Clinical Correlation in Physical Therapy

AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic Lateral Sclerosis (ALS)  20% are a result of one of more than 100 mutations in
superoxide dismutase 1 (SOD1) (Chromosome
 A.K.A Lou Gehrig’s Disease
21q12.1) (binds to molecules of copper and zinc, an
 MC and most fatal Motor Neuron Disease (MND) among antioxidant enzyme protecting the cell from reactive
adults. oxygen species toxicity)
 “Pure” ALS is characterized by the degeneration and loss o 50% of indivs. with an SOD1 ALS variant are
of motor neurons in the spinal cord, brainstem, and brain. symptomatic by 46 years of age, and 90% are
Resulting in variety of UMN and LMN clinical signs and symptomatic by 70 years of age.
symptoms.
 70% to 80% develop limb – onset ALS, initial
involvement in the extremities
Considered as a multisystem disorder with variable
pathological involvement of extra-motor networks and  20% to 30% develop bulbar – onset ALS, initial
connections, in addition to the LMNs and UMNs involvement of bulbar muscles (group of muscles in the
head and neck, involves speaking, swallowing,
chewing, and holding the jaw in place)

EPIDEMIOLOGY
 Incidence increases w/ each decade of life, until at least
the seventh decade

 High-incidence areas, such as Guam (Chamorro people

and Marianas Island), Western New Guinea, and the Kii ETIOLOGY
Peninsula of Japan (Honshu Island) (geographical foci, Exact cause is unknown (for the most part)
Western Pacific form of ALS)
Multiple or cumulative mechanisms including oxidative
 Occurs at any age; average age at onset is mid-to-late stress, aberrant RNA processing, excitotoxicity,
50s impaired axonal transportation, axonal dysfunction,
 M > W ; 1.7:1 ratio after age 65 mitochondrial disruption, protein misfolding, apoptosis
(programmed cell death), and lifestyle factors may be
 5% to 10% of individuals have a FHx of ALS responsible for neuron degeneration in ALS.
 Familial ALS ( FALS )  phenotypically and genetically 1. Superoxide dismutase  group of enzymes that
heterogeneous eliminate oxygen free radicals that have been linked to
neurodegeneration.
 Most familial cases are autosomal dominant, recessive
( juvenile onset ) and X-linked forms have been  Autosomal Dominant
described.  Limb onset (LE>UE)
 Shorter survival
 Death <1.5 years after Dx
FALS is categorized by mode of inheritance and Three distinct SODs
subcategorized by specific gene or chromosomal locus ( the
physical location of a gene on a chromosome ). More than 20 SOD1  found mainly in cytoplasm. However, minor
chromosomal regions and a number of identified genes have amounts are also localized in the mitochondrial
been linked to ALS. intermembrane space and the nucleus of eukaryotic cells.
SOD2  mitochondria
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SOD3  located extracellularly if degeneration occurs, it does so late in the

What happens? course of the disease.

Decreased SOD enzyme activity, free radicals may

 Sensory system is generally spared in ALS
accumulate causing damage.
 The progression of ALS is thought to spread in a
Free radicals  unstable atoms that are naturally formed
during metabolism or by exposure to environmental contiguous manner, e.g., within spinal cord
toxins. In excess, free radicals can damage cells, cause segments (cervical segments to cervical segments),
diseases, and accelerate aging.
before developing rostral or caudal symptoms. Thus,

2. Glutamate  an excitatory neurotransmitter. Excess signs and symptoms spread locally within a region
glutamate triggers a cascade of events leading to cell (e.g., bulbar, cervical, thoracic, lumbosacral) before
death. Increased levels of glutamate in the CSF, plasma,
moving to other regions. Caudal-to-rostral spread
and in post-mortem tissue of indivs with ALS. A deficiency
in excitatory amino acid transporter 2 (EAAT2), a specific within the spinal cord and spread from the cervical to
glutamate transporter protein, in the motor cortex and bulbar region appears to occur faster than rostral-to-
spinal cord of postmortem ALS tissue was reported and caudal spread within the spinal cord.
lends support to the theory of excitotoxicity causing
neurodegeneration

