It is also known as motor neuron disease (MND) or Lou Gehrig's disease, is
a neurodegenerative disease that results in the progressive loss of motor neurons that
control voluntary muscles. ALS is the most common form of the motor neuron
diseases. Early symptoms of ALS include stiff muscles, muscle twitches, and gradual
increasing weakness and muscle wasting. Limb-onset ALS begins with weakness in the
arms or legs, while bulbar-onset ALS begins with
difficulty speaking or swallowing.Around half of people with ALS develop at least mild
difficulties with thinking and behavior, and about 15% develop frontotemporal dementia.
Motor neuron loss continues until the ability to eat, speak, move, and finally the ability to
breathe is lost with the cause of early death usually being respiratory failure.
ALS can be classified by the types of motor neurons that are affected.
Primary lateral sclerosis (PLS) involves only upper motor neurons, and progressive
muscular atrophy (PMA) involves only lower motor neurons.
The disorder causes muscle weakness, atrophy, and muscle spasms throughout the body
due to the degeneration of the upper motor and lower motor neurons. Individuals
affected by the disorder may ultimately lose the ability to initiate and control all
voluntary movement, although bladder and bowel function and the extraocular
muscles (the muscles responsible for eye movement) are usually spared[d] until the
final stages of the disease. Sensory nerves and the autonomic nervous system are
generally unaffected, meaning the majority of people with ALS
maintain hearing, sight, touch, smell, and taste
The start of ALS may be so subtle that the symptoms are overlooked. The earliest symptoms of
ALS are muscle weakness or muscle atrophy. Other presenting symptoms include trouble
swallowing or breathing, cramping, or stiffness of affected muscles; muscle weakness
affecting an arm or a leg; or slurred and nasal speech. The parts of the body affected by early
symptoms of ALS depend on which motor neurons in the body are damaged first.
In limb-onset ALS, the first symptoms are in the arms or the legs. If the legs are affected first,
people may experience awkwardness, tripping, or stumbling when walking or running; this is
often marked by walking with a "dropped foot" that drags gently on the ground. If the arms are
affected first, they may experience difficulty with tasks requiring manual dexterity, such as
buttoning a shirt, writing, or turning a key in a lock.
In bulbar-onset ALS, the first symptoms are difficulty speaking or swallowing. Speech may
become slurred, nasal in character, or quieter. There may be difficulty with swallowing and
loss of tongue mobility. A smaller proportion of people experience "respiratory-onset" ALS,
where the intercostal muscles that support breathing are affected first.
Over time, people experience increasing difficulty moving, swallowing (dysphagia), and
speaking or forming words (dysarthria). Symptoms of upper motor neuron involvement
include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia), including
an overactive gag reflex. An abnormal reflex commonly called Babinski's sign also indicates
upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle
weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen
under the skin (fasciculation's). However, twitching is more of a side effect than a diagnostic
symptom; it either occurs after or accompanies weakness and atrophy
Although the initial symptoms and rate of progression vary from person to person, the
disease eventually spreads to unaffected regions and the affected regions become more
affected. Most people eventually are not able to walk or use their hands and arms, lose the
ability to speak and swallow food and their own saliva, and begin to lose the ability to cough
and to breathe on their own. While the disease does not cause pain directly, pain is a
symptom experienced by most people with ALS and can take the form of neuropathic
pain (pain caused by nerve damage), spasticity, muscle cramps, and nociceptive pain caused
by reduced mobility and muscle weakness; examples of nociceptive pain in ALS
include contractures (permanent shortening of a muscle or joint), neck pain, back pain,
shoulder pain, and pressure ulcers.
The rate of progression can be measured using the ALS Functional Rating Scale -
Revised (ALSFRS-R), a 12-item instrument survey administered as a clinical interview or
self-reported questionnaire that produces a score between 48 (normal function) and 0 (severe
disability), it is the most commonly used outcome measure in clinical trials and is used by
doctors to track disease progression. Though the degree of variability is high and a small
percentage of people have a much slower disorder, on average, people with ALS lose about
0.9 FRS points per month. A survey-based study among clinicians showed that they rated a
20% change in the slope of the ALSFRS-R as being clinically meaningful.
Disease progression tends to be slower in people who are younger than 40 at onset, are
mildly obese, have symptoms restricted primarily to one limb, and those with primarily upper
motor neuron symptoms. Conversely, progression is faster and prognosis poorer in people
with bulbar-onset ALS, respiratory-onset ALS and frontotemporal dementia.
Difficulties with chewing and swallowing make eating very difficult and increase the risk of choking or
of aspirating food into the lungs. 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. As the diaphragm and intercostal muscles of the rib cage that support breathing weaken,
measures of lung function such as vital capacity and inspiratory pressure diminish. In respiratory-onset
ALS, this may occur before significant limb weakness is apparent. The most common cause of death
among people with ALS are respiratory failure or pneumonia and most people with ALS die in their own
home from the former cause, with their breath stopping while they sleep.
