Amyotrophic lateral sclerosis
Last updated date: 12-May-2023
Originally Written in English
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS) was first described as a pure motor neuron disease by Jean Martin Charcot in 1869, but it is today defined as a multisystem neurodegenerative disease with clinical, genetic, and neuropathological variation.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition that predominantly affects the motor system, but extra-motor symptoms are becoming more common. The increasing weakening and wasting of muscles is caused by the loss of upper and lower motor neurons in the motor cortex, brain stem nuclei, and the anterior horn of the spinal cord.
ALS frequently has a localized onset but thereafter spreads to numerous body parts, with loss of respiratory muscles function generally limiting survival to 2–5 years following disease onset. The family history of 10% of ALS patients indicates an autosomal dominant inheritance pattern. The remaining 90% have not afflicted family members and are classified as having sporadic ALS.
The causes of ALS appear to be diverse and are not fully understood. More than 20 genes have been linked to ALS. A genetic mutation is the most prevalent genetic cause, accounting for 30%–50% of familial ALS and 7% of sporadic ALS.
To this day, there is no cure or effective therapy for ALS, and the mainstay of treatment remains multidisciplinary care, which includes nutritional and respiratory support as well as symptom management. Different aspects of ALS are reviewed in this review, including epidemiology, aetiology, pathophysiology, clinical characteristics, differential diagnosis, investigations, therapy, and future prospects.
Epidemiology of Amyotrophic lateral sclerosis
90-95 % of cases of amyotrophic lateral sclerosis are sporadic, with the remaining being familial. The disease's prevalence in the United States is estimated to be 5.2 per 1000 persons. The global incidence is roughly 1.6 cases per 100,000 individuals per year, with comparable rates observed in the United States.
Male-to-female incidence rates ranging from 1.3 to 1.5 have been seen in cases of sporadic ALS. Increased incidence is also observed with increasing age, particularly beyond the age of 40. White ethnicity is correlated with a greater occurrence globally. Age and family history are the main proven risk factors for ALS; nevertheless, some researches shows that cigarette smoking may potentially be a risk factor.
Pathophysiology of Amyotrophic lateral sclerosis
The neuropathological hallmark of ALS is loss of the neuromuscular connections, axonal retraction, and eventual cell death of upper motor neurons and lower motor neurons, surrounded by astrogliosis and microgliosis, with ubiquitin-positive inclusions seen in surviving neurons.
TDP43 is the primary component of these inclusions in almost 95% of ALS patients. TDP43 is an RNA and DNA binding protein that participates in a variety of activities including transcription, splicing, microRNA maturation, RNA transport, and stress granule formation. TDP43 may shuttle between the nucleus and the cytoplasm, which is consistent with its nuclear and cytoplasmic activities, however its primary localization is nuclear. TDP43 mislocalization to the cytoplasm, resulting in nuclear depletion and cytoplasmic protein aggregation, is a characteristic of ALS.
Failure of proteostasis, excite-toxicity, neuro-inflammation, mitochondrial dysfunction and oxidative stress, oligodendrocyte dysfunction, cytoskeletal disturbances and axonal transport defects, disturbed RNA metabolism, nucleocytoplasmic transport deficits, and impaired DNA repair have all been implicated in the pathogenesis of ALS.
Many of the genes linked to ALS appear to be clustered in important pathways, including protein quality control and degradation, RNA metabolism, and cytoskeletal and axonal transport.
Amyotrophic lateral sclerosis causes
Despite the fact that several potential processes have been hypothesized, a specific, single etiology of sporadic amyotrophic lateral sclerosis is not yet approved. Among these processes are disrupted RNA processing, which leads to prion-like self-aggregation, superoxide dismutase type 1 SOD1 mutations, which leads to free radical toxicity, cascade inflammatory responses, and high glutamate concentrations.
The uncommon condition of familial ALS is caused by a variety of genetic pathways, the most common of which are repeat expansion of the C9ORF72 gene and different mutations of the SOD1 gene. SOD1 protein misfolds and clumps, causing cellular damage and, eventually, apoptosis.
