Table Of Contents
Motor Neuron Disease (MND)
Motor Neuron Diseases (MNDs) are neurodegenerative diseases characterised by progressive selective loss of upper motor neurons (motor cortex and cranial nerve nuclei) and lower motor neurons (anterior horn cells). The diseases are purely motor with sensation remaining intact. Bladder and bowel control and extraocular muscles are conserved. This helps differentiate MND from multiple sclerosis, myasthenia gravis and polyneuropathies. It has an insidious and unrelenting course. Diagnosis is clinical. Co-existing upper motor neuron and lower motor neuron signs can help to make the diagnosis.
The average age of onset is 65 years, with 10% of cases presenting before 45 years of age. Affects males more than females.
As mentioned, it may affect either or both of:
- Upper motor neurons – originating from the primary motor cortex of the cerebrum and forming the motor spinal tracts
- Lower motor neurons – originate from cranial nerve motor nuclei in the brainstem and the anterior horn of the spinal cord
Amyotrophic Lateral Sclerosis (ALS), AKA Lou Gehrig’s disease, is a rare disorder characterised by progressive deterioration of both upper motor neurons (of the corticospinal tract) and lower motor neurons.
Definition of terms
| Term | Definition | Causes |
|---|---|---|
| Bulbar palsy | LMN lesion of the nuclei of CN IX – XII in the medulla. Presents with flaccid fasciculating tongue, normal or absent jaw jerk, quiet/hoarse/nasal speech. | Motor neuron disease, Guillain-Barre, polio, myasthenia gravis, syringobulbia, brainstem tumours, central pontine myelinosis |
| Pseudobulbar palsy | UMN lesion of CN IX – XII due to bilateral lesions above the mid-pons, e.g. corticobulbar palsy. It is more common than bulbar palsy. Presents with slow tongue movements, slow deliberate speech, increased jaw jerk, increased pharyngeal and palatal reflexes, and pseudobulbar affect. | Multiple sclerosis, motorneuron disease, stroke, central pontine myelinolysis |
| Pyramidal signs | Damage to either the corticospinal or corticobulbar tracts cause a pyramidal lesion which present with spasticity, hypereflexia, weakness and a positive Babinski sign. |
Clinical patterns of motor neuron disease
| Clinical pattern | Description |
|---|---|
| Amyotrophic lateral sclerosis (ALS, 80%) | AKA Lou Gerigh’s disease. This is the archetypal MND. It is a rare disorder characterized by progressive deterioration of both upper motor neurons (of the corticospinal tract) and lower motor neurons. It presents with combined UMN and LMN signs. Stephen Hawking’s suffered from this disease. |
| Progressive bulbar palsy (10 – 20%) | This only affects cranial nerve IX – XII. Presents with dysarthria, dysphagia, and tongue muscle wasting and fasciculations. Pyramidal signs may be present. |
| Progressive muscular atropy (< 10%) | Affects anterior horn cells and presents with LMN signs only. Affects distal muscle groups more than proximal. Fasciculations and tendon reflexes are present. Has a better prognosis than ALS. |
| Primary lateral sclerosis (Rare) | Characterised by loss of Betz cells in the motor cortex. Mainly presents with UMN signs, marked spastic leg weakness and pseudobulbar palsy. Has no cognitive decline. Gradually progressive. |
- Etiology
- Genetic factors: four genes have ben identified to be the cause
- C9ORF72 – associated with fronto-temporal dementia
- TARDBP
- SOD1
- FUS
- Environmental factors:
- Smoking
- Exposure to heavy metals
- Exposure to certain pesticides
- Past history of military service
- Genetic factors: four genes have ben identified to be the cause
- Pathophysiology
- Involves the progressive degeneration of either/both the upper and/or lower motor neurons due to genetic mutations that lead to:
- Impaired protein homeostasis
- Mitochondrial dysfunction
- Aberrant RNA metabolism
- Dysregulated vesicle transport
- Impaired DNA repair
- Oxidative stress
- Axonal dysfunction
- Neuroinflammation
- Glutamate induced excitotoxicity
- The above processes culminate in motor neuron injury and ultimately denervation of the target.
- Involves the progressive degeneration of either/both the upper and/or lower motor neurons due to genetic mutations that lead to:
- Patient history
- Increasing age (> 40 years)
- Family history (particularly in younger patients)
- Progressive symptoms
- Complaints relating to limb and gait (tripping, stumbling, limp, hand fatigue, cramping and stiffness)
- Symptoms often begin focally then spread progressively to involve muscles through out the body.
- A patient may present at first with either limb symptoms such as weakness or bulbar symptoms such as slurred speech and difficulty talking.
