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Amyotrophic lateral sclerosis (ALS) is a rare motor neuron disease; which affects around 2 in 100,000 patients. The disease affects the whole body damaging the motor neurones in the muscoskeletal, central nervous system and respiratory system  .
ALS mainly affects the elderly population, with the average age of onset between 60 and 70 years, with a small number of patients developing ALS before the age of 45. The prognosis for patients after they have been diagnosed with ALS is between three to five years; however patients who develop ALS before the age of 45 have a better prognosis  .
The cause of ALS is unknown; researchers have found no link between lifestyle choices and ALS. However, around 10% of ALS cases are due to an inherited gene mutation. The gene has been identified, and encodes for copper-zinc dismutase enzyme (SOD-1). Experiments have been carried out in mice, and have found the complete knockdown or over-expression of SOD-1 does not cause ALS, however a gene mutation of SOD-1 causes ALS  .
Mutation of the enzyme causes the build up of toxic substances such as copper. It is the exposure of these toxic chemicals that can cause damage to living cells, as an experiment in transgenic rats showed copper chelators to improve survival  .
Sporadic ALS is the non-familial form of ALS; and differs from familial ALS as the average age of onset is 56, whereas with familial ALS it is 46. Furthermore, sporadic ALS has a greater prevalence in men, which suggests oestrogen may have a role in the development of sporadic ALS.
There is no single assessment criterion for ALS; therefore diagnosis encompasses looking at laboratory tests and clinical assessments. There are no specific biochemical markers for ALS, therefore healthcare professionals examine patients for neurodegeneration of the upper and lower motor neurones.
Signs and Symptoms
ALS is a disabling disease, where patients become dependent on their carer. ALS presents itself with damage to the upper and lower motor neurones, which causes a reduction in the number and size of the motor neurones. The clinical features of ALS relate to the degeneration of motor neurones, for example there is muscle weakness of limbs and difficulty swallowing. Patients may also feel fatigue and experience facial twitching. Fatigue occurs due to the death of the neurones, the surviving neurones compensate for the dead neurones and eventually cannot cope with the workload and so become exhausted.
As the disease progresses the patient feels more pain. ALS patients may also experience depression due to their condition; pain and depression often go under treated by physicians.
Sporadic onset may be asymmetric weakness and atrophy, or bulbar onset. The majority of cases present with asymmetric weakness, symptoms include difficulty carrying out fine movements involving the upper limbs, mainly the arms. Patients may have muscle wasting without showing any symptoms, and a large number of the patients experience muscle twitching and muscle shaking.
Other patients may present with bulbar onset which causes difficulty speaking and swallowing. Bulbar onset is also associated with weakened respiratory muscles hence patients with bulbar onset of symptoms have a poor prognosis  . As the disease progresses the patient experiences difficulty breathing due to muscle wastage of the respiratory muscles. The death of an ALS patient is likely due to respiratory failure.
A study has found that long term survival rates are linked to earlier onset of disease as there is a lower frequency of bulbar onset of symptoms. Furthermore, as the subjects are younger they are less likely to have any other diseases such as pulmonary disorders which would exacerbate the progression of the disease  .
Although the majority of the symptoms are associated with muscle damage, dementia occurs in a third of all ALS patients. Cognitive impairment is composed of damage to the memory for verbal and non verbal materials.
Although the exact cause of ALS is unknown it is likely to compose of a number of factors; extracellular accumulation of glutamate, mitochondrial dysfunction leading to reduced energy production and accumulation of neurofilaments  .
Glutamate levels are around three times higher in the cerebrospinal fluid of ALS patients compared to controls, elevated glutamate levels are seen in other motor neurone diseases such as Parkinson's disease. It is an excitatory neurotransmitter and can cause cell death. Glutamate is normally removed by transporters; however the number of transporters is greatly reduced in ALS patients. Furthermore, the SOD-1 mutation seen in familial ALS inactivates glutamate transporters which further contribute to disease progression. Elevated glutamate levels causes the generation of free radicals, the free radicals damage the neurofilaments resulting in their accumulation. Free radicals also damage glutamate transporters which further contribute to the increased glutamate levels. Post mortem studies have found significant oxidative damage to the proteins in the cortex and spinal cord. A study in mice found administration of antioxidants caused a delay in the onset of symptoms  .
