AMYOTROPHIC LATERAL SCLEROSIS

I. DEFINITION

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is the most
common and devastatingly fatal motor neuron diseases (MND) among adults. ALS is characterized by
the degeneration and loss of motor neurons in the spinal cord, brainstem, and brain, resulting in a
variety of upper motor neuron (UMN) and lower motor neuron (LMN) clinical signs and symptoms.

(0’Sullivan, 2014)

ALS can be defined as a rapidly progressive neurodegenerative disease characterized by

weakness, spasticity, and muscular atrophy with subsequent respiratory compromise leading to
premature death. It is caused by the destruction of motor neurons in the primary motor cortex,
brain stem, and spinal cord.

“Amyotrophy” refers to muscular atrophy occurring from the degeneration of anterior horn
cells in the spinal cord with muscle fiber denervation. “Lateral sclerosis” describes the resultant
hardening of the anterior and lateral corticospinal tracts caused by replacement of dying motor
neurons with subsequent gliosis.

(Braddom, 2011)

A disease leading to the death of motor neurons in the cerebral cortex and gray matter of
the spinal degenerative cord.

(Waxman)

ALS can be classified as sporadic familial or juvenile. Sporadic ALS means that the disease
can affect anyone regardless of gender, ethnicity or age—although it most often affects people
between the ages of 40 and 60. The etiology of sporadic ALS is unknown and likely multifactorial
with a complex interplay of pathogenic cellular mechanisms. Although family members of people
with sporadic ALS are at an increased risk for the disease, the overall risk is very low and most will
not develop ALS. Sporadic ALS is the most common form of ALS.

On the other hand, familial ALS (FALS), means that the disease is capable of being passed
from a parent to his or her child. The vast majority of ALS cases are presumably acquired and occur
sporadically. Approximately 5% to 10% of all ALS cases, however, are familial (FALS) and most
commonly have an autosomal dominant inheritance pattern, although autosomal recessive, X-
linked, and mitochondrial inheritance patterns have been reported. The age of onset of FALS occurs
a decade earlier than sporadic cases, and progression of the disease is more rapid. Males and
females are equally affected. About 20% of FALS cases result from a copper–zinc superoxide
dismutase (SOD1) gene defect.

Juvenile ALS by definition presents before age 25. It is a rarely occurring form of FALS. The
progression of the disease is typically much slower than adult-onset ALS and can present initially
with either UMN or LMN signs. Inevitably the disease progresses to encompass both UMNs and
LMNs. Patients often maintain their ability to ambulate into midlife and can have a normal life span.
(Braddom, 2011)
 II. ETIOLOGY x RISK FACTORS

Epidemiologic evidence has identified several known and possible risk factors for ALS. Some of
the risk factors of ALS include one’s age, gender, race and ethnicity. Although the disease can strike
at any age, symptoms most commonly develop between the ages of 55 and 75. Moreover, men are
slightly more likely than women to develop ALS.

(NIH, 2018)

However, as we age the difference between men and women disappears. ALS was also found to
most likely to develop in Caucasians and non-Hispanics (NIH, 2018).However, other than the small
percentage of hereditary (FALS) cases, etiology for the most part is unknown. It is thought that no
one single mechanism but rather multiple or cumulative mechanisms, including oxidative stress,
exogenous neurotoxicity, excitotoxicity, impaired axonal transportation, protein aggregation,
apoptosis (programmed cell death), and lifestyle factors, may be responsible for neuron
degeneration in ALS:

