Amyotrophic Lateral Sclerosis (ALS) – Motor Neuron Disease

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by upper and lower motor degeneration. Riluzole is the only FDA approved drug for ALS. Although it has adverse effects such as nausea, reduced liver function, asthenia or pneumonia, in many cases Riluzole is revealed as the most effective and safe therapy for ALS. Genetic and molecular factors seem to cause ALS. The drug deals with glutamate and NMDA receptors.

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder which leads to death. It is idiopathic and damages the human motor system. This fatal neurological disease results in paralysis of limbs, swallowing and breathing muscles. ALS has not a treatment. ALS was first described by Charcot 150 years ago. There is a slow development about the knowledge of ALS.

Epidemiology

The incidence of ALS is not known, but men (3. 0 per 100. 000 person-years) tend to have higher indicence of ALS than women (2. 4 per 100. 000 person years. In Europe, the incidence of ALS İS 2. 15 per 100. 000 person-years. The risk for developing ALS is 1. 400 for women and 1. 350 for men. Sporadic ALS onset is between 58-63 ages whereas it is between 47-52 for familial ALS. ALS is rare after the age of 80.

Clinical Manifestations

ALS is detectable in four regions of body which are the limb-onset ALS with upper motor neuron (UMN) and lower motor neuron (LMN), bulbar-onset ALS, pure UMN difficulty and pure LMN difficulty. 25% of patients show bulbar-onset ALS whereas 70% of patients show limb-onset ALS. UMN damage results in spastcity, weakness, brisk deep tendon reflexes whereas LMN leads to wasting, weakness and fasciculations. Bulbar UMN damage results in spastic dysartrthria which is a speech problem described as a slow, laboured and distorted speech. Bulbar LMN dysfunction leads to tongue wasting, weakness and fasciculations. Nasal speech is the result of flaccid speech which is another result of bulbar LMN problem. Patients having flaccid speech showpalatal weakness, hoarseness and weak cough. 50% of the progression of ALS results in death within 30 months. Only 20% of patients can leave for 5-10 years after diagnosis. The progression of ALS depends on its type so that limb variant ALS and predominantly LMN have better prognosis.

There are several symptoms of ALS. Fatigue and reduced exercise capacity are commonly seen in this patients. Weight loss and malnutrition are the results of dysphagia. Respiration problems are in common. Dyspnoea, orthopnoea, hypoventilation and early morning headaches are additional difficulties of ALS. ALS has negative effects on cognitive and executive functions. Judgement, impulsivity, decision making ability, daily tasks are severely affected by ALS. Pseudobulbar-based ALS patients show impaired verbal fluency.

Pathogenesis of ALS

There are multiple factors underlying ALS. The interaction of genetic and molecular factors seem to cause ALS. According to a research, maternal age is another underlying factor of ALS. Both low and old maternal age are associated with ALS. Childhood infections and lifetime long intensive physical exercise are other risk factors of ALS. Smoking, neurotoxins, glutamate induced excitotoxicity play a role in ALS pathogenesis.

Diagnosis

The El Escorial criteria for diagnosis of ALS focuses on the combination of UMN and LMN signs. However, due to early stage ALS patients benefit from therapeutic interventions and the poor sensitivity of this criteria, it was modified to be used in early diagnosis. The diagnosis of ALS is usually late as symptoms begin to appear for about 14 months after the onset. The low suspicion index, misunderstanding of finding results in a delay of diagnosis. In the diagnosis, neurophysiological investigations including electromyography is used. This is useful for the identification of LMN loss. Neuroimaging technics such as MRI enables experts to eliminate alternative pathological causes. PET scan shows extramotor changes in patients.

Pharmacotherapy

Riluzole is a neuroprotective, used for patients having moderate ALS impairment. Researches demonstrated that Riluzole extends the lifetime for about six months. Riluzole is an inhibitor of glutamate release. Symptomatic treatment has a survival effect in patients life. The treatment staff of ALS involves a physiotherapist, occupational therapist, speech therapist, respiratory physicians, gastroenterologists and social workers. There are 3 pharmagodynamic effect of Riluzole. It inhibits both the excitatory amino acids and NMDA mediated event release. In vitro, the drug modulates neurotoxins in central nervous system cell culture. In animal models, ischaemia and other neurodegenerative diseases seemed to be positively regulated by Riluzole.