Current Treatment and Critical Appraisal
A multi disciplinary team is required for the treatment of an ALS patient as they have a range of symptoms, which would be most effectively treated with professionals who are specialised in their respective fields. Healthcare professionals must deal with the symptoms appropriately, as early diagnosis and treatment can have a large impact on preventing disease progression.
Rilutek is the only drug that is licensed by NICE for the use in ALS  . The dose is 50mg twice daily, the drug works by activating the G protein cascade which inhibits the release of glutamate. It also acts as a NMDA receptor inhibitor, preventing glutamate from acting on its receptor  . Rilutek is most effective in the early stages of the disease, where disease progression is reduced. Rilutek increases the patient's time in the early stages of the disease by about 4 to 5 months. During the early stages of the disease patients are most functional, therefore would benefit from staying in this stage. On average Rilutek increases life expectancy by 6 months  . The cost of a pack of 56 tablets is £278.55  , which is not a large cost to the NHS as the incidence of the disease is relatively low, and there are great clinical benefits for the patients. As Rilutek is the only drug licensed for the use in ALS, it is clear more drugs need to be developed for this condition. Rilutek is an effective drug for ALS in that it increases life expectancy.
Symptomatic treatment is also very important for ALS patients to improve their quality of life. Muscle pain can occur due to lack of motility and spasticity, as well as physiotherapy, analgesics such as anti-inflammatory drugs may be used. The medication used for muscle spasticity includes carbamazepine and quinine sulphate.
Uncontrolled dribbling is commonly associated with ALS, and can have a large impact on the patient's social life. Drug treatment normally involves the use of tricyclic antidepressants as they are anti cholinergic drugs, which decrease salivary secretions.
Commonly associated with bulbar symptoms is the incontrollable symptom of laughter and crying. This is also treated with tricyclic antidepressants; a short lasting benzodiazepine may also be added.
Although symptomatic treatment is important to improve the quality of life of an ALS patient, there is a need for a drug that can reverse the disease. Further research is required to find the potential causes of the disease, as this would lead to more drug targets.
Non Pharmacological Treatment
Non pharmacological measures are an effective way to delay disease progression, improve quality of life and provide symptomatic relief.
Exercise such as stretching and muscle building are of great benefit to ALS patients. Range of motion (ROM) exercise is also known to improve the patient's outcome by building muscle strength  . However once the patient stops exercising the benefits are quickly diminished.
Muscle cramps can cause a lot of pain, as well as the pharmacological measures mentioned above; cramps can also be managed with drinking large volumes of water and a healthy balanced diet. Physiotherapy has also shown to be of benefit in patients suffering from muscle cramps.
The diet of an ALS patient should contain fruit and vegetable as the antioxidant vitamins may be of benefit in delaying the progression of the disease. Antioxidants have shown to be beneficial in mice, in preventing disease progression.
Dysphagia occurs in ALS patients as the disease progresses; therefore the nutritional status of the patient may be compromised. Patients are switched to enteral feeding; a naso-gastric tube would be placed through the nose to the stomach, which would provide the patient with the essential nutrients.
Respiratory problems can cause disease progression, and have a large impact on life expectancy. Manually aiding the patient to cough has shown to be beneficial with dyspnoea as it helps to clear the airways  . Mechanical ventilation will be used by most ALS patients due to the damage to the respiratory muscles. There are two types of ventilators; tracheostomy which involves a surgical procedure on the neck, opening a direct airway to the trachea, alternatively a non invasive ventilator is applied directly to the face.
