cough flows to evaluate bulbar muscle function. Continued attainment of adequate peak cough flow is the most important goal for preventing serious pulmonary complications. Routinely measure vital capacity in both sitting and recumbent positions. Usually, recumbent vital capacity is the first to decline, resulting in nocturnal hypoventilation. Oxyhemoglobin saturations (SaO₂) should be monitored, especially at night in patients complaining of nocturnal awakenings or sleep difficulties. Decreased overnight SaO₂ indicate nocturnal hypoventilation and the need for noninvasive intermittent positive pressure ventilation (IPPV) at night. Despite low SaO₂, do not administer oxygen without invasive ventilation. In patients without invasive ventilation, oxygen administration decreases the respiratory drive and may thereby result in exacerbation of hypercapnia.

Respiratory therapists also are involved in educating patient and caregiver. They can instruct caregivers on proper performance of assisted cough techniques and teach submaximal respiratory strengthening exercises to the patient. Respiratory therapists also can provide instruction for proper use of expiratory muscle aids, such as the intermittent abdominal pressure ventilator and mechanical insufflator-exsufflator. In addition, they can teach patients and caregivers to use and manipulate inspiratory muscle aids, including noninvasive and invasive ventilation.

Finally, respiratory therapists can teach patients glossopharyngeal breathing. This involves gulping boluses of air into the lungs to add to the user's deep breath and can be useful in those with nonbulbar ALS who do not have a tracheostomy. One glossopharyngeal breath contains 6-9 gulps and can provide the patient with weak inspiratory muscles and no vital capacity a safe way to breathe if, for any reason, a ventilator cannot be used or there is sudden ventilator failure.

Medical Issues/Complications

Eventually, all deaths directly caused by ALS result from respiratory complications. This occurs primarily from the patient's inability to ventilate as respiratory muscle weakness progresses. In patients with bulbar weakness, aspiration of secretions or food may occur and precipitate pneumonia resulting in further respiratory compromise; therefore, aggressive respiratory management is necessary in the comprehensive care of patients with ALS.

Routinely measure vital capacity in both the sitting and recumbent positions. Most often, the recumbent measurement declines prior to the sitting measurement. Gravity assists in lowering the diaphragm as the patient's angle of inclination is increased. As respiratory weakness progresses, patients have increasing difficulty with diaphragmatic movement when supine because of the elimination of this effect from gravity. This results in alveolar hypoventilation and ultimate oxyhemoglobin desaturation.

Difficulty sleeping may be the first symptom of hypoventilation. Patients should be questioned routinely regarding sleep habits, and, if a sleep disturbance develops, measure vital capacities both sitting and supine. In addition, perform overnight oxygen saturation monitoring to assess for nocturnal hypoxemia and the need for nocturnal noninvasive intermittent positive pressure ventilation (IPPV).

Noninvasive intermittent positive pressure ventilation

Noninvasive IPPV is a form of mechanical ventilation that does not require placement of a tracheal tube. It can be delivered by mouth, oral-nasally, or nasally. Amount of bulbar involvement and personal preference of the patient determine the type of interface used.

Mouthpiece IPPV most commonly is used in patients with nonbulbar ALS and is effective for 24-hour use. Lip-seal retention can be added to increase efficacy while the patient is sleeping. Nasal interfaces can be used in those with bulbar involvement or for nocturnal ventilation. Some prefer nasal interfaces for daytime use as well because they leave the mouth free for other activities. Custom-molded nasal interfaces or oral-nasal shells also can be made to increase efficacy and/or comfort. Increased risk of death is associated with intolerance to noninvasive IPPV, and increased survival has been documented in those who can tolerate this form of ventilation.

Intermittent abdominal pressure ventilator

Another type of respiratory muscle aid is the intermittent abdominal pressure ventilator. This device assists expiratory muscles and provides daytime ventilatory support. The intermittent abdominal pressure ventilator uses an elastic air sac, which intermittently inflates to aid in expiration. The air sac is contained in a corset, which can be concealed under clothing. This device should not be used in patients with significant scoliosis or obesity. Some patients prefer its use compared to the mouthpiece IPPV, as it also leaves the mouth free for mouthstick and other activities.

