Motor Neuron Diseases: Causes, Types, Symptoms, Signs, Treatment, Diagnosis

About Motor Neuron Disease or MNDs

The brain is divided into the cerebral cortex, cerebellum, and brain stem. The cerebral cortex and cerebellum are formed by several thousand nerve cells known as a neuron. Some of these nerve cells in the brain communicate with skeletal and smooth muscles. These nerve cells or neurons are known as upper motor neurons. Upper motor neurons communicate with each other in the brain as well as sends a signal to nerve cells (lower motor neurons) located in the spinal cord. The nerve cells in the spinal cord receiving signals for muscle activities are known as lower motor neurons. The signals generated by upper motor neurons in the brain are carried to the spinal cord by nerve fibers known as upper motor nerve fibers. The bundle of upper motor nerve fibers lies in the brain stem and spinal cord.

The incoming signals from the brain to muscles are interpreted and modified in the spinal cord by lower motor neurons. The modified signals are transmitted to peripheral skeletal muscles by motor nerve fibers known as lower motor nerve fibers. A myelin sheath protects lower motor nerve fiber. The signals transmitted by lower motor nerve fibers to muscles makes the muscle contract or relax. Several impulses are transmitted simultaneously to several muscles to coordinate contraction and relaxations of several muscles during bending joint, walking, jumping, jogging, and changing the body position.

Occasionally children or elderly people suffering from motor neuron disease complain of generalized weakness. Generalized weakness is often caused by several diseases resulting from malnourishment, vitamin deficiency, mineral deficiency, fluid deficiency, and severe depression. One of the rare causes of generalizing weakness is motor neuron disease (MND).

The following anatomical structures are involved in coordinated smooth and skeletal muscle activities-

  1. Upper Motor Neuron- Nerve cells or neurons located in the brain.
  2. Upper Motor Nerve Fibers- Nerve fibers that carry signals from the upper motor neuron (motor nerve cells in the brain) to lower motor neurons (motor nerve cells in the spinal cord).
  3. Lower Motor Neuron- Nerve cells or neuron that lies in the spinal cord
  4. Smaller Motor Nerve Fibers- Nerve fibers that carry signals from the lower motor neuron or spinal nerve cells to skeletal muscles. Motor neuron disease is also known as amyotrophic lateral sclerosis).

Causes of Motor Neuron Disease or MNDs

Causes of Motor Neuron Disease or MNDs

  1. Inherited- Genetic abnormalities cause the inherited disease that is passed down through family genetics. In cases where a motor neuron disease is inherited, it is usually caused by mutations in a single gene. These conditions are often inherited in one of several patterns:

    1. Autosomal dominant
    2. Autosomal recessive
    3. X-linked inheritance
  2. Sporadic or non-inherited Motor neuron diseases – The condition develops sporadic, and there is no family history of similar disease.

  3. Environmental,

  4. Toxic- medications and alcohol consumption

  5. Viral infection and

  6. Genetic factors

Types of Motor Neuron Diseases-

  1. Classical Motor Neuron Disease
  2. Upper Motor Neuron disease and
  3. Lower Motor Neuron disease.
  1. Classical Motor Neuron Disease-

    Classical Motor neuron disease affects both the upper and lower motor neurons. Early treatment is beneficial. Rapid muscle atrophy and stiffness are observed if not treated during an earlier stage of the disease. Prognosis is unfavorable and fatal in 5 to 10 years. The condition is known as Amyotrophic lateral sclerosis (ALS) when both upper and lower motor neurons are affected. ALS progresses faster If not treated during an earlier stage and often fatal. If symptoms caused by primary lateral sclerosis is ignored, then condition progressively affects lower motor neuron. Such a condition is known as Progressive muscular atrophy. Progressive muscular atrophy (PMA) begins as an upper motor neuron disease and progresses as a lower motor neuron disease.

  2. Upper Motor Neuron Disease (Primary Lateral Sclerosis or PLS)-

    Upper motor neuron disease is also known as primary motor neuron disease when disease affects upper motor neuron and upper motor fibers. Primary motor neuron diseases have an excellent prognosis when diseases are observed in upper motor neurons only. Such a condition is also known as primary lateral sclerosis (PLS). PLS progresses slowly and not fatal.