Both genetic abnormalities are inherited in an autosomal dominant manner. Ultimately, rather than a single unifying cause, ALS is a clinical entity with a complex etiology that is the outcome of a slew of independent probable antecedent abnormalities
Risk factors for Amyotrophic lateral sclerosis
There are just a few genetic risk factors for ALS that have been found with the UNC13A is the most common genotype.
Age and male sex, in addition to genetic variables, enhance the chance of ALS. Several studies have revealed that smoking, body mass index, physical exercise, occupational and environmental exposures to metals, pesticides, brain injury, and viral infections are all risk factors for ALS. However, the causal association between these factors and ALS has yet to be demonstrated.
Amyotrophic lateral sclerosis symptoms
The confluence of upper and lower motor neuron signs and symptoms is the most distinguishing hallmark of amyotrophic lateral sclerosis. Lower motor neuron (LMN) findings include muscular atrophy and fasciculations, whereas upper motor neuron (UMN) findings include hyperreflexia and spasticity. There are several phenotypes that influence the pattern of the above-mentioned symptoms and their prognosis:
- Limb onset ALS: It is the most common type, affecting 70% of patients. Flail arm syndrome or brachial amyotrophic diplegia, which is characterized by LMN weakness and wasting, is a subtype of limb onset ALS.
It normally begins proximally and is often symmetric, then advances distally until upper extremity function is severely reduced. Limb onset ALS is also known as flail leg syndrome or pseudo-polyneuritic form, which is distinguished by LMN weakness and wasting in the lower limbs and has a distal omset. Patients advance at a slower rate to the involvement of other body segments and respiratory muscle dysfunction.
- Bulbar onset ALS: It affects 25% of patients and is distinguished by cranial nerve UMN and LMN involvement, which commonly manifests as speech difficulty and dysphagia, followed by limb involvement in later stages.
- Primary lateral sclerosis (PLS): It is an initially exclusive UMN disease . In the first four years of the illness, these individuals had slower progression, little weight loss, and LMN symptoms/signs. Most people will ultimately get them, which is known as upper motor neuron-dominant ALS. These people have a better prognosis than normal ALS patients but a poorer prognosis than PLS patients.
- ALS-plus syndrome: Patients with ALS-plus syndrome have additional symptoms/signs in addition to LMN and UMN illness, such as dementia (usually frontotemporal), extrapyramidal, autonomic dysfunction, ocular motility impairment, and/or sensory loss.
ALS normally progresses in a straight line, with no remissions or exacerbations. While the rate of progression varies from person to person, the pattern of progression is fairly consistent. The most common pattern in patients with unilateral limb onset includes the contralateral limb, then the other ipsilateral extremity (i.e., the leg if the initial weakness was in the arm), followed by the other contralateral extremity, before eventually affecting the bulbar muscles.
Diagnosis of Amyotrophic lateral sclerosis
The updated El Escorial criteria are a commonly accepted set of clinical criteria for the accurate diagnosis of Amyotrophic lateral sclerosis. The criteria include specific results that must be present as well as those that must be lacking. The presence of both upper and lower motor neuron degeneration, as well as the gradual spread of symptoms or signs, is required for the diagnosis.
Furthermore, no evidence (electrophysiological, pathological, or radiological) of other disease processes that may be producing the aforementioned signs and symptoms can exist. Lower motor neuron indicators include weakness, muscular atrophy, and fasciculation, whereas upper motor neuron indications include clonus and pathologic spread of reflexes.
The updated El Escorial criteria state that the diagnosis of ALS requires the presence of one of the following:
- Clinical, electrophysical, or neuropathologic evidence of lower motor neuron degeneration,
- Clinical, electrophysical, or neuropathologic evidence of upper motor neuron degeneration,
- Evidence of progressive spread of symptoms or signs within a region or to other regions,
Combined with the absence of:
- Electrophysiological or pathological evidence of other disease processes that might explain the patient’s motor neuron degeneration,
- Neuroimaging evidence of other diseases that might explain the observed clinical and electrophysiological signs.
