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Treatment and Management of Adult Motor Neuron Diseases
Many diseases specifically affect the motor neurons, ranging from infectious processes such as polio and West Nile viruses to hereditary conditions such as spinal muscular atrophy (SMA) and Kennedy disease ( ). Radiation therapy can cause motor neuron degeneration many years later, mimicking the adult motor neuron disease amyotrophic lateral sclerosis (ALS) ( ). Sometimes, the motor neuron degeneration remains curiously restricted to just the cervical region, such as in Hirayama disease ( ). Central nervous system (CNS) lymphoma can directly infiltrate nerve roots, mimicking motor neuron disease. When motor neuron degeneration is accompanied by an adenocarcinoma, a paraneoplastic syndrome is suspected ( ).
ALS is a disease that is still little understood despite first being described in the late 1800s. It affects 1 in 100,000 people, with a slight male predominance and no ethnic or geographic preference. Incidence of ALS peaks between 60 and 75 years of age ( ). Typically, the disease is sporadic, but familial cases occur 5%–10% of the time. The most common gene mutations implicated in ALS involve the chromosome 9 open reading frame 72 ( C9orf72 ) gene and the superoxide dismutase 1 ( SOD1 ) gene, further discussed later in this chapter. Several other genes have been discovered, causing an even smaller proportion of familial cases ( ; ; ).
In ALS, weakness typically starts in a limb or less frequently in the bulbar region and progressively spreads contiguously until respiratory depression and death occur, approximately 3 to 5 years from symptom onset unless invasive ventilation is desired. Cognitive and behavioral changes can be seen as well. The range of progression is variable, and death can occur within a couple of months from the first symptom or up to decades later. Prognosis may be more favorable in pure upper motor neuron variants of ALS ( ). Diagnosis is difficult, particularly early in the disease course, because many conditions mimic ALS, and no definitive test is available.
No available treatments significantly alter the fatal outcome of the disease; however, tremendous strides have been made in the management of symptoms through technology and medications, leading to an improved quality of life. Furthermore, ongoing research into the pathogenesis of ALS and related neurodegenerative conditions provides fertile ground for drug development. In particular, TAR DNA-binding protein, or TDP-43, found in both ALS and frontotemporal dementia (FTD), provides clues to the pathogenesis of these diseases and will hopefully lead to improved treatments in the future ( ). Lastly, research into stem cell therapy keeps patients and physicians hopeful that we may have a meaningful therapy for ALS even before fully understanding its underlying mechanisms ( ; )
Diagnosis And Evaluation
Despite the lack of curative treatments available, prompt diagnosis of motor neuron disease is important to allow patients to access specialized care, enroll in clinical trials, and make plans for their future. Unfortunately, given the clinical heterogeneity of ALS and lack of a definitive diagnostic test, delay in diagnosis is all too common. In fact, the mean time from symptom onset to diagnosis has been shown to range from 10.2 to 16.1 months ( ). The evaluation of a potential motor neuron disease patient is primarily based on the clinical presentation ( Figs. 12.1–12.3 and Table 12.1 ). Important features to determine what type of workup is needed include the rate of progression of the weakness, the pattern of weakness, family history, associated symptoms such as parkinsonism or dementia, and the age of onset. The degree of upper versus lower motor neuron involvement is critical to identify; the symptoms of such involvement are shown in Fig. 12.2 . Once the degree of upper and lower motor neuron involvement is established and all ALS mimics are excluded, the revised El Escorial criteria can be used to establish the diagnosis (see Fig. 12.1 ). The different types of ALS presentations and the workup recommended in each case are described here and also diagrammed in Fig. 12.3 .
