What is Motor Neuron Disease?
Motor neuron disease (MND) is a progressive condition that affects the nerves in the brain and spinal cord, causing them to become weak over time. Some of these nerves are called lower motor neurons, which travel from the brainstem and spinal cord to our muscles, while others are called upper motor neurons, which send signals from certain parts of your brain to the brainstem and spinal cord.
Research indicates that while MND primarily affects the nerve cells responsible for muscle movement, it can also involve other parts of our nervous system responsible for physical coordination, automatic bodily functions, and movement control. There are four main types of motor neuron disease, and the difference between them lies in where they start and how serious the impact on the nerves is. These include Amyotrophic lateral sclerosis, progressive bulbar palsy, progressive muscular atrophy, and primary lateral sclerosis.
Different systems classify this disease based on where it starts (for example spinal or throat), how closely it follows the certain criteria known as the El-Escorial and Airlie house, and whether it runs in families or occurs randomly. It’s found that MND usually affects people in their middle age, particularly between 58-63 for sporadic cases and 40-60 for familial cases of one type called Amyotrophic lateral sclerosis.
There has been an ongoing discussion and moral debate about the appropriate policies involving euthanasia and doctor-assisted suicide for patients suffering from diseases like MND. This discussion has been brought into the public sphere owing to the push from families of patients and their advocates.
What Causes Motor Neuron Disease?
Research has identified a potential genetic link to familial ALS, a form of Amyotrophic Lateral Sclerosis that runs in families. Four genes – C9ORF72, TARDBP, SOD1, and FUS – have been linked to about 70 percent of these cases. Over 25 genes and locations on the genome have been connected to an increased risk of developing ALS. Of these, C9ORF72, a specific region on Chromosome 9, has been connected to 40 percent of familial (family-related) and 10 percent of sporadic (random) cases of Motor Neuron Disease (MND). This gene has a specific mutation, which involves repetitive sequences of DNA, and it has been found in people with a subtype of dementia, leading to the theory that these conditions could be part of a range of related neurological disorders.
Typically, the C9ORF72 gene has fewer than 30 repetitions in healthy individuals. However, in patients with ALS linked to C9, these repetitions expand to hundreds or thousands. This increase can trigger ALS through various processes such as accumulation of a protein called TDP-43 and the creation of harmful RNA and proteins.
The genes TARDBP, SOD1, and FUS encode for specific proteins involved in the disease. TAR DNA-binding protein 43 is produced by the TARDBP gene, the SOD-1 gene informs cells how to make superoxide dismutase, and the FUS gene codes for an RNA-binding protein called ‘Fused in sarcoma’.
Research suggests that the development of ALS might not solely be about genetics. It has pointed to a complex interaction between genetic mutations (occuring in “at-risk” variants) and environmental factors, contributing to the pattern of the disease.
Dysregulation, or the disordered regulation, of micro RNA and changes in ion channels that make cells prone to excitotoxicity (damage from overactive neurotransmitters) are also thought to contribute to MND.
Familial ALS usually shows a penetrance of less than 50 percent, meaning that less than half of those with a mutated gene will show symptoms. It’s also characterized by genetic pleiotropy, where one gene can affect multiple traits. In contrast, sporadic forms are linked to more complex inheritance involving multiple genes.
Various environmental and lifestyle factors have also been associated with the development of ALS, including cyanotoxins and physical prowess. An increase in cases among athletes, particularly those exposed to repetitive head trauma, was suggested but later discarded due to lack of evidence. However, cigarette smoking and a history of military service have consistently been linked to a heightened risk of developing ALS.
Risk Factors and Frequency for Motor Neuron Disease
Motor neuron disease is a condition that occurs in approximately 2 to 3 out of every 100,000 people. However, in South and East Asian communities, the disease known as ALS occurs less frequently, with less than 1 case per 100,000 people reported. It’s been found that the risk of getting this disease can vary depending on a person’s ancestry. People belonging to racially mixed communities tend to live longer after diagnosis compared to those in White or Black communities. Furthermore, Europeans with ALS typically survive for 2 years after diagnosis, while Asians can live up to 4 years.
About 10 to 15 percent of people with ALS inherited the disease. The odds of a random person getting ALS during their lifetime is 1 in 400. Women are more likely to develop a form of ALS that starts in the throat area (bulbar onset ALS), while men are more likely to have the type that starts in the back (spinal onset ALS).
- Motor neuron disease affects 2 to 3 out of every 100,000 people.
