Amyotrophic Lateral Sclerosis (ALS)

ALS Coronal[1]

Amyotrophic lateral sclerosis (ALS) is one of the most common forms of motor neuron diseases. It is also known as “Lou Gehrig's disease”, after a well-known baseball player in New York.

Amyotrophic Lateral Sclerosis arises due to this process: degenerative.

Presentation

The hallmark of the disease is a mixed upper and lower motor neuropathy that is progressive over time. The upper motor signs include spasticity, hyperreflexia and weakness. The lower motor signs include amyotrophy, weakness and fasciculations. The diagnosis is suspected when there is insidious loss of function in more than one parts of the body. The lower motor neuron signs tend to appear first usually in the tongue and limbs. 80% of patients present with predominately limb symptoms with the rest presenting with bulbar symptoms.

The limb disease may present with altered gate such a foot drag while upper limb involvement usually begins with loss of dexterity and wasting of muscles over time. Eventually the function deteriorates and mobility reduces with spasticity and subsequent contractures.

Patients who present with bulbar symptoms usually present with speech abnormalities and dysphagia. Most patient will tend to preserve ocular movements and bladder control [9].

Jaw & Teeth
  • Drooling ALS progression, lending support to anecdotal reports by some patients that cannabinoids may be efficacious in moderating the disease’s development and in alleviating certain ALS-related symptoms such as pain, appetite loss, spasticity, depression and drooling [source] Some PALS experience sialorrhea , drooling[source] All of these symptoms (depression, uncontrollable laughing/crying, and drooling) can be treated with medications and should be brought to the attention of the physician. [source]
  • Fasciculation of the Tongue Within a month, the patient had slurred speech, difficulty in swallowing liquids and fasciculations of the tongue[source]
  • Tongue Atrophy Damage to the medulla can cause: slurred speech hoarseness difficulty swallowing emotional lability, which is characterized by excessive emotional reactions such as laughing or crying a loss of tongue muscle contour, or tongue atrophy excess saliva difficulty [source] It represents around 5% of all MND cases; (3) Progressive bulbar palsy (PBP), affecting the muscles of the bulbar region, is characterized by dysarthria, dysphagia, tongue atrophy, and fasciculation. [source]
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Entire body system
  • Epilepsy Bilateral occipital calcification associated with celiac disease, folate deficiency, and epilepsy[source] The most common manifestations are ataxia, vertigo (dizziness) and neuropathy, followed by epilepsy (seizures) , ALS and multiple sclerosis-like symptoms. [source] Initial symptom presentation is variable and can include neurologic manifestations that may comprise ataxia, neuropathy, dizziness, epilepsy, and cortical calcifications rather than gastrointestinal-hindering diagnosis and management. [source]
  • Fatigue We ask about general symptoms (anxious mood, depressed mood, insomnia, fatigue, and pain) regardless of condition. [source] Other early symptoms vary but can include tripping, dropping things, abnormal fatigue of the arms and/or legs, slurred speech, muscle cramps and twitches, and/or uncontrollable periods of laughing or crying. [source] Symptoms of ALS include progressive muscle weakness beginning in the limbs, muscle twitching and cramping, slowed speech becoming progressively harder to understand, difficulty in breathing and swallowing; persistent fatigue, weight loss resulting from [source]
  • Nocturnal Leg Cramp FDA bans quinine for nocturnal leg cramps[source]
  • Weakness These are usually seen after weakness becomes obvious. [source] The initial symptom is weakness of skeletal muscles, especially in the limb. [source] It is characterized by weakness, spasticity and muscle atrophy and is fatal in most cases. [source]
  • Weight Loss Symptoms of ALS include progressive muscle weakness beginning in the limbs, muscle twitching and cramping, slowed speech becoming progressively harder to understand, difficulty in breathing and swallowing; persistent fatigue, weight loss resulting from [source] Weight loss[source] This can lead to weight loss from muscle wasting. [source]
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neurologic