    1. Abnormal Upper Motor Neuron (nerve cells)- The upper motor neuron disease is caused by damage or degeneration of brain cells (upper motor neurons). The abnormal upper motor neuron is unable to create, interpret, and send signals to lower motor neurons in the spinal cord.
    2. Abnormal Upper Motor Nerve Fibers- Upper motor neuron disease is also caused by degeneration or anatomical damage of upper motor nerve fibers.
  3. Lower Motor Neuron Disease-

    Abnormal Lower Motor Neuron (nerve cells)- The lower motor neuron disease is caused by damage or degeneration of spinal nerve cells (lower motor neurons). The abnormal lower motor neuron is unable to interpret and modify the signals. The signals or impulses do not pass to the skeletal muscles. Lower motor neuron disease is also caused by degeneration or anatomical damage of lower motor nerve fibers.

Symptoms and Signs of Motor Neuron Disease-

The weakness during the initial phase of motor neuron diseases is observed in legs first. Gradually the weakness spreads to muscles of torso, arms, and hands. During the later phase or advanced stage of motor neuron diseases, individual feels difficulties in breathing, swallowing, speaking, and chewing. Sporadic upper motor neuron diseases or ALS is observed in a group of individuals between 40 and 60 years of age. Family members of these individuals are not at increased risk of developing the disease. Primary lateral sclerosis (PLS) affects upper motor neurons. The earlier treatment results in excellent prognosis in individuals suffering from classical upper motor neuron diseases. The disorder often affects the legs first, followed by the torso, arms and hands, and, finally, the muscles used for swallowing, speaking, and chewing.

  1. Generalized Weakness- The discontinuation of impulses coming to the muscles causes muscle inactivity that results in muscle wastage. The individual with motor neuron diseases is unable to perform coordinated skeletal muscle activities such as walking, breathing, speaking, and swallowing. Initially, a few groups of muscles are functioning normal, and few are flaccid. Such condition causes weakness and restrictions of movements. An individual suffering from such disease during the initial phase can perform such activities for a shorter distance. During this phase of motor neuron diseases, healthy functioning muscles compensate for non-functioning muscles. In such a case, an individual feels tired and weak during any attempt to move. Most prefer to stay in bed or sit on a chair.
  2. Restricted Activities- The outdoor activities become difficult, and most individual avoid going out of the house. Slowly individual tries to stay in bed and occasionally moves around the house. The legs and arms become stiff. Ambulation becomes clumsy, slow, and weak. Hand coordination becomes weak, and most are unable to feed themselves. Speech may become slowed and slurred.
  3. Weakness in Bulbar Muscles- The pharyngeal and skeletal muscles of the mouth are known as bulbar muscles. Weakness in bulbar muscles causes weakness in swallowing and speech.
  4. Shortness of Breath– The intercostal muscle weakness causes difficulties in breathing or results in a feeling of shortness of breath.
  5. Muscle Twitching And Fasciculation- The idle muscles become weak and shrinks in size. The inactive group of muscles start twitching and frequently fasciculate. Involuntary contraction of muscle such as fasciculation is observed in a muscle that lies under the skin.
  6. Muscle Wasting and Atrophy- The inactive muscles eventually result in muscle atrophy and stiffness.
  7. Spasticity– Spasticity follows muscle wasting and atrophy. The lack of signals from the upper motor neurons causes muscle stiffness (spasticity) and overactive reflexes.
  8. Inability to Ambulate Or Walk- During later stage of motor neuron diseases, individual suffering with this condition is unable to walk or control in activities. Most are bedridden in an abnormal joint position with atrophied and stiff muscles. It affects only the upper motor neurons, causing the movements in the arms, legs, and face to be slow and painful. The legs and arms become stiff, clumsy, movement becomes sluggish, and weak, making it difficult to walk or carry out tasks requiring excellent hand coordination. Speech may become slowed and slurred. Individuals may have difficulty balancing, increasing the risk of falls. Individuals affected with motor neuron diseases may also experience emotional changes and become easily startled.

