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Journal List > Can Fam Physician > v.52(12); Dec 10, 2006

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Can Fam Physician. 2006 December 10; 52(12): 1563–1569.
PMCID: PMC1783756
Copyright © 2006, Can Fam Physician
Amyotrophic lateral sclerosis
Update for family physicians
Christen L. Shoesmith, MD, FRCPC and Michael J. Strong, MD, FRCPC
Correspondence to: Dr Michael J. Strong, Room C7-120, University Hospital, London Health Sciences Centre, 339 Windermere Rd, London, ON N6A 5A5; telephone 519 663-3874; fax 519 663-3609; e-mail mstrong/at/uwo.ca
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Abstract
OBJECTIVE
To discuss the epidemiology, pathogenesis, diagnosis, expected course, prognosis, and treatment of amyotrophic lateral sclerosis (ALS), a degenerative disorder of the nervous system associated with progressive weakness.
QUALITY OF EVIDENCE
PubMed and the Cochrane Database of Systematic Reviews were searched using the MeSH headings “amyotrophic lateral sclerosis,” “therapy,” “epidemiology,” and “etiology.” Articles containing the best available evidence were reviewed. Most provided level II and III evidence. There were some level I drug trials.
MAIN MESSAGE
Amyotrophic lateral sclerosis is associated with progressive dysarthria, dysphagia, and weakness in the extremities. Diagnosis is based on physical examination, electrophysiology, and excluding other confounding conditions. There is no cure for this devastating disorder. Certain treatments, however, can improve survival and quality of life.
CONCLUSION
Because ALS is a complex disease, care of ALS patients is best provided at multidisciplinary clinics that specialize in managing patients with this disorder.
Résumé
OBJECTIF
Faire le point sur l’épidémiologie, la pathogénèse, le diagnostic, l’évolution habituelle, le pronostic et le traitement de la sclérose latérale amyotrophique (SLA), une maladie dégénérative du système nerveux qui entraîne une faiblesse progressive.
QUALITÉ DES PREUVES
On a consulté PubMed et la Cochrane Database of Systematic Reviews à l’aide des rubriques MeSH «amyotrophic lateral sclerosis», «therapy», «epidemiology» et «etiology». Les articles fournissant les meilleures preuves ont été révisés. La plupart fournissaient des preuves de niveau II et III. Quelques essais pharmaceutiques étaient de niveau I.
PRINCIPAL MESSAGE
La sclérose latérale amyotrophique s’accompagne de dysarthrie, dysphagie et faiblesse progressives des extrémités. L’examen physique, l’électrophysiologie et l’exclusion des autres conditions permettent de faire le diagnostic. Il n’existe pas de traitement pour cette maladie dévastatrice. Toutefois, certains traitements peuvent améliorer la survie et la qualité de vie.
CONCLUSION
Parce qu’il s’agit d’une maladie complexe, les cliniques multidisciplinaires spécialisées dans le soin des patients atteints de SLA sont les mieux placées pour traiter ces patients.
 
EDITOR’S KEY POINTS
  • Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disease, one in which family physicians have a long-term role.
  • Diagnosis is best made by a neurologist, as there is no one specific test for ALS. Rather, a combination of signs and symptoms suggest the disease. Upper and lower motor neuron signs in at least 3 regions of the body confirm the diagnosis, but there are other variants.
  • Amyotrophic lateral sclerosis is a steadily progressive disease with gradually increasing muscle weakness that affects eating and swallowing, speaking, fine motor control (writing), and ultimately breathing. Most patients die within 3 to 5 years of onset, usually of progressive respiratory failure.
  • Patients with ALS are best treated in multidisciplinary clinics. No specific treatments reverse the disease, but many can ameliorate symptoms, such as spasticity, cramps, depression, and shortness of breath. Family doctors are especially important in end-of-life care.
POINTS DE REPÈRE DU RÉDACTEUR
  • La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative rare mais dévastatrice contre laquelle le médecin de famille joue un rôle à long terme.
  • C’est le neurologue qui est le mieux placé pour en faire le diagnostic puisqu’il n’y a pas de test spécifique pour la SLA. C’est plutôt un ensemble de signes et de symptômes qui fait penser à cette maladie. Le diagnostic est confirmé par des signes d’atteinte des neurones supérieurs et inférieurs dans au moins trois régions du corps, mais d’autres variantes existent.
  • La SLA est une maladie qui progresse de façon régulière, entraînant une faiblesse croissante des muscles, qui affecte l’alimentation et la déglutition, la parole, la motricité fine (écriture) et finalement la respiration. La plupart des patients décèdent entre 3 et 5 ans après le début, habituellement d’insuffisance respiratoire progressive.
