Motor neuron disorders can be thought of as residing on a spectrum, whether upper motor neurons, lower motor neurons, or both are affected. Motor neuron diseases include amyotrophic lateral sclerosis (affects both upper and lower motor neurons), primary lateral sclerosis (affects upper motor neurons), progressive muscular atrophy (affects lower motor neurons ), progressive bulbar palsy (affects lower motor neurons), spinal muscular atrophy (affects lower motor neurons), and post-polio syndrome (affects lower motor neurons). Motor neuron disease is used interchangeably with amyotrophic lateral sclerosis (ALS) as ALS is the most common adult-onset presentation of this disease.
ALS is a neurodegenerative disorder leading to weakness of bulbar, thoracic, limb, and abdominal muscles with sparing of sensory function. Death usually occurs within two to five years from respiratory failure. Roughly 85 to 90% of ALS cases are sporadic, with about 10% being of familial origin. According to the 2014 US Census data, the prevalence of ALS was 5 per 100,000 people.
Though there is variation in clinical presentation, the majority of the patients present with asymmetric limb weakness (80%) or bulbar dysfunction (20%). Bulbar dysfunction can manifest as dysphagia (trouble swallowing) and dysarthria (trouble speaking). There is progressive spread to other areas of the body with accompanying upper motor neuron and lower motor neuron findings. Upper motor findings include spasticity, hyperactive reflexes, and a positive Babinski sign. Lower motor neuron signs include muscle atrophy, weakness, flaccid paralysis, absent reflexes, fasciculations, and fibrillations.
Patients can also display changes in behavior due to frontotemporal dysfunction, and about 15% of patients develop frontotemporal dementia. Some patients may also present with Pseudobulbar affect, which is dysregulation of emotional responses as exhibited by excessive laughter or crying. Many other neurological disorders such as strokes, Alzheimer’s disease, and multiple sclerosis also present with pseudobulbar affect.
Once the diagnosis of ALS is suspected, electrodiagnostic testing is needed. Electrodiagnostic testing assesses the integrity of lower motor neurons and is crucial to diagnosing motor neuron disease as oftentimes, neuroimaging, and laboratory studies are normal. Nerve conduction studies (NCS) and needle electromyography (EMG) are important for supporting the diagnosis of ALS and ruling out other potential mimics of the disease. Some disorders that can mimic motor neuron disease are multifocal motor neuropathy with conduction block, chronic inflammatory demyelinating polyradiculoneuropathy, central nervous system tumors, multiple sclerosis, and polyradiculopathy, among others.
It is important to rule out such mimics with NCS and needle EMG as the treatment regimens and prognosis differ among the varying disorders. Since the prognosis of ALS is poor, it is imperative to accurately diagnose the disorder to appropriately manage the associated symptoms involved and develop a treatment plan.
ALS affects motor neurons located in the spinal cord and brain. Lower motor neurons reside in the anterior horn of the spinal cord and the brainstem. They are an extension of the central nervous system and provide innervation to voluntary skeletal muscles, allowing for contraction. Upper motor neurons, specifically Betz cells, reside in the motor region of the cerebral cortex and give rise to axons that form the descending corticobulbar and corticospinal tracts. C9ORF72 repeat expansions are responsible for about 40% of familial ALS cases.
Neuropathologically, with the loss of motor neurons, there is a buildup of protein TDP-43. TDP-43 plays an important role in RNA regulation and can also be found in patients with frontotemporal dementia. These aggregates are found in the cytoplasm, mainly in neurons of the hippocampus and cerebellum. Since ALS affects the motor neurons, there are no sensory deficits. Cognition is also intact unless there is frontotemporal dementia, which can occur in up to 50% of ALS cases.
Electrodiagnostic testing is critical to the diagnosis of ALS as it detects lower motor neuron involvement. NCS and needle EMG are an extension of the neurological exam and should be performed with any motor neuron disease suspicion. Because the implications of diagnosing a patient with ALS are immense, NCS and needle EMG are vital to rule out other possible mimics of motor neuron disease. Multifocal motor neuropathy with conduction block (MMNCB) is one example of a disorder that closely resembles ALS and must be ruled out.