  • Abnormal Reflex The physical exam may show: Weakness, often beginning in one area Muscle tremors, spasms, twitching, or loss of muscle tissue Twitching of the tongue (common) Abnormal reflexes Stiff or clumsy walk Increased reflexes at the joints Difficulty controlling [source] Signs of the former include muscle tightness or stiffness and abnormal reflexes; signs of the latter include muscle weakness, cramps, twitches and atrophy. [ Related: Nervous System: Facts, Functions & Diseases ] Eventually, individuals with ALS lose [source] Involvement of the upper motor neurons causes spasms and increased tone in the limbs, and abnormal reflexes[source]
  • Ataxia Gluten-associated ataxia had already been linked to the presence of serum transglutaminase 6 antibodies; these had been reported to be present in 62% of patients with gluten ataxia[source] Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. [source] Gluten sensitivity induces a inflammatory reaction in the small intestine mucosa, but it can also cause neurologic manifestations, such as ataxia (impaired coordination, balance and speech), neuropathy, dizziness, epilepsy, and cortical calcifications [source]
  • Dysarthria Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. [source] Dysarthria Hand dysfunction Shoulder dysfunction Foot drop Fasciculation/cramps Spastic gait Respiratory failure Frontal dementia 32.8% 19.7% 13.6% 12.5% 11.4% 4.0% 4.0% 2.0% References Top 1 . [source] Over time, people experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria). [source]
  • Foot Drop This usually begins on one side of the body and can cause loss of hand dexterity, shoulder function, a foot-drop or walking difficulty. [source] Dysarthria Hand dysfunction Shoulder dysfunction Foot drop Fasciculation/cramps Spastic gait Respiratory failure Frontal dementia 32.8% 19.7% 13.6% 12.5% 11.4% 4.0% 4.0% 2.0% References Top 1 . [source] After several months of progressive weakness, she developed a right foot drop[source]
  • Hyperreflexia The UMN findings of hyperreflexia and spasticity result from degeneration of the lateral corticospinal tracts in the spinal cord, which are gliotic and hardened to palpation at autopsy, hence the term "lateral sclerosis." [source] The upper motor signs include spasticity, hyperreflexia and weakness. [source] Muscle pain may be caused by clonus or hyperreflexia[source]
  • Long Tract Signs MRI/CT; no EMG evidence of widespread chronic partial denervation (CPD) in limbs Skull base lesions Lower cranial nerve signs (bulbar symptoms and signs; wasting of tongue, often asymmetrical); seldom significant long tract signs unless foramen magnum [source]
  • Slow Speech Symptoms of ALS include progressive muscle weakness beginning in the limbs, muscle twitching and cramping, slowed speech becoming progressively harder to understand, difficulty in breathing and swallowing; persistent fatigue, weight loss resulting from [source]
  • Slurred Speech ALS is characterized by progressive dysfunction resulting in symptoms such as tripping, clumsiness, difficulty talking, slurred speech, muscle cramps, twitching and ultimately, paralysis. [source] speech Shortness of breath Difficulty chewing, swallowing or breathing Complete paralysis Causes and Risk Factors In a majority of cases, the cause of ALS is unknown. [source] arms, legs or feet Tripping or dropping items Difficulty lifting items Trouble using hands for everyday activities As the disease progresses, patients may experience: Increased muscle weakness and twitching Cramps and stiffness in the hands and feet Slurred [source]
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respiratoric
  • Dyspnea As the disease progresses the patient has difficulty swallowing and talking, with dyspnea as the accessory muscles of respiration are affected. [source] In general, the major problems encountered are those related to (1) dysphagia and the need to meet nutritional requirements and avoid aspiration, (2) dyspnea and maintenance of blood gases within normal range, (3) aphasia and impaired verbal communication [source] Individuals may develop problems with moving, swallowing (dysphagia), speaking or forming words (dysarthria), and breathing (dyspnea). [source]
  • Hoarseness Damage to the medulla can cause: slurred speech hoarseness difficulty swallowing emotional lability, which is characterized by excessive emotional reactions such as laughing or crying a loss of tongue muscle contour, or tongue atrophy excess saliva difficulty [source] worse Commonly involves one part of the body first, such as the arm or hand Eventually leads to difficulty lifting, climbing stairs, and walking Paralysis Speech problems, such as a slow or abnormal speech pattern (slurring of words) Voice changes, hoarseness [source] A person with bulbar weakness may become hoarse or tired after speaking at length, or speech may become slurred. [source]