Invasive ventilators have a severe impact on the quality of life of a patient, as the patient needs to be under nursing care the whole time. Furthermore a tracheostomy is very expensive, however survival is increased. In this case the patient's wishes should be respected, whilst the procedure would increase survival, the quality of life would be greatly impaired, and hence a number of patients may refuse the procedure.
Non invasive ventilators can be negative or positive pressure devices. These ventilators would be more desirable to the patient as they are still able to talk and eat, and is more socially acceptable than the tracheostomy.
Pharmaceutical companies do not find research and development in to ALS a commercially viable option, as there is a low prevalence of the disease, hence there is a small market for the drug. There are also difficulties with carrying out clinical trials on ALS patients as it would be unethical to deny patients from treatment such as Rilutek which is proven to work. As the end point for clinical trials in ALS would be survival, it would be hard to determine whether survival was altered by the intervention or Rilutek.
Future drug treatment will involve targeting the biochemical changes seen in ALS patients for example elevated glutamate levels, damage to neurones and oxidative stress.
Creatinine has shown to be beneficial in mice, and has shown to cause an increase in glutamate uptake, neuroprotection, reduce oxidative damage and increase survival. Furthermore muscle strength was also shown to be increased. Oral creatinine was tried in a small number of ALS patients, and was shown to cause a marginal increase in muscle strength. A large scale study will now be carried out to see if similar effects of creatinine are seen with a greater number of patients.
As discussed in the pathology, the number of free radicals in ALS patients are elevated, hence the use of antioxidants; free radical scavengers, could be of therapeutic use in ALS patients. However, despite antioxidants showing to decrease disease progression in animal models; no clinical benefits have been found in humans.
As accumulation of copper contributes to the damage caused in ALS, metal chelators are thought of as potential drug treatments. d-penicillamine was shown to be of benefit in mice with mutated SOD-1, however, this drug was of no benefit in humans.
Neuronal death is a major component of ALS, so supporting motor neurones should promote survival. A small scale human study found insulin growth factor (IGF-1) to reduce functional impairment, and improve quality of life. Due to these results a larger trial will be carried out in Europe to further explore the potential benefits of the nerve growth factor  .
Non-pharmacological measures for the future treatment of ALS may involve stem cell and gene therapy. Stem cell therapy involves introducing embryonic stem cells which have the potential to differentiate in to motor neurones and astrocytes (which are damaged in ALS). However large amounts of work would need to be carried out before stem cells could be used in practice, as research needs to be carried out to see where exactly the cells should be introduced and what cells to use.
Gene therapy is also an alternative approach for ALS treatment. This would involve the transplantation of the normal gene; expression from this gene would have to overcome the effects of the abnormal gene. Hence a large amount of genes would have to be given, which would cause problems with administration.
Anti sense therapy is also a potential therapeutic approach for ALS. As mutation of the gene SOD-1 has found to be a cause of ALS, silencing this gene should prevent ALS progression. The RNA structure of SOD-1 would have to be identified to determine the DNA counterpart; which would make up the anti-sense molecule. The anti-sense molecule will bind to the specific RNA responsible for the mutation in the cytoplasm, preventing the formation of proteins i.e. the mutated enzyme  . However, there are a number of issues with anti sense therapy for example; the correct sequence must be identified as other proteins may be switched off too. Drug delivery is also a problem as the anti-sense molecule is negatively charged and cellular uptake of the molecule is relatively low.
Neuro-prosthetic implant is a non pharmacological measure that is still under development which could greatly improve the lives of patients suffering from motor neurone diseases. The idea behind the device is, through patients thinking about a movement the wheelchair would carry out the movement through the joystick. It would work by electrodes connected to motor neurones in the brain. When the neurones are fired the signals are translated, to command the joystick of the wheelchair. There is still a number of issues associated with the implant such as compatibility and more complex movements  .
ALS is a very disabling disease, which affects the whole body. Further research needs to be carried out in to the causes of ALS as no definitive causes have been identified. Current treatment is effective in increasing survival; however further research in to finding a drug that could reduce disease progression or reverse damage to motor neurones would be of great clinical benefit.