1. Superoxide dismutases are a group of enzymes that eliminate oxygen free radicals that, although
products of normal cell metabolism, have been implicated in neurodegeneration. There are
three isoforms of SOD in humans: cytosolic copper-zinc superoxide dismutase (CuZnSOD),
mitochondrial manganese superoxide dismutase (MnSOD), and extracellular superoxide
dismutase (ECSOD).SOD1, a gene on chromosome 21, encodes CuZnSOD. Genetic studies of
individuals with adult-onset FALS have determined that about 20% of these individuals have
mutations in SOD1; however, the primary gene defect is unknown. When the SOD enzyme
activity is decreased, as has been observed in individuals with FALS with SOD1 mutations, free
radicals may accumulate causing damage. Most mutations identified in FALS show modest loss in
enzyme activity,20 suggesting the mutant SOD-1 protein may have toxic properties that cause
motor neurons to die. However, the mechanism has yet to be determined.
2. Glutamate, an excitatory neurotransmitter, has also been implicated in neurodegeneration.
Excess glutamate triggers a cascade of events leading to cell death. Increased levels of glutamate
in the cerebrospinal fluid (CSF), plasma, and in postmortem tissue of individuals with ALS have
been reported. A deficiency in excitatory amino acid transporters 2 (EAAT2), a specific
 glutamate transporter protein, in the motor cortex and spinal cord of postmortem ALS tissue
was reported and lends support to the theory of excitotoxicity causing neurodegeneration.
3. Clumping of neurofilament proteins into spheroids in the cell body and proximal axon is one of
the histopathological characteristics of ALS. Whether or not abnormal accumulation is secondary
to the pathology or contributes to motor neuron degeneration has yet to be determined .
4. Several studies have implicated an autoimmune reaction in the etiology of ALS. For example,
serum factors toxic to anterior horn motor neurons in individuals with ALS have been reported,
and antibodies to calcium channels have been identified in individuals with ALS.
5. It has been hypothesized that a lack of neurotrophic factors could contribute to the
development of ALS and other neurodegenerative disorders. In vivo experiments and
experiments with isolated motor neurons in cell culture have shown that neurotrophic factors
are important in motor neuron survival. However, factor deficits in ALS have not been
conclusive. For example, a postmortem study found decreased amounts of ciliary neurotrophic
factor (CNTF) in the ventral horn of the spinal cord, but not in the motor cortex; nerve growth
factors were decreased in the motor cortex, but increased in the lateral column of the spinal
cord.
6. Other potential theories thought to contribute to neurodegeneration in ALS, which have
anecdotal, limited, or indirect evidence, include exogenous or environmental factors, apoptosis,
and viral infections.

(0’Sullivan, 2014)

III. EPIDEMIOLOGY

It is estimated that 30,000 individuals in the United States have ALS at any one time and 15
cases are diagnosed every day. Except in a very few high-incidence areas, such as Guam and the Kii
Peninsula of Japan (geographical foci, Western Pacific form of ALS), the overall incidence of ALS has
been reported to be in the range of 0.4 to 2.4 cases per 100,000, with the incidence increasing with
each decade of life, until at least the seventh decade. The prevalence of ALS has been reported to be
4 to 10 cases per 100,000.

Although ALS can occur at any age, the average age at onset is the mid-to-late 50s. Most
studies have found that the disease affects men slightly more than women, with an approximate
ratio of 1.7:1 however, after age 65, this gender-related incidence is less pronounced. In about 5% to
10% of individuals the disease is inherited as an autosomal dominant trait (familial ALS [FALS])
although rare cases of juvenile-onset ALS are inherited in an autosomal recessive pattern. Of the
hereditary adult ALS cases, approximately 20% are a result of one of more than 100 mutations in
superoxide dismutase 1 (SOD1), a gene that encodes the copper-zinc superoxide dismutase enzyme.
The very large majority of adult individuals with ALS have no family history of the disease (sporadic
ALS), although a very small percentage of individuals with sporadic ALS do have a mutation in SOD1.
Approximately 70% to 80% of individuals develop limb-onset ALS, with initial involvement in the
extremities; 20% to 30% develop bulbar-onset ALS, with initial involvement in the bulbar muscles.
Bulbar-onset ALS is more common in middle-aged women, and initial symptoms may include
difficulty speaking, chewing, or swallowing.

(0’Sullivan, 2014)
 IV. ANATOMY

Motor neurons are unique cells, the longest in the body. All neurons extend a connecting
fiber, the axon, to the next neuron or end organ. Some motor neurons in the spinal cord must
extend their axon up to a meter, to reach the toes, for example, yet the cell body maintaining this
extraordinary fiber is only of ordinary size. Metabolic demands on the motor neurons must be
correspondingly extraordinary.

Other cell types in the central nervous system that support motor neurons, called glia,
including, astrocytes and oligodendrocytes are also involved in ALS disease.