- ALS is less common in South and East Asian communities, with less than 1 case per 100,000 people.
- In ancestral terms, racially mixed communities tend to have longer survival rates after the diagnosis of ALS.
- ALS typically has a 2-year survival rate for Europeans, extending up to 4 years for Asians.
- About 10 to 15 percent of people with ALS inherited the disease.
- In general, the odds of a random person getting ALS during their lifetime is 1 in 400.
- Women commonly have the type of ALS that starts in the throat area, while men typically have the type that starts in the back.
A rarer motor neuron disease is Progressive Muscular Atrophy (PMA), responsible for about 2.5 to 11 percent of motor neuron disease cases. It occurs in around 0.02 out of every 100,000 people and is mostly seen in males. The ratio of males to females with PMA ranges from 3 to 7.5 to 1. Typically, people are diagnosed with this disease around the age of 68, which is older than the common age of onset for ALS patients.
- Progressive Muscular Atrophy (PMA) is a rarer type of motor neuron disease, responsible for 2.5 to 11 percent of such cases.
- PMA strikes 0.02 out of every 100,000 people.
- It is predominantly found in males, with a male to female ratio of 3 to 7.5 to 1.
- The usual age of diagnosis is around 68, higher than the average age of diagnosis for ALS patients.
Signs and Symptoms of Motor Neuron Disease
MND, or Motor Neuron Disease, is diagnosed mainly through careful clinical examination. This starts by checking for certain patterns of muscle weakness, such as whether it’s more present in one side than the other, whether it’s upper or lower limb dominant, closer to the body or further away, and whether there are bulbar symptoms, like difficulty swallowing or speaking.
With Amyotrophic lateral sclerosis (ALS), one of the forms of MND, around 60-80% of patients first display symptoms in their limbs. Another 20-33% begin with bulbar symptoms such as slurred speech and difficulty swallowing. A small group initially show signs of respiratory muscle weakness. Most patients initially show signs related to overactive upper motor neurons, like reflexes that are too strong and stiffness, with signs related to underactive lower motor neurons, like muscle twitching and wasting, becoming more common as the disease progresses.
Common early symptoms include having trouble with actions that involve the distal muscles, like those needed for turning keys or doorknobs, or picking up objects. There may also be problems with balance and walking, and frequent falls. Patients may lose weight due to trouble swallowing, which can interfere with eating. They may have difficulty speaking, and breathing may become increasingly difficult. This can lead to less oxygen, resulting in confusion, and excessive carbon dioxide, leading to headaches. Additionally, some patients may experience cognitive impairment, showing difficulty with attention, working memory, organization, and planning. Changes in behavior, like apathy, mood shifts, disinhibition, and obsessive behavior are also possible.
Similarly, Progressive muscular atrophy (PMA) presents with worsening lower motor neuron signs, like weak and flaccid muscles, muscle atrophy, and fewer or no reflexes. Patients show a pattern of asymmetric weakness and atrophy in the distant limbs initially. Over time, the proximal muscle weakness pattern becomes visible in around 20% of the patients.
During a physical examination, doctors look for various signs in the upper and lower motor neurons. Upper motor neuron signs could include overly strong reflexes, stiff weakness, an exaggerated jaw jerk, or quick, repeated muscle contractions. Lower motor neuron signs could include weak reflexes or no reflexes, sluggish weakness, wasting, and fasciculations (muscle twitching).
- Upper motor neuron signs: hyperreflexia, spastic weakness, exaggerated jaw jerk, clonus
- Lower motor neuron signs: Areflexia or hyporeflexia, flaccid weakness, wasting, fasciculations
Doctors also look for signs in the so-called bulbar muscles, which control swallowing, speech, and other functions in the neck and face. This could manifest as speech and breathing difficulties. A patient may also exhibit an exaggerated emotional response to the stimuli. Further, ALS also involves identifying specific patterns of limb weakness.
- Examples of Physical signs in ALS:
- Fasciculations (muscle twitching), especially if generalized
- The “split hand” sign, where the side of the hand and certain muscles in the hand are weakened, while others are spared
- Head drop due to neck muscle weakness
- Increased response to emotional stimuli, typically crying
Testing for Motor Neuron Disease
To assess a person’s health, doctors often request specific tests. Some initial tests that your doctor might recommend include a full blood count, markers of inflammation such as C-reactive protein and erythrocyte sedimentation rate, and a full biochemical test (which may include thyroid function tests, a measure of calcium levels, and others).