Although respiratory support can ease problems with breathing and prolong survival, it does not affect
the progression of ALS. Most people with ALS die between two and four years after the
diagnosis. Around half of people with ALS die within 30 months of their symptoms beginning, and
about 20% of people with ALS live between five and ten years after symptoms begin. Guitarist Jason
Becker has lived since 1989 with the disorder, while cosmologist Stephen Hawking lived for 55 more
years following his diagnosis, but they are considered unusual cases
Cognitive and behavioural symptoms
Cognitive or behavioural dysfunction is present in 30–50% of individuals with
ALS. Around half of people with ALS will experience mild changes in cognition and
behavior, and 10–15% will show signs of frontotemporal dementia (FTD).Most people
with ALS who have normal cognition at the time of diagnosis have preserved cognition
throughout the course of their disease; the development of cognitive impairment in those
with normal cognition at baseline is associated with a worse prognosis. Repeating
phrases or gestures, apathy, and loss of inhibition are frequently reported behavioural
features of ALS. Language dysfunction, executive dysfunction, and troubles
with social cognition and verbal memory are the most commonly reported cognitive
symptoms in ALS; a meta-analysis found no relationship between dysfunction and
disease severity. However, cognitive and behavioural dysfunctions have been found to
correlate with reduced survival in people with ALS and increased caregiver burden; this
may be due in part to deficits in social cognition.About half the people who have ALS
experience emotional lability, in which they cry or laugh for no reason; it is more
common in those with bulbar-onset ALS
Though the exact cause of ALS is unknown, genetic and environmental factors are
thought to be of roughly equal importance. The genetic factors are better understood
than the environmental factors; no specific environmental factor has been definitively
shown to cause ALS. A liability threshold model for ALS proposes that cellular damage
accumulates over time due to genetic factors present at birth and exposure to
environmental risks throughout life.
A 2015 review found that moderate to severe traumatic brain injury is a risk factor for ALS,
but whether mild traumatic brain injury increases rates was unclear
The defining feature of ALS is the death of both upper motor neurons (located in the motor
cortex of the brain) and lower motor neurons (located in the brainstem and spinal cord). In
ALS with frontotemporal dementia, neurons throughout the frontal and temporal lobes of the
brain die as well. The pathological hallmark of ALS is the presence of inclusion
bodies (abnormal aggregations of protein) known as Bunina bodies in the cytoplasm of motor
neurons. In about 97% of people with ALS, the main component of the inclusion bodies
is TDP-43 protein; however, in those with SOD1 or FUS mutations, the main component of the
inclusion bodies[ is SOD1 protein or FUS protein, respectively. The gross pathology of ALS,
which are features of the disease that can be seen with the naked eye, include skeletal
muscle atrophy, motor cortex atrophy, sclerosis of the corticospinal and corticobulbar tracts,
thinning of the hypoglossal nerves (which control the tongue), and thinning of the anterior
roots of the spinal cord. Aside from the death of motor neurons, two other characteristics
common to most ALS variants are focal initial pathology, meaning that symptoms start in a
single spinal cord region, and progressive continuous spread, meaning that symptoms spread
to additional regions over time. Prion-like propagation of misfolded proteins from cell to cell
may explain why ALS starts in one area and spreads to others. The lymphatic system may also
be involved in the pathogenesis of ALS
The diagnosis of ALS is based on the El Escorial Revised criteria and the Awaji criteria. The original El Escorial
criteria had four levels of diagnostic certainty, based on how many of the four spinal cord regions were involved:
bulbar, cervical, thoracic, and lumbar. Definite ALS was defined as upper motor neuron (UMN) and lower motor
neuron (LMN) signs in three spinal cord regions, probable ALS as UMN and LMN signs in two regions, possible ALS
as UMN and LMN signs in only one region, and suspected ALS as LMN signs only. The El Escorial Revised criteria,
also known as the Airlie House criteria, dropped the "suspected ALS" category and added a "laboratory-supported
probable ALS" category. The Awaji criteria give abnormal EMG tests the same weight as clinical signs of LMN
dysfunction in making the diagnosis of ALS, thus making the "laboratory-supported probable ALS" category
unnecessary. The only three categories in the Awaji criteria are definite ALS, probable ALS, and possible ALS.
The El Escorial Revised criteria are specific for ALS, which means that someone who meets the criteria is very likely to
have ALS; however, they are not especially sensitive for ALS, which means that someone who does not meet the
criteria can still have ALS. Their sensitivity is particularly poor in the early stages of ALS. The Awaji criteria have
better sensitivity than the El Escorial Revised criteria, especially for bulbar-onset ALS. A 2012 meta-analysis found
that the El Escorial Revised criteria had a sensitivity of 62.2%, while the Awaji criteria had a sensitivity of 81.1%; both
sets of criteria had a specificity of about 98%. The El Escorial criteria were designed to standardize patient groups
for clinical trials but are not as useful in clinical practice; possible ALS as described by the El Escorial criteria is
almost always clinically ALS
There is no cure for ALS. Management focuses on treating symptoms and providing
supportive care, with the goal of improving quality of life and prolonging survival.
Non-invasive ventilation (NIV) is the main treatment for respiratory failure in ALS.In people with normal bulbar function, it
prolongs survival by about seven months and improves quality of life. One study found that NIV is ineffective for people with
poor bulbar function while another suggested that it may provide a modest survival benefit. Many people with ALS have
difficulty tolerating NIV. Invasive ventilation is an option for people with advanced ALS when NIV is not enough to manage
their symptoms. While invasive ventilation prolongs survival, disease progression and functional decline continue. It may
decrease the quality of life of people with ALS or their caregivers. Invasive ventilation is more commonly used in Japan than
North America or Europe.
Physical therapy can promote functional independence through aerobic, range of motion, and stretching exercises.
