Amyotrophic Lateral Sclerosis

Author(s): Jennifer Yang, MD and Nicholas Georgelos DO

Originally published:11/10/2011

Last updated:03/27/2017

1. DISEASE/DISORDER:

Definition

Amyotrophic lateral sclerosis (ALS), the most common cause of adult onset motor neuron disease, is characterized by progressive lower motor neuron degeneration with muscle atrophy and fasciculations, and upper motor neuron degeneration with spasticity and hyperreflexia. It starts in the limbs in more than two-thirds of the patients, upper limb involvement more prevalent than lower. Bulbar involvement is observed initially in one-third of cases, and a presentation of respiratory muscle weakness is seen in 1% to 2%.

Etiology

90% of cases are sporadic without specific risk factors, classified as sporadic ALS (sALS); 10% are familial (fALS). Up to 25% of the familial cases are associated with a superoxide dismutase 1 mutation (SOD1). Other newer genetic associations identified include chromosome 9 open reading frame 72 (C90RF72) in 10% of sALS and 40-50% of fALS cases, Fused in Sarcoma gene (FUS) in 1% of sALS and 4% of fALS, and mutation in transactivation response DNA-binding protein (TARDBP) in 2% of sALS and 3% of fALS. 1

Epidemiology including risk factors and primary prevention

  • Global incidence is 1 to 2 per 100 000. 2
  • Lifetime risk of sporadic ALS is 1/600 to 1/2000.
  • Peak incidence occurs in ages 65 to 74 years, with average onset of age 65. 3
  • The incidence is 20% to 60% higher in men than women.
  • Exposure to heavy metals, electromagnetic fields, pesticides, smoking and head injury have all been linked to increased incidence of ALS, however a strong association has only been shown with pesticide exposure. 4 The risk is doubled in individuals with jobs combining intense physical activity and hypoxia (e.g., firefighter). 3
  • Survival is 2 to 5 years after symptom onset with a five- year survival of 20%. Disease onset with respiratory or bulbar involvement are prognostic indicators of poor prolonged survival. 5
  • Higher body mass index (BMI) has been associated with slower disease progression; however faster functional decline has been associated with BMI greater than 30. 5

Patho-anatomy/physiology

  • Glutamate-induced excitotoxicity is evidenced by decreased astrocyte glutamate transporter in the motor cortex and anterior horn cells. The pathway to axonal death is overstimulation of glutamate receptors, increased calcium influx into cells with impaired calcium buffering capacity, then resultant enzyme activation with free radical accumulation including nitrogen activation. The latter results in tyrosine nitration that can lead to apoptosis.
  • High frequencies of mitochondrial mutations affect energy production, control of apoptosis and calcium homeostasis. 1
  • Oxidative stress contributes to motor neuron injury, excitotoxicity, mitochondrial damage, excess protein aggregation and changes to cellular signaling. 1
  • 10% have a monoclonal gammopathy, and 15% have elevated anti-GM1 levels. Viral etiologies for motor neuron disease exist, including poliovirus, West Nile virus, HTLV-1/2 and human immune virus. However, anti-inflammatory and immunotherapies failed to demonstrate efficacy.
  • Neurofilament dysfunction is implied due to increased numbers and decreased axonal transport in motor axons. However, these might also be secondary findings. Rare neurofilament mutations have been found in families with familial ALS.
  • Gene susceptibility may also be a cause of sporadic ALS, since 4% of patients have superoxide dismutase 1 mutations.

Specific secondary or associated conditions and complications

Specific secondary conditions include frontal and temporal lobe degeneration associated with cognitive and behavioral problems in up to 50% of patients. Of those who develop dementia, 5% have an associated transactive response (TAR) DNA-binding protein 43 mislocation.

2. ESSENTIALS OF ASSESSMENT

History

History is variable and dependent on the site of onset. Most patients present with painless weakness and atrophy, although associated stiffness is common. Some patients present with dysphagic symptoms, and with insidious onset of respiratory dysfunction or inability to wean from a ventilator after an illness or surgery.

Physical examination

Physical examination focuses on assessment of motor deficits, characterized by asymmetric weakness, wasting, fasciculations, and cramping. Spread is to contiguous muscles in the same region before involvement of another region. Monomelic presentation is most common, although pseudoneuritic presentation can also occur. Pseudopolyneuritic is even more uncommon. Bilateral upper extremity involvement is seen in 10% of patients; some present with hemiparesis. Patients usually have normal sensation, although deficits in dorsal column function can be seen. Sphincter control, autonomic functions, and eye movements are normal. Spasticity (brisk reflexes, extensor plantar responses, Hoffman reflexes, increased Ashworth scores) is common.

Functional assessment

Functional assessment is variable depending on the location of first involvement and the rate/location of progression, but should be comprehensive to include mobility, activities of daily living, speech and swallowing, cognition and behavior, and affective state.

