MED-NERD

Amyotrophic lateral sclerosis (Lou Gehrig Disease; Lou Gehrig's Disease; Muscle Stimulation Disorders)

Outline:

• Introduction
• Epidemiology
• Etiology
• Clinical presentation
• Diagnosis
• Differential diagnosis
• Management and treatment
• References

Introduction:

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease affecting the central nervous system. It is a fatal disease that is usually missed especially in early stages. However, recently, ALS is known as a complex syndrome including behavioral deficits which helps in early detection of early stages of ALS. Identification of genetic risk factors in addition to establishment of new diagnostic criteria also helped in the diagnostic process of ALS. 

Prognosis of ALS may be determined through identification of the behavioral and cognitive changes of ALS, using scoring system and predictive models and therefore providing the proper care for the patient. Further studies in the pathophysiology, etiology, and therapies of ALS can improve the prognosis of ALS. 

Epidemiology:

A global incidence was estimated through a meta-analysis of 110 studies was 1.59 per 100,000 individuals and a prevalence of 4.42 per 100,000 individuals was estimated through 58 prevalence studies. Age, sex, and genetics play a role in determination of ALS risk. Male carriers of C9orf72 repeat expansion develop ALS two years earlier compared to females.

Age:

The National ALS Registry in the United states (US) reported the age 60-79 years a peak for ALS prevalence. The risk of ALS is increased due to aging process.

Sex:

Male-to-female ratio at the age 25-34 years was 3.7, 1.2 at the age 65-74 years, and 1.4 above the age of 75 years according to South East England ALS Registry. About 60% of ALS patients are males according to the US National ALS Registry. The lifetime risk of ALS was 1:347 for males and 1:436 for females according to the Irish ALS Registry.

Etiology:

The etiology of ALS is a combination of genetic, environmental, and age-related factors. Over 20 genes have been discovered related to ALS. About 15% of ALS cases are due to monogenetic mutations with high effect size. However, genetic mutations with low and moderate effect size are also related to ALS. About 30-60% of ALS is heritable with 2-fold risk of developing ALS in first-degree relatives of ALS patients.

Autosomal dominant etiology of ALS:

The first gene related to ALS was discovered in 1993 which is "SOD1" contributing to about 20% of fALS and 1-2% of sALS. Mutations in SOD1 gene cause increased aggregation of proteins leading to disturbed cellular functions. Other mutations include mutations in TARDBP and FUS genes that where discovered in 2008-2009. TARDBP and FUS gene encode RNA‐binding proteins TDP‐43 and FUS. Mutations in these genes contribute to 3%–5% of fALS cases and <1% of sALS. C9orf72 gene mutation was discovered in 2011 contributing to 30%–50% of fALS and 7%–10% of sALS cases. In case of hexanucleotide repeat expansions in C9orf72, patients are more liable to develop bulbar symptoms in addition to cognitive and behavioural impairment. 

The fifth most common autosomal dominant cause of ALS is mutation in TBK1 gene contributing to nearly 1% of ALS cases and up to 10% of ALS‐FTD patients. Genetic counselling of ALS is complicated as most SOD1 mutations are characterized by high penetrance while other genes have reduced penetrance. Some rare cases of ALS have mutations in more than one gene which is known as oligogenic origin. Some rare variants have been identified using next‐generation sequencing.

Risk factors of ALS:

-Genetic factor:

UNC13A genotype is at risk for ALS. Intermediate repeat expansions in ATXN2 also increase the risk of developing ALS.

-Age and male sex increase the risk of getting ALS.

-Environmental risk factor:

•Smoking

•Physical exercise

•Body mass index (BMI)

•Exposure to pesticides, metals, β‐methylamino‐l‐alanine.

-Head injury

-Viral infection

Clinical presentation:

Progressive muscle weakness associated with muscle cramps, muscle atrophy, muscle stiffness, fasciculations, and slowness of movements are the main presentation of ALS. Muscle weakness in ALS is characterized by focal onset with spread to adjacent body regions in relation to the disease progression within the motor system (The spinal cord segments and motor cortex).

Spinal ALS represent about two-thirds of ALS patients with unilateral distal muscle weakness and atrophy in upper or lower limb muscles. Bulbar ALS represent about one-third of ALS cases with weakness in bulbar muscles.