Occupational therapy can assist with activities of daily living through adaptive equipment. Speech therapy can assist people
with ALS who have difficulty speaking. Preventing weight loss and malnutrition in people with ALS improves both survival
and quality of life. Initially, difficulty swallowing (dysphagia) can be managed by dietary changes and swallowing techniques.
A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot safely
swallow food and water. The feeding tube is usually inserted by percutaneous endoscopic gastrostomy (PEG). There is weak
evidence that PEG tubes improve survival. PEG insertion is usually performed with the intent of improving quality of life.
Palliative care should begin shortly after someone is diagnosed with ALS.Discussion of end-of-life issues gives people with
ALS time to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures. Hospice
care can improve symptom management at the end of life and increases the likelihood of a peaceful death. In the final days
of life, opioids can be used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety.
Riluzole has been found to modestly prolong survival by about 2–3 months. It may have a greater survival benefit for those
with bulbar-onset ALS It may work by decreasing release of the excitatory neurotransmitter glutamate from pre-synaptic
neurons. The most common side effects are nausea and a lack of energy (asthenia).People with ALS should begin treatment
with riluzole as soon as possible following their diagnosis.
Edaravone has been shown to modestly slow the decline in function in a small group of people with early-stage ALS. It may
work by protecting motor neurons from oxidative stress.The most common side effects are bruising and gait
disturbance. Treatment with edaravone is expensive and requires daily hour-long IV infusions for 10 days in a two-week
Other medications may be used to help reduce fatigue, ease muscle cramps, control spasticity, and reduce excess saliva
and phlegm. Gabapentin, pregabalin, and tricyclic antidepressants (e.g., amitriptyline) can be used for neuropathic pain, while
nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids can be used for nociceptive pain.
Depression can be treated with selective serotonin reuptake inhibitors (SSRIs) or tricyclic
antidepressants, while benzodiazepines can be used for anxiety. There are no medications to treat cognitive
impairment/frontotemporal dementia (FTD); however, SSRIs and antipsychotics can help treat some of the symptoms of
FTD. Baclofen and tizanidine are the most commonly used oral drugs for treating spasticity; an intrathecal baclofen pump
can be used for severe spasticity. Atropine, scopolamine, amitriptyline or glycopyrrolate may be prescribed when people with
ALS begin having trouble swallowing their saliva (sialorrhea).
Invasive ventilation bypasses the nose and mouth (the upper airways) by making a cut in the trachea
(tracheostomy) and inserting a tube connected to a ventilator. It is an option for people with
advanced ALS whose respiratory symptoms are poorly managed despite continuous NIV use. While
invasive ventilation prolongs survival, especially for those younger than 60, it does not treat the
underlying neurodegenerative process. The person with ALS will continue to lose motor function,
making communication increasingly difficult and sometimes leading to locked-in syndrome, in which
they are completely paralyzed except for their eye muscles. About half of the people with ALS who
choose to undergo invasive ventilation report a decrease in their quality of life but most still
consider it to be satisfactory. However, invasive ventilation imposes a heavy burden on caregivers and
may decrease their quality of life. Attitudes toward invasive ventilation vary from country to
country; about 30% of people with ALS in Japan choose invasive ventilation, versus less than 5% in
North America and Europe
A man with ALS communicates by pointing to letters and words using a head-mounted laser pointer.
Physical therapy plays a large role in rehabilitation for individuals with ALS. Specifically, physical,
occupational, and speech therapists can set goals and promote benefits for individuals with ALS by
delaying loss of strength, maintaining endurance, limiting pain, improving speech and swallowing,
preventing complications, and promoting functional independence.
Occupational therapy and special equipment such as assistive technology can also enhance people's
independence and safety throughout the course of ALS. Gentle, low-impact aerobic exercise such as
performing activities of daily living, walking, swimming, and stationary bicycling can strengthen
unaffected muscles, improve cardiovascular health, and help people fight fatigue and depression. Range of
motion and stretching exercises can help prevent painful spasticity and shortening (contracture) of muscles.
Physical and occupational therapists can recommend exercises that provide these benefits without
overworking muscles, because muscle exhaustion can lead to worsening of symptoms associated with ALS,
rather than providing help to people with ALS. They can suggest devices such as ramps, braces,
walkers, bathroom equipment (shower chairs, toilet risers, etc.), and wheelchairs that help people remain
A gastrostomy tube is placed through the wall of the abdomen into the stomach.
Preventing weight loss and malnutrition in people with ALS improves both survival and quality of life. Weight loss in
ALS is caused by muscle wasting due to motor neuron death, increased resting energy expenditure, and decreased
food intake. Difficulty swallowing (dysphagia) develops in about 85% of people with ALS at some point over the
course of their disease and is a major cause of decreased food intake, leading to malnutrition and weight loss.It is
important to regularly assess the weight and swallowing ability of people with ALS.Initially, dysphagia may be
managed by dietary changes and modified swallowing techniques. Difficulty swallowing liquids usually develops first
and can be managed by switching to thicker liquids like fruit nectar or smoothies, or by adding fluid thickeners to thin
fluids like water and coffee. People with ALS should eat soft, moist foods, which tend to be easier to swallow than
dry, crumbly, or chewy foods. They should also be instructed on proper head posture during swallowing, which can
make swallowing easier. There is tentative evidence that high-calorie diets may prevent further weight loss and
A feeding tube should be considered if someone with ALS loses 5% or more of their body weight or if they cannot
safely swallow food and water. This can take the form of a gastrostomy tube, in which a tube is placed through the
wall of the abdomen into the stomach, or a nasogastric tube, in which a tube is placed through the nose and down the
oesophagus into the stomach. A gastrostomy tube is more appropriate for long-term use than a nasogastric tube, which
is uncomfortable and can cause oesophageal ulcers. The feeding tube is usually inserted by percutaneous
endoscopic gastrostomy (PEG). There is some evidence that a PEG tube should be inserted before vital capacity drops
below 50% of expected, as a low vital capacity may be associated with a higher risk of complications. However, a
large 2015 study showed that PEG insertion is safe in people with advanced ALS and low vital capacities, as long as
they are on NIV during the procedure.