Imaging

  • Cervical spine magnetic resonance imaging (MRI) is recommended to rule out myelopathy; however it is rarely utilized for diagnostic purposes, despite usual anterior horn involvement. 6
  • Brain MRI is recommended to evaluate for abnormalities in the motor tracts and to rule out multiple sclerosis. ALS-associated findings include atrophy of precentral gyri, temporal cortex, parietal cortex, frontal lobe, with poor survival correlated to volume loss in basal ganglia and limbic structures. 6

Supplemental assessment tools

  • Electromyography is essential to confirm the diagnosis and to distinguish from pre-/postsynaptic neuromuscular junction disorders and polyneuropathy. Electrodiagnostic criteria now include fasciculations as a sign of motor unit denervation, which in early disease identification has resulted in improved sensitivity (61%) with high specificity (96%).8
  • The ALS Functional Rating Scale is used to predict outcome after the diagnosis is made. Prognosis is worse for patients who have a shorter time between symptom onset and diagnosis and patients with respiratory or multiple area (bulbar + upper limb + lower limb) involvement at the time of diagnosis.9
  • Respiratory assessment should be performed at least every 3 months, including measure of forced vital capacity (FVC) and sniff nasal inspiratory pressure. With any decline of measures, arterial or capillary blood gases should be analyzed. 2
  • The supine Borg Scale to measure dyspnea is a good bedside assessment in ALS. Scores higher than 3 should trigger a full pulmonary function evaluation.10

Early predictions of outcomes

  • Rapid disease progression is associated with creatine phosphokinase (CPK) elevation, and decrement on repetitive stimulation during electrodiagnosis.
  • Low sniff transdiaphragmatic pressure detects hypercapnea with 90% sensitivity and 87% specificity; low sniff nasal pressure correlates with nocturnal hypoxia and earlier death.
  • Elevated bicarbonate and low serum chloride correlate with poor survival.
  • High-density motor unit estimates (MUNE) better predict functional deterioration, using the ALS Functional Rating Scale, than compound muscle action potential (CMAP) amplitudes using the Medical Research Council muscle strength rating, or the ALS Functional Rating Scale.11

Environmental

Environmental evaluation of the living space for durable medical equipment and home modifications help identify interventions that conserve energy and reduce falls. Hospital beds, transfer lifts, power mobility, one-floor living arrangements that include access to adequate toileting and bathing facilities and ramps or entry lifts that provide community and general access should be considered. Computer-based communication devices should be considered for individuals who have poor speech intelligibility.

Social role and social support system

  • Keeping individuals engaged in their work and filial roles as long as possible is important: balance must be achieved between energy-conserving interventions to maintain these roles in the near future, and planning for inevitable loss of function in the distant future.
  • Caregiver support should include assisting informal caregivers to consider and purchase nursing care/home health aids/companions to decompress them from basic personal care so that household management can occur.

Professional Issues

  • Disclosing the diagnosis should be done as soon as diagnostic certainty is established.
  • End of life issues including use of life sustaining enteral feedings, and assisted negative- and positive-pressure ventilation, should be discussed early in the disease course.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Current treatment guidelines are available.12,13

At different disease stages

New onset/acute

  • There is no known cure. The aim of care is maximizing quality of life and minimizing morbidity.
  • Pain control using opioids and non-opioids as detailed in the WHO Analgesic Ladder guidelines. Therapeutic injections of painful joints may be performed.
  • Spasticity management with oral or intrathecal antispasticity agents (e.g., baclofen, tizanidine). Overdosing of muscle relaxants is a common concern causing weakness worse than baseline.
  • Rehabilitation strategies
  • Moderate exercise in early stage disease shows no evidence of deleterious effect.
  • Positive impact of exercise on survival has been demonstrated in animal models but human studies lack sufficient data. 14

Subacute

  • Riluzole results in slower strength deterioration in all ALS patients with survival prolongation of 2-3 months on average. Riluzole protects against neuronal damage caused by excitotoxicity. 1
  • Cramping (present in 44-55%) is near universally treated with quinine, however it is restricted in the USA due to possible cardiac complications. 2,5 Exercise is the first line of treatment in the USA, with focus on range of motion exercises. 14
  • Identifying weight loss and preventing cachexia associated with dysphagia is best managed by early enteral feeding tube placement. A formal nutritional assessment can facilitate this decision. Current guidelines reflect a threshold of 5% weight loss for gastrostomy tube placement; further weight loss has shown irreversible metabolic change and inability to regain weight. 2
  • Mechanical insufflator-exsufflator may increase mobilization of respiratory secretions.
  • Sleep disorders should be evaluated. Easy fatigability can be treated with pyridostigmine, amantadine, modafinil, and methylphenidate.
  • Siaborrhea can be treated with scopolamine patch, atropine, glycopyrrolate, tricyclic agents, carbamazepine, hyoscyamine sulfate and diphenhydramine. Botulinum toxin B or low-dose radiation to the salivary glands also can be considered.2
  • Multidisciplinary treatment is associated with better survival and coordination of care, although evidence is not universal

