Motor Neuron Disease — Presentation, Evaluation and Treatment

Motor Neuron Disease — Presentation, Evaluation and Treatment Definition and classification

Motor neuron diseases (MNDs) are a heterogeneous group characterised by degeneration or dysfunction of the upper motor neurons (UMN) of the precentral gyrus and/or the lower motor neurons (LMN) of the ventral horn of the spinal cord.

Amyotrophic lateral sclerosis (ALS) is the commonest MND in adults and involves both UMN and LMN. It shows considerable phenotypic heterogeneity and is better regarded as a syndrome — sporadic and genetic forms, pure motor and extra-motor (frontotemporal dementia) presentations, pure LMN or pure UMN variants, and localised forms.

Variants: progressive muscular atrophy (LMN only), primary lateral sclerosis (UMN only), progressive bulbar palsy, flail arm and flail leg syndromes, and the ALS–FTD spectrum. Although histopathologically similar, individualisation matters because prognosis differs.

Epidemiology: incidence roughly 2–3 per 100,000 per year, peak onset 60–75 years, slight male predominance; about 10% familial. More than 30 genes are implicated — C9orf72 (commonest, links ALS with FTD), SOD1, TARDBP, FUS.

The neuropathological hallmark of most ALS is cytoplasmic inclusions containing ubiquitinated and hyperphosphorylated TDP-43 (except in SOD1- and FUS-linked familial ALS, which represent under 3% of cases).

TDP-43 is normally nuclear and regulates transcription, splicing and mRNA stability. In disease it is mislocalised — nuclear depletion causes aberrant RNA metabolism and impaired chromatin remodelling, while cytoplasmic accumulation disturbs autophagy, proteasome function, protein quality control and mitochondrial function. TDP-43 aggregates have a seeding capability and prion-like cell-to-cell transmission.

Converging mechanisms: disrupted RNA metabolism, aberrant protein quality control, mitochondrial dysfunction, oxidative stress, glutamate excitotoxicity, trafficking abnormalities and hypermetabolism.

Motor symptoms are frequently preceded for months by non-specific features: fatigue, weight loss secondary to hypermetabolism, cramps and diffuse fasciculation related to loss and hyperexcitability of lower motor neurons.

Limb-onset ALS (commonest): difficulty performing fine hand movements, difficulty raising the arms, foot drop and difficulty walking — typically asymmetrical, painless, progressive weakness.

Bulbar-onset ALS (about one-third): swallowing and phonation disorders with sialorrhoea, dysarthria, tongue wasting and fasciculation. Commoner in older women and carries a worse prognosis.

Respiratory-onset (rare): onset in the trunk musculature with isolated restrictive respiratory impairment causing effort dyspnoea and orthopnoea, frequently with unexplained weight loss.

Signs: mixed UMN (spasticity, hyperreflexia, extensor plantars, brisk jaw jerk, clonus) and LMN (wasting, fasciculation, hypotonia) findings in the same body region, with contiguous spread. Pseudobulbar affect (emotional lability) is common.

Cognitive and behavioural change occurs in up to 50%, with frank FTD in 10–15%. Revised criteria for ALS– frontotemporal spectrum disorder (ALS-FTSD, Strong 2017) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) are the standards. The frontotemporal syndrome of ALS is associated with poor survival and negatively affects caregiver burden and quality of life.

Characteristically spared until late: extraocular movements, sphincter function, sensation, and cognition in the majority — the preservation of cognitive capacity in most patients is precisely why advance directives can and should be discussed early.

In the absence of positive diagnostic markers, diagnosis rests on precise clinical and electrophysiological analysis, the study of the disease course, and elimination of the differential diagnoses referred to as "ALS mimics". Diagnostic delay is common.

Diagnostic criteria: El Escorial (1994), revised El Escorial / Airlie House (2000), and the Awaji electrodiagnostic criteria (de Carvalho 2008), in which fasciculation potentials count as evidence of acute denervation.

EMG: fibrillations, positive sharp waves, fasciculations, large-amplitude long-duration polyphasic motor units and reduced recruitment, in at least two of four regions (bulbar, cervical, thoracic, lumbosacral). Nerve conduction studies show normal sensory responses and no conduction block.

Exclude the treatable mimics — many are eminently treatable: cervical and lumbar spondylotic myeloradiculopathy (MRI brain and whole spine), multifocal motor neuropathy with conduction block (anti-GM1 antibodies; responds to IVIG), CIDP, myasthenia gravis, inclusion body myositis, Kennedy disease, vitamin B12 deficiency, thyrotoxicosis, hyperparathyroidism, paraneoplastic syndromes, HIV, syphilis and lymphoma.

Laboratory work: CK (mildly raised), TSH, calcium and PTH, vitamin B12, ESR, serum protein electrophoresis, anti-GM1, HIV and VDRL. CSF neurofilament proteins (NfL, pNfH) are established diagnostic and prognostic biomarkers.

Respiratory assessment at diagnosis and every 3 months: erect and supine FVC, sniff nasal inspiratory pressure (SNIP), overnight oximetry and arterial blood gases. Also assess nutrition, weight trajectory, swallow and cognition (ECAS).

Despite more than 200 trials, ALS remains incurable. Aetiologic treatment slightly improves survival; symptomatic and supportive management improves both survival and quality of life.

Riluzole (approved 1995), 50 mg twice daily, acts on Na+ and K+ currents and glutamatergic transmission. Median survival gain is modest, about three months; the one-year survival gain was 9% (58% vs 49%), with small effects on bulbar and limb function. All population-based registries confirm riluzole is an independent factor influencing long-term survival, and it is recommended by the EFNS and the AAN for all ALS patients, even in later stages. Monitor liver enzymes.

Edaravone, a free-radical scavenger, was FDA-approved on the basis of a second Japanese phase 3 trial in a narrowly selected group (definite or probable ALS, duration ≤2 years, normal respiratory function, ALSFRS-R item scores ≥2), showing a least-squares mean difference of 2.49 points in favour of edaravone. However a slight deterioration in quality of life was observed, and in May 2019 the EMA withdrew the marketing authorisation application because of baseline imbalance, lack of effect on survival, breathing and muscle strength, and too short a study duration.

Multidisciplinary care is itself an evidence-based intervention — multidisciplinary clinics improve survival compared with general neurology care.

Respiratory failure is the commonest cause of death and one of the most important determinants of quality of life and anxiety. Non-invasive ventilation prolongs survival and should be offered for symptomatic nocturnal hypoventilation, FVC <50%, or SNIP <40 cmH2O. Cough augmentation and secretion management are essential adjuncts.

Nutrition: early dietitian involvement, high-calorie diet to offset hypermetabolism, texture modification, and gastrostomy (PEG or radiologically inserted) before FVC falls below 50%, when the procedure becomes hazardous.

Symptom control: sialorrhoea (glycopyrrolate, hyoscine, amitriptyline, botulinum toxin to salivary glands, salivary gland radiotherapy); spasticity (baclofen, tizanidine, physiotherapy); cramps (levetiracetam, mexiletine, quinine); pseudobulbar affect (dextromethorphan–quinidine, amitriptyline, SSRIs); thick secretions (carbocisteine, nebulised saline); pain; insomnia; depression and anxiety; and communication through augmentative and alternative communication devices.

Early palliative care and collection of advance directives must be an early objective, while cognition is preserved — but clinicians must respect patient autonomy, including the inability of some patients to project themselves into perspectives of death or dependence. End-of-life issues and symptom relief are inextricably linked.