Common known disease mechanisms:

1. Axon Structure and Dynamics

Transport of materials up and down the length of the motor neuron is an important cellular
process that may play into the damage seen in ALS. Neurons normally move cellular materials along
their axons, to keep nerve cell messages flowing and to maintain the health of the whole nerve cell
itself. Active transport along the extensive axons of motor neurons conveys newly made materials to
even the farthest-reaching nerve endings and needed nutrients back to the cell body. Motor neurons
may be particularly vulnerable to any genetic defect or cellular insult that impedes axon transport.

2. Cell Death: Apoptosis and Necrosis

Cells that do not receive the proper supplies will die, through a step-wise process called
apoptosis (or programmed cell death). Unlike the messy death of infected or traumatized cells in
necrosis, apoptosis is a process of carefully choreographed steps to self-destruction. But halting
apoptosis when it is producing degenerative change in the nervous system is now a prime goal for
researchers trying to design effective treatments for ALS as well as for other neurological disorders.
 3. Mitochondria

Mitochondria, a type of cell organelle (little organ) is the power plants of all animal cells and
has many roles. In the case of motor neurons, they must sustain the amazing energetic capacity of a
single cell to span from the spinal cord all the way to a person’s fingers and toes. It is also the umpire
of apoptosis (i.e. programmed cell death) in that it can call the play into action or delay it using
specialized enzymes.

4. Glutamate

Abundant evidence points to glutamate as a destructive factor in ALS and investigators are
working to find out how this can be changed. Gene therapy approaches are under investigation to
deliver glutamate transporters to cells affected by ALS. Other avenues towards control of glutamate
in ALS are also under active investigation. The first approved specific treatment for ALS is riluzole, a
drug that modulates glutamate.
http://www.alsa.org/research/focus-areas/disease-mechanisms/

ALS AFFECTATIONS

ALS is a disease of both upper and lower motor neurons and is diagnosed in part through the
use of NCS/EMG which evaluates lower motor neuron function. All motor neurons are upper motor
neurons so long as they are encased in the brain or spinal cord. Once the neuron exits the spinal
cord, it operates as a lower motor neuron.

Upper Motor Neurons

The upper motor neurons are derived from corticospinal and corticobulbar fibers that
originate in the brain’s primary motor cortex. They are responsible for carrying impulses for
voluntary motor activity from the cerebral cortex to the lower motor neurons.
 Axons from these two tracts (collectively referred to as the pyramidal tracts) begin at the
motor cortex of the brain but travel different paths in the central nervous system:

 The corticospinal tract projects to control extremity muscle activity

 The corticobulbar tract projects to cranial nerves

The corticospinal tract fibers traverse through the brainstem where most of them cross at
the medulla becoming the lateral pyramidal tract. Their course then continues on down the spinal
cord where they travel in the anterior horn before exiting the spinal cord to control extremity
muscle activity.

Unlike the corticospinal tract, the corticobulbar fibers do not project down the spinal cord.
Instead they provide supply to the cranial nerve nuclei. Most specifically, the corticobulbar fibers
affect the following cranial nerves and functions:

 V (Trigeminal – facial, mouth and some tongue sensation)

 VII (Facial – facial expression)

 IX (Glossopharyngeal – salivary controls)

 X (Vagus – laryngeal supply)

 XII (Hypoglossal – tongue innervation)

In some instances, the motor neuron pathways can also affect the brain’s limbic system
which has impact on mood, expression and memory. This especially occurs in ALS patients who have
a more bulbar or corticobulbar involvement with their disease.

Lower Motor Neurons

Once a nerve exits the spinal cord it is no longer an upper motor neuron, it becomes a lower
motor neuron providing direct supply to peripheral structures.

V. PATHOPHYSIOLOGY

Amyotrophic lateral sclerosis is characterized by a progressive degeneration and loss of