Chronic

  • Noninvasive ventilation (NIV) improves quality of life, improves sleep, and prolongs survival by about 7 months. Secretion management and humidfication may be needed in conjunction with NIV.
  • Patients under age 60 with poor tolerance of NIV and poor secretion management may require invasive ventilation (tracheotomy tube). In these patients, it is critical to provide assistive communicative training and devices. 2
  • Mechanical inssuflation-exsufflation devices may be necessary in patients with bulbar impairment to prevent infection. 2
  • Enteral feeding stabilizes weight and may improve survival.
  • Dextromethorphan with quinidine can be considered for pseudobulbar affect, but is known to cause QT prolongation. SSRIs and tricyclics are recommended for patients at risk for arrhythmia.2
  • Antidepressant medications heavily used in ALS patients with depressive symptoms have shown poor effect in patients not diagnosed with concomitant depressive disorders. Depressive symptoms in these patients are typically linked to perception of physical and functional losses and not clinical depression. 15
  • Cognitive decline or behavioral changes occur in at least 50% of patients. No current standard of care exists for this, although screening is recommended. 2

Emerging/unique Interventions

Impairment-based measurement

  • Respiratory failure is the most common cause of death in ALS. Respiratory function testing every 3 months is recommended.
  • Monitoring cough effectiveness via peak cough flow helps identify patients at greater risk of ineffective clearance and management
  • Bedside pulmonary function tests are important to monitor clinical progression over time; forced vital capacity (FVC) below 30% of predicted value is sometimes used to justify the need for hospice services; shortness of breath at rest and during activity associated with weak ventilatory muscles can be palliated with supplemental oxygen.
  • If sleep is problematic, nighttime oximetry is indicated to determine need for use of positive airway pressure; weak pharyngeal muscles may cause an obstructive sleep apnea.
  • Swallowing assessment including formal videoflouroscopic evaluation by speech and language pathologists will support decision-making regarding whether oral feeding can maintain caloric support and if enteral feeding is necessary.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

  • Multidisciplinary treatment at centers of excellence are accepted as superior treatment, compared to a single physician
  • Respiratory monitoring and early use of noninvasive ventilation and secretion mobilization strategies
  • Dysphagia management and use of enteral feeding with early enteral feeding to stabilize function and improve survival
  • Some evidence now exists suggesting that skeletal myocytes play an active role in the disease process, showing affected muscle without evidence of denervation. This suggests a “dying-back” process where muscle dies followed by neuronal degeneration.16
  • O-benzylserine is a derivate of riluzole being studies which is more metabolically stable and inert and may allow steadier plasma riluzole levels.17
  • Rasagaline, an MAOI, has shown improved motor performance and survival in mice when used with riluzole.17
  • Edavarone, an antioxidant, showing potential to delay neuron degeneration in mice.17
  • Celastrol, a natural herbal compound, demonstrates a strong antioxidative effect.17
  • Cannabis has been shown in mice to prolong neuronal survival, delay onset, and slow progression of disease. No human clinical trials have begun yet.14
  • Although higher BMIs are associated with delayed disease onset and statins have been linked to increased muscle cramping in patients, there is no evidence to support discontinuing statins in patients already on statin therapy.14
  • Numerous other medications are being researched as antioxidants, anti-apoptotic agents, and neurotrophic factors.
  • Q-ball imaging (QBI) is a new MRI technique that allows better estimation of white matter involvement in disease process.5

Emerging/unique interventions

  • Stem cell based therapies with immune-modulating effects are postulated to improve axonal regeneration, remyelination, and functional improvements. Preclinical trials have shown good efficacy and no serious adverse effects associated with stem cell treatment.18
  • SOD1 mice demonstrated increase in lifespan after administration of SOD1 vaccine. The proposed mechanism is the vaccine targets and eliminates the misfolded SOD1 mutant protein.17
  • Recent evidence supports use of inspiratory muscle training for long-term respiratory benefit as well as lung volume recruitment training (via breath stacking, cough augmentation) for predominantly short-term benefit. Lung volume recruitment is beneficial in improved secretion clearance.19