Table 12.1
Workup for Adult Motor Neuron Disease
| Symptom | Workup |
|---|---|
| Pure lower motor neuron syndrome | EMG and nerve conduction studies of at least one arm and one leg, tongue, and thoracic paraspinal muscles Neuroimaging of the affected body segments Routine blood work a Genetic testing for Kennedy’s, ALS, and SMA if familial or if clinical presentation is classic in the absence of a family history HIV test if patient has risk factors Anti-GM1 antibodies Spinal tap with fluid sent for cytology, cell count, protein, glucose, and IgG index |
| Pure upper motor neuron syndrome | EMG and nerve conduction studies of at least one arm and one leg, thoracic paraspinal muscles, and tongue Neuroimaging of the affected body segments Routine blood work a Genetic testing for hereditary spastic paraplegia if familial Spinal tap with fluid sent for cytology, cell count, protein, glucose, IgG index, HTLV-I and -II, and VDRL Serum copper Paraneoplastic antibody tests HIV test if patient has risk factors |
| Progressive bulbar palsy | EMG and nerve conduction studies of at least one arm and one leg, thoracic paraspinal muscles, and tongue Neuroimaging of the brain Routine blood work a MuSK antibody if EMG not clearly neurogenic Spinal tap with fluid sent for cytology, cell count, protein, glucose, and IgG index |
| Upper and lower motor neuron syndrome | EMG and nerve conduction studies of at least one arm and one leg, thoracic paraspinal muscles, and tongue Neuroimaging of the affected body segments Routine blood work a Genetic testing for ALS if familial |
ALS , amyotrophic lateral sclerosis; EMG , electromyography; HTLV , human T-cell lymphotropic virus; IgG , immunoglobulin G; SMA , spinal muscular atrophy; VDRL , Venereal Disease Research Laboratory.
a Routine blood work: complete blood count, electrolytes, calcium, thyroid-stimulating hormone, vitamin B12, liver function tests, serum protein electrophoresis, immunofixation, urine protein electrophoresis, glucose, blood urea nitrogen, creatinine, creatine kinase, erythrocyte sedimentation rate, antinuclear antibody, and Lyme antibody (if in endemic area).
Family History
When there is a known family history of progressive weakness, it is important to determine the age of onset in family members, the disease duration, and the rate and pattern of the spread of weakness. It is also important to inquire about any family history of dementia or psychiatric disturbances, given co-occurrence of/pathogenetic overlap between FTD and ALS ( ).
Symmetric proximal greater than distal lower motor neuron weakness in the limbs and bulbar involvement that is slowly progressive may indicate Kennedy disease. This is an X-linked, trinucleotide repeat, genetic disorder that occurs in 1 in 50,000 males and involves progressive degeneration of anterior motor neurons. Androgen receptor function is impaired, the severity of this impairment correlating with the length of the expansion of the CAG repeat within the receptor. There is also an inverse correlation between the number of CAG repeats and the age of onset of the disease. The key features include gynecomastia (in more than 50% of cases), areflexia, a subtle sensory neuropathy, and progressive, proximal greater than distal weakness in the limbs and bulbar muscles. Onset is usually in the third or fourth decade of life but may occur in the teenage years or later in life. Muscle cramps often occur years before the onset of weakness; fasciculations are common, particularly in the lower face and tongue. Creatine kinase (CK) measurements may be up to 5 times the upper limit of normal. Tremor of the limbs and chin is reported. Dysphagia and dysarthria usually occur later (10 to 20 years after symptoms start). Life expectancy in Kennedy disease is not particularly reduced unless complicated by aspiration pneumonia, so it is critical for the prognosis to distinguish this disorder from ALS. Testes may be small, and infertility is common. There can be associated diabetes ( ; ; ). Treatment is largely based on symptoms because treatment with testosterone makes the symptoms worse ( ). Although antisense oligonucleotide treatment shows promise in animal models of Kennedy disease, no such therapeutics have yet advanced to clinical trials ( ).
