Motor Neuron Disease

Motor Neuron Disease Fifteen–Twenty High-Yield Points Definition and classification

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

Amyotrophic lateral sclerosis (ALS) is the commonest MND in adults. It is best regarded as a syndrome with considerable phenotypic heterogeneity — sporadic and genetic, pure motor and with extra-motor signs, and forms affecting only LMN or only UMN.

Related entities include primary lateral sclerosis (PLS) (pure UMN), progressive muscular atrophy (PMA) (pure LMN) and progressive bulbar palsy. Although histopathologically similar, they must be separated because prognosis differs.

Motor symptoms are frequently preceded by months of non-specific features: fatigue, weight loss secondary to hypermetabolism, cramps and diffuse fasciculation from LMN loss and hyperexcitability.

Limb-onset ALS (commonest): difficulty with fine hand movements, raising the arms, or walking.

Bulbar-onset ALS (about one-third): swallowing and phonation disorders with sialorrhoea. Rarely, trunk-onset with isolated restrictive respiratory impairment causing exertional dyspnoea and orthopnoea with unexplained weight loss.

LMN signs: fasciculation, amyotrophy, weakness and cramps. UMN signs: pyramidal signs with spastic hypertonia, stiffness, clonus and gait disorder. At bulbar level, pseudobulbar features are dysarthria and dysphagia from hypertonia without atrophy, frequently with pseudobulbar affect (inappropriate crying and laughing).

Oculomotor nuclei and Onuf's nucleus are spared until very advanced disease — hence eye movements and sphincter function are preserved, a key diagnostic point.

Progression follows a pattern consistent with cell-to-cell, prion-like spread, extending rostrocaudally or contralaterally. The insidious, non-specific onset explains a diagnostic delay frequently exceeding one year.

Extra-motor involvement is frequent: with appropriate routine tests, cognitive or behavioural changes are detected in about 50% of patients, and 5–15% have frank frontotemporal dementia (FTD).

The cognitive profile is dominated by executive dysfunction and reduced verbal fluency, with impaired social cognition. Memory and visuoconstructive disorders are uncommon and non-specific.

Neuropsychological impairment matters clinically: it is associated with lower quality of life, greater caregiver burden, altered capacity to engage in life-prolonging interventions, and reduced survival. The revised Strong criteria classify this on three axes: Axis I motor neuron disease variant, Axis II cognitive and behavioural dysfunction, Axis III additional non-motor manifestations.

TDP-43 is central: except for SOD1- and FUS-linked familial ALS (under 3% of cases), the neuropathological hallmark is cytoplasmic inclusions of ubiquitinated, hyperphosphorylated TDP-43. Nuclear depletion causes aberrant RNA metabolism and impaired chromatin remodelling; cytoplasmic accumulation disturbs autophagy, proteasome function and mitochondrial function, and the aggregates show seeding and prion-like cell-to-cell transmission.

Common mechanisms are therefore: disrupted RNA metabolism, aberrant protein quality control, mitochondrial dysfunction, oxidative stress and trafficking abnormalities.

Genetics: up to 20% of European ALS patients have a family history of ALS or FTD. About 10% of apparently sporadic cases carry a known familial ALS mutation, and first-degree relatives of a sporadic patient have roughly an eight-fold increased risk.

Four genes account for up to 70% of familial ALS: C9orf72, SOD1, FUS and TARDBP. A GGGGCC hexanucleotide repeat expansion in C9orf72 is found in nearly 40% of familial ALS, about 25% of familial FTD-ALS, and about 5% of sporadic ALS. C9orf72 is pleiotropic, also causing FTD, PLS, PMA, Huntington phenocopies, parkinsonism and corticobasal degeneration.

Environmental risk factors: exposure to lead and heavy metals (with PON1 polymorphisms as a susceptibility factor), pesticides, and sports-related trauma. Relative risk is 4.07 for professional sport versus 1.13 for non-professional, 5.98 for sports with repetitive spinal and head trauma, and 8.52 when both risks combine.

In the absence of positive diagnostic markers, diagnosis rests on precise clinical and electrophysiological analysis, observation of the course, and exclusion of ALS mimics — cervical spondylotic myelopathy, multifocal motor neuropathy with conduction block, inclusion body myositis, myasthenia gravis, Kennedy's disease and thyrotoxic myopathy.

Riluzole, approved in 1995, was developed to reduce excitotoxicity by inhibiting glutamatergic transmission and probably acts on Na+ and K+ currents. Two pivotal studies in over 1,100 patients showed a median survival gain of about three months, confirmed by meta-analysis, with the probability of surviving one year rising by 9% (58% versus 49%), and small effects on bulbar and limb function. Despite more than 200 trials, ALS remains incurable.

Multidisciplinary symptomatic care is what improves survival and quality of life — non-invasive ventilation, nutritional support with gastrostomy, secretion management, treatment of spasticity and cramps, pseudobulbar affect, communication aids and mobility support. ALS is also the model disease for discussing advance directives and palliative end-of-life care early, because cognitive capacity is preserved in most patients throughout.