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gastrointestinal
  • Choking Choking is common. [source] Symptoms include: Difficulty breathing Difficulty swallowing Choking easily Drooling Gagging Head drop due to weakness of the neck muscles Muscle cramps Muscle contractions called fasciculations Muscle weakness that slowly gets worse Commonly involves [source] Because choking is common as ALS progresses, patients may need a tube called a percutaneous endoscopic gastrostomy (PEG) tube or feeding tube to be placed into the stomach for feeding. [source]
  • Dysphagia Symptoms include progressive weakness, atrophy, fasciculation, dysphagia, and eventual paralysis of respiratory function. [source] Patients with bulbar onset ALS usually present with dysarthria and dysphagia for solids or liquids. [source] Patients who present with bulbar symptoms usually present with speech abnormalities and dysphagia[source]
  • Gagging Symptoms include: Difficulty breathing Difficulty swallowing Choking easily Drooling Gagging Head drop due to weakness of the neck muscles Muscle cramps Muscle contractions called fasciculations Muscle weakness that slowly gets worse Commonly involves [source] tremors, spasms, twitching, or loss of muscle tissue Twitching of the tongue (common) Abnormal reflexes Stiff or clumsy walk Increased reflexes at the joints Difficulty controlling crying or laughing (sometimes called emotional incontinence) Loss of gag [source] Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. [source]
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musculoskeletal
  • Muscle Cramp ALS is characterized by progressive dysfunction resulting in symptoms such as tripping, clumsiness, difficulty talking, slurred speech, muscle cramps, twitching and ultimately, paralysis. [source] Some with ALS experience painful muscle cramps, which can sometimes be alleviated with medication. [source] Other early symptoms vary but can include tripping, dropping things, abnormal fatigue of the arms and/or legs, slurred speech, muscle cramps and twitches, and/or uncontrollable periods of laughing or crying. [source]
  • Muscle Spasticity ALS symptoms The first symptoms usually include weakness or tight and stiff muscles (spasticity) in a particular area, said Dr. [source] Doctors can prescribe medications for reducing fatigue, muscle cramps, muscle spasticity, and excessive saliva or phlegm, as well as pain, depression, sleeping problems or constipation. [source] Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. [source]
  • Muscle Twitch These persistent muscle twitches are generally not painful, but can be annoying or interfere with sleep. [source] ALS often begins with muscle twitching and weakness in a limb, or slurred speech. [source] Symptoms of ALS include progressive muscle weakness beginning in the limbs, muscle twitching and cramping, slowed speech becoming progressively harder to understand, difficulty in breathing and swallowing; persistent fatigue, weight loss resulting from [source]
  • Muscular Atrophy A disease of the motor tracts of the lateral columns and anterior horns of the spinal cord, causing progressive muscular atrophy, increased reflexes, fibrillary twitching, and spastic irritability of muscles. [source] atrophy, progressive bulbar palsy, pseudobulbar palsy, and spinal muscular atrophy[source] Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy, and spinal and bulbar muscular atrophy can also mimic certain aspects of the disease and should be considered. [source]
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psychiatrical
  • Emotional Lability Emotional lability can occur in all ALS sufferers, even those without dementia. [source] Damage to the medulla can cause: slurred speech hoarseness difficulty swallowing emotional lability, which is characterized by excessive emotional reactions such as laughing or crying a loss of tongue muscle contour, or tongue atrophy excess saliva difficulty [source] lability Scientists are investigating the use of the following for a subtype of hereditary ALS: coenzyme Q10 COX-2 inhibitors creatine minocycline However, they have not yet been proven effective. [source]
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Workup