If the weakness has an onset in childhood or late adulthood and the patient has a pure lower motor neuron presentation that is predominately proximal, SMA should be considered along with familial ALS. SMA is an autosomal recessive disorder with a defect in the survival motor neuron ( SMN1 ) gene on chromosome 5 ( ). It can also occur in infants, in whom it can be rapidly fatal. Due to the pattern of weakness and age of presentation, it can be difficult to distinguish from the limb-girdle muscular dystrophies without electromyographic (EMG) studies. Treatment for SMA had, for many years, been primarily supportive. However, in recent years, three different disease modifying therapies have been Food and Drug Administration (FDA) approved for treatment of SMA. Nusinersen, an antisense oligonucleotide, modifies splicing of the SMN2 gene and promotes increased production of full-length SMN protein, which is deficient in this condition ( ). Risdiplam, the first orally administered drug for treatment of SMA, also modifies SMN2 splicing to increase levels of functional SMN protein. This was FDA approved in 2020 for patients 2 months of age and older ( ). Onasemnogene abeparvovec, a gene replacement therapy, utilizes a viral vector to replace mutated SMN1 with normal SMN1 and is currently FDA approved only for children under the age of 2 with biallelic mutations ( ).
Other inherited conditions that can be confused with ALS include adult-onset Tay-Sachs disease, Charcot-Marie-Tooth disease (CMT), and adult polyglucosan body disease. Adult-onset Tay-Sachs disease is caused by a mutation in the gene for hexosaminidase A and may cause upper more than lower motor neuron involvement. This disease tends to be slowly progressive; cerebellar atrophy on neuroimaging is a clue to this diagnosis. CMT can present with myriad clinical features that can be confused with those of ALS, including a mixture of upper and lower motor neuron involvement in rare cases and vocal cord paralysis. Adult polyglucosan body disease can also mimic ALS and should be included in the differential, particularly in patients of Ashkenazi Jewish background with associated dementia ( ). Commercially available genetic tests can exclude many of these possibilities. Muscular dystrophies may also be confused with ALS, particularly facioscapulohumeral muscular dystrophy (FSHD). FSHD is an autosomal dominant disorder affecting 1 in 20,000 persons. Many patients are unaware of their condition, and new mutations can also occur, making it difficult to rely on family history to help with the diagnosis. FSHD is caused by a deletion of tandem 3.3 kb repeats on chromosome 4q35. This results in the overexpression of upstream genes due to loss of binding of a transcriptional repressor protein. It is variable in severity and age of onset but is generally slowly progressive, with only about 20% of patients eventually needing a wheelchair. Typical onset is in the second or third decade, with a nearly normal or normal life span. The facial muscles are involved, causing difficulty closing the eyes, smiling, and whistling. The face can appear to be pouting. The shoulder and upper arm muscles are affected, with relative sparing of the deltoid muscles and significant scapular winging. Foot drop occurs in the scapuloperoneal variety; interestingly, the extensor digitorum brevis muscle tends to be hypertrophied rather than atrophic as in neurogenic causes of foot drop. In the arms, the extensors are also affected more than the flexor muscles. The weakness can progress slowly with periods of arrests. Asymmetry of the weakness is not unusual. EMG studies show a myopathic pattern. CK level may be normal or only mildly elevated, despite inflammation found on muscle biopsy ( ).
