Introduction
Motor neuron diseases are the result of dysfunction of upper motor neurons in the precentral gyrus of the frontal lobe and/or lower motor neurons in the ventral horn of the spinal cord. In general, they cause weakness without notable sensory symptoms or pain. The most common motor neuron disease is amyotrophic lateral sclerosis (ALS), which is the primary focus of this review. Other motor neuron diseases include hereditary spastic paraparesis, spinobulbar muscular atrophy, and infectious motor neuron diseases including polio and West Nile virus. Spinal muscular atrophy (SMA) is a genetic motor neuron disease with advances in therapy, including the antisense oligonucleotide nusinersen, which was approved in 2016. While adult-onset SMA exists, SMA more often affects infants and toddlers and is therefore not discussed further in this review. Motor neuron disease mimics, including multifocal motor neuropathy, are also briefly discussed because disease-modifying therapy is available for them.
AMYOTROPHIC LATERAL SCLEROSIS
ALS is the most common motor neuron disease with an incidence of about 2 in 100,000. Although the average age of onset is in the seventh decade, ALS can present at a wide range of ages. The pathophysiology of ALS is unknown. Current theories include dysregulation of microRNA, changes in ion channels resulting in cellular excitotoxicity, and endoplasmic reticular and mitochondrial stress, among others. Areas of current research are ongoing to identify serologic/cerebrospinal fluid markers, genetic tests, and other biomarkers to better stratify patients to determine whether one or more of these factors are involved in the pathophysiology of disease in individual patients. Expansion of information in this area will help to identify better treatments for ALS. Interestingly, an increased incidence of ALS in the veteran population has been reported. While the exact etiology for this has not been identified, environmental exposure, strenuous exercise, and potential head injuries have all been postulated as potential causes. Some reports have suggested that athletes who experience repeated head trauma are more likely to develop ALS; however, more rigorously controlled studies have failed to demonstrate a clear correlation between head trauma and ALS. Additionally, pathologic evaluation of ALS patients with head trauma were not significantly different from evaluations of those without head trauma.
Clinical Features
The hallmark of ALS is a combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement with progression of weakness over time. The degree of UMN and LMN involvement varies among patients, and since UMN and LMN findings are common in neurologic disease, there are many mimics for ALS, particularly when patients present early in the disease process, at which time UMN and LMN features may not be present simultaneously. The initial symptom in ALS is often painless extremity weakness, manifested as difficulty writing, turning keys in locks, raising the arm overhead, or tripping due to foot drop. Patients may or may not notice muscle atrophy, stiffness, or fasciculations in this stage, and fasciculations, which are one of the hallmark findings of ALS, may not be present in every case. About 80% of patients present with this limb-onset disease, with the remaining 20% presenting with dysarthria and dysphagia, the so-called bulbar-onset. A small group of patients may present with isolated respiratory symptoms at the onset, without clear involvement of limb or bulbar muscles. In the following months and years, extremity weakness progresses gradually, resulting in impaired mobility and difficulty with activities of daily living (ADLs). Progressive dysphagia results in inadequate caloric intake and weight loss. ALS itself may also change metabolism, contributing to weight loss. Many patients with ALS develop dysarthria, which impedes communication. Respiratory symptoms in ALS are important to be screened for and recognized, since frank dyspnea is a late symptom and may be missed, given limited patient mobility. Symptoms that may suggest respiratory involvement include overall fatigue and mental slowness, morning headaches, and dyspnea on exertion and even with lying down (orthopnea). Most patients who do not opt for vent/tracheostomy die 3–5 years after symptom onset as a result of pneumonia and/or hypoxia related to bulbar dysfunction and respiratory failure. A small minority of patients may present with primary lateral sclerosis (PLS) or progressive muscular atrophy (PMA), which are considered the extreme cases of upper motor neuron–predominant and lower motor neuron–dominant disease, respectively. The prognosis for PLS is comparatively longer (8–10 years median survival) than that for PMA. Both PLS and PMA may transition to ALS in time, with progression to having both upper and lower motor neuron features. At present, methods to prognosticate a clinical course for individual patients remain obscure.