Like ALS, it typically presents with progressive asymmetric weakness, sparing sensory nerves. Usually, the motor nerve of more than one nerve is affected. With MMNCB, there is typically significant muscle weakness compared to muscle atrophy, lack of upper motor neuron findings, and more upper extremity involvement with a lack of bulbar findings. Electrodiagnostic findings, which are discussed later on, also differ among the two conditions.
Practitioners should always consider the risks versus benefits of any procedure to be performed on patients. Usually, electrodiagnostic studies have little risk to patients, but there are some instances in which NCS and needle EMG are contraindicated. Such contraindications include serious bleeding disorders or an automatic cardiac defibrillator.
Areas of active infection should not have needles inserted into them. Patients with pacemakers should not undergo stimulation over the pacemaker site, as it may be mistaken for an abnormal cardiac rhythm. Though not an absolute contradiction, caution should be taken in patients with lymphedema, as there is a potential risk for infection.
The early stages of ALS may be difficult to diagnose if there is a lack of associated clinical findings. NCS and needle EMG can be thought of as an extension of the neurological examination. Clinicians should always obtain a detailed history and perform a thorough physical examination before recommending an electrodiagnostic study. Imaging and laboratory testing should also be done to rule out possible brain/spinal cord tumors, multiple sclerosis, myelopathies, radiculopathies, myasthenia gravis, inflammatory myopathies, multifocal motor neuropathy with conduction block, and other diseases which may present similarly to ALS.
Clinicians should also explain to patients how the testing will be conducted as the study, particularly the needle EMG portion, can be an uncomfortable experience for some patients. Of note, the limb should be kept warm as colder body temperature can lead to erroneous findings such as decreased conduction velocities, prolonged latencies, increased duration, and increased amplitudes of sensory nerve action potentials and compound muscle action potentials.
NCS includes both sensory and motor testing and is performed by placing electrodes onto the desired area of study and stimulating the nerve that innervates that area. The waveform that is generated should be examined for any abnormalities. Needle EMG is performed by inserting a needle into a muscle and observing that muscle's electrical activity without any stimulation. For NCS of ALS, at least one upper and one lower limb should be tested with both sensory and motor studies. F waves studies should also be performed. If there is a concern for multifocal motor neuropathy with conduction block, then stimulation should be done proximally with various upper and lower extremity nerves.
Needle EMG should be performed on areas where LMN signs (atrophy, weakness, flaccid paralysis, absent reflexes) are present. There should be testing of proximal and distal muscles of at least three limbs for the needle study, with muscles that have a minimum of two different nerve innervations. At a minimum, one bulbar muscle should be tested as well as two thoracic paraspinal muscles.
As with any procedure that involves introducing a foreign substance into the body, there is a risk of infection. The risk of infection with needle EMG is very low, less than 1 in 10,000. There is also a risk of bleeding, which is why EMG should be avoided in patients with severe bleeding disorders.
The diagnosis of ALS is made clinically and is supported by electrodiagnostic evaluation. Electrodiagnostic testing is critical to the diagnosis of ALS as it detects lower motor neuron involvement. Clinically, there is a history of motor dysfunction such as limb weakness or difficulty swallowing along with physical examination findings of upper and motor neuron involvement. The diagnostic criteria of ALS have been standardized through the El Escorial criteria. Per the El Escorial criteria, there should be clinical evidence of upper motor neuron signs, lower motor neuron signs, and the progressive spread of signs from one area of the body to the next, such as the cervical region to the thoracic region. Electrodiagnostic testing and neuroimaging studies should rule out other possible explanations for the findings. The criteria were revised in 2006, which helped to increase the sensitivity of EMG by refining the criteria. Per the revision, fasciculation potentials in the setting of suspected ALS can indicate denervation, without the presence of positive sharp waves or fibrillations on EMG.