Additionally, your doctor may also check your creatine kinase—a protein that provides energy to your muscles levels, immunoglobulins—which are antibodies that fight against diseases, and serum electrophoresis—a test that separates proteins in the blood for further study. If your creatine kinase levels total more than 1000iu/l, this is generally not typical in patients with Motor Neuron Disease (MND).
Beyond these tests, your doctor may recommend additional diagnostic procedures like electromyography—which assesses the health of your muscles and the nerve cells that control them, nerve conduction studies—which measure the speed of signal transmission in your nerves, and an MRI of your brain and spine to detect any abnormalities.
Nerve conduction studies help your doctor understand more about any nerve damage you have, and whether it might be connected to problems with the protective covering of your nerves (demyelination), or blockages in nerve signal pathways. If needed, certain tests like vitamin B12, folate, HIV, Lyme’s disease test and a lumbar puncture (spinal tap) can help rule out other diseases similar to MND.
The diagnosis of a specific MND condition, known as Amyotrophic lateral sclerosis (ALS), is rooted in recognizing specific patterns of weakness, ruling out other causes of the symptoms, and monitoring any progression of the disease. The progression of the disease could be noted from one part of the body to another through neurological or electrophysiological tests. Different diagnostic criteria, including the El Escorial, Airlie house, Awaji, and ALS diagnostic index, may be used in this process. These criteria require evidence of damage to both upper and lower motor neurons—cells that transmit messages from your brain to your muscles, and the progression of the disease.
Different strategies classify the level of certainty in an ALS diagnosis, ranging from suspected to definitive. Some strategies consider additional factors like electrophysical parameters or the use of transcranial magnetic stimulation (TMS)—a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain.
Additionally, researchers have discovered that certain biomarkers—substances that can indicate the presence of a disease, such as specific proteins in cerebrospinal fluid (the fluid surrounding your brain and spinal cord), can help differentiate ALS from similar conditions. However, techniques like F-fluorodeoxyglucose positron emission tomography (FDG PET)—an imaging technique that measures body functions like blood flow and glucose metabolism, haven’t been found to be clinically helpful in establishing a definite diagnosis of MND.
Treatment Options for Motor Neuron Disease
Riluzole, a specific type of medication, can help slow down the progression of conditions like ALS by blocking certain chemicals in the brain that can harm nerve cells. Studies have shown that this medication doesn’t improve muscle strength, but it can extend a patient’s life by about three months. However, it’s worth noting that this medication can cause side effects like nausea and liver problems.
Another medication called Edaravone may slow down the progression of early-onset ALS. Edaravone works mainly by acting as an antioxidant, which helps to protect the body’s cells from damage.
Patients with ALS also experience several symptoms that require targeted treatment. For example, symptom called spasticity, which is a feeling of stiffness and involuntary muscle spasms, is often treated with medications like gabapentin, baclofen, tizanidine, benzodiazepines, and levetiracetam.
An additional symptom is sialorrhea, which is the inability to swallow saliva, often resulting from muscle weakness. This condition can be managed with medications such as atropine and amitriptyline, and even some specialized procedures like salivary gland irradiation.
Patients with ALS frequently experience pain, which is often treated with anti-inflammatory drugs, opioids, and occasionally cannabinoids. Other symptoms such as muscle cramps and dysphagia (difficulty in swallowing) are generally managed with medication and lifestyle changes such as dietary adjustments.
Around 30 percent of ALS patients develop dysarthria, a condition that impairs speech, and this percentage can rise to 80 percent over time. This symptom can be managed through a combination of speech therapy and tailored computer software.
Other complications associated with ALS include respiratory symptoms due to weakened respiratory muscles, and muscle fatigue. These symptoms can be managed through the use of devices to assist with breathing and medications. As there isn’t a specific drug found to treat cognitive symptoms in ALS, managing the condition often involves a combination of medication and therapy.
End-stage care for patients with ALS also involves palliative services that focus on providing relief from the symptoms and stress of the illness. The goal is to improve quality of life for both the patient and the family. These services often include symptom control, anticipatory planning, and bereavement support, among others.
Lastly, advancements in medicine have resulted in potential future therapies for conditions like ALS. For example, trials are underway to examine the use of stem cell therapy, in which new cells are introduced to the body to try and replace or repair the damaged nerve cells.
What else can Motor Neuron Disease be?
