Amyotrophic lateral sclerosis (ALS)


A fatal neurodegenerative disorder that affects lower and upper motor neurons

A disorder characterized by motor neuron degeneration in the motor cortex and spinal cord that leads to progressive muscle weakness.

This neurodegenerative process mainly affects the motor system, with loss of the upper motor neurons in the motor cortex and the lower motor neurons in the brain stem and spinal cord.

Characterized by selective degeneration of motor neurons.

Incidence of about two in 100,000.

The average age of onset is in the seventh decade.

The median survival from symptom onset is 2–5 years, with respiratory failure the predominant cause of death.
Typically leads to death from ventilatory failure within five years after onset.
In 10% of patients with ALS, the disease is hereditary and caused by a single gene mutation.
Genetic factors account for half of the variance in the risk of the disorder.

Up to 15% of patients have a family history of ALS or frontotemporal dementia.

Progressive neurodegenerative disorder of unknown cause and pathogenesis.

Amyotrophic lateral sclerosis is a disease in which motor neurons are selectively targeted for degeneration.

This disease causes neuronal loss and gliosis, which can include the subthalamic nucleus and other areas of the brain.

Missense mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in a subsets of patients with familial ALS.

TDP-43 and FUS protein aggregates have been implicated in some cases of the disease, and a mutation in chromosome 9 (C9orf72) is thought to be the most common known cause of sporadic ALS.

In populations of European origin variants in the gene including superoxide dismutase one (SOD1) account for 13-20% of familial ALS, with variants accounting for most of the remainder: C9orf72, TDP43, and FUS.

Amyotrophic lateral sclerosis is a disease in which motor neurons are selectively targeted for degeneration.

Missense mutations in the gene encoding the antioxidant enzyme Cu/Zn superoxide dismutase 1 (SOD1) were discovered in a subsets of patients with familial ALS.

Up to 2% of all cases of ALS results from mutations in the gene encoding super oxide dismutase 1 (SOD 1).

More than 180 different SOD 1 mutations have been identified in ALS.

Possibly caused by dysregulation of micro RNA and changes in ion channels resulting in cellular excitotoxicity.

There is no correlation between head trauma and ALS.

The initial symptom is often weakness of the extremities manifested by difficulty in writing, turning keys, raising the alarm overhead, or tripping.

About 80% of patients present with limb-onset disease.

Extremity weakness progresses gradually with impaired mobility and difficulty with activities of daily living.

Progressive dysphasia resulting inadequate calorie intake and subsequent weight loss.

ALS may change metabolism contributing to weight loss.

Many patients develop dysarthria, which impedes communication.

Patients may notice or may not notice muscle atrophy, stiffness, or fasciculations.

20% patients present with dysarthria and dysphasia, the bulbar-onset.

The small minority patients present with isolated respiratory symptoms at the onset.

Most patients develop respiratory failure and most die at 3-5 years after symptom onset as a result of pneumonia or hypoxia related to bulbar dysfunction and respiratory failure.

Progressive loss of motor neurons from the spinal cord, brainstem, and cerebral cortex, leads to paralysis and death within 2-5 years.

Relentlessly progressive, presently incurable, neurodegenerative disorder that causes muscle weakness, disability, and eventually death.

The hallmarks of ALS on examination is both upper motor neuron signs of spasticity, hypeereflecia and lower motor neuron signs of flaccidity, weakness, fasciculations, and diminished reflexes.

The distribution of weakness extends beyond the single nerve distribution.

Reflexes may be increased in the case of upper motor neuron involvement and decreased in the case of a lower motor neuron involvement.

A preserved reflects in an atrophied and weak limb is indicative of both upper and lower motor neuron involvement.

ALS is also known as Lou Gehrig’s disease.

Loss of lower motor neurons, which extend from the spinal cord to the muscles, leads to muscle weakness, wasting, cramps, and fasciculations.

The lower motor neuron features contribute to mortality more so than the abnormalities caused by the loss of upper motor neurons in the brain, which includes spasticity, clumsiness, brisk reflexes and functional limitations.

The degree of upper motor neuron and lower motor neuron involvement varies among patients.

A variety of factors may underlie the disease process-genetic, environmental, and occupational.

Affects motor neurons at 2 or more levels.

It affects lower motor neurons in the anterior horn of the spinal cord and in the brain stem.

It affects the corticospinal upper motor neurons in the precentral gyrus.

It may affect the prefrontal motor neurons that are involved in the processing of the upper and lower motor neurons.

Loss of lower motor neurons leads to progressive muscle weakness and atrophy.

The loss of corticospinal upper motor neurons may produce spasticity, abnormally active reflexes, and pathologic reflexes.

Extramotor systems are also involved and some patients develop neuronal loss in the frontal temporal cortex with approximately half of all patients experiencing cognitive and behavioral signs or symptoms.

About 60% of patients have cognitive impairment in 30% of the Haviar all impairment.

Cognitive impairment is characterized most often by executive dysfunction-impaired attention, working memory, organization, and planning, while typical behavior features include personality changes, obsessions, and disinhibition.

The disease is called primary lateral sclerosis (PLS), when only upper motor neurons are involved, and the natural history is measured in decades.

The process rarely is restricted to bulbar muscles, known as progressive bulbar palsy (PBP).

Usually bulbar palsy progresses to classic ALS.

A clinically diagnosed disorder.

Bulbar involvement associated with slurred speech, hoarseness, and choking when eating.

Patients with lower limb involvement may trip, and fall while walking.

Patients present initially with cramping, stiffness, and weakness of intrinsic muscles with upper limb involvement.