Due to it slow progression it may take a neurologist a few months to come to a diagnosis, unless there is a strong family history of the illness. Needle electromyography and nerve conduction studies and will aid in diagnosis and exclude any other conditions that may mimic the disease. Genetic testing is only performed if there is a suspicion that there may be a genetic or familial cause. If there is uncertainty a muscle biopsy may have to be done to exclude other courses.

Pathology

Biopsy
Cytology
Other Pathologies

Test Results

Other Test Results

Laboratory

Serum
Cerebrospinal Fluid

Treatment

The treatment for this condition is totally supportive and includes, speech, physical and occupational therapy. It is very important that the patient and relatives are educated well on the condition and prognosis. There are also a number of support groups that help families and suffers deal with the condition. The only drug available currently is riluzole that has been shown to delay the time to tracheostomy by about 2 months [10].

Prognosis

As mentioned before, amyotrophic lateral sclerosis is a fatal disease with the median time to death from diagnosis being 3 years. The patients who survive long tend to get the disease at a younger age, with primary limb involvement. Most individuals succumb to secondary infections such a pneumonia [8].

Complications

  • Acute Respiratory Failure PubMed Google Scholar Chen R, Grand'Maison F, Strong MJ, Ramsay DA, Bolton CF: Motor neuron disease presenting as acute respiratory failure: a clinical and pathological study. [source]
  • Alzheimer Disease Many of the genes identified have been associated with other neurological diseases such as dementia and Alzheimer disease[source] In particular, mortality from ALS and Alzheimer disease was 4-fold higher than expected. [ 122 ] These results are based on 7 individuals who died with Alzheimer disease and 7 individuals who died with ALS, out of a cohort of 3439 individuals. [source] found in motor neuron cytoplasm of patients with sporadic ALS, they are not specific for this disease and have been found in affected nonmotor cells in patients with Guamanian parkinsonism-dementia complex, [45] British familial dementia, [ 46 ] and Alzheimer [source]
  • Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) is one of the most common forms of motor neuron diseases. [source] Amyotrophic lateral sclerosis (ALS) is overall a fatal disease with no active treatments. [source] The pathophysiology of amyotrophic lateral sclerosis is unknown, but a number of theories exist. [source]
  • Aspiration Pneumonia Morbidity usually occurs from aspiration pneumonia and other medical complications related to mobility. [source] In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. [source] In later stages of the disorder, aspiration pneumonia can develop, and maintaining a healthy weight can become a significant problem that may require the insertion of a feeding tube. [source]
  • Dementia complex, [45] British familial dementia, [ 46 ] and Alzheimer disease, [84] as well as in most patients with frontotemporal dementia[source] . [65, 66 ] This expansion of hexanucleotide repeats (from 23 in normal individuals to thousands in affected individuals) appears to be the most common genetic abnormality in ALS and in frontotemporal dementia[source] et al found the C9orf72 expansion in 23.5% of patients with ALS cases and 11.7% of patients with familial frontotemporal dementia. [ 65 ] More recent reports have found the C9ORF72 repeat expansion in 22-57% of familial ALS patients (depending in part [source]
  • Inspiration The event promises emotional and inspiring encounters for all.  [source] The enchanting site promises emotional and inspiring encounters for all.  [source] This family friendly and inspiring event draws people of all ages and athletic abilities coming together to honor a loved one with the disease, to remember those who’ve passed and to show their support for the cause. [source]
  • Motor Neuron Disease Motor neuron diseases have various forms, such as the following: Motor neuron diseases are more common among men and usually develop in people who are in their 50s. [source] In motor neuron diseases, these nerve cells progressively deteriorate. [source] For example, some forms of motor neuron disease affect the mouth and throat first. [source]
  • Paraparesis Asymmetrical onset; combined UMN and LMN signs in arm(s); spastic paraparesis; occasionally fasciculations in arms. [source] Rarely, patients may notice focal muscle wasting before onset of weakness, and some patients may present with a spastic paraparesis[source]
  • Paraplegia PubMed Google Scholar Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA: A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). [source] Although no such findings have been observed in humans with ALS, mutations in the kinesin genes are known to cause neurodegenerative motor nerve diseases in humans such as hereditary spastic paraplegia and Type 2A Charcot-Marie-Tooth disease [ 125 , 126 [source] Clinical presentations of ALS and their prognoses, as the form distal in limbs and bulbar, are well known, however, knowledge of specific forms such as brachial paraplegia or "flail arm syndrome", monomelic atrophy of Hirayama, progressive muscular atrophy [source]
  • Parkinson's Disease The severity of Parkinson's Disease symptoms changes faster than researchers thought, so clinical trials should be designed differently. [source] ALS is a Neurodegeneration having shared characteristics with Alzheimer's and Parkinson's diseases[source] ’s disease[source]
  • Progressive Bulbar Palsy Bulbar Palsy (1). [source] four additional gene loci have been identified so far and may either predominantly lead to ALS (ALSI-ALS6) or cause multisystem neurodegeneration with ALS as an occasional symptom (tauopathies, ALS-dementia complex) This form of the disease includes Progressive [source] Amyotrophic Lateral Sclerosis (ALS), Progressive Muscular Atrophy (PMA), Progressive Bulbar Palsy (PBP) and Primary Lateral Sclerosis (PLS) are all subtypes of motor neurone disease. [source]
  • Pseudobulbar Palsy Some others include: primary lateral sclerosis (PLS) progressive bulbar palsy (PBP) pseudobulbar palsy What Happens When You Have ALS With ALS, motor neurons in your brain and spinal cord break down and die. [source] palsy, and spinal muscular atrophy. [source] of neurological disorders that selectively affect motor neurons, the cells that control voluntary muscles of the body, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, pseudobulbar [source]
  • Respiratory Acidosis Abnormalities of arterial or venous (ear lobe) blood gases, such as respiratory acidosis are a late but important finding that signifies the need for respiratory support. [source]
  • Respiratory Muscle Weakness Symptoms vary in severity and may include muscle weakness and atrophy, fasciculations, emotional lability, and respiratory muscle weakness[source] The presenting symptoms of respiratory muscle weakness include dyspnoea on exertion or talking, orthopneoa, disturbed sleep, excessive daytime somnolence, morning headaches, fatigue, anorexia, depression, poor concentration, vivid nightmares and nocturia [source] muscle weakness Characteristic wasting and weakness of deep finger flexors and quadriceps femoris; EMG evidence of myopathy; muscle biopsy as definitive test (rimmed vacuoles) Cramp/fasciculation/myokymia syndromes Cramps, undulating muscle contractions [source]
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Etiology