Palliative care, which relieves symptoms and improves quality of life without treating the underlying disease, should
begin shortly after someone is diagnosed with ALS. Early discussion of end-of-life issues gives people with ALS time
to reflect on their preferences for end-of-life care and can help avoid unwanted interventions or procedures. Once they
have been fully informed about all aspects of various life-prolonging measures, they can fill out advance
directives indicating their attitude toward non-invasive ventilation, invasive ventilation, and feeding tubes. Late in the
disease course, difficulty speaking due to muscle weakness (dysarthria) and cognitive dysfunction may impair their ability
to communicate their wishes regarding care. Continued failure to solicit the preferences of the person with ALS may
lead to unplanned and potentially unwanted emergency interventions, such as invasive ventilation. If people with ALS or
their family members are reluctant to discuss end-of-life issues, it may be useful to use the introduction of gastrostomy or
non-invasive ventilation as an opportunity to bring up the subject.
Hospice care, or palliative care at the end of life, is especially important in ALS because it helps to optimize the
management of symptoms and increases the likelihood of a peaceful death. It is unclear exactly when the end-of-life
phase begins in ALS, but it is associated with significant difficulty moving, communicating, and, in some cases,
thinking. Although many people with ALS fear choking to death (suffocating), they can be reassured that this occurs
rarely, about 0–3% of the time. About 90% of people with ALS die peacefully. In the final days of life, opioids can be
used to treat pain and dyspnea, while benzodiazepines can be used to treat anxiety
Progressive bulbar palsy (PBP)
It belongs to a group of disorders known as motor neuron diseases. PBP is a disease
that attacks the nerves supplying the bulbar muscles. These disorders are characterized
by the degeneration of motor neurons in the cerebral cortex, spinal cord, brain stem,
and pyramidal tracts. This specifically involves the glossopharyngeal nerve (IX), vagus
nerve (X), and hypoglossal nerve (XII).
SIGNS AND SYMPTOMS
Prognosis for PBP patients is poor. Progressive bulbar palsy symptoms can include
progressive difficulty with talking and swallowing. Patients can also exhibit reduced
gag reflexes, weak palatal movements, fasciculation's, and weak movement of the facial
muscles and tongue. In advanced cases of PBP, patients may be unable to protrude their
tongue or manipulate food in their mouth.
Patients with early cases of PBP have difficulty with pronunciations, particularly lateral
consonants (lingual) and velars, and may show problems with drooling saliva. If the
corticobulbar tract is affected a pseudobulbar affect with emotional changes may
occur. Because PBP patients have such difficulty swallowing, food and saliva can be
inhaled into the lungs. This can cause gagging and choking, and it increases the risk of
pneumonia. Death, which is often from pneumonia, usually occurs 1 to 3 years after the
start of the disorder.
About twenty-five percent of patients with PBP eventually develop the widespread
symptoms common to ALS
The cause of PBP is unknown. One form of PBP is found to occur within patients that have a CuZn-superoxide
dismutase (SOD1) mutation. Progressive bulbar palsy patients that have this mutation are classified with FALS
patients, Familial ALS (FALS) accounts for about 5%-10% of all ALS cases and is caused by genetic factors. Within
these, about 20–25% are linked to the SOD1 mutation. It is not currently known if and how the
decreased SOD1 activity contributes to Progressive Bulbar Palsy or FALS, and studies are being done in patients and
transgenic mice to help further understand the impact of this gene on the disease.
A case study was done on a 42-year-old woman who complained of muscle weakness 10 months prior to admission in
the hospital. Upon neurological examination, the patient showed muscle atrophy, fasciculation in all limbs and
decreased deep tendon reflexes. The patient’s older brother, father, and paternal uncle had previously all died of ALS
or an ALS type syndrome. The patient developed progressive bulbar palsy, became dependent on a respirator, and had
two episodes of cardiac arrest. The patient died from pneumonia two years after the onset of the disease. After
studying the patient, it was found that the patient had a two base pair deletion in the 126th codon in exon 5 of
the SOD1 gene. This mutation produced a frameshift mutation, which led to a stop codon at position
131. SOD1 activity was decreased by about 30%. The patient’s histological examination showed severe reduction in
lower motor neurons. Upon further study, this case proved to be important because it demonstrated
that SOD1 mutations might not effect steady neuropathological changes, and that environmental and genetic factors
might affect the phenotype of the SOD1 mutations.