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, can often be confused with another ailment called degenerative spondylotic myeloradiculopathy. This disorder affects the neck and/or lower back and can cause sharp pains. As the disease progresses, the symptoms often worsen before eventually leveling off. To distinguish between these two diseases, doctors may use imaging tools, like X-rays or MRIs. It’s critical to note that someone can have ALS and a degenerative illness at the same time.
When a patient shows certain symptoms – like equal weakness on both sides of the body, sensory loss, excessive weakness in the absence of muscle wasting, and unbalanced involvement of thigh muscles – doctors might want to look into alternative diagnoses.
In cases where the patient exhibits a sudden onset of lower motor neuron syndrome – a condition characterized by muscle weakness and loss of reflexes – the doctor must consider a range of potential causes including immune, toxic, metabolic, and infectious diseases. Some of the main diseases to rule out are motor neuron disease, multifocal motor neuropathy, and monomelic amyotrophy.
There are several diseases that can mimic motor neuron disease. These fall under several categories:
- Genetic disorders such as spinal muscular atrophy, Kennedy’s disease, and adrenoleukodystrophy.
- Toxic or metabolic disorders such as radiation myelopathy and lead poisoning.
- Infectious diseases like post-polio syndrome and Lyme disease.
- Immunological or inflammatory disorders such as myasthenia gravis and Inclusion body myositis.
- Structural diseases like spondylotic myelopathy and intrinsic or extrinsic cord tumors.
- Various other conditions such as cramp fasciculation syndromes and paraneoplastic neuromuscular disease.
There are also some conditions that mimic lower motor neuron syndromes in particular. These include:
- Brachial neuritis, also known as Parsonage-Turner syndrome
- Hirayama’s disease
- Kennedy’s syndrome
- Inclusion body myositis
In addition, there are disorders that present upper motor neuron signs, these include:
- Hereditary spastic paraparesis
- Primary progressive multiple sclerosis
- Metabolic myelopathies
- X linked adrenoleukodystrophy
What to expect with Motor Neuron Disease
Negative factors that can impact the prognosis of a disease include the disease’s onset in the areas responsible for swallowing and speech (bulbar) or breathing (respiratory), loss of executive abilities like problem-solving and multitasking, a type of dementia that affects language and behavior (frontotemporal dementia), and weight loss. Moreover, a decrease in respiratory function or forced vital capacity – the amount of air that one can forcefully exhale after maximum inhalation – or sniff nasal inspiratory pressure, also signals a poor prognosis.
Common symptoms like speech and swallowing difficulties, weight loss, reduced ability to breathe, being an older individual, lower overall functioning as measured by the amyotrophic lateral sclerosis functional rating scale, and a shorter interval between the onset of first symptoms and diagnosis can serve as indicators of a poor prognosis.
The King’s criteria and Milano-Torino system use information about the number of body parts affected and the presence of respiratory/nutritional failure. They record changes in areas like speech and swallowing (bulbar), fine motor skills, gross motor skills, and respiratory function. The King’s system is known to indicate changes early on in the disease, while the Milano-Torino system is more sensitive to detect changes later in the disease’s course.
However, these systems have been criticized for not considering cognitive and emotional functioning. Other scales like the Edinburgh cognitive and behavioral functional (ALS) stream (ECAS), focus on such aspects. This is crucial as the presence of executive impairments (disruptions in a person’s ability to plan, organize and complete tasks) can be associated with a more rapidly worsening disease course and impact the additional responsibilities caregivers might have to undertake.
Possible Complications When Diagnosed with Motor Neuron Disease
Most people with ALS, also known as Lou Gehrig’s disease, typically pass away from respiratory failure, usually within three years from when they first begin to show symptoms. This outcome often results from a steady weakening and wasting away of the muscles used in moving the limbs and breathing.
Eating difficulties can also significantly impact a patient’s well-being. Severe cases of difficulty in swallowing (known as ‘dysphagia’) can cause weight loss, choking hazards, and risk of food or liquid entering the airways (‘aspiration’). Even activities as basic as eating a meal can become laborious and protracted, and coughing can occur when trying to swallow.
The disease can also affect a patient’s lifestyle, making every day activities challenging and movement difficult. Prolonged physical immobility may also lead to other problems.
Common difficulties experienced by patients:
- Performing day-to-day activities
- Walking difficulties
- Superficial skin infections
- Pressure sores or ‘decubitus ulcers’
- Blood clots in the deep veins of the body, known as ‘deep vein thrombosis’