The underlying etiology is unknown. Most cases are sporadic with approximately 10% of the cases being familial or genetic. The genes in familial causes are numerous and no single gene has been identified that can explain the pathology. Many of the genes identified have been associated with other neurological diseases such as dementia and Alzheimer disease. In the families which have identified genes the mode of transmission is usually autosomal dominant. There is no clinical difference between the familial variant compared to the sporadic cases.

The only establish risk factor that has been identified is smoking. Studies have shown that smokers are at twice the risk of suffering from this disease as compared to non-smokers [2] [3].

Epidemiology

The annual incidence is approximately 2 per 100,000 population. Finland has the highest incidence in the world with rates almost twice that of other countries. It tends to affect whites more than other races and is higher in men as compared to women.
Amyotrophic lateral sclerosis may occur between teenager years to as high as the 80s. There is increasing risk with age [4] [5] [6].

Sex distribution
Age distribution

Pathophysiology

The pathophysiology of amyotrophic lateral sclerosis is unknown, but a number of theories exist. The disease is named after the pathology is causes - amyotrophy - muscular atrophy, and lateral sclerosis refers to the changes seen in the lateral tracts.

It is thought that there are multiple mechanisms involved, few which have been noted include derangements in free radical scavenging, and derangements in cellular cytoskeletons. The most upcoming theory that has a lot of research focused on it is the theory that aggregation in mRNA processing may be a significant contributor, leading to neuronal dysfunction and death [7].

