Motor neurone disease

Motor neurone disease (MND) refers to a group of neurodegenerative conditions that result in damage to the motor neurons in both the central and peripheral nervous systems. The most common form of MND is amyotrophic lateral sclerosis (ALS)

It is a rare disease with a mean onset at 50-60 years old. It has a male predominance (2:1). 5-10% of cases are inherited while the rest are sporadic.

🦴 Anatomy and physiology

Motor neurons are responsible for controlling voluntary (skeletal) muscles. We can split motor neurons into upper motor neurons (UMN) and lower motor neurons (LMN) as follows:

1. Upper motor neurons (UMNs) - originate from the cerebral cortex, and convey the signal to the LMNs in the brainstem (with the corticobulbar tract) or spinal cord (with the corticospinal tract).
1. Corticobulbar tract (CBT) is the tract that UMN's descend through, terminating in the brainstem, at the motor nuclei of cranial nerves.
2. Corticospinal tract (CST) is the tract that UMN's descend though, terminating in the ventral horn of the spinal cord.

Often, these 2 tracts are referred to as the pyramidal tracts.

2. Lower motor neurons (LMNs) - originate from the brainstem or the ventral horn of the spinal cord, and convey the signal to the muscles that they innervate, leading to muscle contraction.

Pathophysiology

ALS is mostly caused sporadically. However, 10% of patients have an autosomal dominant gene inherited (superoxide dismutase 1 [SOD1] or C9orf72). The disease leads to loss of motor neurons in the cortical, bulbar (pons and medulla) or ventral spinal cord regions.

The pathophysiology is unknown but it is theorised to be due to mitochondrial dysfunction. This dysfunction is believed to be due to misfolding of proteins that then aggregate and lead to dysfunction of the mitochondria. This then leads to oxidative stress, calcium-induced excitotoxicity (glutamate excitation leads to excessive activation of NMDA receptors which results in excessive calcium influx into the neurones which disrupts cellular homeostasis) and impaired atonal transport. Dysfunctional RNA processing leads to misfolding of proteins such as SOD1, TDP-43 and FUS which also disrupts cellular homeostasis. These factors lead to neuronal death and ultimately the clinical manifestations of MND. Activation of glial cells also leads to neuroinflammation which contributes to the disease process.

🔢 Classification

As we said, MND's are usually classified based on the motor neurons involved (UMN or LMN or mixed).

Other ways of classifying them include the site of onset (site of initial symptom) such as bulbar onset (head and neck symptoms), limb onset, or respiratory onset.

Primary MNDs include:

1. Amyotrophic lateral sclerosis (ALS) - the most common form and as a result, it is often synonymous with the term MND. We will discuss it in more depth specifically at the end of this page.
2. ALS with frontotemporal dementia - presents with signs indicative of ALS but also has a combination of symptoms that indicate fro to temporal dementia. This includes cognitive deficits in language, execute function, personality and behaviour.
3. Primary lateral sclerosis - this is an isolated UMN disorder as compared to the mixed presentation of ALS. It may go on to present with LMN signs, after which it is essentially the same as ALS.
4. Progressive muscular atrophy - this is an isolated LMN disorder but also can present with UMN signs later when it converts to ALS.
5. Progressive bulbar palsy - this is an isolated bulbar MND. However, it may progress to involve the limbs (to become ALS) once again.

😷 Presentation

The typical patient is a late middle-aged (e.g., 60) man. There is an insidious, progressive weakness of the muscles throughout the body, affecting the limbs, trunk, face and speech. The weakness is often first noticed in the upper limbs. There may be increased fatigue when exercising. They may complain of clumsiness, dropping things more often or tripping over. They can develop slurred speech (dysarthria).

Depending on whether the UMN's or LMN's have been damaged, we get the following:

💡 Eye and sphincter muscles are generally spared until late in the disease course. Sensory dysfunction is usually absent, and if present, one should consider an alternative diagnosis.

🔍 Investigations

⭐️ The diagnosis of MND is a clinical diagnosis.

For all MNDss, a thorough history and physical examination are central to the diagnostic process, followed by electrodiagnostic testing when required for additional evidence of occult lower motor neuron involvement.

Other investigations primarily aim to rule out treatable differential diagnoses. This may include:

• TFTs - to exclude thyrotoxicosis syndrome.
• Protein electrophoresis - to rule out paraproteinaemias
• MRI brain and spinal cord - to assess for brainstem lesions mimicking MND or cervical spondylopathy.
• EMG & nerve conduction studies - to look for a myasthenic syndrome, chronic inflammatory demyelinating polyneuropathy, or multifocal mononeuropathy.

🧰 Management

Let’s quickly discuss ALS in further detail:

AMYOTROPHIC LATERAL SCLEROSIS (ALS)

ALS, or Lou Gehrig disease, is an MND that involves a progressive loss of cortical (frontotemporal), bulbar (pons, medulla), and ventral cord motor neurons. It is an MND with both UMN and LMN signs. It is a progressive, and aggressive disease with a median survival of 3-5 years only. Stephen Hawking had ALS and lived until 76 years old - this is extraordinary and may be due to the level of medical attention which he received.

😷 Presentation

Early signs and symptoms:

• ⭐️ Asymmetric limb weakness - often beginning with weakness in the hands and feet.
• Bulbar symptoms - such as dysarthria or subtle vocal changes, and tongue atrophy.
• Bulbar palsy is caused by bilateral damage or injury of the nerve nuclei of cranial nerves IX, X, XI, and XII. Clinical features include dysphagia, drooling, anarthria, fasciculations of the tongue, and loss of the gag reflex.
• Fasciculations, painful cramps, and muscle stiffness
• Weight loss
• Split hand sign - a wasting pattern in which the muscles of the thenar eminence atrophy disproportionately to the hypothenar eminence. It is a useful bed side clinical sign that may point towards ALS.

Progressed signs and symptoms:

• Cognitive impairment & frontotemporal dementia - seen in 15% of ALS patients
• Pseudobulbar palsy (emotional lability) with pseudobulbar affect - for example: inappropriate, involuntary, and uncontrollable excesses of laughter or crying
• Paralysis - as muscle weakness in the limbs progresses
• Autonomic symptoms - such as constipation & bladder dysfunction may develop, but the aetiology behind this is unclear.
• Dysphagia - due to progressive bulbar palsy, manifests as coughing on solids, and later on liquids.
• Respiratory failure - due to paralysis of respiratory muscles.

🔍 Investigations

As mentioned above.

Consider:

• Physical examination
• EMG and nerve conduction studies
• Neuroimaging - to exclude other causes
• Creatine kinase - elevated
• Pulmonary function tests
• Spirometry - restrictive lung disease.
• DLCO - normal.

🧰 Management

• Riluzole
• Edavarone - a free radical scavenger that limits the damage to the neuronal membrane that occurs with free radicals and oxidative stress. Its antioxidant effect is neuroprotective and delays progression of the disease.
• Sodium phenylbutyrate-taurursodiol