The hallmark of the disease is involvement of both upper and motor neurons.

Sensory functions are spared.

Nerve conduction studies and electromyography confirm the diagnosis of ALS, and to exclude peripheral conditions that resemble ALS.

The diagnosis of ALS is mainly based on history and physical examination.

Laboratory test results generally are normal.

Laboratory work up and imaging is obtained to exclude other potential etiologies, such as infections or radiculopathies.

Nerve conduction studies support the diagnosis by demonstrating intact sensory studies and motor conduction velocities in the presence of decreased muscle action potential amplitudes.

CSF examination usually is not necessary in establishing diagnosis.

Genetic testing may be performed to identify gene defects in some familial types of ALS.

Motor unit number estimation (MUNE), a nerve conduction study is helpful in that it can quantify the numbers of motor units innervating an individual muscle.

Up to 80% of motor neurons may be lost before first clinical symptoms appear.

Most common motor neuron disease.

Incidence 0.2 to 2.4 cases per 100,000 population.

Prevalence about five cases per 100,000 population.

About 30,000 people in the United States suffer with this disease and about 5600 new cases diagnosed each year.

Men affected more than women and whites more than nonwhites.

Onset usually in middle to late life.

More than 90% of cases are sporadic.

Median survival of three to five years.

Median survival of 32 months from the onset of symptoms and 19 months from the time of diagnosis.

Most patients die within 25 years of onset, although 10% live. More than 10 years.

5-year survival 5-30%.

Universally fatal.

Death is usually by respiratory failure.

More common in men than in women by a factor of 1.5, and the rate of disease progression may be more rapid in patients with an older age of onset, bulbar onset, and cognitive impairment.

Clinical diagnosis correct in more than 95% of cases.

Factors associated with a shorter survival include: older age at onset, female sex, onset with bulbar rather than limbic symptoms, and a short interval from onset of symptoms to diagnosis.

Approximately 10% of ALS is familial and caused by an inherited Mendelian autosomal dominant manner.

A G4C2 repeat expansion in chromosome 9 is the most common genetic known cause of ALS, accounting for 30-40% of familial ALS.

C9orf72 repeat expansion in genes encoding copper zinc superoxide dismutase (SOD1), transactive response DNA binding protein 43 (TDP-43), and fusion sarcoma account for more than 50% of the familial cases, and another 30 or so genes have been identified as possibly causing ALS, increasing the risk of developing ALS, or hastening disease progression.

TDP-43 protein accumulates in most ALS patients throughout the nervous system.

Most patients with ALS have cytoplasmic mislocalization and aggregation of the TAR DNA-binding proteins (TDP-43) in the affected regions of the CNS.
ALS neurodegeneration is accompanied by the release of drivers of  inflammation, that is cytokines with synthesis and release of type I interferons and other pro inflammatory cytokines.

TDP-43 triggers an inflammatory response consisting of activation of nuclear factor kappa beta and type I interferon signaling.

There is no specific diagnostic test.

Virtually all skeletal muscles eventually are involved.

Age and family history only established risk factors.

Immunotherapy has not been effective in patients with ALS.

Pathological hallmarks are the degeneration and loss of motor neurons with astrocytic gliosis.

Selective killing of upper motor neurons that send signals from the motor cortex and the lower motor neurons in the spinal cord that receive these signals and send them to the muscles, resulting in muscle weakness, paralysis and respiratory failure.

5-10% of cases are familial and 20% of these patients have a superoxide dismutase gene mutation (SOD1).

Familial cases are predominantly autosomal dominant.

SOD1 gene mutation produces a protein that impairs motor neuron function.

SOD1 scavenges superoxide radicals in cytoplasm and the mutation impairs this ability.

The mutant gene effect is variable from little or no loss to complete loss of its ability to scavenger.

Mutant SOD1 protein is expressed in all and cell structures but damages motor neurons alone.

Activation of mutant SOD1 in microglia increases the demise of motor neurons.


Riluzole (Rilutek) is the only medication that has shown efficacy in extending life in ALS.

Riluzole (Rilutek) is a glutamate pathway antagonist, that prolongs median tracheostomy-free survival by 2 to 3 months in patients younger than 75 years with ALS of less than 5 years’ duration.

Riluzole is the only drug approved for ALS and prolongs survival by three to six months.

Less rigorous studies have found that riluzole may extend survival up to 21 months.

Riluzole associated with nausea and fatigue.

Some commissioners may improve survival and include percutaneous gastrostomy nutritional support, treatment of respiratory insufficiency with noninvasive ventilationtechniques and use of botulinum toxin for refractory silorrhea.

Current management has not improved survival.

Radicava (edaravone) approved for the treatment of amyotrophic lateral sclerosis.

An intravenous infusion administered daily for 14 days at initiation of treatment, followed by a 14-day drug-free period.

After initiation, Radicava is administered daily for 10 days out of the 14-day cycle, followed by a 14-day rest.

Patients who took Radicava showed less decline on a clinical assessment of daily functioning at 24 weeks compared with participants who received the placebo.

Common adverse reactions include: contusion and gait disturbance, hives, swelling, shortness of breath, and allergic reactions to sodium bisulfite.

Tofersen an anti-sense oligonucleotide decreases CSFSOD1 concentrations when administered intrathecally over a period of 12 weeks.
Tofersen also reduced neurofilament light change in plasma over 28 weeks but did not improve clinical endpoints and was associated with adverse events.
Riluzole and edaravone modulate the course of ALS.

Sodium phenylbutyrate-taurursodiol results in slower functional decline than placebo over a period of 24 weeks (Paganoni).

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