motor neurons in the spinal cord, brainstem, and motor cortex. UMNs in the cortex are affected, as
are the corticospinal tracts. Brainstem nuclei for cranial nerves V (trigeminal), VII (facial), IX
(glossopharyngeal), X (vagus), and XII (hypoglossal) and anterior horn cells in the spinal cord are also
involved. Brainstem nuclei for cranial nerves controlling external ocular muscles (III: oculomotor, IV:
trochlear, and VI: abducens) are usually spared; if degeneration occurs, it does so late in the course
of the disease. Motor neurons of the Onufrowicz nucleus (Onuf’s nucleus), located in the ventral
margin of the anterior horn in the second sacral spinal level, are also generally spared; if they are
affected, it is to a very limited extent. These neurons control striated muscles in the pelvic floor,
including anal and external urethral sphincters.
 The sensory system and spinocerebellar tracts are also generally spared in ALS. Some
studies suggest that sensory neurons may be involved in ALS, but to a much lesser extent than the
motor neurons. Morphological studies have found that peripheral sensory nerves exhibit axonal
atrophy, demyelination, and degeneration, and dorsal root ganglia cells at autopsy reveal loss of
large ganglion cells. Degeneration of Clarke’s neurons and of the spinocerebellar tracts has also been
reported. Degeneration of the spinocerebellar tracts is a well recognize pathological feature of FALS
and has been described in sporadic ALS, although it is rare.

Posterior column degeneration is more common in FALS, but is rare in sporadic ALS. As
motor neurons degenerate, they can no longer control the muscle fibers they innervate. Healthy,
intact surrounding axons can sprout and reinnervate the partially denervated muscle, in essence
assuming the role of the degenerated motor neuron and preserving strength and function early in
the disease; however, the surviving motor units undergo enlargement. Reinnervation can
compensate for the progressive degeneration until motor unit loss is about 50% and
electromyography (EMG) studies have found evidence of motor unit reinnervation in individuals
with ALS. As the disease progresses, reinnervation cannot compensate for the rate of degeneration,
and a variety of impairments develop. The progression of ALS is thought to spread in a contiguous
manner, e.g., within spinal cord segments (cervical segments to cervical segments), before
developing rostral or caudal symptoms. Thus, signs and symptoms spread locally within a region
(e.g., bulbar, cervical, thoracic, lumbosacral) before moving to other regions. Caudal-to-rostral
spread within the spinal cord and spread from the cervical to bulbar region appears to occur faster
than rostral-to-caudal spread within the spinal cord.

VI. CLINICAL SIGNS AND SYMPTOMS x COMPLICATIONS

Clinical manifestations of ALS vary depending on the localization and extent of motor neuron
loss, the degree and combination of LMN and UMN loss, pattern of onset and progression, body
region(s) affected, and stage of the disease. At onset, signs or symptoms are usually asymmetrical
and focal. Progression of the disease leads to increasing numbers and severity of impairments.
(0’Sullivan, 2014)
 Early signs and symptoms of ALS include:

 Difficulty walking or doing your normal daily activities

 Tripping and falling

 Weakness in your leg, feet or ankles

 Hand weakness or clumsiness

 Slurred speech or trouble swallowing

 Muscle cramps and twitching in your arms, shoulders and tongue

 Difficulty holding your head up or keeping good posture

ALS often starts in the hands, feet or limbs, and then spreads to other parts of your body. As
the disease advances and nerve cells are destroyed, your muscles progressively weaken. This
eventually affects chewing, swallowing, speaking and breathing.

ALS doesn't usually affect your bowel or bladder control, your senses or your thinking ability.
It's possible to remain actively involved with your family and friends.

As the disease progresses, people with ALS experience complications, which may include:

 Breathing problems

Over time, ALS paralyzes the muscles you use to breathe. You may need a device to help you
breathe at night, similar to what someone with sleep apnea might wear. For example, you may be
given continuous positive airway pressure (CPAP) or bi-level positive airway pressure (BiPAP) to
assist with your breathing at night.

Some people with advanced ALS choose to have a tracheostomy — a surgically created hole
at the front of the neck leading to the windpipe (trachea) — for full-time use of a respirator that
inflates and deflates their lungs.

The most common cause of death for people with ALS is respiratory failure. On average,
death occurs within three to five years after symptoms begin.

 Speaking problems

Most people with ALS will develop trouble speaking over time. This usually starts as
occasional, mild slurring of words, but progresses to become more severe. Speech eventually
becomes more difficult for others to understand, and people with ALS often rely on other
communication technologies to communicate.

 Eating problems

People with ALS can develop malnutrition and dehydration from damage to the muscles that
control swallowing. They are also at higher risk of getting food, liquids or saliva into the lungs, which
can cause pneumonia. A feeding tube can reduce these risks and ensure proper hydration and
nutrition.