Physical examination is used to verify the upper motor neuron signs (spasticity, hyperreflexia) and lower motor neuron signs (flaccid weakness, fasciculations, and diminished reflexes). Weakness is mostly asymmetric, and its pattern, in time, extends beyond a single nerve distribution and appears to be myotomal. For example, a “split hand” results in atrophy of the abductor pollicis brevis and first dorsal interosseous on the radial aspect of the hand, while the bulk and strength of the abductor digit minimi may be relatively preserved, suggesting T1>C8 myotome involvement. Conversely, an isolated ulnar neuropathy would involve the first dorsal interosseous and abductor digiti minimi but not the abductor pollicis brevis. The absence of sensory loss in the distribution of nerves and roots is further supportive of involvement of motor neurons rather than other possibilities. Reflexes may be increased in the case of upper motor neuron involvement and decreased in the case of lower motor neuron involvement. A preserved reflex in an atrophied and weak limb may be indicative of both upper and lower motor neuron involvement.
Cognitive and behavioral impairment can occur with ALS. Cognitive impairment in the form of frontotemporal dementia most often is characterized by executive dysfunction—impaired attention, working memory, organization, and planning—while typical behavioral features include personality changes, obsessions, and disinhibition. Because patients may have communication impairment and fatigue, specialized screening instruments such as the Amyotrophic Lateral Sclerosis Cognitive Behavioral Screen are favored over traditional comprehensive neuropsychiatric evaluation.
Symptoms that are notably absent in ALS are diploplia, sensory symptoms, and urinary/fecal incontinence. The presence of these symptoms should suggest an alternative diagnosis.
Diagnostic Workup
The diagnosis of ALS is mainly based on history and examination. A laboratory workup and imaging are done to exclude other potential etiologies ( Table 20.1 ). Most importantly, these studies are used to exclude diseases that mimic ALS but have treatments and/or to identify diseases with a more favorable prognosis.
| Workup | Diseases being considered | |
|---|---|---|
| UMN |
| Vitamin deficiencies, autoimmune disorder, infections, demyelinating disease, genetic disorders (adrenoleukodystrophy, hereditary spastic paraplegia), neurodegenerative diseases such as corticobasal degeneration, PSP |
| LMN |
| Renal dysfunction, endocrine dysfunction, hematologic malignancy, monoclonal gammopathy, polyneuropathy, polyradiculopathy, myopathy, Lyme disease, W. Nile infection, post-polio syndrome, multifocal motor neuropathy, CIDP variants, vasculitis, cancer cachexia |
| UMN and LMN |
| Cervical spondylosis, systemic lupus erythematosus, sarcoid, Lyme disease, HIV, HSP |
| Bulbar |
| Myasthenia gravis/Lambert-Eaton myasthenic syndrome, stroke, neurodegenerative diseases such as PSP, genetic disorders (OPMD, Kennedy disease) |
The differential diagnosis for ALS varies based on the presenting symptoms. It is helpful to identify the differential diagnosis/diagnostic workup based on how the patient is presenting:
- A.
UMN
- B.
LMN
- C.
UMN and LMN
- D.
Bulbar
For patients who present with UMN-predominant symptoms, important mimics are vitamin B12 deficiency (subacute combined degeneration), copper-deficiency/zinc toxicity, hereditary spastic paraplegia, cervical spinal stenosis, autoimmune disease with spinal cord involvement (multiple sclerosis, sarcoid, etc.), or degenerative CNS disorders (PSP). Obtaining brain and spinal imaging with MRI is an important part of the workup for ALS to exclude these possibilities.
For patients who present with LMN-predominant symptoms, the most important differential diagnosis is multifocal motor neuropathy, Lyme disease, West Nile encephalitis, and other viruses affecting motor neurons, post-polio syndrome, and spinal muscular atrophy. Multifocal motor neuropathy is an important diagnosis to identify, since the weakness that is seen in this condition is completely reversible with immunotherapy. Occasionally, diseases such as inclusion body myositis or some hereditary myopathies may present with asymmetric patterns of weakness and exhibit widespread fibrillation potentials and positive sharp waves on needle electromyography (EMG), mimicking the EMG findings that are seen in ALS.
For patients who present with a combination of UMN and LMN findings, the most important differential diagnostic considerations are cervical spondylosis with cervical stenosis and neural foraminal narrowing. Conversely, patients with ALS may coincidentally have cervical spinal stenosis, and it is important to correlate the areas with profound weakness with findings on spine imaging to prevent patients from having unnecessary spinal surgery. Systemic disorders that can involve the peripheral and central nervous systems, such as Lyme disease, sarcoid, systemic lupus erythematosus, and HIV, should also be considered in patients with this type of presentation. Occasionally, malignancy seeding the CNS and meninges may present in a similar manner, mimicking ALS.
