Definition

The term motor neuron disease encompasses a heterogeneous group of progressive neuromuscular disorders characterized by the selective loss of upper or lower motor neurons. However, motor neuron disease is also used interchangeably with amyotrophic lateral sclerosis (ALS), which can be confusing for the uninitiated. ALS is the most common adult motor neuron disease. To meet diagnostic criteria for ALS, both upper and lower motor neuron involvement is necessary. In sporadic cases with only lower motor neuron dysfunction, the disease is called progressive muscular atrophy; if upper motor neuron dysfunction is singularly present, it is primary lateral sclerosis; and if dysfunction is localized to the bulbar region, the disease is called progressive bulbar palsy. Most patients initially diagnosed as having progressive muscular atrophy, primary lateral sclerosis, or progressive bulbar palsy eventually progress to meet diagnostic criteria for ALS. Those who do not convert have a slower rate of disease progression. This chapter focuses on ALS, as the management principles are similar for the entire class of motor neuron diseases.

The prevalence of ALS is about 6 to 8 per 100,000 people, with an annual incidence of 1.75 cases per 100,000 person-years worldwide. Men are more commonly affected than women, with a ratio nearing 2:1. Most cases of ALS are sporadic, having unknown etiology. Only 5% to 10% of patients have familial ALS, which is most commonly transmitted in an autosomal dominant fashion. Approximately 30% to 40% of familial cases in the United States and Europe are caused by mutations in the C9orf72 gene; 13% worldwide are caused by mutations in the SOD1 (superoxide dismutase) gene; and rarer forms of familial ALS have been linked to mutations in a growing number of genes including: ALS2, ANG, ATXN2, CHCHD10, CHMP2B, DCTN1, ERBB4, FIG4, FUS, GRN, HNRNPA1, MATR3, NEFH, OPTN, PFN1, PRPH, SEXT, SIGMAR1, SMN1, SPG11, SQSTM1, TARDBP, TAU, TBK, TRPM7, TUBA4A, UBQLN1, VAPB, and VCP genes. Other inherited adult motor neuron diseases are Kennedy disease (X-linked recessive) and adult spinal muscular atrophy (autosomal recessive), which are purely lower motor neuron disorders with greatly increased life span compared with ALS.

ALS causes rapid, progressive skeletal muscle atrophy and weakness, leading to premature death by respiratory failure. Weakness begins in a focal region, such as a single limb, the bulbar muscles, or the respiratory muscles, and spreads to affect other regions. Extraocular muscles and bowel and bladder sphincter function are often spared until late in the disease course.

Mean age at onset is the mid-50s, but ALS may develop in adults of any age. Rare juvenile familial forms exist with onset before the age of 25 years. Mean survival, without tracheostomy, is 3 years from diagnosis, but ranges from less than 1 year to more than 20 years. One explanation for this extreme variability is that ALS is multiple disorders without a single etiology, sharing a common final step in the pathophysiologic pathway—motor neuron apoptosis. This is illustrated by the varying phenotypes associated with familial forms of ALS. Theories about the pathogenesis of sporadic ALS have implicated RNA toxicity, glutamate excitotoxicity, oxidative stress, neuroinflammation, protein misfolding, glial cell activation, and mitochondrial dysfunction, to name a few.

Symptoms

Early symptoms of ALS can be subtle and include muscle twitching and cramping, weakness, and loss of coordination. Patients with a predominantly upper motor neuron syndrome often present with muscle stiffness, weakness, loss of dexterity, and loss of voluntary motor control from spasticity that may affect vocal quality or limb function. Patients with a predominantly lower motor neuron syndrome may present with weakness and muscle atrophy, fasciculations, muscle cramps, and flaccid dysarthria. Bulbar symptoms include dysarthria, dysphagia, sialorrhea (drooling), and pseudobulbar affect—laughing or crying in exaggeration of or incongruent with mood. Symptoms are initially painless and asymmetric across limbs. As the disease relentlessly progresses, weakness and atrophy spread to affect all skeletal muscles, causing significant impairment and disability. If patients do not succumb first to respiratory failure, they will ultimately transition from independent function to total dependence.

Respiratory failure is the presenting symptom in a rare few. Constitutional symptoms of weight loss and generalized fatigue are common. Cognitive symptoms including behavioral or executive dysfunction have been reported to occur in 33% to 51% of patients. Most have milder symptoms; however, approximately 5% to 14% meet clinical criteria for a diagnosis of frontotemporal dementia.

Physical Examination

Physical examination of a patient with suspected motor neuron disease should be aimed at establishing the certainty of diagnosis. ALS is diagnosed clinically, requiring a thorough neurologic examination to assess each of the four major body regions (bulbar, cervical, thoracic, and lumbar) for signs of upper and lower motor neuron involvement. The “gold standard” for the diagnosis of upper motor neuron disease is establishment of the presence of pathologic reflexes—a brisk jaw jerk, Hoffmann sign, palmomental reflex, abdominal skin reflex, and Babinski sign. Increased muscle stretch reflex responses as demonstrated by increased spread, amplitude, or clonus are considered pathologic. Reflexes that would be graded normal but are elicited from atrophied and weak muscles should also be considered pathologic. Evidence of lower motor neuron disease includes muscle weakness, atrophy, hypotonia, hyporeflexia, and fasciculations. A patient with ALS may be both hyperreflexic and hyporeflexic, depending on the stage at which they are in the disease process. For example, hyperreflexia occurs in the patient with upper motor neuron dysfunction, but this sign can be overcome and silenced by concomitant lower motor neuron loss causing muscle atrophy and weakness. Because ALS is an asymmetric and spreading process, the upper motor neuron signs may be more predominant than the lower motor neuron signs, or vice versa, within any single limb or between limbs and body regions. These examination findings change over time as the disease progresses. The tongue should be examined for fasciculations, atrophy, strength, and range of motion. The patient’s mental status, non-motor cranial nerve function, sensory examination, and cerebellar examination findings are usually normal.