With advances in commercially available genetic testing and many testing companies offering financial assistance, genetic testing for ALS is now an option for most patients with a compelling family history. Genetic testing can assist in the diagnosis of at-risk family members, can help diagnose potential comorbidities (e.g., FTD) earlier, and can allow patients and family members to make informed decisions regarding family planning. It can also provide opportunities for patients to participate in clinical trials targeting patients with particular gene mutations, several of which are currently ongoing or in development. Over 40 ALS-causing gene mutations have been identified. Most of these gene mutations are inherited in an autosomal dominant fashion, although autosomal recessive and X-linked mutations have been described. Genetic counseling should be obtained both before and after testing, given potential profound implications for other family members. The incidence of different genetic mutations varies across different ethnic populations. In European populations, C9orf72 mutations are most common, followed by SOD1 gene mutations, while SOD1 gene mutations are more common in Asian populations ( ). Other gene mutations frequently implicated in familial ALS involve the TAR DNA binding protein ( TARDBP ) gene, fused in sarcoma ( FUS ) gene, FIG4 phosphoinositide 5-phosphatase ( FIG4 ) gene, and ( ANG ) gene. These different gene mutations can have certain phenotypic associations. For example, patients with C9orf72 mutations have an earlier mean age of onset and a substantially higher rate of comorbid FTD than ALS patients without this mutation ( ). The SOD1 gene has over 180 identified mutations, with considerable phenotypic variability among them, from very rapidly progressive symptoms in the A4V variant to very slowly progressive with sensory involvement in the D90A recessive Scandinavian type. Although it is frequently requested, asymptomatic genetic testing is not covered by insurance. Because genetic testing will not identify a gene mutation in all familial cases, it is important to also screen for more common etiologies of weakness and not automatically assume that the weakness is from familial ALS rather than cervical radiculopathy, for example.
Pure Lower Motor Neuron Syndrome
When patients present with a pure lower motor neuron syndrome and no family history, it is important to still consider the differential discussed in this chapter for cases with a family history, because many patients with Kennedy disease and various muscular dystrophies are not aware of any family history until they are diagnosed themselves. This is not necessarily due to new sporadic mutations but may be due to incomplete penetrance or undiagnosed cases that are too mild to seek clinical attention.
It is also important to consider the most common cause of lower motor neuron weakness—a polyradiculopathy. Neuroimaging of the affected areas is critical to look for this possibility. West Nile virus, Lyme disease, porphyria, diphtheria, Creutzfeldt-Jakob disease, acute motor axonal neuropathy (AMAN syndrome), and polio all cause a pure lower motor neuron syndrome, but the time from onset to deficit is much more rapid than in typical ALS, and they are usually easily distinguishable from that disorder. Botulism also presents with rapidly progressive weakness but has characteristic findings on EMG and nerve conduction studies that distinguish this entity from motor neuron disease. Monoclonal gammopathies can be difficult to differentiate clinically but can be screened by testing serum protein electrophoresis, immunofixation, and urine protein electrophoresis. Myasthenia gravis can easily be identified on nerve conduction studies with a decremental response on repetitive stimulation, and antibodies can be sent for the acetylcholine and MuSK receptors. Of note, ALS can sometimes cause decrement on repetitive nerve, particularly if rapidly progressive, and so EMG studies may still be necessary to differentiate myasthenia gravis from ALS. If an incremental response is seen on high-frequency repetitive stimulation, suggesting a presynaptic disorder, then antibodies can be tested for the calcium channel. Lambert-Eaton syndrome presents with symmetric limb weakness and decreased reflexes, which can be confusing in the differential diagnosis of a pure lower motor neuron syndrome. Myopathies and muscular dystrophies can also be differentiated based on EMG studies and muscle biopsy. Blood should be tested for the presence of human immunodeficiency virus (HIV), particularly in patients with risk factors for HIV ( ).
When patients with a history of polio and residual weakness in a limb present later in life with new weakness, it is important to differentiate postpolio syndrome from other neurologic processes, including superimposed ALS. Postpolio syndrome occurs in a moderately severe or severely weak limb and usually involves small changes in the degree of strength that can sometimes lead to significant functional changes. It never occurs in a limb that is full strength, is not rapidly progressive, and does not occur in patients who have never had polio or had polio and recovered fully ( ).