- As you take history ensure to ask whether:
- Presentation is symmetrical or asymmetrical
- Proximal or distal
- Upper or lower limb predominance
- Presence or absence of bulbar symptoms
- Signs and symptoms
- Upper motor neuron signs
- Primitive reflexes e.g. Babinski
- Hyperreflexia
- Spasticity
- Hypertonia
- Clasp-knife reflex
- Pronator drift
- Lower motor neuron signs
- Fibrillation
- Fasciculations
- Hypotonia
- Hyporeflexia
- Weakness
- Signs of cranial nerve palsy
- Dysarthria (CN V, CN VII, CN IX, CN X, CN XII)
- Hoarsness (CN X)
- Dysphagia and choking (CN X and CN XII)
- Psudobulbar affect (inappropriate and involuntary laughing or crying)
- Respiratory involvement is a terminal event (primarily presents with type 2 respiratory failure)
- Upper motor neuron signs
- Amyotrophic lateral sclerosis
- A majority of patients present with limb symptoms with upper limb weakness being noticed first (classic Charcot ALS) with about 30-50% presenting with bulbar symptoms initially (Bulbar-onset ALS) A small minority will present with respiratory symptoms. Starts with the distal muscles, asymmetrically.
- Clumsiness – dropping things, falling down
- Inability to perform fine movements such as writing, turning door knobs, turning keys in doors
- Fatigue when exercising
- Impaired gait and imbalance – falls
- Slurred speech
- Difficulty swallowing leading to progressive weight loss
- Breathlessness
- Symptoms of carbon dioxide retention and hypoxia – headache, confusion, warm hands
- Behavioural changes such as apathy, personality changes, obsessive behaviour
- Impaired executive functioning – inability to plan, inattention and poor working memory
- About 10% present with symptoms of fronto-temporal dementia.
- Progressive bulbar palsy
- Slurred speech
- Difficulty swallowing leading to loss of weight
- Weakened tongue muscles
- Progressive muscle atrophy
- Paralysis of limbs
- Asymmetric weakness and atrophy of limbs
- Bulbar involvement is uncommon but can occur
- Flail arm variant – predominantly upper limb involvement with progressive, proximal to distal weakening of the limb
- Flail leg variant – progressive, asymmetrical involvement of the lower limbs
- Stiff or rigid muscles
- Dysarthria in a subset of patients
- Physical exam
- Gait abnormalities
- Reduced muscle bulk
- Weakness of limbs (axial)
- Positive babinski
- Upper motor neuron signs
- Hyperreflexia
- Spastic weakness
- Exaggerated jaw jerk to clonus
- Lower motor neuron signs
- Areflexia or hyporeflexia
- Flaccid weakness
- Muscle wasting
- Fasciculations
- Bulbar signs
- Dysarthria
- Dysphagia
- Emotional lability
- Nasal speech
- Spilt hand pattern – preferential wasting of the first dorsal interossei and thenar muscles with sparing of the hypothenar muscles
- Split leg pattern – preferential involvement of the planter flexors with sparing of the dorsiflexors
- There is no sensory or autonomic involvement
- Differentials
- Spinal muscle atrophy: lower motor neurons signs in younger patients or infants. Has a family history
- Spinal canal stenosis: restricted to particular sensory levels. Features pain or change in sensory funciton
- Stroke: acute onset and localizes to one limb, unilateral, sensory symptoms may be present.
- Gullian-Barre syndrome: younger patient with acute onset weakness and hyporeflexia/areflexia. Post-infectious history. CSF analysis shows elevated proteins and absent cells
- Myasthenia gravis: acute onset with extraocular muscle symptoms, smaller muscles affected more than large muscles. Worsens throughout the day. History of autoimmune disease e..g T1DM.
- Investigations
- Electromyography: most accurate diagnostic test
- Complete blood count
- Erythrocyte sedimentation rate
- C-reactive protein
- Biochemical tests such as Thyroid function tests
- Creatine kinase – elevated
- Serum immunoglobulins
- Serum electrophoresis
- Nerve conduction studies
- MRI brain and spine
- Vitamin B12 and folate levels
- HIV
- Lyme serology
- Lumbar puncture
- Muscle biopsy
- Biomarker – specific for ALS
- Genetic testing to look for mutations in the SOD1, FUS, TARDBP, C9orf72 to predict risk and phenotype
- Treatment
- Riluzole: NMDA receptor antagonist and inhibitor of glutamate release. Shown to increase survival
- Dextromethorphan/quinidine for pseudobulbar affect
- Baclofen or tizanidine for muscle spasms
- Oral care, positioning and suctioning for excessive saliva
- Antimuscarinics and botulinum toxin for excessive saliva
- Blended food and gastrostomy for dysphagia
- Exercise and orthotics for spasticity
- Augmentative and alternative communcation equipment for communication difficulty
- Palliative care
- Prognosis
- Poor
- < 3 years post onset in 50% of patients
- Negative prognostic factors
- Bulbar onset
- Respiratory onset
- Cognitive impairment
- Weight loss
- Older age at onset
- Shorter time from developing symptoms to diagnosis
Prognosis according to phenotype
| Phenotype | Median survival time from start of symptoms |
|---|---|
| Amyotrophic lateral sclerosis | 2-5 years |
| Primary lateral sclerosis | 8-10 years |
| Progressive muscular atrophy | 2-4 years |
| Progressive bulbar palsy | 6 months-3 years |
- Complications
- Aspiration pneumonia (most common cause of death)
- Respiratory failure
- Difficulty swallowing leading to weight loss, choking and aspiration
- Inability to walk
- Prolonged immobilization leading to bed sores, increased risk of deep vein thrombosis and superficial skin infections