Diagnosis of Motor Neuron Disease-

Following investigations are performed to diagnose the motor neuron disease.

  • Neuro examination
  • Electromyography
  • Nerve conduction study
  • Laboratory Test- Measure Creatine Kinase
  • Blood
  • Urine
  • CSF
  • MRI
  • Muscle or Nerve Biopsy.

Treatment of Motor Neuron Disease-

Early treatment of motor neuron diseases is necessary for a better prognosis. The prognosis is favorable if an individual is suffering from Primary Motor Neuron Disease or Primary Lateral Sclerosis ( PLS) that affects only upper motor neurons.

Most people who have ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms. However, about 10 percent of people with ALS survive for ten or more years. Amyotrophic lateral sclerosis or Classical Motor Neuron Disease affects upper and lower motor neurons.

Following treatments are advised for Motor Neuron Disease-

  1. Physical Therapy

  2. Rehabilitation

  3. Medications-

    1. Riluzole- The molecular abnormalities are causing motor neuron damage is not yet fully understood. Riluzole blocks sodium channel and decreases the release of glutamate within the neuron that, in most cases, restricts the progression of the disease. The drug cannot reverse the damage already done to motor neurons. The survival rate is increased by a few months in advanced cases.1

    2. Edaravone- Edaravone functions as an antioxidant. The drug slows down the intracellular damages and prevents disease progression in people suffering from upper and lower motor neuron diseases like ALS.2 The drug is administered intravenously and slows the progression of disease but cannot restore function.

    3. Nusinersen- FDA approved Nusinersen in 2016. Initial studies suggest if treated earlier with Nusinersen, then disease progression is restricted.3 The outcome of a published clinical trial yet does not suggests a complete reversal of the disease.

  4. Nutrition and a Balanced Diet-

    Nutritional and balance diet are essential to maintaining weight and strength in people affected with motor neuron diseases. People who cannot chew or swallow may require a feeding tube.

  5. Stem Cells Transplant-

    Beneficial effects observed following transplantation therapy in animal models of motor neuron disease.4 Stem cells are injected in cerebrospinal fluid. The initial animal lab study suggests stem cells may trigger slowing of the progression of the disease and reverse the cellular damage caused by motor neuron disease.5 Several early-stage clinical trials have been launched to assess the potential of stem cells for ALS treatment.

  6. Gene Therapy-6

    Gene therapy for motor neuron diseases involves the delivery of antisense oligonucleotides into the central nervous system (CNS). The treatment is effective against patients suffering mutations in SOD1 or C9orf72 genes. Viral vectors are used to stabilized molecular structures of the motor neuron in the brain and spinal cord. Vectors derived from adeno-associated virus (AAV), can efficiently target genes and have been tested in several pre-clinical settings with promising outcomes. Recently, the Food and Drug Administration (FDA) approved Zolgensma.

References:

  1. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND)

Miller RG1, Mitchell JD, Lyon M, Moore DH., Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001447.

  1. Edaravone: a new hope for deadly amyotrophic lateral sclerosis.

Bhandari R1, Kuhad A2, Kuhad A3., Drugs Today (Barc). 2018 Jun;54(6):349-360.

  1. New treatments in spinal muscular atrophy: an overview of currently available data.

Ramdas S1, Servais L1,2., Expert Opin Pharmacother. 2020 Feb;21(3):307-315.

  1. Stem cell transplantation for motor neuron disease: current approaches and future perspectives.

Gowing G1, Svendsen CN., Neurotherapeutics. 2011 Oct;8(4):591-606.

  1. Stem cell treatments for amyotrophic lateral sclerosis: a critical overview of early phase trials.

Goutman SA1,2, Savelieff MG1,2, Sakowski SA1,2, Feldman EL1,2., Expert Opin Investig Drugs. 2019 Jun;28(6):525-543.

  1. Gene Therapy for ALS-A Perspective.

M1, Ciotti C1, Cohen-Tannoudji M1, Biferi MG2., Int J Mol Sci. 2019 Sep 6;20(18). pii: E4388. doi: 10.3390/ijms20184388.

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