Oxygen administration

Oxygen administration depresses the respiratory drive as in chronic obstructive pulmonary disease (COPD). The underlying reason for the patient's hypoxemia is not lack of perfusion, but rather lack of adequate ventilation. Oxygen administration can lead to worsening hypercapnia; therefore, hypoxia in these patients initially should be treated by increasing ventilation, either noninvasively or invasively.

Reserve oxygen administration for patients whose hypoxemia is not reversed with ventilatory support. In such patients, usually an underlying process, such as pneumonia, has resulted in decreased pulmonary perfusion. This situation necessitates oxygen administration, but oxygen should be given only once the airway has been secured and the patient is invasively ventilated. Invasive ventilation in this instance should be temporary until the secondary process has been treated. Following adequate treatment, the patient should be able to return to his or her previous respiratory management.

Peak cough flows

As mentioned earlier, assisted peak cough flows also should be performed regularly and used to monitor bulbar functioning. Once peak cough flows drop below 160 L/min, flows likely are inadequate to clear debris, thereby resulting in mucous plugging. Risk of mucous plugging is significantly increased during periods of intercurrent respiratory infection and can result in acute respiratory distress necessitating placement of an endotracheal tube. Patients with peak cough flows below this level may require permanent tracheostomy tube placement to allow suctioning and invasive ventilation when needed.

Suctioning alternative

An alternative (or adjunct) to suctioning can be provided with a mechanical insufflator-exsufflator. This respiratory aid assists in clearing debris by providing deep insufflation, immediately followed by a forced exsufflation to create artificially about 10 L/sec of expiratory flow (a normal cough expels air at approximately 16 L/sec). This can be administered directly via a tracheostomy tube with the cuff inflated, or via an oral nasal mask. The mechanical insufflator-exsufflator can be used acutely to relieve mucous plugs, but it also may be used routinely to provide assisted coughs and maintain clear airways. When used in combination with other respiratory muscle aids, it can avert tracheostomy tube placement, maintain quality of life, and prolong survival.

Weight loss

Weight loss is another common symptom in ALS and usually relates to the progression of dysphagia, which results in the patient's inability to maintain adequate caloric intake with oral feedings alone. Weight loss also may develop in patients with and without bulbar involvement because of generalized fatigue, poor appetite, and associated depression. Malnutrition is a poor prognosticating factor and correlates with increased risk of death; therefore, once a patient has lost 5-10% of normal body weight, consider enteric feeding and discuss options with the patient and caregivers.

Consult a gastroenterologist early so that placement of feeding tube is not delayed while weight loss progresses. Placement is preferred while the patient still is able to eat by mouth. In this situation, enteric feeding can be presented as a positive option because it allows the patient to eat for enjoyment, rather than simply for nutritional necessity. This prevents the fatigue and frustration associated with mealtimes experienced by some of these patients.

Initially, nasogastric or orogastric feeding may be an option, but these methods can lead to traumatic irritation of the mucosa with prolonged use. For long-term feeding, options include standard gastrostomy, percutaneous endoscopic gastrostomy (PEG), or jejunostomy. Preferred intervention is usually PEG tube placement because other types of long-term feeding tubes require placement under general anesthesia, while a PEG tube can be placed under local anesthesia. Increased risk of regurgitation is associated with gastrostomy/PEG tubes; therefore, some may prefer placement of a jejunostomy tube, which decreases the risk of aspiration.

Spasticity

Spasticity occurs from loss of inhibition from upper motor neurons. Baclofen acts as a gamma amino butyric acid (GABA) agonist and is the drug of choice for treatment of spasticity in patients with ALS. Alpha-adrenergic agonists, such as tizanidine and clonidine, also may be effective, but hypotension is a potential side effect that may limit their use. Dantrolene interferes with excitation-contraction coupling and usually is used as an adjunct agent. Dantrolene does have potential for hepatotoxicity; therefore, monitor liver function tests closely in those treated with this medication. Benzodiazepines facilitate GABA in the CNS and are effective in treatment of spasticity.