Symptoms:

□Upper limb weakness is chatacterized by : 

-Weakness mainly affects the dominant hand

-Thenar muscles are more affected than hypothenar muscles which is known as "split‐hand syndrome"

-Early affection of the first interosseous muscle 

-Finger extensors more affected than finger flexors 

□Lower limb weakness is characterized by:

-Early affection of anterior tibial muscle before the gastrocnemius muscle

-The hamstrings are affected earlier than the quadriceps muscles

□Bulbar onset ALS is characterized by:

-Most commonly dysarthria or dysphagia

-Less commonly dysphonia, reduced mouth closure or chewing problems

-In late stages, axial muscle weakness with head drop and postural problems may occur

-Pseudobulbar affect may occur in about one-third of patients with bouts of uncontrolled laughing or crying 

 Some ALS patients present with fasciculations, muscle cramps or mild weight loss before muscle weakness.

Signs:

Classic ALS cases have signs of both Upper Motor Neuron (UMN) and Lower Motor Neuron (LMN) involvement on neurological examination.

□Signs of UMN lesion include:

-Hyperreflexia (or retained reflexes in atrophic muscles)

-Hypertonia (especially in upper limb flexors and lower limb extensors)

-Slow movement such as tongue movement

□Signs of LMN lesion include:

-Muscle weakness 

-Muscle atrophy 

-Fasciculations

-Hypotonia

ALS is a heterogenous syndrome regarding the motor manifestations of the disease itself which can be accompanied by variable degrees of frontotemporal involvement leading to different phenotypic presentations of the disease. A new classification system is required for the heterogenous phenotypes of ALS.

Diagnosis:

Diagnosis of ALS is mainly clinical through patient history and careful neurological examination. There is no specefic test for diagnosis of the disease. Exclusion of other similar conditions is done through laboratory tests and imaging techniques. 

Clinical diagnosis of ALS: 

-Patient history:

•History of progressive muscle weakness with involvement of adjacent regions.

•Clinical evidence of UMN and LMN lesion, with or without predominance of one of these motor neuron lesions early in the ALS course.

Tests:

-Electromyography (EMG) used to evaluate the transmission of nerve impulse to muscles. EMG can show positive waves, fibrillations, fasciculations, and giant motor units even in spared limbs.

-Nerve conduction studies (NCS) used to assess the conduction of nerve impulse through the neurons. Velocity of nerve conduction is often affected late in the disease and usually normal in earlier stages.

Both EMG and NCS can show more evidence of motor neuron dysfunction and used to detect neuromuscular transmission defect or demyelination.

-Magnetic resonance imaging (MRI) is often performed to exclude other motor neuron diseases and can reveal brain atrophy that may be seen in some cases of ALS. MRI is also performed over cervical spine region to exclude compression of the spinal cord.

-Genetic testing is performed if familial ALS is suspected. Genetic tests include detection of genetic abnormalities causing spinal muscular atrophies, mutations in superoxide dismutase gene, hexosaminidase A enzyme for Tay-Sachs disease, and are mainly performed for genetic counselling. There is no specific treatment for genetic disorders detected by genetic testing.

-Laboratory tests include complete blood count (CBC), creatine kinase, electrolytes, and thyroid function tests for detection of treatable causes and exclusion of other conditions that mimic ALS.

-Serum and urine protein electrophoresis with immunofixation for detection of paraproteinemia that is rarely associated with motor neuron diseases (MNDs). However, evidence of paraproteinemia indicates paraneoplastic nature of MNDs which can be treated leading to improvement of MNDs.

-Antimyelin-associated glycoprotein (MAG) antibodies can be detected with demyelinating motor neuropathy which is similar to the condition of ALS.

-Heavy metals detection through 24-hour urine collection.

-Lumbar puncture is performed to exclude other similar conditions. 

-Erythrocyte sedimentation rate (ESR), the serum Venereal Disease Research Laboratories (VDRL) test, detection of some antibodies (antinuclear [ANA], rheumatoid factor, anti-Hu [for anti-Hu paraneoplastic syndrome], Lyme titer, hepatitis C virus markers, HIV) are also performed to detect susceptable causes.