Prevention

The only risk factor identified is smoking so cessation or avoidance would assume to be beneficial. Suspected family cases should have testing and counselling when appropriate.

Summary

Amyotrophic lateral sclerosis (ALS) is overall a fatal disease with no active treatments. With good support, suffers may lead meaningful, but restricted lives. It is one of many motor neuron diseases, but what makes it stand out is that it presents with both upper and lower motor neuron signs [1].

Patient Information

  • Definition: Amyotrophic lateral sclerosis (ALS) is a disease that affects the nerves that control muscle movement. This causes the muscles to weaken and become shrunken. This makes it difficult for the person to do daily activates and eventually they may be unable to walk, talk or eat as the disease progresses. 
  • Cause: The cause of this disease is unknown, but there are some families that are known to pass it down generations. In these families a few genes have been affected. Most of the cases have no family links. There has been some information that smoking may contribute to its onset.
  • Symptoms: The will be weakness of the affected region of the body, with either rigid limbs or floppy limbs. Speech and swallowing may be the first to be affected in some individuals. 
  • Diagnosis: Most of the diagnosis is made by history and examination, with few tests being done to see if the nerves are functioning well.
  • Treatment: Treatment is very limited with only one drug available called riluzole that slows down the disease, briefly. Most of the other treatment is supportive to help the patient not to get stiffness in the joints and bedsores. They may require speech therapy and devices to aid in movement such as wheel chairs. As speech is also affected communication devices may be required to aid. They may also require breathing support and feeding tubes. 
  • Overall the disease has a poor outcome and family support is very important. There are groups that aid the families psychologically, helping them understand and process all the information.

Self-assessment

References

  1. Mitsumoto H, Chad DA, Pioro EP. Amyotrophic lateral sclerosis. In: Contemporary Neurology Series, 49, F.A. Davis Company, Philadelphia 1998.
  2. l-Chalabi A, Lewis CM. Modelling the effects of penetrance and family size on rates of sporadic and familial disease. Hum Hered. 2011;71(4):281-8. 
  3. Hanby MF, Scott KM, Scotton W, Wijesekera L, Mole T, Ellis CE, et al. The risk to relatives of patients with sporadic amyotrophic lateral sclerosis. Brain. Dec 2011;134:3454-7. 
  4. Chiò A, Mora G, Calvo A, Mazzini L, Bottacchi E, Mutani R. Epidemiology of ALS in Italy: a 10-year prospective population-based study. Neurology. Feb 24 2009;72(8):725-31. 
  5. Alonso A, Logroscino G, Jick SS, Hernán MA. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol. Jun 2009;16(6):745-51.
  6. Johnston CA, Stanton BR, Turner MR, Gray R, Blunt AH, Butt D, et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. Dec 2006;253(12):1642-3.
  7. Barber SC, Shaw PJ. Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radic Biol Med. Mar 1 2010;48(5):629-41
  8. Visser J, van den Berg-Vos RM, Franssen H, et al. Disease course and prognostic factors of progressive muscular atrophy. Arch Neurol 2007; 64:522.
  9. Hirano A. Neuropathology of ALS: an overview. Neurology 1996; 47:S63.
  10. 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;73:1218-1226

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  • Amyotrophic lateral sclerosis - LC Wijesekera, PN Leigh - Orphanet journal of rare diseases, 2009 - ojrd.com
  • A study of the early stage of dysphagia in amyotrophic lateral sclerosis - S Kawai, M Tsukuda, I Mochimatsu, H Enomoto - Dysphagia, 2003 - Springer
  • Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis - CLG Lin, LA Bristol, L Jin, M Dykes-Hoberg, T Crawford - Neuron, 1998 - tonto.stanford.edu
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  • A placebo‐controlled trial of recombinant human ciliary neurotrophic (rhCNTF) factor in amyotrophic lateral sclerosis - RG Miller, JH Petajan, WW Bryan, C Armon - Annals of , 1996 - Wiley Online Library
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