Understanding Amyotrophic Lateral Sclerosis (ALS)

• Amyotrophic lateral sclerosis (ALS) is the most common progressive motor neuron disease, also known as Lou Gehrig’s disease.
• ALS is a neurodegenerative disorder characterized by progressive muscle weakness and eventual death.

Characteristics and Demographics

• ALS involves dysfunction of both upper and lower motor neurons.
• It affects the corticospinal and corticobulbar tracts, anterior motor horn cells, and bulbar motor nuclei.
• Onset typically occurs between 55 to 75 years of age.
• Males are slightly more likely than females to be diagnosed.
• Caucasians and non-Hispanics have a higher likelihood of developing ALS.
• Most cases (90% or more) are sporadic with no clear risk factors.
• 5-10% of cases are familial, linked to defects in genes like C9orf72 (25-40%) and SOD1 (12-20%).

Clinical Variants

• Progressive muscular atrophy and progressive bulbar palsy affect lower motor neurons in limb and bulbar muscles, respectively.
• Primary lateral sclerosis and progressive pseudobulbar palsy affect upper motor neurons in limb and bulbar muscles.
• All variants eventually affect both upper and lower motor neurons.
• Limb-onset ALS accounts for 70% of cases, bulbar onset for 25%, and initial trunk or respiratory involvement for 5%.
• Symptoms of autonomic, ocular movement, sensation, and cognitive dysfunction can occur.
• The prevalence in the U.S. is 5.0 cases per 100,000 population.

Genetic Discoveries

• In June 2021, NIH and the Uniformed Services University discovered a form of genetic ALS affecting children as young as 4 years old.
• This form is linked to the SPTLC1 gene, part of the body’s fat production system.
• It may be caused by changes in lipid metabolism.

Pathophysiology Hypotheses

• The exact cause of ALS is unknown, but several hypotheses exist.
• Accumulation of glutamate in the central nervous system leads to excitotoxic stimulation.
• Functional abnormalities of mitochondria contribute to the disease.
• Impaired axonal structure or transport defects are observed early in the disease process.
• Altered function of the SOD1 enzyme leads to accumulation of free oxygen radicals, causing cell damage.
• Oxidative stress, mediated by free radicals, is important in the initiation of the disease.

Neuronal Damage

• Proposed mechanisms lead to neuronal damage in both upper and lower motor neurons.
• Upper motor neurons are initially altered in the motor cortex.
• Lower motor neurons are affected at the anterior motor horn cells in the spinal cord and at motor nuclei in the brainstem.
• Death of motor neurons leads to denervation and atrophy of muscle fibers.

Clinical Presentation

• Detailed history of symptoms and a complete neurologic examination are essential.
• Early lower motor neuron cell death leads to asymmetrical weakness, initially in the limbs.
• Early findings include foot drop, difficulty walking, and weakness with lifting arms.
• Assessment of upper motor neurons, lower motor neurons, and bulbar signs and symptoms is important.

UMN and LMN Dysfunction Manifestations

• Upper motor neuron dysfunction: hyperreflexia, spasticity, Babinski signs, incoordination, and weakness.
• Lower motor neuron dysfunction: weakness, muscle atrophy, and fasciculations (spontaneous twitching).
• Bulbar signs and symptoms: dysarthria, dysphagia, sialorrhea, tongue atrophy, and tongue fasciculations.
• Bulbar presentation often leads to reduced vital capacity, affecting speaking and swallowing.
• Older age of symptom onset and early respiratory muscle dysfunction suggest a poor prognosis.
• As the disease progresses, both upper and lower motor neuron involvement becomes more symmetrical.

Cognitive and Sensory Aspects

• Sensation and bowel and bladder function are typically spared, even in late stages.
• Executive dysfunction in the frontal and temporal lobes can lead to subtle cognitive issues.
• Dementia can occur even before ALS symptoms.
• The C9orf72 gene mutation is linked to both ALS and frontotemporal dementia.