 Dementia

Some people with ALS experience problems with memory and making decisions, and some
are eventually diagnosed with a form of dementia called frontotemporal dementia.

(https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/symptoms-causes/
syc-20354022)

VII. ASSESSMENT

Physical assessment

 Pain

Pain is common in individuals with ALS and should be examined subjectively and objectively,
using a Visual Analogue Scale (VAS) for example. Pain is not necessarily a direct impairment of ALS,
but rather an indirect (decreased ROM, adhesive capsulitis) or a composite impairment (joint
malalignment secondary to spasticity and faulty posture). Further examination of underlying causes
of pain is often required.

 Joint Integrity, Range of Motion, and Muscle Length

Functional ROM, active, active-assisted, and passive range ROM, muscle length, and soft
tissue flexibility and extensibility should be examined using standard methods.

 Muscle Performance

Specific deficits of muscle strength, power and endurance, and muscle performance during
functional activities should be determined. Specific deficits can be measured with manual muscle
testing (MMT), isokinetic muscle strength testing, or handheld dynamometry. In clinical trials,
muscle strength has been examined as maximum voluntary isometric contraction (MVIC) using a
strain gauge tensiometer system. This method eliminates muscle length and velocity as factors in
testing and produces reliable, valid, interval data. MVIC is considered the most direct technique for
investigating motor unit loss, and has been used extensively for examining muscle strength in
individuals with ALS for the past 10 years. Its range and sensitivity have been validated by several
natural history studies. However, MVIC testing requires specialized equipment and training in its use.
Test reliability of MMT and MVIC scores among uniformly trained physical therapists at several
institutions has been examined. Reproducibility between MMT and MVIC was found to be
equivalent. Sensitivity to detect progressive muscle strength changes in individuals with ALS favored
MMT. However, muscles were tested with MVIC and muscles were tested with MMT; thus, the
difference in detecting change was largely accounted for by the number of muscles sampled by MMT
versus MVIC.

 Motor Function
 Impairments in dexterity, coordination of large movement patterns, as well as gross and
fine motor control may be evident owing to spasticity and muscle weakness. Hand function and
initiation, modification, and control of movement patterns should be examined.

 Tone and Reflexes

Muscle tone may be examined using the Modified Ashworth Scale. Deep tendon and
pathological reflexes should be tested to distinguish between UMN and LMN involvement.

 Cranial Nerve Integrity

The cranial nerves commonly affected by ALS include V, VII, IX, X, and XII. Cranial nerves
should be tested to determine the extent of bulbar involvement. Screening for oral motor function,
phonation, and speech production can be accomplished through the interview and observation.
Referral to a speech-language pathologist is recommended.

 Sensation

If the patient complains of sensory symptoms or if sensory involvement is suspected,

sensory testing should be completed.

 Postural Alignment, Control, and Balance

Static and dynamic postural alignment and body mechanics during self-care, functional
mobility skills, functional activities, and work conditions and activities should be examined.
Postural stability, reactive control, anticipatory control, and adaptive postural control should
also be determined. No ALS-specific balance test or measure exists. A variety of balance status
measures, originally designed for use with other patient populations, including the Tinetti
Performance Oriented Mobility Assessment (POMA), the Berg Balance Scale, the Timed Up and Go
Test (TUG), and the Functional Reach Test, can be used. Low total Tinetti Balance Test scores,
indicating impaired balance, were found to be moderately to strongly related to LE muscle weakness
and disability in individuals with ALS Kloos et al suggest that the POMA is a reliable measure for
individuals in the early or early-middle stages of ALS. A study of 31 individuals with ALS who
underwent monthly TUG, Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-
R), forced vital capacity (FVC), MMT, and quality-of-life assessments for 6 months found that the
TUG was significantly associated with the chance of falling.

 Gait

No ALS-specific gait test or measure exists. Documentation of gait within a particular time
period (e.g., within 15 seconds) or over a certain distance (e.g., 10 feet [3 meters]) has been
measured in clinical trials. Gait stability, safety, and endurance should be examined. Energy
expenditure, alignment, fit, practicality, safety, and ease of use of orthotic and assistive devices
should also be examined at regular intervals.