CLINICAL MANIFESTATIONS
PATHOPHYSIOLOGY
 Vary depending on the localization and extent of motor
 Characterized by progressive degeneration and loss of neuron loss, the degree and combination of LMN and
motor neurons in the spinal cord (degeneration), UMN loss, extrapyramidal areas affected and
brainstem, and motor cortex. (Hallmark features of associated signs and symptoms, pattern of onset and
ALS) progression, body region(s) affected, and stage of the
disease.
o For normal muscle function, muscle tissue and
 At onset, signs or symptoms are usually asymmetrical
nerve connections between the brain and
and focal.
muscle must be normal. Muscle movement is
initiated by nerve cells (neurons) that are located
IMPAIRMENTS on LMN Pathology
in the spinal cord and in the front part of the
 Focal
brain (called the motor cortex). Nerve cells in the  Asymmetrical muscle weakness (CARDINAL
motor cortex connect with the nerve cells in the SIGN) on LE / UE or weakness of bulbar muscles
spinal cord that stimulate muscles to move (grp of muscles in the head and neck)

(called motor nerves). In motor neuron diseases,  Initial muscle weakness usually occurs in
these nerve cells progressively wither away and isolated muscles, most often distally, and is
the peripheral nerves that connect them to the followed by progressive weakness and activity
limitations.
muscle deteriorate.
 Individuals with bulbar onset may notice changes in
 Brainstem nuclei for cranial nerves V (trigeminal), VII their voice, difficulty moving the tongue, or
(facial), IX (glossopharyngeal), X (vagus), and XII decreased ability to move the lips or open or close
the mouth
(hypoglossal) and anterior horn cells in the spinal
 Head Droop (HALLMARK SIGN) Cervical extensor
cord are also involved. 1097512 weakness is typical. Indivs may initially notice neck
stiffness, feel “heavy-headed” after reading or
o External ocular muscles (III: oculomotor, IV: writing, or may have difficulty stabilizing the head
with unanticipated movements, such as in an
trochlear, and VI: abducens) are usually spared;
accelerating car. As weakness progresses, the
head may begin to fall forward, and in more
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advanced stages the neck becomes completely A VC of less than 25% to 30% of predicted indicates
flexed with the head dropped forward, causing significant risk of impending respiratory failure or death. If
cervical pain and impairments in ambulation and
feeding. an individual does not receive ventilatory support, eventual
 Foot drop, secondary to distal weakness, and CO2 retention will lead to acidosis, coma, and respiratory
instability, secondary to proximal weakness, are
failure.
common.
 Falls are also common, reported to occur in 46% of
individuals with ALS.
DIAGNOSIS
 Fasciculations, random spontaneous twitching of
muscle fibers often seen through the skin, are EL ESCORIAL CRITERIA in 1994 and revised in
common in individuals with ALS, although they are
1998
rarely an initial symptom.
 LMN signs include hyporeflexia, decreased or AWAJI – SHIMA – created to address criticism in the
absent reflexes, decreased muscle tone or flaccidity,
El Escorial Criteria.
and muscle cramping.

EL ESCORIAL CRITERIA
IMPAIRMENTS on UMN Pathology Suspected ALS (removed in El Escorial Revised)
 Spasticity - Both >/= 1 region
- LMN signs only or UMN signs only
 Loss of dexterity
 Hyperreflexia Possible ALS
- 1 region
 Clonus - LMN + UMN
 Hypertonicity - Identified DNA Gene
- Definite Familial ALS (Lab Supported)
 Pathological reflexes (e.g. Babinski or Hoffmann sign)
Probable ALS Lab Supported
- 1 region
IMPAIRMENTS on BULBAR Pathology - LMN + UMN or UMN >/= 1 region
 Spastic bulbar palsy or Flaccid bulbar palsy - EMG Acute denervation >/= 2 limbs
 Mixed palsy, include both flaccid and spastic Probable ALS
components, is common. - 2 regions
- LMN + UMN
 Dysarthria (impaired speech)
 Dysphagia (impaired chewing or swallowing) Definite ALS
- 3 regions
 SIALORRHEA, excessive saliva and drooling. - LMN + UMN
Absence of automatic, spontaneous swallowing to
clear excessive saliva, because lower facial muscles Clinically definite
are too weak to close the lips.
- UMN and LMN findings in at least THREE or FOUR
regions (Bulbar, Cervical, Thoracic, or Lumbosacral) or
RESPIRATORY IMPAIRMENTS UMN and LMN signs in the bulbar region and at least
TWO spinal regions.
 Loss of respiratory muscle strength and decrease in
Vital Capacity. Clinically probable