Use these medications with extreme caution in patients with ALS because of their adverse effect of respiratory depression. These patients may already be compromised from a respiratory standpoint, and this class of medications may worsen residual respiratory function. Carefully monitor use of antispasticity agents because they can cause sedation, dizziness, increased weakness, or other adverse effects that may be potentially harmful to the patient.

Pain

Pain can occur for many reasons, but in these patients, it is usually musculoskeletal in origin. Pain may be caused by muscle spasms, contractures, or altered joint biomechanics. First-line treatment for pain is with nonsteroidal anti-inflammatory drugs (NSAIDs). If the patient is intolerant to these medications, use acetaminophen. Muscle cramps occur frequently. Traditional treatment was with quinine, but this drug is no longer recommended because of its side-effect profile. NSAIDs may provide some benefit, but antispasticity medications discussed above are currently recommended for treatment of muscle cramps and usually are effective. In some instances, pain may be neuropathic in origin, and anticonvulsant medications may be beneficial. Tricyclic antidepressants also are indicated for this type of pain and may be tried. For severe pain, unresponsive to the above treatments, narcotics are indicated. Use them with caution, however, as they too can cause respiratory depression, especially at

higherdoses.

Fasciculations

Fasciculations can be troublesome or even embarrassing for some patients. Avoiding caffeine and nicotine can reduce them, but in those patients with severe symptoms, benzodiazepines can be effective. Use these medications with caution because of their side-effect profile.

Sialorrhea

Sialorrhea (drooling) is a problem for almost all patients with bulbar involvement. Treatment includes use of direct cholinergic inhibitors or medications such as tricyclic antidepressants that have anticholinergic side effects. CNS stimulants, such as methylphenidate, also have been used and are effective in some patients. Upright positioning is essential, and, for those with labial incompetence, intermittent mechanical suctioning can be beneficial.

Psychological symptoms

Psychological symptoms are common and are indirectly related to the disease and its progression. Patients with ALS generally have preserved cognitive functioning with a progressive loss of control over their disease process and daily functioning. This can be very distressing to both the patient and caregivers, and symptoms of fear, anxiety, and depression may manifest. If left untreated, these symptoms may result in a decline in the patient's functioning out of proportion to disease severity.

Early recognition of psychological disorders is important. This allows appropriate interventions to be made to provide support to the patient and caregivers. Interventions can be provided through individual and family psychotherapy, as well as psychoactive medications. Selective serotonin re-uptake inhibitors (SSRIs) most commonly are used for the treatment of depression. Tricyclic antidepressants usually are used as second-line treatments. In some patients with anxiety, SSRIs also may be beneficial, but, in those with severe anxiety that limits function, benzodiazepines are indicated.

Assistance of a psychologist is recommended early on to help identify and treat clinical symptoms. Psychotherapy and counseling can be used alone or in combination with medications, but treatment with medications alone is not recommended. Symptoms such as anxiety and fear can be treated through role-playing and relaxation techniques. Other potential problems, such as caregiver burnout and patient loss of control, also may be identified and treated through the assistance of a psychologist. In addition, psychologists can aid the patient in developing advanced directives, addressing financial concerns, and assisting in planning for total care.

Incidence of suicide is surprisingly rare in patients with ALS. This may be attributed to the fact that, in the early stages of the disease, the patient either denies, or does not fully comprehend the impact of the disease. Once patients realize fully the devastation caused by their illness, they may be too weak to perform the act of suicide.

Physician-assisted suicide

Recently, a study looked at attitudes of ALS patients and their primary caregivers toward physician-assisted suicide. Among the patients studied, mean duration of illness was 4 years from onset of symptoms. Researchers found that 56% percent of ALS patients studied were willing to consider assisted suicide. Of these patients, 79% felt that, if physician-assisted suicide were legal, they would request a lethal prescription from a physician. Most said they probably would keep the prescription available for potential use in the future, and only one patient expressed readiness to request the prescription with the intent of taking it to cause death in the next month. Of the caregivers studied, 73% had attitudes toward assisted suicide similar to those of the patients, and 76% were able to predict accurately the patient's willingness to consider taking a lethal dose of medication.