  • C’est dans des cliniques multidisciplinaires que les patients souffrant de SAL sont le mieux traités. Aucun traitement spécifique ne renverse le cours de la maladie, mais plusieurs interventions peuvent soulager certains symptômes comme la spasticité, les crampes, la dépression et la dyspnée. Le médecin de famille est particulièrement important pour les soins terminaux.
Amyotrophic lateral sclerosis (ALS) is a diagnosis no patient wants to receive. It is a progressive neurodegenerative disorder that results in loss of brain-stem and spinal motor neurons and gives rise to painless weakness and muscle atrophy with few or no sensory symptoms. “Amyotrophic” means muscle atrophy, and “lateral sclerosis” refers to pathologic changes in the spinal cord that include degeneration of the lateral columns where the corticospinal tracts are located. Diagnosis of ALS is made on the basis of a combination of upper motor neuron (UMN) and lower motor neuron (LMN) findings.
The first symptoms of ALS can include weakness in the extremities, head drop, dysarthria, and dysphagia. About 75% of patients present with onset in the limbs; about 21% present with onset in the bulbar area. Weakness usually progresses slowly, but can progress rapidly. Average survival time ranges from 3 to 5 years after onset of symptoms (for bulbar and limb onset, respectively), although some patients survive much longer.
Care of ALS patients is provided collaboratively by multidisciplinary ALS clinics and patients’ family physicians. After referring patients to neurologists, family physicians’ role is to help with treatment of symptoms, to monitor pulmonary status and provide early treatment for pneumonia, to provide emotional support, and to assist with end-of-life care. The role of multidisciplinary clinics is to keep family physicians informed of important changes in treatment regimens and to provide suggestions for ongoing monitoring of symptoms.
Quality of evidence
PubMed and the Cochrane Database of Systematic Reviews were searched using the MeSH headings “amyotrophic lateral sclerosis,” “therapy,” “epidemiology,” and “etiology.” Articles containing the best available evidence were reviewed. Several drugs for prolonging survival have been subjected to randomized controlled trials (level I evidence). Evidence for therapies to control symptoms is mostly level II (observational studies) and level III (expert opinion).
Epidemiology
Annual incidence of ALS is 2/100 000 population and prevalence is 6/100 000. Most cases are sporadic; only 5% to 10% are familial. Although ALS most often affects those older than 40, 10% of cases involve patients younger than 40, and 5% involve patients younger than 30. Male-to-female ratio is 1.4:1, but approaches unity after age 70.1
Pathogenesis
Amyotrophic lateral sclerosis is generally classified as a single disease entity, but evidence suggests that it is a clinical syndrome resulting from several possible causes.2 It is most likely that sporadic cases of ALS are multifactorial and related to several environmental factors and a genetic predisposition. Epidemiologic studies, however, have not been able to identify any definite causative factors. Smoking is the only probable risk factor identified so far. Unproven risk factors include ingestion of lead or agricultural chemicals, physical prowess (excellence in athletics), and intake of dietary glutamate.3,4 A causative retrovirus has been considered, but is not yet supported by evidence.
Between 5% and 10% of cases of ALS follow a familial inheritance. Many causative gene mutations have been identified, of which superoxide dismutase 1 (SOD1) is the most common.2 Researchers have typically used mice with SOD1 mutations to try to decipher the pathogenesis of ALS. This research has identified several factors involved in pathogenesis, including protein aggregation, glutamate excitotoxicity, oxidative injury, inflammation, mitochondrial dysfunction in motor neurons, and defective axonal transport.2-5
Diagnosis
If ALS is suspected, diagnosis is best made by a neurologist with expertise in the area of ALS (usually a neuromuscular expert). Although there is no single diagnostic test, diagnosis can be made on the basis of physical examination and electrophysiology findings and by excluding other conditions in the differential diagnosis.6 Common clinical findings include dysarthria, tongue atrophy and fasciculations, amyotrophy (muscle atrophy), extremity fasciculations, weakness, and hyperreflexia. Finding hyperreflexia in a weak and wasted extremity is highly suggestive of ALS. Extraocular movements, sensation, and bladder function are typically normal.
