Motor Neurone Disease

(Amyotrophic lateral sclerosis)

Epidemiology. 1

Pathology. 1

Clinical 1

Epidemiology

· Incidence 1.5-2.0 per 100,000/year

· Prevalence of 6 per 100,000/year

· Male:female 1.6:1

· Onset increasing incidence from 40yrs to 70years then decreases

· Higher incidence in Pacific rim

· Exposure to natural toxin methylaminoalanine is putative risk

· ~10% have a significant family history (first degree relative affected or multiple other more distant relatives affected)

Pathology

· No unifying hypothesis

· Excitotoxicity theory

o Supraphysiological concentrations of amino-acid neurotransmitters causes toxicity

· Cortical hyperexcitability (as measured with TMS) seems to occur early in disease (work by Matthew Kiernan)

· Cytoplasmic aggregates of Phosphorylated TDP-43 found in 97% of patients

o Patients with SOD1 and FUS mutations being exceptions

Genetics

· Small proportion familial (~10%)

o 70% of familial cases will have a pathogenic gene variant found

· Sporadic cases (~90%)

o 10% will have pathogenic gene variant

· >40 pathogenic gene variants identified

· Mostly autosomal dominant with variable penetrance

· Most common variants vary by geographic location.

· Patients of European ancestry:

o C9ORF72 40%

o SOD1 20%

o FUS 5%

o TDP 5%

o Other variants <1% each

§ VAPB very common in South America

· SOD1 (copper/zinc superoxide dimutase).

o Deficiency results in reduced processing of free radicals

o Mutations in SOD found in up to 4% of sporadic cases

· C9ORF72

o Hexanucleotide repeat expansion (GGGGCC)

o Inherited mutation (autosomal dominant) and sporadic

o In patients with both MND-FTD mutation is found in 20-40%

o FTD 7-12% of all patients

o MND 11% of all cases, 7% of sporadic, ~40% of familial cases

o In Finland – 21% of all MND patients have this mutation

o Clinical

§ Slightly younger age of onset (50s vs 60s)

§ Higher rate of bulbar onset

§ More rapid disease progression

§ Presentation with psychoic symptoms is strong predictor of this mutation

Genetic Testing

· No consensus on who should be tested

o However is not useful for diagnosis or prognosis on an individual level

· Some advocate offering testing to all (Dharmadasa et al. Practical Neurology 2022; 22:107)

· 30% of familial cases will have fail to have pathogenic gene identified

· There are a large number of variants of unknown significance so need to be prepared for uncertainty

· Counselling of relatives

o Lifetime risk 1/400

o Lifetime risk of relative of sporadic patients <3%

o Relative of familial form – 50% chance of being carrier

o Penetrance variable – depends on mutation

· Usual testing protocol:

o Test for C9ORF72 – specific test required (given repeat expansion may not be picked up on high panel)

o If C9ORF72 negative then proceed to panel for other variants

Clinical

· Loss of neurones at all levels of the motor system

· Sensory changes DO NOT occur

· Three levels

o Bulbar

§ Dysarthria, dysphagia

§ LMN (bulbar palsy) – upper and lower facial weakness and poverty of palatal movement with wasting, weakness and fasciculation of the tongue

§ UMN (pseudobulbar palsy) – emotional lability, brisk jaw jerk and dysarthria

o Cervical

§ Upper limb symptoms – proximal or distal. Extensors and muscles of ab and adduction are affected before flexors (split hand sign).

§ Respiratory – diaphragmatic involvement with type II respiratory failure

o Lumbar

§ Lower limb symptoms – proximal (difficulty with stairs), distal (foot drop, tripping)

o (Rarely Thoracic)

· Presentation

o Bulbar 25%

o Limb 70%

o Respiratory 5%

o Other rare presentations: weight loss, cognitive change, emotional change

· Cognitive changes

o Apathy, disinhibition mood changes and executive dysfunction – subtle changes frequently noted

o Association with more severe, frontotemporal dementia in 5% of cases

· Bladder and bowel function preserved (until very late disease)

· Split hand – FDI/ABP/thenar affected more than ADM/hypothenar

· Split leg – Selective involvement of plantar flexor muscles relative to dorsiflexion muscles.

· Most (~60%) of the time presents with focal onset

· Progression – usually progresses up initially diagnosed limb before crossing to other side

· UMN and LMN signs tend to colocalise in same limb

· Progression rate appears to be linear (does not accelerate), however different patients have different rates of deterioration.