For patients who present with bulbar symptoms, important differential diagnostic considerations include myasthenia gravis, foramen magnum tumors, degenerative CNS disorders, and cerebrovascular disease. Since cerebrovascular disease is common and may be incidentally seen on brain imaging, it is important to review the history of the onset of bulbar symptoms for correlation with the time of prior stroke. In ALS the bulbar symptoms are insidious in onset, whereas in stroke the onset is sudden. In patients with myasthenia gravis, the bulbar symptoms fluctuate and are worse after a long conversation or meal and can improve with rest. Kennedy’s disease is an X-linked lower motor neuron condition presenting with atrophy/fasciculations of facial, bulbar, and limb muscles associated with gynecomastia. This disorder has a much more favorable prognosis compared to bulbar ALS and is therefore important to recognize.
Electromyography
Nerve conduction studies support the diagnosis by demonstrating intact sensory studies and motor conduction velocities in the presence of decreased compound muscle action potential amplitudes (depending on the myotomes that are involved). Fibrillation potentials and reduced recruitment of motor units on needle EMG suggest acute denervation; and tall, long motor units suggest chronic reinnervation changes. Fasciculation potentials are less specific but, in the appropriate clinical context, are suggestive of lower motor neuron dysfunction. EMG findings can be notably absent in cases in which UMN findings are predominant. The diagnostic criteria for ALS are mainly for research purposes and are designed to minimize a false positive diagnosis. The categories are based on how many of the four body regions (bulbar, cervical, thoracic, and lumbosacral) are involved. Diagnostic certainty increases with the number of body regions affected.
Biomarkers and Genetic Testing
The study of biomarkers for ALS is an ongoing area of research, and biomarkers are not yet available commercially or reliable for testing. Genetic testing can play an important role in diagnosis in ALS. However, given the complexity of these tests, they should be performed in consultation with a genetics and ALS expert. It is typically pursued in patients who have a family history of motor neuron disease or frontotemporal dementia or those who are particularly young at disease onset (less than 50 years old). However, this is an evolving topic as precision medicine expands, for example, the approval of tofersen for superoxide dismutase (SOD1)-associated ALS. C9orf72 is the most common genetic mutation in the United States, present in about 40% of cases of familial ALS and 7% of cases of sporadic ALS. This genetic mutation is also associated with frontotemporal dementia. SOD1 , FUS , and TARDBP are the other most common genetic mutations that have been identified. At present, identification of a genetic mutation will change management only for patients with SOD1 genetic mutation. However, genetic testing may be useful for family-planning purposes and, in some cases, inclusion in clinical trials.
Primary care physicians should consider the diagnosis of ALS, and referral to a neurologist, for patients who develop painless progressive weakness without sensory changes, particularly if accompanied by muscle atrophy and hyporeflexia or hypereflexia, dysarthria, dysphagia, or dyspnea. Delay in diagnosis can lead to patient distress, and misdiagnosis can lead to unnecessary procedures (e.g., cervical laminectomy). Rarely, patients are first diagnosed with ALS during a hospitalization for respiratory failure. Intensivists should consider motor neuron disease as a possible etiology for inability to wean patients from a ventilator, particularly if they have a history of prehospitalization muscle weakness. In this case, additional history about symptoms of respiratory insufficiency in the weeks prior to hospitalization should be sought (dyspnea on exertion, orthopnea, morning headaches).
Management
Although ALS is not a curable disease, there are several treatment options. These treatments can be divided into disease-modifying therapies and symptomatic management. The goal of treatment interventions is to focus on maximal function and independence while reducing pain and suffering. It is important to provide patients with information and strategies to help preserve their dignity and autonomy.
Disease-Modifying Therapy
Currently in the United States there are four disease-modifying therapies for ALS ( Table 20.2 ). Each of these therapies targets different processes of neural degeneration. Since there are currently no markers to identify which pathophysiology is playing a role in individual ALS patients, the current standard of care in the United States is to utilize three of these agents for all patients with ALS. In the pivotal trials leading to approval of these agents, patients were in early stages of the disease (i.e., <2–3 years from diagnosis, no respiratory symptoms, ambulating), with the thought that early initiation of these agents is likely to yield the most benefit.
| Medication | Administration | Side Effects |
|---|---|---|
| Riluzole | 50 mg orally twice daily | GI symptoms (abdominal pain, nausea, diarrhea), hepatotoxicity |
| Edaravone intravenous |
| Anaphylaxis, headache |
| Edaravone oral |
| Anaphylaxis/hypersensitivity reaction, gait abnormalities |
| Tofersen | 100 mg (15 mL) intrathecally q 14 days for 3 doses, then q 28 days thereafter |
|
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