Motor nerve conduction studies should examine the median, ulnar and peroneal muscles. Findings consistent with ALS include normal or decreased compound muscle action potential (CMAP), prolongation of distal motor latency, and slowing of conduction velocity. Typically, CMAP should be normal as the myelin is intact but due to axonal loss, CMAPs and conduction velocity may be decreased. Distal motor latency should also be normal but can be increased with axonal loss. MMNCB, as described earlier, can be a mimic of ALS. In this disease, there is also a decreased CMAP, however, that is due to a conduction block. Conduction blocks are evidence of demyelination and reflect myelin pathology rather than axonal pathology. Conduction blocks should not be seen on NCS in ALS patients.
Sensory nerve conduction studies should be normal in ALS as the dorsal root ganglion is spared in this disease. Sensory nerve action potentials (SNAPs) are not affected in ALS and must be performed to rule out other diseases such as peripheral neuropathy, or plexopathies, in which SNAPs are affected. The sural nerve and ulnar nerves in particular should be tested. It is possible to have an abnormal SNAP with ALS patients if there is a coexisting unrelated medical condition such as peripheral neuropathy.
F wave studies are performed via antidromic stimulation of motor neurons. F wave latencies are typically normal earlier on in the disease but as the disease progresses can be prolonged due to motor neuron loss. It is important to note that abnormalities in F waves are not specific for MND and can be seen in radiculopathy.
On needle EMG, there is evidence of widespread acute denervation with chronic reinnervation. There should be a sampling of at least three limbs with muscles innervated by at minimum two different nerve roots, thoracic paraspinal and bulbar muscles. Acute denervation is manifested with fasciculations, which are spontaneous firing potentials from a motor unit of an affected nerve. They are not specific for ALS as they can be found in patients without ALS. However, in the majority of patients with ALS, there is a display of fasciculations on EMG. Fibrillations and positive sharp waves are also expected in ALS patients. These are spontaneous discharges from a muscle that is no longer innervated.
Chronic denervation is manifested via changes in the motor unit potential (MUP) of nerves. There is an increased duration and amplitude of MUPs as collateral sprouts from unaffected anterior horn cells reinnervate muscle fibers that have lost their innervation. These MUPs are polyphasic and will vary in configuration, having more than four phases in an MUP. Decreased recruitment of MUPs is seen with abnormally increased firing rates. This reflects the loss of MUPs and can be seen early in the disease.
Because there is no cure for ALS and the prognosis is grave, it is imperative for clinicians to diagnose the disease with confirmation by NCS and needle EMG as soon as possible so that the appropriate interventions can be taken. There are only a few approved FDA treatments for ALS. Riluzole blocks the release of glutamate from neurons and has been shown to prolong survival by a few months. Riluzole can cause an elevation in liver enzymes, therefore, liver function testing should be ordered prior to administering this medication as well as periodically
A combination of dextromethorphan and quinidine sulfate has been approved for pseudobulbar affect. It is contraindicated in patients using monoamine oxidase inhibitors and caution should be taken with patients on selective serotonin reuptake inhibitors due to the risk of serotonin syndrome Edaravone, a free radical scavenger is a recently approved drug that works via decreasing oxidative stress, which contributes to neuron cell death. It has been shown in some clinical trials to slow the functional decline in ALS patients
The treatment plan should include a multidisciplinary approach in order to manage a patient’s symptoms and improve overall function and quality of life. Physical and occupational therapists can assist with maintaining mobility and improving functional ability, allowing patients to remain as independent as possible with their activities of daily living. Patients can benefit from exercise regimens that prevent joint contractures, manage spasticity, and increase mobilization. Therapists can also provide recommendations for bracing, wheelchairs, and home equipment.
Speech therapists are important for monitoring a patient’s swallowing as well as assisting those who have difficulty speaking. Speech therapists are able to recommend assistive devices to help patients communicate more efficiently. Respiratory therapists are needed to monitor respiratory function and the need for non-invasive ventilation. Patients who exhibit excess salivation may require anticholinergic medications. Patients and their families should undergo psychosocial counseling to help with the emotional toll of the disease
In order for patients to be treated in an appropriate and timely manner, it is important for clinicians to confirm the diagnosis of ALS with NCS and needle EMG studies, as well as rule out other possible etiologies.
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