· Flail arm variant

o Men >> women

o Pure LMN

o “Man in a barrel”

Variants

Progressive muscular atrophy

· Pure LMN syndrome – no UMN signs - i.e. reflxes decreased or absent

· Some progress to classic/full ALS

· ? variant of ALS or spinal muscular atrophy (or maybe some of each)

· Longer survival – 5yr survival 72% in

Primary lateral sclerosis

· Pure UMN

· Very rare

Mimics

Spinal Muscular Atrophy

Family of selective LMN disease
Onset in childhood
Proximal muscle weakness common and must be distinguished from primary myopathy

Bulbospinal muscular atrophy (Kennedy’s syndrome)

Technically a variant of spinal muscular atrophy
X-linked recessive LMN syndrome with bulbar involvement
Tongue wasting, fasciculation, gynaecomastia, testicular atrophy, infertility, occasional primary sensory neuropathy.
CAG repeat sequence on androgen receptor gene

Multifocal motor neuropathy (with conduction block)

Weakness, generally distal arm muscles, can be in distribution of individual nerves.
Cranial nerves and respiratory muscles are rarely affected.
LMN disease - UMN signs absent and the disease can be very slowly progressive over up to 30years.
Conduction blocks
IgM anti-GM1 ganglioside antibodies frequently positive.
Improvement can be achieved with immunomodulatory treatment.

Other

· Benign fasciculations

· Inflammatory myopathy

· Post-polio syndrome

· MG

Diagnosis

El Escorial criteria – more of a research tool

Definite	UMN and LMN signs in 3 regions
Probable	UMN and LMN signs in 2 regions
Probable with laboratory support	UMN and LMN in one region or UMN signs in one or more regions WITH EMG evidence of acute denervation in two or more limbs
Possible	LMN and UMN in one region
Suspected	LMN only OR UMN only

EMG

· Features of acute and chronic denervation

o Acute – fibrillations and positive sharp waves

o Chronic – large amplitude, long duration complex motor unit action potentials with neurogenic recruitment and reduced interference pattern

· Fasciculation potentials

· Features are not specific for disease, however if such changes are widespread in many muscle groups then is highly suggestive

NCS

· Sensory and motor NCS should be (relatively) normal

Imaging

· Some subtle changes may be seen due to degeneration of corticospinal tracts

· Role of MRI is really to rule out other possibilities

Bloods

· CK often elevated

· Check TFTs etc. to exclude

Muscle biopsy

· Shows non-specific findings of denervation

Treatment

· Riluzole

o Glutamate release inhibitor acting on sodium channels

o Prolongs lifespan by ~3months

o SE: nausea, fatigue, elevated LFTs

· No other treatment proven to slow disease progression

Respiratory

Chronic nocturnal hypoventilation

· Disordered sleep and daytime fatigue

Markers of respiratory failure

· FVC <50%

· FVC <80% and symptoms

· SNIP or MIP <40cmH20

· SNIP or MIP <65 (men) or <55 (women) + symptoms

· Decreased SNIP or MIP >10% in 3 months

· Daytime arterial CO2 >45mmHg

· Daytime oxygen saturation <94%

Non-invasive ventilation

· 4hrs per day (usu at night)

· Can increase survival (7 months in one study)

Useful resource: https://mymnd.org.uk/

Exercise

· Can be helpful, no evidence of harm

· There is some suggestion that increased amounts of exercise are a risk factor for disease development.

Physical aids

· Neck support – e.g. Sheffield support snood

· Communication aids

o Voice banking – to allow more natural text to speech

Symptom treatment

Fasciculations and muscle cramps
Mg	5mmol TDS
Vit E	400IE BD
Quinine sulphate	200mg BD
Carbamazepine	200mg BD
Phenytoin	100mg TDS
Levetiracetam		Very low grade evidence
Mexilitine
Spasticity
Baclofen	10-80mg
Memantine	10-60mg
Benzodiazapines
Excessive oral secretions (thin) - Drooling
Amitriptyline	10-150mg
Hyoscine patches	1-2 patches
Glycopyrrolate	0.1-0.2mg sc/im TDS
Atropine or benztropine	0.25mg-0.75mg or 1-2mg
Grape juice
Excessive respiratory secretions (thick)
N-acetyl cysteine
Carbocysteine
Nebulised saline
Pathological laughing or crying	Up to 50%
Amitriptyline	10-150mg
Fluvoxamine	100-200mg
Lithium	400-800mg
Levodopa	500-600mg
Pain	Occurs in up to 73% Due to atrophy and altered tone, especially around joints
Standard pain management medications
Fatigue
Modafinil		Moderate evidence
Depression	44-75% reactive depression/adjustment disorder 10% develop major depression
SSRI’s
Dysphagia and weight loss
PEG	Consider when there is 5-10% loss of weight Studies suggest that delaying tube does not improve quality of life and leads to more complications

Prognosis

· 50% die within 3 years of onset, 90% within 6 years.

· Average prognosis of 18months from diagnosis

· 90% die ‘peacefully’ in their sleep from hypercapnia.

· Poor prognostic features

o Older age

o Early involvement of bulbar or respiratory function

References

Lancet Vol369 June 16/2007 JD Mitchell, Amyotrophic lateral sclerosis.

Lancet 2011 ALS Kiernan

Simon NG, Huynh W, Vucic S, Talbot K, Kiernan MC. Motor neuron disease: current management and future prospects. Intern Med J. 2015 Oct;45(10):1005-13

Hobson EV, McDermott CJ. Supportive and symptomatic management of amyotrophic lateral sclerosis. Nat Rev Neurol. 2016 Sep;12(9):526-38 (https://pubmed.ncbi.nlm.nih.gov/27514291/)