Surprisingly, incidence of depression was not associated with the patient's willingness, or unwillingness, to consider assisted suicide. Patients who were willing to consider assisted suicide tended to be male, had more years of education, had higher scores of hopelessness, and rated their quality of life (QOL) as lower than those who opposed assisted suicide. Patients and caregivers who would consider assisted suicide were less likely to be religious on all measures.

This has strong implications for physicians, multidisciplinary team members, and caregivers who work closely with these patients. Most caregivers were able to predict whether patients would consider assisted suicide if it were offered to them. Discussing these matters with both the patient and primary caregiver is important. By recognizing signs of hopelessness and diminished QOL in these patients, physicians can institute cognitive therapies and other interventions in an effort to help the patient find meaning in the future, reduce fears, and avoid focusing on the worst outcomes.

Surgical Intervention

For patients with respiratory failure due to bulbar and respiratory muscle involvement, a permanent tracheostomy may be required should nonsurgical management fail. Severe bulbar involvement may also preclude oral feeding due to significant aspiration and therefore a PEG feeding tube may be necessary for adequate nutritional support.

Consultations

Appropriate consultations for ALS patients are discussed in detail in Medical Issues/Complications.

Other Treatment

Patients who have severe generalized spasticity, resulting in pain or impaired function, may initially be given oral medications discussed previously; however, if these medications are ineffective or poorly tolerated at higher doses, consider referral for placement of an intrathecal baclofen pump.

Patients with severe spasticity limited to specific muscle groups may be treated with isolated nerve or motor point blocks with phenol or botulinum toxin. The type of block generally used is based on the size of the muscle groups involved, risk of paresthesias with phenol injections, cost, and physician preference.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Currently, riluzole is the only medication approved by the Food and Drug Administration (FDA) as a disease-modifying agent in ALS treatment. Riluzole is discussed in further detail below.

Other medications have been studied or currently are being studied in clinical trials for treatment of ALS. The only medications discussed in this section are the ones currently available for use in the United States. These medications have been approved by the FDA for other indications but are not specifically labeled for ALS treatment.

Gabapentin is labeled for use as an anticonvulsant medication, but has been studied in patients with ALS. The exact mechanism of gabapentin is not understood well. This drug is structurally related to the neurotransmitter GABA. In animal studies, radiolabeled gabapentin has shown binding sites in the neocortex and hippocampus. Identity and function of these binding sites, however, are unknown. A single trial of gabapentin was completed in 1999 and presented at the Annual Meeting of the American Neurological Association in October of 1999. The study found no significant improvement in either function or survival among patients treated with gabapentin versus placebo.

Topiramate currently is labeled for use in treatment of epilepsy, but it is now being studied for use in ALS. Topiramate has been shown to decrease effects of glutamate in the brains of animals and may limit glutamate toxicity in patients with ALS. At the time of this writing, the results of this study had not been reported.

Antioxidants have also been studied, and, currently, evidence of efficacy for individual antioxidants, or antioxidants in general, in the treatment of ALS is insufficient. Most physicians, however, still recommend vitamin E supplementation.

Creatine is a nutritional supplement that can be purchased without a prescription. Creatine occurs naturally and is involved in energy metabolism of muscle. Abnormal metabolism of creatine produced in the body has been linked to progression of neuromuscular diseases such as ALS. A multicenter clinical trial currently is underway involving ALS patients, but results of this study also were pending at the time of this writing. For up-to-date information on these and other clinical trials currently underway, visit ALS Association - Drug Development Update.