Diagnostics Criteria

• Diagnosis is made when there are widespread upper and lower motor neuron signs.
• Exclusion of other diseases through electrophysiologic and pathologic tests.
• Neuroimaging is used to rule out other conditions.
• Diagnostic criteria include the Airlie House criteria (formerly El Escorial criteria) and Awaji criteria.
• Awaji criteria place equal importance on electromyographic (EMG) and clinical abnormalities.
• Proposed new diagnostic criteria aim to simplify diagnosis while closely resembling Awaji criteria.
• Cognitive and behavioral changes are present in 50% of patients.

Diagnostic Tests

• There are no specific biochemical or laboratory markers for ALS.
• Tests are used to exclude other disorders.
• Electrodiagnostic evaluation with EMG and nerve conduction studies.
• MRI may reveal changes indicating upper motor neuron dysfunction.

Essential Diagnostic Tests

• General chemistry profile, liver function tests, thyroid function tests.
• Erythrocyte sedimentation rate (ESR), serum protein and immunofixation electrophoresis.
• Cerebrospinal fluid (CSF) analysis, vitamin B12 and creatine kinase (CK) levels.
• EMG, nerve conduction studies, and MRI.

Additional Diagnostic Tests

• Heavy metal screening (if there is a history of exposure).
• Screening for hereditary disorders, Lyme disease, and HIV.

Priority Differentials

• Motor neuropathy with conduction block.
• Spondylotic cervical myelopathy.
• Kennedy disease.
• Hirayama disease.

Importance of Differentiation

• Differentiation of ALS from other neurologic disorders is critical due to available treatments.
• Early diagnosis and appropriate medical therapy initiation are crucial.
• Atypical features (restriction to UMNs or LMNs, involvement of non-motor neurons, inconsistent EMG findings) should raise suspicion of other diseases.

Pharmacologic Management: Riluzole

• Riluzole is an FDA-approved antiglutamate that extends ventilator-free survival by ~2-3 months.
• It slows ALS progression and improves survival, especially in early bulbar involvement.
• Common side effects: asthenia, dizziness, gastrointestinal distress, neutropenia, and elevated liver enzymes.
• Regular monitoring for neutropenia and liver function is recommended.

Pharmacologic Management: Edaravone

• Edaravone is an FDA-approved free radical scavenger that reduces oxidative stress.
• Patients taking edaravone had 33% less decline in functional status compared to placebo at week 24 in a study.
• Administered via infusion with a specific schedule of daily and off-treatment periods.
• Common side effects: injection site contusion, headache, and gait disturbance.
• Recommended as an adjunct to riluzole.

SSRIs/SNRIs

• Used for depressive symptoms, with a prevalence of mild depression around 29% and severe depression around 6% in ALS patients.
• Anxiety in patients with ALS ranges from 0% to 30%.
• Sleep disturbances may be addressed with SARIs like trazodone.

Pseudobulbar Affect Treatment

• Affects 20% to 50% of ALS patients, especially those with bulbar symptom onset.
• Characterized by sudden, involuntary emotional outbursts.
• Emotional lability is common, and SSRIs or SNRIs can be helpful.

Benzodiazepines Use

• Can help with anxiety, sleep disturbances, spasticity, and muscle cramps.

Anticholinergics

• Used for sialorrhea, including tricyclic antidepressants (TCAs), glycopyrrolate, and atropine.
• TCAs can also treat pseudobulbar affect, depression, anxiety, sleep disturbances, and pain.
• Caution is advised in older patients due to anticholinergic side effects like delirium.

Botulinum Toxin Use

• Studied for sialorrhea refractory to oral medical therapy.
• Involves injection into the bilateral parotid and submandibular glands.
• 50% of patients receiving botulinum toxin type B expressed improved symptoms.

Muscle Relaxants Use

• Tizanidine and baclofen are used for spasticity.
• Intrathecal baclofen pump may be helpful if oral medications fail.

Dextromethorphan/Quinidine: Nuedexta

• Shown to significantly reduce emotional lability in patients with pseudobulbar affect.