One of the most important conditions to consider in the differential is multifocal motor neuropathy with conduction block; this is a highly treatable condition that mimics ALS. Patients have fasciculations; progressive weakness, typically in the distal upper limbs; preserved or brisk reflexes; and abnormalities on nerve conduction studies to support the diagnosis. Antibodies are produced to gangliosides, such as anti-GM1, which then, it is hypothesized, cause focal demyelination of motor nerves. When nerves are stimulated electrically at multiple points, a dropoff in the amplitude of the CMAP signifies conduction block, and, ideally, this is demonstrated at a noncompressible site. Anti-GM1 levels may be elevated or normal, making it difficult to achieve a definitive diagnosis with this test. To confound the issue more, patients with a classical clinical presentation but no conduction block identified on nerve conduction studies are sometimes responsive to intravenous immunoglobulin (IVIg), the treatment most typically given in this condition, with a 94% response rate ( ). In contrast to chronic inflammatory demyelinating polyneuropathy, the spinal fluid protein in a patient with multifocal motor neuropathy with conduction block is typically normal. Sometimes a 3-month trial of IVIg at 2 g/kg/month is warranted to look for a treatment response in patients with a pure lower motor neuron syndrome where conduction block is not found on nerve conduction studies but the patient otherwise fits the clinical syndrome.
Inclusion body myositis (IBM) may be mistaken for motor neuron disease, as patients often present with asymmetric limb weakness, muscle atrophy, and dysphagia. CK may be mildly elevated, as can also be the case in motor neuron disease. In more severely affected muscle groups, it is not uncommon for EMG to show a “chronic neurogenic” pattern of findings such as long duration, polyphasic motor unit action potentials, likely due to extensive muscle fiber splitting ( ). Certain features are helpful in differentiating IBM from motor neuron disease, including the pattern of muscle involvement (predominantly deep finger flexors and quadriceps in IBM), lack of fasciculations, and myopathic findings on EMG—particularly in less severely affected muscle groups. The diagnosis can be readily made via muscle biopsy and/or testing for anti-NT5c1A antibodies ( ). In younger patients with weakness restricted to one limb, the clinician may consider a diagnosis of Hirayama disease (also known as “cervical flexion-induced myelopathy”), a form of monomelic or focal amyotrophy. Weakness typically progresses over a period of years, then plateaus and remains restricted to the one limb. This condition most commonly involves a single arm, although it rarely may affect a single leg instead. Dynamic MRI may demonstrate asymmetric cord flattening in the neutral position and forward displacement of the dura with neck flexion ( ). Treatment is controversial, but some clinicians advocate use of a cervical collar to help prevent neck flexion that may theoretically accelerate progression of weakness ( ).
After all the ALS mimics are excluded, patients with a pure lower motor neuron presentation of ALS are considered to have progressive muscular atrophy variant of ALS. This condition often starts with limb weakness; sometimes these patients progress more slowly than those with typical ALS, with progression more like that seen with SMA, but other times they progress just as rapidly as typical ALS patients. Over time, these patients may develop upper motor neuron signs and bulbar involvement, changing the diagnosis to classic ALS ( ; ). Development of these signs may change management of the disorder; for example, baclofen may be added to the treatment regimen to help with spasticity. In addition, the change in diagnosis may allow patients to be eligible for ALS clinical trials, because currently most trials exclude patients with a pure lower or upper motor neuron presentation and require a diagnosis of probable or definite ALS (see Fig. 12.1 ).
Pure Upper Motor Neuron Syndrome
Patients with a pure upper motor neuron syndrome need a fairly aggressive workup to exclude mimics of primary lateral sclerosis , the term used for a pure upper motor neuron presentation of ALS. EMG studies should initially be performed in these patients to look for any subclinical motor neuron involvement, which might help to narrow the workup. If the EMG is normal or shows suprasegmental weakness (an interference pattern on EMG that is proportional to effort, consistent with an upper motor neuron pattern of weakness), extensive neuroimaging is critical to look for multiple sclerosis, tumor, or a compressive spinal cord lesion. Some conditions, such as spinal arteriovenous malformation or dural arteriovenous fistula, can be missed if the quality of the magnetic resonance study is poor or the neuroradiologist is inexperienced. These conditions may present with a more stepwise pattern of weakness. A lumbar puncture can help guide the workup, looking for elevated protein, IgG, and cells. The spinal fluid can also be tested for human T-cell lymphotropic virus 1 and 2 (HTLV-1 and HTLV-2), as well as syphilis with the VDRL. Serum can also be examined for the presence of HTLV-1. Copper deficiency is a very rare cause of upper motor neuron syndrome, but it can be tested by examining serum copper levels. Paraneoplastic syndromes are also important to consider; measuring antineuronal antibodies is a typical part of the workup. It is also important to assess HIV status, as with pure lower motor neuron presentations ( ).