Interesting recent but ineffective interventions

  • Diaphragmatic pacing has been shown to increase mortality by 11.5 months,2 and did not prove effective in improving FVC largely due to difficulty in mastering technique. 19
  • Mechanically assisted cough (abdominal thrust, etc.) is significantly less effective in cough and clearance than mechanical insufflation-exsufflation.19
  • Ceftriaxone trial targeting the expression of up-regulation of excitatory amino acid transporter 2 (EAAT2) did not effectively improve disability scores.17
  • Reversing glutamate induced excitability with talampanel, an alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)-type glutamate receptor antagonist, failed in Phase III trials.17
  • Mitochondrial CoQ10 increased survival time in SOD1 mice, but ineffective in humans.14
  • Supplemental oxygen should be avoided in ALS patients as it further suppresses respiratory drive, hypoventilation, carbon dioxide retention, and possible respiratory arrest.14

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

  • Stem cells and their role in managing ALS are fertile grounds for research at this time.
  • SOD1 vaccine, which appears to be effective in mice, has not been studied in human subjects.

References

  1. Moujalled D, White AR. Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis. CNS Drugs. 2016;30(3):227-43. doi:10.1007/s40263-016-0317-8
  2. Hobson EV, Mcdermott CJ. Supportive and symptomatic management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2016;12(9):526-38. doi:10.1038/nrneurol.2016.111
  3. Garzillo EM, Miraglia N, Pedata P, Feola D, Lamberti M. Risk agents related to work and amyotrophic lateral sclerosis: An occupational medicine focus. Int J Occup Med Environ Health. 2016;29(3):355-67. doi:10.13075/ijomeh.1896.00368
  4. Bozzoni V, Pansarasa O, Diamanti L, Nosari G, Cereda C, Ceroni M. Amyotrophic lateral sclerosis and environmental factors. Funct Neurol. 2016;31(1):7-19. doi:10.11138/fneur/2016.31.1.007
  5. Riva N, Agosta F, Lunetta C, Filippi M, Quattrini A. Recent advances in amyotrophic lateral sclerosis. J Neurol. 2016;263(6):1241-54. doi:10.1007/s00415-016-8091-6
  6. Grolez G, Moreau C, Danel-brunaud V, et al. The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review. BMC Neurol. 2016;16(1):155. doi:10.1186/s12883-016-0672-6
  7. de Carvalho M, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin neurophys. 2008;119:497-503.
  8. Douglass CP, Kandler RH, Shaw PJ. McDermott CJ. An evaluation of neurophysiological criteria used in the diagnosis of motor neuron disease. J Neurol Neurosurg Psychiatry. 2010;81:646-649.
  9. Kimura F, et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology. 2006;66(2):265-267.
  10. Just N, Bautin N, Danel-Brunaud V, Debroucker V, Matrian R, Perez T. The Borg dyspnea score. Eur RespirJ. 2010;35:353-360.
  11. vanKijk JP, Schelhaas HJ, VanSchaik IN, Janssen HMHA Stegeman DF, Zwarts MJ. Monitoring disease progression using high density motor unit number estimation in amyotrophic lateral sclerosis. Muscle Nerve. 2010;42:239-244.
  12. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1227-33. doi: 10.1212/WNL.0b013e3181bc01a4
  13. Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009;73(15):1218-26. doi: 10.1212/WNL.0b013e3181bc0141
  14. Karam CY, Paganoni S, Joyce N, Carter GT, Bedlack R. Palliative Care Issues in Amyotrophic Lateral Sclerosis: An Evidenced-Based Review. Am J Hosp Palliat Care. 2016;33(1):84-92. doi:10.1177/1049909114548719
  15. Carvalho TL, De almeida LM, Lorega CM, et al. Depression and anxiety in individuals with amyotrophic lateral sclerosis: a systematic review. Trends Psychiatry Psychother. 2016;38(1):1-5. doi:10.1590/2237-6089-2015-0030
  16. Loeffler JP, Picchiarelli G, Dupuis L, Gonzalez de aguilar JL. The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis. Brain Pathol. 2016;26(2):227-36. doi:10.1111/bpa.12350
  17. Kumar V, Islam A, Hassan MI, Ahmad F. Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning. Eur J Med Chem. 2016;121:903-17. doi:10.1016/j.ejmech.2016.06.017
  18. Moura MC, Novaes MR, Zago YS, Eduardo EJ, Casulari LA. Efficacy of Stem Cell Therapy in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis. J Clin Med Res. 2016;8(4):317-24. doi:10.14740/jocmr2495w
  19. Macpherson CE, Bassile CC. Pulmonary Physical Therapy Techniques to Enhance Survival in Amyotrophic Lateral Sclerosis: A Systematic Review. J Neurol Phys Ther. 2016;40(3):165-75. doi:10.1097/npt.0000000000000136

Original Version of the Topic

Anthony Chiodo, MD. Amyotrophic Lateral Sclerosis. 12/27/2012.

Author Disclosure

Jennifer Yang, MD
Nothing to Disclose

Nicholas Georgelos DO
Nothing to Disclose

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