Modafinil

• Stimulant medication that may be helpful for fatigue.
• It is important to address the cause of fatigue, such as poor sleep, pain, or nocturnal hypoventilation.

Other Treatments: Oxybutynin

• Anticholinergic commonly used for autonomic symptoms like urinary urgency (reported in 29% of ALS patients).
• Short-acting version can be crushed and used in a PEG tube if needed.
• Use with caution in older patients.

Other Treatments: Pain Management

• Pain is reported in 57% to 72% of patients and can be generalized.
• Causes include spasticity, immobility, and cramps, and may be described as burning, aching, cramping, or shock-like.
• Therapeutic options include NSAIDs, opioids, muscle relaxants, gabapentin, and steroids.

Non-Pharmacologic Management: Physical Therapy

• Has benefits for immobility, pain, spasticity, and cramping.
• Hydrotherapy, cryotherapy, heat, and ultrasound can be used.
• Can help with fatigue.
• Treating hypoventilation with noninvasive ventilation can be useful for oxygenation, fatigue, sleep disturbances, and concentration.
• Meditation, biofeedback, and cognitive-behavioral therapy can help with emotional readjustment.
• Timed voiding and avoiding caffeine and alcohol may help manage urinary urgency.
• Communication should be assessed by a speech therapist every 3 to 6 months to determine the need for modalities such as computerized speech synthesizers.

Referrals and Collaborative Team

• Diagnostic delays in ALS range from 10 to 16 months.
• A prompt referral to a neurologist or neuromuscular clinic is warranted.
• Necessary referrals for supportive care by a multidisciplinary team (physicians, nurses, physical therapists, occupational therapists, speech therapists, dietitians, social workers, pulmonology and palliative medicine specialists, and the local ALS resource group)
• The collaborative team can help clarify the patient’s wishes about artificial feeding or hydration, resuscitation, intubation, treatment of infection with antibiotics, and even hospitalizations.

Hospitalization Indications

• Based on the patient’s goals for care.
• Unstable symptoms, inability to swallow, respiratory compromise, suspicion of pneumonia, or failure to thrive.
• Respiratory failure, pneumonia, and aspiration pneumonia are the major determinants of hospitalizations and emergency admissions.

Life Span Considerations

• Some patients live for 10 to 20 years, but average life expectancy after diagnosis is 3 to 5 years.
• Most patients die of respiratory failure or infection.
• Patient age and presence/absence of bulbar symptoms influence survival.
• Patients with bulbar symptoms at onset and older patients have a poorer prognosis.

Malnutrition Prevention

• Can positively affect quality of life and length of survival.
• Can impair respiratory and immune system function and exacerbate muscular weakness.
• The American Academy of Neurology (AAN) recommends a nutrition consultation every 3 months.
• Collaboration between dietitian and speech language pathologist to determine appropriate food and fluid consistency, especially if bulbar symptoms are present.

PEG Tube Placement Suggestion

• May be indicated if this aligns with the patient’s goals for care as dysphagia progresses.
• AAN ALS Practice Parameters suggest PEG placement while the patient’s forced vital capacity (FVC) is greater than 50% of the predicted value or when there is dysphagia and/or a nutritional status decline, which can be indicated by a 5% to 10% loss of body weight.
• For further discussion of gastrostomy tube placement, a referral to a gastroenterologist and discussion with palliative medicine providers would be warranted.

Respiratory Impairment

• The leading cause of death in patients with ALS.
• Management includes pulmonary function monitoring (e.g., FVC), respiratory therapy, incentive spirometry, and noninvasive positive-pressure ventilation (NIPPV) as needed.
• Initiate of NIPPV when the patient first demonstrates difficulty with ventilation.

Explore the key characteristics, affected areas, and typical onset of ALS, a neurodegenerative disorder. Review sporadic occurrences, familial genes like C9orf72, and clinical variants such as progressive muscular atrophy. Understand the complexities and interventions for managing symptoms like communication difficulties.