Drug Category: Benzathiazoles

Used as disease-modifying agents to increase survival in patients with ALS.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Acute care hospitalization
  • An inpatient stay in the acute care setting may be necessary at onset of symptoms if diagnosis of ALS is uncertain, and a full diagnostic workup is indicated to rule out other diseases which may mimic ALS.
  • Once diagnosis has been made, inpatient stays in an acute care hospital may be necessary in times of acute decompensation related to other intercurrent illnesses such as pneumonia.
  • Additionally, an acute stay may be indicated as respiratory function declines and appropriate ventilatory options are explored and implemented.
• Rehabilitation hospitalization
  • The patient's rehabilitation program may be initiated in the inpatient setting, at the time of diagnosis, or at a follow-up outpatient visit with a physiatrist.
  • An inpatient rehabilitation stay is indicated when the patient has had a significant decline in function, and appropriate resources or equipment have not been set up in the patient's home yet to provide for current needs.
  • An inpatient stay also may be necessary after noninvasive or invasive ventilation has been initiated to monitor the patient and allow time to educate patient and caregivers on appropriate use of equipment while the ventilator and other respiratory aids are being set up in the home.
• Long-term care
  • If patient's decline in function has progressed to a level where care can no longer be provided at home, then an alternate disposition must be found.
  • Discuss appropriate options with the patient and primary caregiver, as well as family members involved.
  • Placement may be made with a different caregiver who can provide for the patient's increased needs.
  • In some cases, the care of a skilled nursing facility or inpatient hospice program may be indicated.

Further Outpatient Care

• Coordinate care in the outpatient setting with a multidisciplinary team to provide the patient with timely interventions appropriate for current and upcoming needs.
• Visits with the physiatrist should include a thorough history and repeat clinical examination to monitor the patient's disease progression.
• At each visit, discuss code status, as studies have shown that patient preferences regarding code status may change within a 6-month period because of changes in physical functioning and increased medical needs.

Prognosis

• As mentioned earlier, most patients die within 5 years of diagnosis without ventilatory assistance. Survival can be improved with aggressive respiratory management and ventilator support, invasively or noninvasively. Prognosis tends to be less favorable for older patients and for patients with the bulbar form of the disease.

Patient Education

• Provide patient education at the time of diagnosis and throughout the course of disease. There are many resources available to patients and families. Provide the names and numbers of local support groups as soon as the diagnosis has been confirmed. Some excellent online resources for both physicians and patients include the ALS Association, World Federation of Neurology - Amyotrophic Lateral Sclerosis, and American Academy of Neurology.
• For excellent patient education resources, visit eMedicine's Dementia Center and Brain and Nervous System Center. Also, see eMedicine's patient education articles Amyotrophic Lateral Sclerosis (Lou Gehrig Disease) and Dementia in Amyotrophic Lateral Sclerosis (Lou Gehrig Disease).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Although unlikely, malpractice suits may arise from a delay in the diagnosis of ALS since the disease can be mimicked by other neurologic problems (eg, cervical spondylosis, motor polyradiculopathy, multifocal motor conduction block).

Special Concerns

• An attorney should be consulted regarding a "living will" and power of attorney established prior to the terminal phase of this ultimately fatal disease.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Hanayama K, Ishikawa Y, Bach JR. Amyotrophic lateral sclerosis. Successful treatment of mucous plugging by mechanical insufflation-exsufflation. Am J Phys Med Rehabil. Jul-Aug 1997;76(4):338-9. [Medline].
• Klausmeier WH. A patient-supported strategy for therapy development in amyotrophic lateral sclerosis (als). Am J Ther. Sep-Oct 2001;8(5):329-32. [Medline].
• Miller RG, Rosenberg JA, Gelinas DF, et al. Practice parameter: the care of the patient with amyotrophic lateral sclerosis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology: ALS Practice Parameters Task Force. Neurology. Apr 22 1999;52(7):1311-23. [Medline].
• Walling AD. Amyotrophic lateral sclerosis: Lou Gehrig''s disease. Am Fam Physician. Mar 15 1999;59(6):1489-96. [Medline].

Article Last Updated: Mar 2, 2006