 Cognition

No ALS-specific cognitive test or measure exists. If dementia or cognitive impairments are

suspected, executive function, language comprehension, memory, and abstract reasoning should be
examined. The Mini-Mental State Examination has been used in clinical studies, although it may not
be sensitive to frontotemporal function impairments. Referral for a neuropsychological evaluation
may also be indicated to identify specific cognitive impairments.

 Psychosocial Function

As depression and anxiety are common in individuals with ALS, screening is important and referral
to a psychologist or psychiatrist for further evaluation may be indicated. The Beck’s Depression
Inventory,the Center of Epidemiologic Study Depression Scale, the Hospital Anxiety and Depression
Scale (HADS),and the State-Trait Anxiety Inventory have been used in clinical studies.

 Respiratory Function

Determination of respiratory status and function includes examination of respiratory symptoms

and muscle function, breathing pattern, chest expansion, respiratory sounds, cough effectiveness,
and VC or forced vital capacity (FVC) using a handheld spirometer. Supine FVC may be a better
indicator of diaphragm weakness than erect FVC, and maximal inspiratory pressure (MIP) may also
be useful in respiratory function monitoring because it can detect early respiratory insufficiency.
Sniff nasal pressure (SNP) may be effective in detecting hypercapnia, and peak cough expiratory flow
(PCEF) is the most widely used measure of cough effectiveness. Aerobic capacity and cardiovascular–
pulmonary endurance may be tested in the early stages of ALS using standardized, modified
protocols to evaluate and monitor responses to aerobic conditioning.

 Integument

In general, even in the late stage of ALS skin integrity is rarely a problem. Skin inspection should
be used to examine contact points between the body and assistive, adaptive, orthotic, protective,
and supportive devices, mobility devices, and the sleeping surface. Such inspection is especially
important when the patient’s mobility becomes increasingly more dependent. If present, swelling
should also be examined and monitored. Swelling of the distal limb may develop owing to lack of
muscle pumping action in a weakened extremity.

 Functional Status

Functional mobility skills, safety, and energy expenditure are important considerations. Basic
and instrumental activities of daily living and the need for adaptive equipment should be examined.
The Functional Independence Measure (FIM) has been used to document functional status in clinical
trials. The Schwab and England Activities of Daily Living Scale134 is an 11-point global measure of
functioning that asks the rater to report activities of daily living (ADL) function from 100% (normal)
to 0% (vegetative functions only), and has been used to examine function in individuals with ALS
(Appendix 17.A). The ALS Ciliary Neurotrophic Factor (CNTF) Treatment Study Group found the scale
to have excellent test-retest reliability, to correlate well with qualitative and quantitative changes in
function, and to be sensitive to changes over time.

 Environmental Barriers

The patient’s home and work environments should be examined for current and potential
barriers, access, and safety.
  Fatigue

Fatigue is very common in individuals with ALS. No ALS-specific measures exist; the Fatigue
Severity Scale has been used in clinical trials.

(0’Sullivan, 2014)

VIII. Medical Diagnosis

Electromyogram (EMG)

During an EMG, your doctor inserts a needle electrode through your skin into various
muscles. This test evaluates the electrical activity of your muscles when they contract and when
they’re at rest. Abnormalities in muscles seen in an EMG can help doctors diagnose ALS, or
determine if you have a different muscle or nerve condition that may be causing your symptoms. It
can also help guide your exercise therapy.

Nerve conduction study

this study measures your nerves ability to send impulses to muscles in different areas of
your body. This test can determine if you have nerve damage or certain muscle diseases.

Magnetic resonance imaging (MRI)

Using radio waves and a powerful magnetic field, an MRI produces detailed images of your
brain and spinal cord. An MRI can spot spinal cord tumors, herniated disks in your neck or other
conditions that may be causing your symptoms.

Blood and urine tests

Analyzing samples of your blood and urine in the laboratory may help your doctor eliminate
other possible causes of your signs and symptoms.

Spinal tap (lumbar puncture)

Sometimes a specialist may remove a sample of your spinal fluid for analysis. A specialist
inserts a small needle between two vertebrae in your lower back and removes a small amount of
cerebrospinal fluid for testing in the laboratory.

