Motor Neuron Disease — Presentation, Evaluation and Treatment

Definition and classification. Progressive degeneration of upper and lower motor neurons. Variants: amyotrophic lateral sclerosis (commonest, UMN + LMN), progressive bulbar palsy, progressive muscular atrophy (pure LMN) and primary lateral sclerosis (pure UMN). About 90% are sporadic; familial forms involve C9orf72, SOD1, TARDBP (TDP-43) and FUS. The neuropathological hallmark of most cases is cytoplasmic TDP-43 inclusions.

Presentation. Painless, progressive, asymmetrical weakness with wasting, fasciculations and cramps, with brisk reflexes in a wasted limb (the mixed UMN–LMN signature). Bulbar onset — dysarthria, dysphagia, tongue wasting and fasciculation, nasal regurgitation — is commoner in older adults and carries a worse prognosis. There is no sensory loss and no sphincter or extraocular involvement.

Cognitive and behavioural change occurs in up to half of patients; 10–15% develop frank frontotemporal dementia (ALS–FTSD revised criteria). The ECAS is the validated screen for motor-impaired patients. The frontotemporal syndrome is associated with poor survival and heavy caregiver burden.

Evaluation. Diagnosis is clinical plus electrophysiological, using the El Escorial / revised Awaji criteria. EMG shows active and chronic denervation in at least three of four regions (bulbar, cervical, thoracic, lumbosacral). MRI brain and whole spine excludes structural mimics; CSF and serum neurofilament serve as diagnostic and prognostic biomarkers.

Exclude the treatable mimics — a key examination point, since many MND-mimic disorders are eminently treatable: cervical spondylotic myelopathy, multifocal motor neuropathy with conduction block, myasthenia gravis, inclusion body myositis, Kennedy’s disease, thyrotoxicosis and vitamin B12 deficiency.

Treatment. Riluzole (anti-glutamatergic, acts on Na+/K+ currents) is the only established oral disease-modifying drug — it prolongs survival by a median of about 3 months and raised one-year survival from 49% to 58%; monitor liver enzymes. Non-invasive ventilation prolongs survival and quality of life; PEG feeding is offered for dysphagia and weight loss. Symptom control: glycopyrrolate/amitriptyline or botulinum toxin for sialorrhoea, baclofen for spasticity, quinine for cramps. Multidisciplinary clinic care independently improves survival, and early palliative care with advance directives is essential.

Tofersen — the first gene-targeted therapy in ALS. Tofersen is an intrathecal antisense oligonucleotide that reduces SOD1 protein synthesis, approved for SOD1-mutation ALS (about 2% of cases) under accelerated approval based on reduction of plasma neurofilament light chain. Long-term VALOR and open-label extension data (JAMA Neurology 2026) showed slowed functional decline and prolonged survival with early initiation. The EAN 2024 ALS guideline accordingly recommends genetic testing for all patients with ALS, alongside riluzole, early NIV and multidisciplinary care.