 Dyspnea - UMN and LMN signs in two regions, with at least one
UMN finding rostral to the LMN findings.
 Difficulty sleeping in supine
 Frequent awakening at night Clinically probable w/ lab support

 Excessive daytime sleepiness - UMN and LMN in ONE region only, or UMN present in
 Morning headaches d/t HYPOXIA ONE region and LMN defined by EMG criteria (include
signs of active denervation, such as fibrillation potentials
and positive sharp waves; and signs of chronic denervation,
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AMYOTROPHIC LATERAL SCLEROSIS

such as large motor unit potentials (increased duration, Radicava/Radicut, a free radical scavenger, more
increased proportion of polyphasic potentials, increased effective in the earlier stages of the disease.
amplitude) and unstable motor unit potentials) present in at  Delivered intravenously daily for 14 days, followed by
least TWO regions. no drug for the next 14 days.
 Followed by another administration over 10 of the next
Clinically possible
14 days, followed by another 14-day period without the
- UMN and LMN signs found together in only one region, drug.
or UMN signs found alone in two or more regions, or
LMN signs found rostral to UMN signs and the inability to SIALORRHEA – Anti-cholinergic medications that
establish a diagnosis of clinically probable, laboratory- decrease saliva production. Glycopyrrolate (Robinul),
supported ALS Benztropine (Cogentin), transdermal hyoscine
(scopolamine).

DISEASE COURSE
Thick mucus production – Mucolytics or Beta-blockers
 Five-year and 10-year survival rates range from 9% to such as Propranolol (Inderal) or Metoprolol (Toprol).
40% and 8% to 16%, respectively.

 A 50% survival probability after the first symptom of ALS Muscle cramps – Anticonvulsant medication such as

appears is slightly greater than 3 years. Phenytoin (Dilantin) and Carbamazepine (Atretol, Tegretol),
Benzodiazepine such as Diazepam (Valium), Clonazepam
 Most patients die within 3 to 5 years after symptom
(Klonopin), or Lorazepam (Ativan).
onset and usually results from respiratory failure.

 About 10% of patients have a much slower disease Fasciculation – Lorazepam (Ativan)
progression, living 10 years or longer.
Pain – analgesics such as acetaminophen or NSAIDs.
PROGNOSIS Severe pain, opioids such as codeine, hydrocodone, or
 AGE at time of onset has the strongest relationship to methadone. MORPHINE may also be prescribed for
prognosis terminal stages.
 Pt’s less than 35 to 40 years of age at onset had better 5-
year survival rates than older indivs. CRANIAL NERVES AFFECTED
 Indivs. with LIMB-ONSET ALS have a better prognosis V – Trigeminal
than those with bulbar-onset ALS with 5-year survival VII – Facial
rates reported to be 37% and 44%. IX – Glossopharyngeal
X – Vagus
MANAGEMENT XII –Hypoglossal
THERE IS NO CURE FOR ALS
Riluzole (Rilutek), a glutamate inhibitor, for treatment of
ALS. One 50 mg tablet two times a day.
 Side effect include liver toxicity (which requires
discontinuation
 Effect of riluzole can extend survival for 2 to 3 months.
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AMYOTROPHIC LATERAL SCLEROSIS