Riluzole is the only anti-ALS drug commonly used in Japan and around the world. It is the only drug approved by FDA for ALS treatment. The trade name of Riluzole is Rilutek. This inhibits glutamate release and NMDA receptors and it opens potassium channels. Riluzole’s clinical manifestation was in the mid-1990s in the US for motor neuron disease treatment which includes ALS or Lou Gehric’s disease results in progressive cell death and damage of LMN in the spinalcord and brain stem and UMN in motor cortex.

Although the modest effect of Riluzole, it was shown that this drug is beneficial for symptomatic ALS treatment. In 2012, the clinical trial of Riluzole was examined for human spinal cord injury treatment in the US. Gabapentin and topiramate are anticonvulsants decrasing glutamatergic neurotransmisson, but it is not effective in clinical setting. Memantine is a NMDA receptor antagonist used in Europe and it passed the Phase 3 for Alzheimer’s disease.

The main cause of motor neuron degeneration in ALS remains unclear but one of the cause is believed to be excitotoxicity which is a neuronal death due to glutamate receptor overactivity due to dysregulation of glutamate neurrotranmission.

Mechanism Of Action

In the low concentration, Riluzole increases the ambient glutamate uptake by astrocytes and presynaptic glutamergic nerve terminals. It also decreases endogenous glutamate release from highly active synapses. As a result, extracellular glutamate level binding to different ionotrophic and metabotrophic receptors is limited. Persistent ionotrophic activation increases intracellular calcium that triggers part of intracellular signal pathways causin cell death by excitotoxicity. Besides, Riluzole can prevent persistent sodium which has a slow inactivity and enables long lasting firing of motoneurons. This effect of Riluzole prevents excessive amount of glutamate realese and increased neuronal death. A study carried in 2011, Riluzole 100 mg revealed to be safe and it prolong the syrvival for up to three months.

Cefriaxone increses the expresssion leve of glutamate transporter. It is a beta-lactam antibiotic. To prevent glutamate neurotoxicity in ALS, glutamate transporters needed to be modulated. Cefriaxone enhances the glutamate reuptake in astroglial cells so that the glutamate concentretion in extracellular space is decreased. Methylcobalamine is a vitamin B12 analogue, effective for peripheral neuropathy by increasinf myelination in Schwann cells and oligodendroglia. The high concentration of methylcobalamine has neuroprotective effect on cultured neurons against glutamate neurotoxicity.

Recently, cell transplantation is proposed as an alternative for neuronal dysfunction in neurodegenerative disease including ALS. In spinal cord injury, cell transplantation therapy demonstrated to be effective in motor impairment improvement.

Route of Administration and Adverse Effects

In ALS patients, 50 mg needed to be administered every 12 hours at least an hour befoore or 2 hours after food. Oral administration of Riluzole is the only FDA approved therapy for ALS. The optimal dose of Riluzole is 100 mg per day. Although it is effective in modest ALS symptoms, this drug results a damage in liver. The study of Gutierrez et al. (2016) demonstrated that the intrathecal Riluzole administration at a dose of up to 2. 4mg per day is safe and effective in spinal cord.

50 mg at a dose per day of Riluzole was demonstrated to have side effets such as myalgia, fever and increased function of liver. A study carried in 39 countries with 7916 ALS patients demonstrated that 100 mg at a dose per day of Riluzole has several side effects such as reduced lung function, nausea, asthenia, pneumonia and abdominal pain. Reduced lung funciton was the most common side effect of Riluzole (7.3%). In addition to this, the hepatic impact is the most important potential safety issue with Riluzole. For this reason, liver enzymes of ALS patients havin Riluzole treetment must be checked regularly (24). Nausea, vomitting, diarrhea, anorexia, dizziness and circumora paraesthesia are additional side effects of Riluzole.

Riluzole has its peak concentration in 1 to 1. 5 hours after oral administration. Its The elimination half life is 12 to 14 hours. The administration must be controlled in old patients and patients having an abnormal liver or renal function history.

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