While ALS has traditionally been diagnosed clinically, electrodiagnostic testing can help confirm the diagnosis if the clinical picture is uncertain. EMG is beneficial in identifying acute denervation (fibrillation and positive sharp waves), chronic denervation (long-duration, complex motor unit action potentials), and chronic reinnervation (large amplitude motor unit action potentials). Normal sensory action potentials will be shown in nerve conduction investigations.
The World Federation of Neurology has also established categories to help describe ALS. Although the language appears to indicate degrees of certainty, these categories really represent the level of clinical involvement shown during an examination. They are mentioned as follows:
Clinically definite ALS: UMN and LMN signs in at least 3 body segments.
Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs.
Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by EMG in at least two limbs.
Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs.
Clinically suspected ALS: Pure LMN syndrome with other causes of LMN disease adequately excluded.
Specific radiologic abnormalities are not included in the El Escorial or the World Federation of Neurology diagnostic models. As a result, while radiology's involvement in the assessment of ALS is mostly to rule out other probable etiologies of a patient's clinical picture, a few minor imaging abnormalities have been associated with the upper motor disease present in ALS.
ALS neuroimaging is entirely based on magnetic resonance imaging (MRI). According to research, persons with ALS exhibit iron buildup in the precentral gyrus. As a result, on susceptibility-weighted imaging, the reduced signal across the precentral gyrus, known as the "motor band sign," is seen. Reduced signal intensity within the motor cortex on conventional MRI has been linked to ALS and may be utilized to support the diagnosis.
Upper motor neuronal disease symptoms have also been identified using advanced MRI technologies such as spectroscopy and diffusion tensor imaging (DTI). MR spectroscopy can identify and measure chemical quantities in imaged tissues, specifically N-acetyl aspartate and choline. Several investigations have found that patients with ALS had lower absolute and relative levels of N-acetyl aspartate.
Once a diagnosis has been made, genetic testing is suggested, especially for people who have a suspected familial type. Genetic testing can be utilized as a screening tool as well as a prognosis tool for patients who have a family history of autosomal dominant illness. Patients with a family history of ambiguous inheritance may benefit from genetic testing to reveal low penetrance or when information about family relatives is inadequate.
Treatment of Amyotrophic lateral sclerosis
Unfortunately, symptomatic management is the primary treatment in patients with amyotrophic lateral sclerosis, and it is recommended that their care team be multidisciplinary, including caregivers from neurology, physical therapy, occupational therapy, respiratory therapy, dietary, social work, and nursing.
Patients with ALS frequently have persistent respiratory failure owing to diaphragmatic and intercostal muscular weakening. Because this weakness worsens over time, it is best to have an early and thorough conversation about respiratory management and future possibilities such as tracheostomy, chronic ventilatory support, and noninvasive positive pressure breathing (NIV).
When NIV is poorly tolerated or the patient remains hypoxic and/or hypercarbic despite NIV, invasive ventilation is explored. It is especially critical to provide accurate information concerning terminal stage ALS when dyspnea and nocturnal hypoventilation occur, or when vital capacity (VC) falls below 50% of anticipated values.
As thoughts of "choking to death" are widespread, patients should be made aware of palliative treatments for symptom management such as anxiolytics, opiates, and/or sedation. Patients frequently get symptomatic when their VC falls below 50%. There is a considerable danger of respiratory failure or rapid death when VS exceeds 25% to 30%. Hypoxia and hypercarbia are late results that should not be used to forecast the need for respiratory assistance by physicians.
Dysphagia is caused by a progressive weakening of the muscles of mastication and swallowing, which should be treated first with dietary changes. Because weight loss (especially during the first two years following diagnosis) is connected with a poorer prognosis, calorically rich diets and additional nutritional drinks should be prioritized. As the dysphagia develops, so do the chances of aspiration and weight loss.
Numerous studies have shown that enteral feeding by percutaneous gastrostomy is effective, and it should be explored in patients with poor oral intake.
Mexiletine, which was well-tolerated and demonstrated good symptomatic in a small sample study, can be used to treat frequent and painful muscle spasms. Other options include levetiracetam and, to a lesser extent, gabapentin, baclofen, and tizanidine.