PBP is aggressive and relentless, and there were no treatments for the disease as of
2005. However, early detection of PBP is the optimal scenario in which doctors can
map out a plan for management of the disease. This typically involves symptomatic
treatments that are frequently used in many lower motor disorders.[c
is a medical condition characterized by the inability to control facial movements (such
as chewing and speaking) and caused by a variety of neurological disorders. Patients
experience difficulty chewing and swallowing, have increased reflexes and spasticity in
tongue and the bulbar region, and demonstrate slurred speech (which is often the initial
presentation of the disorder), sometimes also demonstrating uncontrolled emotional
The condition is usually caused by the bilateral damage to corticobulbar pathways,
which are upper motor neuron pathways that course from the cerebral cortex to nuclei
of cranial nerves in the brain stem.
SIGNS AND SYMPTOMS
Slow and indistinct speech
Dysphagia (difficulty in swallowing)
Small, stiff and spastic tongue
Brisk jaw jerk
Gag reflex may be normal, exaggerated or absent
Examination may reveal upper motor neuron lesion of the limbs
Pseudobulbar palsy is the result of damage of motor fibers traveling from the cerebral
cortex to the lower brain stem. This damage might arise in the course of a variety of
neurological conditions that involve demyelination and bilateral corticobulbar lesions.
Vascular causes: bilateral hemisphere infarction, CADASIL syndrome, artery of
Progressive supranuclear palsy
Amyotrophic lateral sclerosis
Parkinson's disease and related multiple system atrophy
Various motor neuron diseases, especially those involving demyelination
Multiple sclerosis and other inflammatory disorders
High brain stem tumors
Metabolic causes: osmotic demyelination syndrome
Neurological involvement in Behçet's disease
The proposed mechanism of pseudobulbar palsy points to the disinhibition of the motor
neurons controlling laughter and crying, proposing that a reciprocal pathway exists
between the cerebellum and the brain stem that adjusts laughter and crying responses,
making them appropriate to context. The pseudobulbar crying could also be induced by
stimulation in the region of the subthalamic nucleus of the brain.
DIAGNOSIS AMD TREATMENT
Diagnosis of pseudobulbar palsy is based on observation of the symptoms of the condition. Tests
examining jaw jerk and gag reflex can also be performed. It has been suggested that the majority of
patients with pathological laughter and crying have pseudobulbar palsy due to bilateral corticobulbar
lesions and often a bipyramidal involvement of arms and legs. To further confirm the condition, MRI
can be performed to define the areas of brain abnormality.
Since pseudobulbar palsy is a syndrome associated with other diseases, treating the underlying disease
may eventually reduce the symptoms of pseudobulbar palsy.
Possible pharmacological interventions for pseudobulbar affect include the tricyclic
antidepressants, serotonin reuptake inhibitors, and a novel approach
utilizing dextromethorphan and quinidine sulfate. Nuedexta is an FDA approved medication for
pseudobulbar affect. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, inhibits
glutamatergic transmission in the regions of the brainstem and cerebellum, which are hypothesized to be
involved in pseudobulbar symptoms, and acts as a sigma ligand, binding to the sigma-1 receptors that
mediate the emotional motor expression
Progressive muscular atrophy (PMA)
also called Duchenne–Aran disease and Duchenne–Aran muscular atrophy, is a
disorder characterised by the degeneration of lower motor neurons, resulting in
generalised, progressive loss of muscle function.
PMA is classified among motor neuron diseases (MND) where it is thought to account
for around 4% of all MND cases.
PMA affects only the lower motor neurons, in contrast to amyotrophic lateral
sclerosis (ALS), the most common MND, which affects both the upper and lower motor
neurons, or primary lateral sclerosis, another MND, which affects only the upper motor
neurons. The distinction is important because PMA is associated with a better prognosis
SIGNS AND SYMPTOMS
As a result of lower motor neuron degeneration, the symptoms of PMA include:
Some patients have symptoms restricted only to the arms or legs (or in some cases just
one of either). These cases are referred to as flail limb (either flail arm or flail leg) and
are associated with a better prognosis.
PMA is a diagnosis of exclusion, there is no specific test which can conclusively establish whether a patient has the condition. Instead, a number of other possibilities
have to be ruled out, such as multifocal motor neuropathy or spinal muscular atrophy. Tests used in the diagnostic process include MRI, clinical examination,
and EMG. EMG tests in patients who do have PMA usually show denervation (neuron death) in most affected body parts, and in some unaffected parts too.
It typically takes longer to be diagnosed with PMA than ALS, an average of 20 months for PMA vs 15 months in ALS.
In contrast to amyotrophic lateral sclerosis or primary lateral sclerosis, PMA is distinguished by the absence of:
The importance of correctly recognizing progressive muscular atrophy as opposed to ALS is important for several reasons.
The prognosis is a little better. A recent study found the 5-year survival rate in PMA to be 33% (vs 20% in ALS) and the 10-year survival rate to be 12% (vs 6% in
Patients with PMA do not have the cognitive change identified in certain groups of patients with MND.
Because PMA patients do not have UMN signs, they usually do not meet the World Federation of Neurology El Escorial Research Criteria for "Definite" or
"Probable" ALS and so are ineligible to participate in the majority of clinical trials conducted in ALS.
Because of its rarity (even compared to ALS) and confusion about the condition, some insurance policies or local healthcare policies may not recognize PMA as being
the life-changing illness that it is. In cases where being classified as being PMA rather than ALS is likely to restrict access to services, it may be preferable to be
diagnosed as "slowly progressive ALS" or "lower motor neuron predominant" ALS.