Muscle biopsy

If your doctor believes you may have a muscle disease rather than ALS, you may have
undergo a muscle biopsy. While you’re under local anesthesia, a small portion of your muscle is
removed and sent to lab analysis.

IX. OUTCOME MEASURE

The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS)

The ALS Functional Rating Scale (ALSFRS) is a validated rating instrument for monitoring the
progression of disability in patients with amyotrophic lateral sclerosis (ALS). One weakness of the
 ALSFRS as originally designed was that it granted disproportionate weighting to limb and bulbar, as
compared to respiratory, dysfunction. We have now validated a revised version of the ALSFRS, which
incorporates additional assessments of dyspnea, orthopnea, and the need for ventilatory support.
The Revised ALSFRS (ALSFRS-R) retains the properties of the original scale and shows strong internal
consistency and construct validity. ALSFRS-R scores correlate significantly with quality of life as
measured by the Sickness Impact Profile, indicating that the quality of function is a strong
determinant of quality of life in ALS.

X. DIFFERENTIAL DIAGNOSIS

Disease/Condition Differentiating Signs/Symptoms Differentiating Tests

Cervical spondylosis with Presents with lower motor neuron (LMN) signs MRI cervical spine shows cord compression
myelopathy and radiculopathy at lesion level and upper motor neuron (UMN) and multiple spinal root compressions.
signs below the lesion level.
Usually has associated sensory symptoms and
bladder and bowel disturbances.

Multifocal motor neuropathy
Inclusion body myositis
Presents with LMN-only signs, involving 1 or
both upper extremities.
Might begin with severe weakness in a limb
without significant atrophy, with atrophy
occurring later in the disease course.
Slowly progressive.
Weakness affecting mainly the finger flexors
and thigh flexors.
There are no UMN signs.
Electrodiagnostic studies: multifocal nerve
conduction block (with other locations than
the usual entrapment sites). High GM1
ganglioside antibody titer (up to 80% of
patients).
Electromyography: evidence for myopathy.
Clinical examination should not show UMN
signs.

Monomelic amyotrophy
Focal, predominantly LMN signs and Clinical evaluation distinguishes this entity
symptoms, with usual occurrence in young from ALS.
people.
Commonly involves an upper extremity.
Severity of symptoms may progress over a few
years while remaining limited to the initially
involved limb.
More frequent in Indian and Japanese
populations.

Myasthenia gravis Symptoms fluctuate. Acetylcholine receptor antibodies present.

Ocular symptoms (ptosis, diplopia, extraocular Edrophonium (Tensilon) test shows
muscle dysfunction) are possible. improvement in weakness with
acetylcholinesterase inhibitors.
UMN/LMN signs are absent.
Disease/Condition Differentiating Signs/Symptoms Differentiating Tests

Can mimic bulbar-onset ALS, if presents with
dysphagia, dysarthria, or facial diplegia.
Weak but otherwise normal tongue in
electromyography (EMG).
Repetitive nerve stimulation may be abnormal
in both conditions, but in ALS, the EMG of
tongue and facial muscles shows ongoing and
chronic denervation.

Benign fasciculations Focal or diffuse fasciculations, without other Electromyography shows only simple
neurologic symptoms or signs. fasciculations, without any motor unit
potential abnormalities.

Post-polio syndrome Only LMN symptoms. Clinical evaluation distinguishes this

Primary lateral sclerosis
Progressive muscular atrophy Isolated LMN disorder.
Slow progressive course. entity from ALS.
Occurs in the segments initially involved by
polio a long time after the initial viral disease.
Initially an isolated UMN disorder. Serial clinical evaluation provides data for
diagnosis. EMG excludes the LMN signs.
Most patients may develop LMN features in
time, converting into an UMN-dominant ALS.
Slowly progressive weakness with associated
spasticity.
Progresses at a slower pace when compared
with ALS.
Serial clinical evaluations used for diagnosis.
Progressive weakness, atrophy, and
fasciculation.
Some patients develop UMN symptoms and
signs later during the disease course,
converting into LMN-dominant ALS.

XI. PT MANAGEMENT

Aerobic exercise

Can increase muscle efficiency and endurance by increasing heart rate, respiratory rate and
overall cardiovascular fitness. Remember to exercise in moderation - exercising to the point of
fatigue may actually result in increased muscle weakness.