Botulinum toxin injections into spastic muscles can be helpful when oral medication is ineffective or not tolerated. Patients should be given assistive devices (canes, orthoses, crutches, and eventually wheelchairs) as their weakness and functional decline progresses, as well as removable headrests in those with neck weakness, specialized utensils and holders, and eventually a pressure-relieving mattress with frequent repositioning to prevent pressure ulcers.
Riluzole is the only drug that has proven improved overall survival (74 % vs. 58 %placebo at 12 months) and survival without tracheostomy (57 % vs. 50% at 18 months) in two multicenter randomized trials. it's recommended using it in patients with definite or probable ALS by El Escorial criteria in whom other causes of progressive muscle atrophy have been ruled out, symptoms have been present less than 5 years, VC >60 % of predicted, and who do not have a tracheostomy.
Edaravone is a free radical scavenger that has been shown to benefit a subset of individuals with probable or definite ALS in the early stages (less than two years of symptoms, independent living, VC >80%, and scores of 2 or higher on all items of the ALSFRS-R). At a 24-week follow-up, one research found that patients had a 33 % slower functional deterioration.
Edaravone has the disadvantages of being extremely costly, costing roughly $146,000 per year, and is given in 60 mg daily infusions for 14 days followed by 14 days off for the first cycle, and then 60 mg/day for 10 days followed by 14 days off for the following cycles. Edaravone should be taken with caution in asthma patients since it can induce severe asthmatic symptoms in up to 5% of them.
Pain is a typical symptom of ALS patients, and it may be caused by a variety of factors, including muscular cramps, stiffness, and impaired movement. Spasticity, as previously stated, requires special treatment. Pain can be reduced with the use of assistive equipment such as modified mattresses, pillows, and wheelchairs. Many patients eventually require nonopioid analgesics and anti-inflammatory medicines, and when these fail, opioids become the therapy of choice.
End-of-life care and advanced directives should be considered as soon as possible after a diagnosis. The insertion of a tracheostomy and the use of artificial ventilation are two of the most crucial issues to discuss. Invasive ventilation is used by only a small percentage of patients with ALS in the United States (less than 10%). This is due to increased caregiver load and considerable related expenses.
Hospice care can give numerous resources that aren't available or as accessible at home, increasing the chances of a peaceful death. Anxiety and dyspnea are two typical problems that can be addressed with morphine, as well as lorazepam or diazepam.
Prognosis of Amyotrophic lateral sclerosis
The median survival is of 3 to 5 years; however, around 30% of individuals are surviving after five years of diagnosis and 10% to 20% after ten years. Increased weight at diagnosis, younger age at onset, higher ALS functional rating scale score, and limb rather than bulbar symptoms are all related with improved survival.
Complications of Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis is associated with a number of complications, including respiratory decline with eventual need for ventilatory support, dysphagia, dysarthria, malnutrition, spasms, spasticity, fatigue, functional decline due to muscular weakness, sialorrhea, thick mucus secretions, and pseudobulbar affect.
Furthermore, some consequences may emerge as a result of the less-common drugs used to address the disease's symptoms. Mexiletine's adverse effects include gastrointestinal upset and arrhythmias, Riluzole's side effects include transaminitis and asthenia, while edaravone's side effects include gait disruption and headache.
Amyotrophic lateral sclerosis (ALS), originally known as Lou Gehrig disease, is a neurodegenerative disorder characterised by malfunctioning of the upper and lower motor neurons. The condition most usually presents between the ages of fifty and seventy, and it frequently begins with asymmetric weakness in the hands or feet.
However, the first presentation is very diverse, with some individuals exhibiting atypical/non-specific symptoms such as mild voice alterations. Most patients eventually acquire one or both of the life-threatening symptoms as the illness progresses: respiratory impairment and dysphagia.
Currently, the two medications licensed for the treatment of ALS are riluzole and edaravone. Nursing care, physiotherapy, and, eventually, assisted breathing and enteral nutrition are all part of multidisciplinary treatment. The majority of patients will die within 3–5 years, with around 30% having a possibility of living longer.