An initial diagnosis of PMA could turn out to be slowly progressive ALS many years later, sometimes even decades after the initial diagnosis. The occurrence of upper
motor neuron symptoms such as brisk reflexes, spasticity, or a Babinski sign would indicate a progression to ALS; the correct diagnosis is also occasionally made on
Primary lateral sclerosis (PLS)
is a very rare neuromuscular disease characterized by progressive muscle weakness in
the voluntary muscles. PLS belongs to a group of disorders known as motor neuron
diseases. Motor neuron diseases develop when the nerve cells that control voluntary
muscle movement degenerate and die, causing weakness in the muscles they control.
PLS only affects upper motor neurons. There is no evidence of the degeneration of
spinal motor neurons or muscle wasting (amyotrophy) that occurs in amyotrophic
lateral sclerosis (ALS).
SIGNS AND SYMPTOMS
Onset of PLS usually occurs spontaneously after age 50 and progresses gradually over a number of years, or even
decades. The disorder usually begins in the legs, but it may start in the tongue or the hands. Symptoms may
include difficulty with balance, weakness and stiffness in the legs, and clumsiness. Other common symptoms
are spasticity (involuntary muscle contraction due to the stretching of muscle, which depends on the velocity of the
stretch) in the hands, feet, or legs, foot dragging, and speech and swallowing problems due to involvement of the facial
muscles. Breathing may also become compromised in the later stages of the disease, causing those patients who develop
ventilatory failure to require non-invasive ventilatory support. Hyperreflexia is another key feature of PLS as seen in
patients presenting with the Babinski's sign. Some people present with emotional lability and bladder urgency, and
occasionally people with PLS experience mild cognitive changes detectable on neuropsychological testing, particularly on
measures of executive function.
PLS is not considered hereditary when onset is in adulthood; however, juvenile primary lateral sclerosis (JPLS) has been
linked to a mutation in the ALS2 gene which encodes the cell-signalling protein alsin.
The issue of whether PLS exists as a different entity from ALS is not clear, as some patients initially diagnosed as having
PLS ultimately develop lower motor neuron signs. When this happens it is classed as ALS.
Primary lateral sclerosis (PLS) usually presents with gradual-onset, progressive, lower-extremity stiffness and pain due to
muscle spasticity. Onset is often asymmetrical. Although the muscles do not appear to atrophy as in ALS (at least
initially), the disabling aspect of PLS is muscle spasticity and cramping, and intense pain when those muscles are
stretched, resulting in joint immobility. A normal walking stride may become a tiny step shuffle with related instability
Researchers do not fully understand what causes PLS, although it is thought it could be
due to a combination of environmental and genetic factors. Studies are being done to
evaluate the possible causes, although linking causality can be difficult due to the
relatively low number of people who are diagnosed with PLS.
Juvenile PLS may be caused by the ALS2 gene, although this condition is very rare.
DIAGNOSIS AND TREATMENT
There are no specific tests for the diagnosis of PLS. Therefore, the diagnosis occurs as the result of eliminating other possible causes of the
symptoms and by an extended observation period.
Like ALS, diagnosing PLS is a diagnosis of exclusion, as there is no one test that can confirm a diagnosis of PLS. The Pringle Criteria, proposed
by Pringle et al., provides a guideline of nine points that, if confirmed, can suggest a diagnosis of PLS. Due to the fact that a person with ALS
may initially present with only upper motor neuron symptoms, indicative of PLS, one key aspect of the Pringle Criteria is requiring a minimum of
three years between symptom onset and symptom diagnosis. When these criteria are met, a diagnosis of PLS is highly likely. Other aspects of
Pringle Criteria include normal EMG findings, thereby ruling out lower motor neuron involvement that is indicative of ALS, and absence of family
history for Hereditary Spastic Paraplegia (HSP) and ALS. Imaging studies to rule out structural or demyelinating lesions may be done as well.
Hoffman's sign and Babinski reflex may be present and indicative of upper motor neuron damage.
Treatment for individuals with PLS is symptomatic. Baclofen and tizanidine may reduce spasticity. Quinine or phenytoin may decrease cramps.
Some patients who do not receive adequate relief from oral treatment may consider intrathecal baclofen (i.e., infusion of medication directly
into the cerebrospinal fluid via a surgically placed continuous infusion pump). However, patients are carefully selected for this type of procedure
to ensure that they will likely benefit from this invasive procedure.
Physical therapy often helps prevent joint immobility. Speech therapy may be useful for those with involvement of the facial muscles.
Physiotherapy treatment focuses on reducing muscle tone, maintaining or improving range of motion, increasing strength and coordination, and
improving functional mobility. In PLS, stretching is thought to improve flexibility and can also reduce muscle spasticity and cramps.
Patients with PLS may find it beneficial to have an evaluation, as well as follow-up visits at multidisciplinary clinics, similar to those available for
people with ALS. These multidisciplinary clinics may provide patients with the necessary treatment that they require by having an occupational
therapist, physical therapist, speech language pathologist, dietician and nutritionist, all in one site.