Diagnosis of ALS is made by confirming a progressive course of weakness, with both UMN and LMN findings in 4 anatomically defined regions of the body: craniobulbar, cervical, thoracic, and lumbosacral. The El Escorial criteria6 were developed to increase diagnostic consistency in ALS (Table 1,6). For a definitive diagnosis of ALS, UMN and LMN findings in 3 regions and UMN signs above LMN signs must be found. Cases classified as probable ALS, however, will usually be confirmed as ALS at post-mortem examination.7
Table 1
Table 1
Revised El Escorial criteria6 for diagnosing ALS
Electrophysiologic testing with nerve conduction studies and electromyography are used to document LMN dysfunction. Typically, conduction velocities and sensory studies are normal, and evidence of denervation and chronic neurogenic changes is revealed by electromyography. Magnetic resonance imaging of the head and spine is frequently ordered to exclude structural causes of weakness. Scans are usually normal in ALS, but can show a high T2 signal within the corticospinal tracts that could indicate Wallerian degeneration.8
Several conditions can mimic ALS in the early stages9 (Table 2,9). Neurologists can exclude other diagnostic considerations based on history, physical examination, and results of investigations.
Table 2
Table 2
Differential diagnosis of amyotrophic lateral sclerosis9
Expected course of disease
Amyotrophic lateral sclerosis is a steadily progressive disease and does not usually have abrupt exacerbations. Swallowing gradually becomes more difficult to the point that a gastrostomy tube might be required to improve caloric intake and safety of eating. Dysarthria progresses, and a writing tablet or computerized device might be required for communication. Pulmonary function usually declines to shortness of breath at rest. Patients sometimes develop severe orthopnea related to diaphragmatic weakness and early morning headaches related to development of nocturnal hypercapnia. Mobility can be improved with a variety of assistive devices, including ankle-foot orthotics for foot drop and electric wheelchairs.
Depression and anxiety are not uncommon and can develop at any time. Traditionally, cognition was thought to be spared in ALS. Cognitive or behavioural features consistent with frontotemporal degeneration, however, have been observed,10,11 and neuropsychologic evaluation can often identify personality changes, deficits in verbal fluency, and difficulty with planning and abstraction. Pseudobulbar dysfunction or inappropriate laughing and crying can also develop.
Prognosis
Progressive deterioration results in death within an average of 3 years after symptom onset. Patients can find some hope in the fact that 20% of patients survive for more than 5 years, and 10% survive for more than 10 years. Bulbar onset has a worse prognosis than limb onset does. Younger patients typically survive longer.11,12
Treatment
Treatment of ALS patients is best provided at multidisciplinary clinics that have neurologists or physiatrists, speech language pathologists, occupational therapists, physiotherapists, and dietitians on staff. Clinic visits typically focus on treatment of symptoms, assessment of swallowing, evaluation of nutrition, and assessment of respiratory function. Patients treated at multidisciplinary clinics appear to survive as much as 7.5 months longer than patients not followed by such clinics13 (level II evidence).
Although there is no cure for ALS, there is treatment. Riluzole, a glutamate antagonist, is the only pharmacologic treatment for ALS approved by Health Canada and the United States Food and Drug Administration. By reducing glutamate excitotoxicity, this drug could prolong the lifespan of motor neurons. Previous studies have suggested that this drug extends life expectancy by 2 months on average14 (level I evidence). Riluzole is a controlled medication and can be prescribed only by certain ALS specialists in Canada. Side effects include fatigue, nausea, and raised transaminase levels.
A recent Cochrane review assessed antioxidants as treatment for ALS and concluded that the evidence did not support their use15 (level I evidence). According to another recent Cochrane review, recombinant human insulin–like growth factor 1 (IGF-1) might be somewhat effective, but available evidence is insufficient to recommend its regular use16 (level I evidence).
Several ongoing drug trials are evaluating medications for reducing mortality and treating symptoms in ALS.17 It is unlikely, however, that a single medication will stop disease progression. More likely, patients will require a cocktail of medications to increase their survival time. Compounds currently being evaluated in phase III trials include minocycline, IGF-1 polypeptide, ceftriaxone, and ONO-2506. Several drugs being considered for trials include tamoxifen, coenzyme Q10, memantine, sodium phenylbutyrate,18 and thalidomide. Recent trials of creatine, lamotrigine, gabapentin, and topiramate have had negative results. Ceftriaxone was identified after a search through already approved drugs for a compound that was effective at stimulating expression of astrocytic glutamate transporter, which could reduce excitotoxicity by inactivating synaptic glutamate.19,20 Stem-cell therapy for ALS is starting to be explored, but research is in its earliest stages and no randomized controlled studies have been published.21 Patients should be cautioned about exploring stem-cell therapies for which protocols have not been scientifically validated.