The diagnosis of ALS is complicated and often delayed, with average 1 year delay from the onset of symptoms.

 

Differential diagnosis:

-Amyotrophic lateral sclerosis strongly suspected when UMN and LMN signs with facial muscle weakness are found. 

-Spinal muscular atrophies mainly affect children

-Myopathies

-Neuromuscular transmission disorders

-Autoimmune motor neuropathies 

-Dermatomyositis

-Polymyositis

-Cervical spinal stenosis 

-Infections such as hepatitis C, Lyme disease, HIV, syphilis

-About 15-20% of frontotemporal dementia patients develop MNDs.

-Exposure to heavy metal toxicity such as lead and mercury

-Thyroid and adrenal glands disorders

-Electrolyte abnormalities including hypokalemia, hypercalcemia, and hypophosphatemia

Management and Treatment:

There is no specific treatment for ALS. Management of ALS involves care of different systems of the body to improve the survival for patients. Treatment of ALS includes disease-modifying therapy to slow the progression of the disease, and supportive therapy to improve the quality of life.

Disease-modifying therapy:

The first drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ALS was riluzole (Rilutek). Riluzole in clinucal tirals prolonged the average survival rate for ALS by 3 to 5 months without marked delay in the deterioration of muscle. Another disease-modifying therapy approved by the FDA is edaravone (Radicava) which slowed tbe functional deterioration in some ALS patients especially in earlier stages of the disease.

Recently, sodium phenylbutyrate/taurursodiol (Relyvrio) was approved by the FDA in 2022, and tofersen (Qalsody) was approved in 2023. Tofersen is used mainly for superoxide dismutase 1 (SOD1) gene (SOD1-ALS). 

Symptomatic therapy:

-Medications:

•Muscle relaxants such as baclofen, tizanidine or diazepam can be used for muscle spasticity and fasciculations. Intrathecal administration of baclofen may be used in severe spasticity.

•Quinine sulfate, levetiracetam or mexiletine may be used for muscle cramps.

•Atropine, scopolamine, amitriptyline, glycopyrrolate, botulinum toxin injections, or oral suction devices may be useful for ALS patients with hypersalivation (sialorrhea).

•Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) can be used for mood and behavioral changes such as depression. 

 •Analgesics can be used to relieve pain.

 Supportive treatment:

•Adequate nutrition and fluids are essential for ALS patients. Weight loss is an indicator of poor prognosis. Nasogastric tube for nutrition can be used in case of dysphagia.

•Physical and occupational therapy should be started as early as possible to prevent muscle contractures and improve the flexibility of affected joints.

•Speech therapy and augmentative communication devices for dysarthria.

•Breathing assist devices such as non-invasive positive pressure ventilation (NIPPV) can be used due to weakness of respiratory muscles. Secretion can be cleared through cough assist devices. Tracheostomy and permanent mechanical ventilation may be used in severe cases of respiratory muscle weakness and in late stages of the diseass.

References:

(1)Feldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, Sobue G. Amyotrophic lateral sclerosis. Lancet. 2022 Oct 15;400(10360):1363-1380. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10089700/

(2)Goutman SA, Hardiman O, Al-Chalabi A, Chió A, Savelieff MG, Kiernan MC, Feldman EL. Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol. 2022 May;21(5):480-493. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9513753/

(3)Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023 Mar;22(3):185-212. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9768794/

(4)Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020 Oct;27(10):1918-1929. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540334/

(5)Etienne Leveille, MD, Yale School of Medicine and Christina Fournier, MD, MSc, Associate Professor of Neurology, Interim Director, Neuromuscular Division, Emory University Department of Neurology,Amyotrophic Lateral Sclerosis

https://rarediseases.org/rare-diseases/amyotrophic-lateral-sclerosis/

(6)Michael Rubin , MDCM, New York Presbyterian Hospital-Cornell Medical Center, msdmanuals, Amyotrophic Lateral Sclerosis (ALS) and Other Motor Neuron Diseases (MNDs).

https://www.msdmanuals.com/professional/neurologic-disorders/peripheral-nervous-system-and-motor-unit-disorders/amyotrophic-lateral-sclerosis-als-and-other-motor-neuron-diseases-mnds