Spinal muscular atrophy (SMA
is a rare neuromuscular disorder that results in the loss of motor neurons and
progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if
left untreated it is the most common genetic cause of infant death. It may also appear
later in life and then have a milder course of the disease. The common feature is
progressive weakness of voluntary muscles, with arm, leg and respiratory
muscles being affected first.Associated problems may include poor head control,
difficulties swallowing, scoliosis, and joint contractures
SIGNS AND SYMPTOMS
The symptoms vary depending on the SMA type, the stage of the disease as well as
individual factors. Signs and symptoms below are most common in the severe SMA
type 0/I:[medical citation needed]
Areflexia, particularly in extremities
Overall muscle weakness, poor muscle tone, limpness or a tendency to flop
Difficulty achieving developmental milestones, difficulty sitting/standing/walking
In small children: adopting of a frog-leg position when sitting (hips abducted and knees
Loss of strength of the respiratory muscles: weak cough, weak cry (infants),
accumulation of secretions in the lungs or throat, respiratory distress
Bell-shaped torso (caused by using only abdominal muscles for respiration) in severe
Fasciculations (twitching) of the tongue
Difficulty sucking or swallowing, poor feeding
Spinal muscular atrophy has an autosomal recessive pattern of inheritance.
Spinal muscular atrophy is caused by a genetic mutation in the SMN1 gene.
Human chromosome 5 contains two nearly identical genes at location 5q13:
a telomeric copy SMN1 and a centromeric copy SMN2. In healthy individuals,
the SMN1 gene codes the survival of motor neuron protein (SMN) which, as its name
says, plays a crucial role in survival of motor neurons. The SMN2 gene, on the other
hand – due to a variation in a single nucleotide (840.C→T) – undergoes alternative
splicing at the junction of intron 6 to exon 8, with only 10–20% of SMN2 transcripts
coding a fully functional survival of motor neuron protein (SMN-fl) and 80–90% of
transcripts resulting in a truncated protein compound (SMNΔ7) which is rapidly
degraded in the cell
the SMN1 gene in over 95% of cases, and a compound SMN1 mutation in the remaining patients. Genetic testing is usually carried out using a blood sample,
and MLPA is one of more frequently used genetic testing techniques, as it also allows establishing the number of SMN2 gene copies, which has clinical
Symptomatically, SMA can be diagnosed with a degree of certainty only in children with the acute form who manifest a progressive illness with paradoxical
breathing, bilateral low muscle tone and absent tendon reflexes.
Early diagnosis of SMA, at the asymptomatic stage of the disease, allows to introduce causative therapies early enough to prevent the manifestation of symptoms.
Preimplantation genetic diagnosis can be used to screen for SMA-affected embryos during in-vitro fertilisation.
Prenatal testing for SMA is possible through chorionic villus sampling, cell-free fetal DNA analysis and other methods.
Routine newborn screening for SMA is becoming increasingly commonplace in developed countries, given the availability of causative treatments that are most
effective at the asymptomatic stage of the disease.In 2018, newborn screening for SMA was added to the US list of recommended newborn screening
tests and as of April 2020 it has been adopted in 39 US states. As of February 2023, SMA screening has been incorporated in national newborn screening
programmes in around 15 countries and pilot projects are under way in further countries.
Those at risk of being carriers of SMN1 deletion, and thus at risk of having offspring affected by SMA, can undergo carrier analysis using a blood or saliva sample.
The American College of Obstetricians and Gynaecologists recommends all people thinking of becoming pregnant be tested to see if they are a carrier. The
carrier frequency of SMA is comparable to other disorders like thalassemia and in a north Indian cohort has been found to be 1 in 38. However, genetic testing
will not be able to identify all individuals at risk since about 2% of cases are caused by de novo mutations and 5% of the normal population have two copies of
SMN1 on the same chromosome, which makes it possible to be a carrier by having one chromosome with two copies and a second chromosome with zero copies.
This situation will lead to a false negative result, as the carrier status will not be correctly detected by a traditional genetic test
Nusinersen (marketed as Spinraza) is used to treat spinal muscular atrophy. It is an
antisense nucleotide that modifies the alternative splicing of the SMN2 gene. It is given
directly to the central nervous system using an intrathecal injection. Nusinersen
prolongs survival and improves motor function in infants with SMA. It was approved
for use in the US in 2016, and for use in the EU in 2017.
Onasemnogene abeparvovec (marketed as Zolgensma) is a gene therapy treatment
which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to
deliver the SMN1 transgene. The therapy was first approved in the US in May 2019 as
an intravenous formulation for children below 24 months of age. Approval in the
European Union, Japan and other countries followed, albeit often with different
Risdiplam (marketed as Evrysdi) is a medication taken by mouth in liquid form. It is
a pyridazine derivative that works by increasing the amount of functional survivor
motor neuron protein produced by the SMN2 gene through modifying its splicing
pattern. Risdiplam was first approved for medical use in the United States in
August 2020 and has since been approved in over 30 countries.
