Corticosteroids (Ch. 44) are often used to treat an acute relapse (e.g. intravenous methylprednisolone for 3 days or oral prednisolone for 3 weeks). They probably shorten the duration of an attack but have no effect on long-term outcome.
Interferon beta-1a or -1b reduces the inflammatory response in an acute attack and can reduce the frequency of relapses. Interferons are translocated to cell nuclei and act as transcription factors by binding to enhancer elements, where they stimulate gene expression. Proposed mechanisms for the clinical effect include decreased expression of major histocompatibility complex molecules on antigen-presenting cells (Ch. 38), inhibition of T-cell activation, decreased release of inflammatory cytokines and enhanced activity of suppressor T-cells. After a single episode of demyelination about 50% of people will subsequently develop the clinical syndrome of multiple sclerosis. The use of interferon beta at the time of this clinically isolated syndrome significantly reduces the risk of developing multiple sclerosis two years after treatment. Otherwise, the use of interferon beta is reserved for ambulant individuals who have had at least two attacks of relapsing and remitting disease over the previous 2 or 3 years. However, although the drug may reduce relapses by about one-third, it does not prevent ultimate disability. Interferon beta is given by intramuscular or subcutaneous injection. The most frequent unwanted effects are influenza-like symptoms, which occur commonly and may persist for several months, and pain or ulceration at the injection site. Neutralising antibodies are produced during repeated administration in 5% of people, which leads to treatment failure within two years of starting treatment.
Glatiramer acetate is a synthetic tetrapeptide immunomodulator that has some structural similarities to myelin basic protein. It may produce immunological tolerance by increasing the number of regulatory T-cells. Its use may reduce the frequency of relapses but, like interferon beta, it does not influence long-term disability. Glatiramer acetate is mainly used when antibodies reduce the effectiveness of interferon beta. It is given by subcutaneous injection. Unwanted effects include flushing, chest pain, palpitation and dyspnoea immediately after injection, and reactions at the injection site.
Mitoxantrone, a cytotoxic antibiotic (Ch. 52), has shown encouraging results in reducing disability when given at 1–3-monthly intervals. It is not licenced for this use in the UK, but is an option when people do not respond to interferon beta or glatiramer acetate.
Natalizumab is a monoclonal antibody that selectively inhibits the α4-integrin adhesion molecule on the surface of T-lymphocytes. This prevents T-cells from interacting with receptors on the vascular endothelium and crossing the blood–brain barrier. Natalizumab reduces relapse rate in relapsing–remitting multiple sclerosis. It increases the risk of infection, and there is a small risk of developing the brain disease progressive multifocal leucoencephalopathy when it is used in combination with interferon beta. Natalizumab is currently used when interferon beta or glatiramer acetate have failed.
Fingolimod is an oral prodrug that undergoes reversible phosphorylation to an agonist of sphingosine 1-phosphate receptors on lymphocytes, causing their internalisation. This inhibits lymphocyte egress from lymph nodes and therefore reduces their migration into demyelinating lesions in the CNS. It is used for relapsing–remitting disease that remains active despite use of interferon beta.
Other agents that modify the behaviour of lymphocytes have shown promising results in the treatment of relapsing–remitting disease. These include the cancer chemotherapeutic drugs cladribine and alemtuzumab (Ch.52), as well as several newer drugs currently under investigation.
A new voltage-gated potassium channel blocker, fampridine, blocks exposed K+ channels in demyelinated axons and inhibits repolarisation. This prolongs the nerve action potential and improves walking time. However, fewer than 50% of people with multiple sclerosis will respond. The main unwanted effects are gastrointestinal disturbances, urinary tract infection, insomnia, ataxia, dizziness, paraesthesia, tremor, headache and seizures. Symptomatic treatment of spasticity may be necessary, for example with baclofen (Ch. 24). A multidisciplinary team approach is essential for the management of the numerous disabling symptoms that may occur in multiple sclerosis.Motor neuron disease
Motor neuron disease is an uncommon, rapidly progressive disorder of motor neurons that occurs most often in middle-aged males. The most common form, amyotrophic lateral sclerosis, leads to both upper motor neuron signs and symptoms (hypertonia, impaired fine movement and hyperreflexia) and lower motor neuron signs and symptoms (fasciculations, muscle cramps, weakness and muscle atrophy). Other forms affect either upper or lower motor neurons. Up to half of affected people develop cognitive impairment. Death from respiratory failure usually occurs 2–5 years from the onset of symptoms. The pathophysiology involves neuronal loss among the anterior horn cells of the spinal cord, motor cortex and hypoglossal nucleus in the lower medulla. The cause is unknown, but recent evidence suggests that there is dysfunction in a nuclear RNA splicing factor known as TDP-43, leading to aberrant mRNA splicing. There is evidence of excessive activation of excitatory glutamate receptors in the CNS which may lead to prolonged depolarisation of motor neurons, intracellular Ca2+ overload, mitochondrial damage and cell death (excitotoxicity). Oxidative stress from excessive free radical generation may be important, and familial forms of the disease are associated with mutations of genes coding for the free radical-scavenging enzyme, superoxide dismutase.
Drug treatment
Riluzole is the only available agent that alters the course of motor neuron disease. It crosses the blood–brain barrier and inhibits the release of glutamate, as well as acting as an indirect antagonist at glutamate N-methyl-D-aspartate (NMDA) receptors on damaged neurons. These actions may inhibit glutamate-induced excitotoxicity. Treatment with riluzole does not arrest the disease but may slow its progression to a modest extent, improving survival by an average of three months after 18 months of treatment. Unwanted effects of riluzole include nausea, vomiting, diarrhoea, lethargy and dizziness.
Physiotherapists can help with advice on posture and exercise early in the disease, and later with passive movement to reduce musculoskeletal pain. Symptomatic treatment is often necessary for complications such as pain, breathlessness or dysphagia.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