Stretching exercises

May help decrease the frequency or intensity of muscle cramping. These should be done
daily to prevent pain and stiffness.

Range of motion exercises (ROM)

 Help move the joints through their full range of motion. These should be performed actively,
if possible, or passively if muscle weakness limits movement. These should be done daily to prevent
pain and stiffness.

Strengthening exercises

Are not recommended. Working out with weights will not strengthen those muscles already
weakened by ALS and could result in increased muscle weakness.

Assistive Devices

There are various types of assistive devices that can make walking safer. A cane may be the most
useful tool when one leg is weaker than the other, or when there are mild balance deficits. Here are
some guidelines for cane use:

 The cane is held on the stronger side of the body while the weight is shifted away from the
weaker side.
 A quad cane (or four-legged cane) provides more stability than a standard cane.
 Walkers may be more appropriate when there is significant leg weakness. They can also
provide support for maintaining balance. Wheels or platforms may be added to the walker if
necessary.

Bracing

Weakness of the leg muscles may make it more difficult to maneuver on stairs, rise from a
chair or walk. Bracing or other aids may be recommended.

An ankle-foot brace can stabilize the ankle when there is weakness in the foot muscles. This brace
fits into an ordinary shoe and prevents the toes from dragging during the swing phase of walking.

Weakness in the neck muscles may make it difficult to hold your head up. A neck brace may be
recommended to make you more comfortable.

Wheelchairs

Wheelchairs may provide patients with more independence and less reliance on others.
Wheelchairs are usually recommended when a patient experiences excessive fatigue, unsteadiness
or occasional falls.

XII. MEDICAL MANAGEMENT

Stem cells

One phase I trial of human spinal cord-derived neural stem cells implanted in the ventral
horn of both cervical and lumbar spine has been completed in ALS patients. The study showed that
injections can be performed safely. A phase II study is in progress. Studies have been carried out on
both peripheral and intrathecal injections of treated adult bone marrow-derived mesenchymal
stromal cells (MSCs) designed to produce a variety of neurotrophic factors. Results from one further
small study in Israel suggest the procedure is safe; further trials are planned in the US. 

Diaphragm pacing
 In one open-label study of patients with ALS, a diaphragm pacing system was tested and
appeared safe, with results suggesting a potential beneficial effect. Following on from this, the FDA
approved this device under the Humanitarian Device Exemption (HDE) program. However,
randomized controlled studies of the same diaphragm pacing system in the UK and France
demonstrated shortened survival for patients using diaphragm pacing.

XIII. PHARMACOLOGICAL MANAGEMENT

Two Medications are currently approved by the food and drug administration for the
treatment of ALS.

1. Riluzole(Rilutek)

This drug appears to slow the disease’s progression in some people, perhaps by reducing levels
of a chemical messenger in the brain (glutamate) that’s often present in higher levels in people
with ALS. Riluzole is taken as a pill and may cause side effects such as dizziness, gastrointestinal
conditions and liver function changes.

2. Edaravone(Radicava)

The FDA approved edaravone in 2017 based on six month clinical trial that showed it reduced
the decline in daily functioning associated with ALS. The drug is given via intravenous infusion
(typically 10-14 days in a row, once a month), and side effects may include bruising, gait
disturbance, hives, swelling, and shortness of breath.

Edaravone contains sodium bisulfite, which may cause serious allergic reactions in people with
sulfite sensitivity.

References:

O'Sullivan, S. B., & Schmitz, T. J. (2007). Physical rehabilitation. Philadelphia, PA: F.A. Davis.

Braddom, R. L. (1996). Physical medicine & rehabilitation. Philadelphia: Saunders.

https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/diagnosis-
treatment/drc-20354027

https://online.epocrates.com/diseases/33043/Amyotrophic-lateral-sclerosis/Emerging-
Therapies

https://my.clevelandclinic.org/health/diseases/16729-amyotrophic-lateral-sclerosis-als/physical-
therapy-and-als

https://online.epocrates.com/diseases/33035/Amyotrophic-lateral-sclerosis/Differential-
Diagnosis?fbclid=IwAR3Buc2KNK553TmMI0JV5BTnwKscBzN0Z4aBUrqC-i40U8HfqDpsiZe5iMU