In patients with an established diagnosis, the physical examination documents disease progression and includes the musculoskeletal and cardiorespiratory systems in addition to the neurologic evaluation. The musculoskeletal examination focuses on assessment of range of motion and evaluation of painful joints or soft tissue structures. Because progressive respiratory failure is a ubiquitous manifestation of ALS, follow-up appointments should be scheduled regularly (i.e., every 3 months) and the cardiorespiratory system assessed at each visit. Forced vital capacity (FVC), maximal inspiratory, maximal expiratory, and peak cough pressures can be measured with a spirometer in the office setting and should be considered along with respiratory rate, spot oxygen saturation, heart rate, and blood pressure as part of the regular cardiorespiratory follow-up evaluation, providing relevant information for clinical decision-making and prognosis ( Table 133.1 ).

Functional Limitations

The pattern of progressive functional limitation is directly related to the patient’s motor neuron disease phenotype. Bulbar-onset ALS initially affects the patient’s ability to speak and to swallow. Eventually, bulbar-predominant patients become anarthric with accompanying severe dysphagia that limits their ability to control their secretions and to swallow their own saliva.

The functional limitations that develop in patients with spinal-onset ALS are the direct or indirect result of muscle weakness and atrophy. In lumbar spine onset, gait is abnormal early in the disease secondary to foot drop or hip flexion weakness. As the disease progresses, the patient’s mobility worsens. Eventually, even the most basic activities of daily living become impossible to perform. Reactive depression, generalized fatigue, and musculoskeletal pain may further limit function. Zinman et al. reported in their systematic review on the economic burden of ALS that functional limitations associated with ALS have significant vocational impact, causing burdensome indirect costs suffered by both the patient and caregiver. Early retirement and transitions to disability reduce patients’ income while caregivers lose wages at an increasing rate that is directly related to the severity of disease. The annual indirect costs were estimated to be as high as $50,000 per patient per year (standard US$ 2015 currency year).

Diagnostic Studies

The diagnosis of ALS is based on the combined clinical and electrodiagnostic examinations. Neuroimaging and clinical laboratory studies are used to exclude conditions that mimic ALS. All patients thought to have a motor neuron disease should undergo electrodiagnostic testing. The Awaji-shima revised El Escorial criteria ( Table 133.2 ) are used to establish the certainty level of the diagnosis of ALS. These criteria were developed as a tool for clinical trial enrollment, but are commonly used in the clinic. The revised criteria classify the certainty level of diagnosis into one of three categories: definite, probable, and possible. Certainty level of diagnosis depends on how many regions reveal upper motor neuron and lower motor neuron disease. In addition to both upper and lower motor neuron findings, a diagnosis of ALS requires evidence of progressive spread of signs or symptoms within a single body region or from one of the four body regions to another. Electrophysiologic findings of denervation, including positive sharp wave, fibrillation, and fasciculation potentials, are used to confirm lower motor neuron dysfunction in clinically affected regions and to detect subclinical lower motor neuron dysfunction, thereby extending the clinical examination. Signs of denervation observed during electromyography are now considered equivalent to lower motor neuron symptoms on clinical examination.

Imaging studies are used to exclude possibilities other than motor neuron disease from the differential diagnosis. Magnetic resonance imaging is the primary imaging modality in the evaluation of patients with suspected ALS. Almost all patients should have magnetic resonance imaging of the cervical spine to exclude cord compression, syrinx, or other spinal cord disease. The location of symptoms will dictate whether other regions of the spinal cord should be imaged. In those presenting with bulbar symptoms, brain magnetic resonance imaging should be performed to exclude stroke, tumor, syringobulbia, and other pathologic processes.

In most neuromuscular clinics, a routine panel of laboratory tests is performed for all patients thought to have ALS. A suggested set of such tests is provided in Table 133.3 . The rationale behind the performance of this extensive battery of tests is to assess the general health of the patient and to exclude treatable conditions. The differential diagnosis, developed after the history and physical examination, may suggest that more specialized testing be performed. Table 133.4 suggests additional tests that may be warranted when the presentation is atypical with a progressive muscular atrophy, primary lateral sclerosis, or progressive bulbar palsy phenotype. When there is a family history of motor neuron disease or evidence of frontotemporal dementia (common in patients with C9orf72 mutations), genetic testing may be considered. If the patient presents with a purely lower motor neuron phenotype, genetic testing is warranted for spinal muscular atrophy, as there is an effective Food and Drug Administration (FDA)-approved antisense oligonucleotide therapy, Nusinersen, that in clinical trials improved strength and function in 51% of patients treated.

Table 133.3

Suggested Laboratory Studies

Hematology

Complete blood count

Sedimentation rate

Chemistry

Electrolytes, blood urea nitrogen, creatinine

Glucose

Hemoglobin A 1c

Calcium

Phosphorus

Magnesium

Creatine kinase

Liver function tests

Serum lead level

Urine heavy metal screen

Vitamin B 12

Folate

Endocrine

Thyroxine

Thyroid-stimulating hormone

25-Hydroxyvitamin D

Intact parathyroid hormone

Immunology

Serum immunoelectrophoresis

Urine assay for Bence Jones proteins

Antinuclear antibody

Rheumatoid factor

Microbiology

Lyme titer

VDRL test

Optional

Human immunodeficiency virus test (if risk factors are present)

Anti-Hu antibody (if malignant disease is suspected)

DNA test for SOD1 mutation (with family history)

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