11th August 2024

Motor neuron disease

Overview of motor neuron disease

Motor neuron disease (MND) is a heterogeneous group of incurable neurodegenerative disorders affecting the motor neurons. The disease is characterised by progressive degeneration of both upper (UMN) and lower motor neurons (LMN). Sensory examination in patients with MND is often unremarkable as there is no sensory neuron involvement.

MND is often classified as affecting primarily the upper or lower motor neurons, or involving both, and symptoms can vary depending on which neurons are affected.

Types of MND

Amyotrophic lateral sclerosis (ALS)

ALS is the most common MND of adult onset with incidence peaking at the age of 75 years. It is a fatal disorder characterised by progressive skeletal muscle weakness, fasciculation, spasticity and atrophy due to UMN and LMN degeneration. Therefore ALS presents with a combination of both UMN and LMN signs.

ALS has sporadic and familial forms; 5-10% of cases are due to a superoxide dismutase-1 (SOD1) gene mutation.

It often presents with asymmetric lower limb motor neuropathy. However, regardless of which muscles are first affected, the symptoms spread to affect all four limbs and bulbar muscles. Death in ALS occurs due to progressive respiratory muscle paralysis.

Riluzone, a glutamate release inhibitor, is licensed for slowing down ALS progression, but there is no cure.

Primary lateral sclerosis (PLS)

PLS is a rare idiopathic disorder involving mostly UMNs. It is characterised by progressive spinobulbar weakness, and usually presents with lower limb spasticity with hyperactive reflexes and clonus. LMNs are generally spared.

Hereditary spastic paraparesis

This group of genetic disorders is characterised by a slowly progressive spastic, UMN pattern of weakness. Early presentations are with gait disturbance; upper limb involvement is usually mild.

Genetically they are classified by mode of inheritance, with the autosomal dominant form most common, however autosomal recessive and X-linked forms also occur. There can be significant clinical overlap with PLS.

Progressive bulbar palsy

This presents with LMN weakness of the glossopharyngeal, vagus, accessory and hypoglossal nerves (CN IX-XII) due to degeneration of their motor nuclei in the medulla. Symptoms include tongue weakness and fasciculations, dysarthria and dysphagia. Patients may present with a history of regurgitation of food and  fluids, tongue wasting and  fasciculations. Spinal cord involvement often occurs late in the disease course. Infantile forms also exist.

Spinal muscular atrophy

This is a genetic disorder characterised by degeneration of LMNs with no sensory or UMN involvement. The commonest inheritance pattern is autosomal recessive, however autosomal dominant and X-linked forms do exist. It is often first diagnosed in childhood and presents with weakness and progressive muscle atrophy

X-linked spinobulbar muscular atrophy (Kennedy disease)

This is an adult-onset X-linked recessive trinucleotide expansion disorder, with CAG repeats in the androgen receptor gene. It is characterised by progressive bulbar and limb muscle weakness, but also presents with endocrine disturbances such as androgen insensitivity. As an X-linked disorder it exclusively affects males but is transmitted by female carriers.

Post-polio syndrome

This presents after an acute attack of paralytic poliomyelitis and is characterised by late-onset skeletal and bulbar muscle weakness. Is a diagnosis of exclusion.

Diagnosis of MND

Electromyography (EMG) and nerve conduction studies (NCS) are the most useful investigations in the diagnosis of motor neuron disease. Findings include:

• Evidence of widespread denervation
• Preservation of motor conduction velocity

The exception is primary lateral sclerosis, as this typically only involves the upper motor neurons.

Differentials to consider

Key differentials for motor neuron disease include:

• Cervical radiculopathy – may present with sensory symptoms as well; MRI will show disc compression
• Syringomyelia – loss of sensitivity to pain or temperature, primarily in the upper limbs; MRI will show a fluid-filled syrinx
• Motor neuropathies, e.g. multifocal motor neuropathy (MMN) – both MMN and MND present with progressive pure motor weakness. MMN only has LMN weakness, and the progression of weakness is typically slower than in MND. Additionally, NCS will differentiate between MND and MMN: in MMN there will be a conduction block, however motor nerve conduction velocities are preserved in MND
• Inflammatory myopathies, e.g. inclusion-body myopathy – muscle biopsy and EMG will differentiate these from MND. EMG can confirm the presence of a myopathy and identify a muscle biopsy site. Additionally, patients with MND, depending on the pattern of weakness (UMN vs LMN), will show abnormal electrical activity in their muscles, e.g. fasciculations, which will be recorded on an EMG

Staging and  management of MND

There is no formal staging for MND. However bulbar presentations have been associated with a poorer prognosis as respiratory muscles are involved earlier, and patients are generally dependent on parenteral nutrition and have a high risk of aspiration. Death is usually within 1 to 5 years of diagnosis.

Management is guided by a multidisciplinary team. Discussions around the ceiling of care should be had early, including patient preference for the use of non-invasive ventilation. Additionally discussions surrounding long-term feeding options are also best had early in the disease course. Long-term PEG (percutaneous endoscopic gastrostomy) or RIG (radiologically inserted gastrostomy) feeding is often recommended, especially if the patient has bulbar weakness.

Riluzone is the only pharmacological treatment currently licensed for MND and has been shown to increase average survival by 2-3 months.

References

• McDermott C J, Shaw P J. Diagnosis and management of motor neurone disease  BMJ 2008;  336 :658 doi:10.1136/bmj.39493.511759.BE
• Brooks BR, Miller RG, Swash M, et al; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1:293-299
• Yedavalli VS, Patil A, Shah P. Amyotrophic lateral sclerosis and its mimics/variants: a comprehensive review. J Clin Imaging Sci. 2018. 8:53
• Oskarsson B, Gendron TF, Staff NP. Amyotrophic lateral sclerosis: an update for 2018. Mayo Clin Proc. 2018 Nov. 93 (11):1617-28
• Wais V, Rosenbohm A, Petri S, et al. The concept and diagnostic criteria of primary lateral sclerosis. Acta Neurol Scand. 2017 Sep. 136 (3):204-11