Hereditary spastic paraplegia can mimic an upper motor neuron presentation of ALS and can be difficult to distinguish from that disorder. Patients with spastic paraplegia usually have an earlier age of onset and a strong autosomal dominant family history, which is helpful in diagnosis. There can also be a superimposed neuropathy and cognitive deficits, and, despite the name, arm involvement can occur. Vitamin B 12 deficiency can cause a motor myelopathy, as can thyroid disease; these disorders can easily be ruled out with blood testing ( ).
As with the pure lower motor neuron presentation of ALS, patients with a pure upper motor neuron form can develop lower motor neuron involvement over time, even decades later. EMG studies at diagnosis and every 1 to 2 years can be useful in helping identify subclinical lower motor neuron involvement. This can allow patients to be eligible for clinical trials if their diagnosis changes to ALS based on their EMG results (see Fig. 12.1 ).
Progressive Bulbar Palsy
Progressive bulbar palsy is a condition presenting with bulbar weakness. The differential is quite broad because patients can present with either pure lower motor neuron or pure upper motor neuron findings. Detailed neuroimaging is critical in a pure upper motor neuron presentation to look for any evidence of a structural lesion, such as stroke, tumor, or multiple sclerosis. In a pure lower motor neuron presentation, the Miller-Fisher variant of Guillain-Barré syndrome, myasthenia gravis, Lyme disease, and tumor infiltrating the cranial nerves are part of the differential. MuSK-positive antibody myasthenia gravis is particularly difficult to distinguish from bulbar ALS because patients have proximal weakness, bulbar involvement, and sometimes significant muscle atrophy. Fasciculations, however, are not present in this condition ( ). A lumbar puncture, with a large volume of cerebrospinal fluid sent for cytology, is important to aid in the diagnosis if neuroimaging is negative. When both upper and lower motor neuron findings are present and basic blood work, neuroimaging, and lumbar puncture results are negative, there is not much utility in further evaluations, because ALS is the most likely diagnosis. However, it may take years for the disease to involve the limbs. An EMG study can be useful to document the lower motor neuron involvement in the tongue and to establish any subclinical disease in the limbs.
Flail Arm and Flail Leg
Brachial amyotrophic diplegia, also called “flail arm” syndrome, manifests primarily as asymmetric, progressive lower motor neuron weakness that typically spreads proximally to distally. Flail leg syndrome, also known as “pseudopolyneuritic” motor neuron disease, causes asymmetric lower motor neuron leg weakness, usually starting distally and spreading upward. Both flail arm and flail leg syndromes tend to progress more slowly to respiratory involvement than typical limb-onset ALS. While median survival of limb-onset ALS patients in one research cohort was found to be 31 months, it was 66 months for patients with flail arm syndrome and 71 months for patients with flail leg syndrome ( ).
Facial-Onset Sensory and Motor Neuronopathy
First reported in 2006, facial-onset sensory and motor neuronopathy is a rare variant of motor neuron disease that is characterized by gradually progressive facial-onset sensory impairment that can then go on to involve the neck, upper extremities, and trunk. Sensory abnormalities are eventually accompanied by lower motor neuron findings of atrophy, fasciculations, and weakness. Corneal reflexes will be characteristically reduced or absent. Electrodiagnostic testing is notable for delayed or absent blink reflexes, low or absent sensory responses in affected limbs, and active and chronic motor axonal changes on EMG. Extensive evaluations are often indicated to rule out disease mimics, including brain and cervical spine MRI and cerebrospinal fluid analysis ( ).
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