Although we do not have pharmacologic agents that cure ALS, several can help with its symptoms. Respiratory insufficiency related to neuromuscular weakness can be managed with either invasive or noninvasive ventilation. Invasive ventilation involves tracheostomy and mechanical ventilation and is declined by most ALS patients at our clinic. Noninvasive ventilation usually involves bi-level intermittent positive air pressure (BiPAP). Those who can tolerate BiPAP for 4 hours or longer daily survive an average of 7 to 14 months longer than those who use it for less than 4 hours daily22-24 (level II evidence). Use of BiPAP also improves patients’ satisfaction with life.25 It is typically started when patients have symptoms, have frequent nocturnal oxygen desaturations (less than 88% for more than 5 minutes), have carbon dioxide retention, and have a vital capacity less than 50% of predicted26 (level III evidence). While BiPAP is typically used only at night, it can be used during the day also. Unfortunately, about half of ALS patients with respiratory insufficiency cannot tolerate BiPAP.
Oxygen therapy should not be considered for ALS patients except as a comfort measure. Delivery of oxygen alone can suppress respiratory drive and lead to worsening hypercapnia. Oxygen should be prescribed to ALS patients only as a palliative measure to relieve symptoms of air hunger in the terminal phases of the disease.
Managing nutrition is an important aspect of treating ALS patients. Insufficient caloric intake can be related to fatigue while eating, fear of choking, difficulty manipulating food in the mouth, and difficulty transferring food to the mouth due to arm weakness. Malnutrition can lead to further muscle weakness and can cause immunodeficiency. Patients’ ability to swallow should be evaluated by speech-language pathologists using bedside swallowing assessments and modified barium swallows. If dysphagia is mild, the consistency of food can be altered to make swallowing safer. When dysphagia is severe or nutrition is impaired, patients could benefit from invasive enteral feeding. Enteral feeding options include a percutaneous endoscopic gastrostomy tube that is typically inserted by a general surgeon or gastroenterologist and a gastrojejunostomy (GJ) tube that is put in under fluoroscopy by a radiologist. These options carry similar risks27 (level II evidence). Prospective studies have not shown that enteral feeding increases survival time, perhaps because it was initiated too late in the course of disease28 (level II evidence). Insertion of a GJ tube is associated with a 30-day mortality risk of 9.6% and a 30-day morbidity risk of 4.1%29 (level II evidence). The most frequent complications include local infection, aspiration during the procedure, gastric hemorrhage, tube dislodgment, and tube blockage. Current treatment guidelines suggest instituting enteral feeding when forced expiratory volume is 50% or less of predicted to reduce the possibility of pulmonary complications.26,30
Treatment of other common symptoms of ALS is based on standard therapies developed by clinical experience. Such treatment is not usually based on evidence from randomized controlled trials31,32 (Table 3,33-54).
Table 3
Table 3
Therapies for symptoms of amyotrophic lateral sclerosis (ALS)
End-of-life care
In the terminal phase of ALS, keeping patients comfortable is paramount, and peaceful dying is the goal. Air hunger can be managed with opioids33 (level I evidence) and oxygen34 (level I evidence), anxiety with benzodiazepines, and nausea with antiemetics. End-of-life care can be provided in various settings depending on patient preferences and caregiver capacities. Some prefer to pass away at home, others prefer a hospice setting, and others a hospital. Our data suggest that 50% die at home and that death is usually due to respiratory failure.
Conclusion
Amyotrophic lateral sclerosis is a devastating neurodegenerative condition that typically begins with focal muscle weakness and eventually progresses to death from respiratory failure. Although there is no cure for ALS, treatment can improve both the quality and length of life. Care of ALS patients is best provided by multidisciplinary ALS clinics (Table 4) in conjunction with family physicians.
Table 4
Table 4
Canadian amyotrophic lateral sclerosis (ALS) clinics: ALS Canada website (http://www.als.ca).
Levels of evidence
Level I: At least one properly conducted randomized controlled trial, systematic review, or meta-analysis
Level II: Other comparison trials, non-randomized, cohort, case-control, or epidemiologic studies, and preferably more than one study
Level III: Expert opinion or consensus statements
Acknowledgments
This CME Update was supported by the Muscular Dystrophy Association.
Biographies
•
Dr Shoesmith is a Neuromuscular Fellow at the London Health Sciences Centre in Ontario.
•
Dr Strong is Director of the London Motor Neuron Diseases Clinic, a Professor at the University of Western Ontario, and a Scientist at the Robarts Research Institute.
Footnotes
Competing interests: None declared
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