The respiratory system is the most common system to be affected and the complications are the leading cause of death in SMA
types 0/1 and 2. SMA type 3 can have similar respiratory problems, but it is more rare. Complications arise due to weakened
intercostal muscles because of the lack of stimulation from the nerve.. Therefore, breathing is more difficult and pose a risk of not
getting enough oxygen/shallow breathing and insufficient clearance of airway secretions. These issues more commonly occur while
asleep, when muscles are more relaxed. Swallowing muscles in the pharynx can be affected, leading to aspiration coupled with a
poor coughing mechanism increases the likelihood of infection/pneumonia. Mobilizing and clearing secretions involve manual
or mechanical chest physiotherapy with postural drainage, and manual or mechanical cough assistance device. To assist in
breathing, Non-invasive ventilation (BiPAP) is frequently used and tracheostomy may be sometimes performed in more severe
cases; both methods of ventilation prolong survival to a comparable degree, although tracheostomy prevents speech
The more severe the type of SMA, the more likely to have nutrition related health issues. Health issues can include
difficulty in feeding, jaw opening, chewing and swallowing. Individuals with such difficulties can be at increase risk
of over or undernutrition, failure to thrive and aspiration. Other nutritional issues, especially in individuals that are
non-ambulatory (more severe types of SMA), include food not passing through the stomach quickly enough, gastric
reflux, constipation, vomiting and bloating. Therein, it could be necessary in SMA type I and people with more severe
type II to have a feeding tube or gastrostomy.Additionally, metabolic abnormalities resulting from SMA impair β-
oxidation of fatty acids in muscles and can lead to organic academia and consequent muscle damage, especially when
fasting. It is suggested that people with SMA, especially those with more severe forms of the disease, reduce intake
of fat and avoid prolonged fasting (i.e., eat more frequently than healthy people) as well as choosing softer foods to
avoid aspiration. During an acute illness, especially in children, nutritional problems may first present or can
exacerbate an existing problem (example: aspiration) as well as cause other health issues such as electrolyte and
blood sugar disturbances
Skeletal problems associated with weak muscles in SMA include tight joints with limited range of movement, hip
dislocations, spinal deformity, osteopenia, an increase risk of fractures and pain. Weak muscles that normally
stabilize joints such as the vertebral column lead to development of kyphosis and/or scoliosis and joint
contracture. Spine fusion is sometimes performed in people with SMA I/II once they reach the age of 8–10 to
relieve the pressure of a deformed spine on the lungs. Furthermore, immobile individuals, posture and position on
mobility devices as well as range of motion exercises, and bone strengthening can be important to prevent
complications. People with SMA might also benefit greatly from various forms of physiotherapy, occupational
therapy and physical therapy.
Orthotic devices can be used to support the body and to aid walking. For example, orthotics such as AFOs (ankle
foot orthoses) are used to stabilise the foot and to aid gait, TLSOs (thoracic lumbar sacral orthoses) are used to
stabilise the torso. Assistive technologies may help in managing movement and daily activity and greatly increase
the quality of life.
MMA) is a rare motor neuron disease first described in 1959 in Japan. Its symptoms
usually appear about two years after adolescent growth spurt and is significantly more
common in males, with an average age of onset between 15 and 25 years. MMA is
reported most frequently in Asia but has a global distribution. It is typically marked by
insidious onset of muscle atrophy of an upper limb, which plateaus after two to five
years from which it neither improves nor worsens. There is no pain or sensory loss
associated with MMA. MMA is not believed to be hereditary
In terms of the signs and symptoms that are consistent for an individual who has
monomeric amyotrophy are the following (although this does not reflect a complete
Atrophy of hand and forearm
Sharp pains (from neck to hand)
The disability originates with impaired functioning of the anterior horn cells of the
lower cervical cord (lower neck), but the cause of the decline is not fully understood
and is still considered unknown. Researchers, including Hirayama, believe that
"forward displacement of the cervical dural sac and compressive flattening of the lower
cervical cord during neck flexion is the contributing factor. Studies consistently note a
loss of normal neck curvature (the cervical lordosis) and compression of the cervical
chord by the dural sac in forward flexion.
There is a debate about whether this condition represents a focal form of primary LMN
degeneration (i.e., a focal form of spinal muscular atrophy) or a local consequence of
chronic compression from a dural expansion in the cervical spine.
A familial link has been found in a minor percentage of cases, including parent-child
and sibling-sibling. Because of the unusual distribution of the disease, some researchers
speculate that there could be an ethnic link.
The condition presents almost exclusively in 15- to 25-year-old adults experiencing weakness in hand and arm. A patient
history and a neurological exam narrows down the possible diagnosis; this preliminary exam typically includes strength
and reflex tests. Cold paresis (increased weakness in cold weather) is reported by most patients (> 80%). Fasciculations are
reported as uncommon (< 20%) to common; larger tremors are more consistently cited. Males are far more likely to be
diagnosed with the condition.
The disease is rare and several cited cases deviate from the expected norm, making diagnosis more difficult. Proposed
Distal predominant muscle weakness and atrophy in forearm and hand
Involvement of the unilateral upper extremity almost always all the time
Onset between the ages of 10 to early 20s
Insidious onset with gradual progression for the first several years, followed by stabilization
No lower extremity involvement
No sensory disturbance and tendon reflex abnormalities
Exclusion of other diseases (e.g., motor neuron disease, multifocal motor neuropathy, brachial plexopathy, spinal cord tumors,
syringomyelia, cervical vertebral abnormalities, anterior interosseous, or deep ulnar neuropathy
At present there is no cure for MMA. The impact on the affected individual ranges from
minimal to significant depending on the extent of the weakness. Physical and
occupational therapies include muscle strengthening exercises and training in hand
coordination. Early use of a cervical collar is increasingly encouraged as therapeutic for
arresting further compression of the cervical spinal cord. Spinal surgery on patients
with more advanced symptoms has met with reported success, but is still regarded as