Other neurological disorders - Medical Pharmacology and Therapeutics, 4e

Medical Pharmacology and Therapeutics, 4e

25. Other neurological disorders

multiple sclerosis, motor neuron disease and Guillain–Barré syndrome

Multiple sclerosis

Drug treatment

Motor neuron disease

Drug treatment

Guillain–Barré syndrome

Management

Multiple sclerosis

Multiple sclerosis is characterised by an immunologically mediated inflammatory demyelination of the central nervous system (CNS). The cause is unknown, but it may be initiated by exposure of genetically susceptible individuals to an infective agent with an antigenic structure similar to myelin basic protein (molecular mimicry). This trigger initiates a peripheral immune response and the blood–brain barrier is then breached by primed T- and B-lymphocytes and macrophages. The initiating agent may also upregulate adhesion molecules (integrins) on T-lymphocytes, promoting their adhesion to cerebrovascular endothelium and transport across the blood–brain barrier. The inflammation in the brain has the characteristics of a Th1-lymphocyte autoimmune response (Ch. 38), with the T-cells secreting inflammatory cytokines such as interferon-γ, interleukin (IL)-17 and lymphotoxin (or tumour necrosis factor β, TNFβ). The destruction of myelin is probably initiated by B-cell-derived autoantibodies. Deficient numbers of regulatory T-cells may also contribute to the lack of tolerance to self-antigens.

The T-cell cytokines activate macrophages that phagocytose myelin coated with antimyelin antibody, and destroy the myelin sheath around nerves, particularly in white matter. The immunological damage also affects oligodendrocytes, the cells that produce the myelin. The result of these processes is the generation of demyelinated plaques that disturb normal conduction of electrical impulses in the CNS. However, the long-term disability in multiple sclerosis is mainly due to axonal damage, which occurs most extensively in the acute stages of the disease. Demyelination may predispose axons to damage from upregulation of Na⁺ channels, with subsequent reversal of the Na⁺–Ca²⁺ exchanger and Ca²⁺-induced cytotoxicity. Axon degeneration may also be enhanced by oligodendrocyte dysfunction and failure to remyelinate the nerves.

Multiple sclerosis usually begins in the second or third decades of life and in 85% of cases presents with relapsing and remitting symptoms and signs of multifocal CNS dysfunction. The usual clinical course is initially one of stepwise deterioration, but eventually there is progressive deterioration (secondary progressive multiple sclerosis). In the other 15%, the course is slowly progressive from the outset (primary progressive multiple sclerosis). To secure the diagnosis, episodes of neurological dysfunction must be separated in both time and place (more than one episode in more than one area of the brain). A single clinical episode of demyelination with several areas of demyelination on magnetic resonance scanning of the brain that have not caused symptoms is known as clinically isolated syndrome. The areas of the CNS most often involved in multiple sclerosis are the optic nerves, spinal cord, brainstem and cerebellum. Common clinical presentations are optic neuritis, weakness with spasticity, ataxia, and bladder and bowel dysfunction.

Drug Treatment

There is no cure for multiple sclerosis, but drugs can be used to reduce the symptoms. In relapsing–remitting disease there is increasing evidence that modulating the immune response as early as possible in the disease process may reduce disability. By contrast, most treatments are ineffective in primary or secondary progressive multiple sclerosis.

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.

Guillain–Barré syndrome

Guillain–Barré syndrome is an autoimmune acute inflammatory demyelinating polyradiculopathy, triggered in about three-quarters of cases by infection, of which Campylobacter jejuni infection is the most frequent. It only affects the peripheral nervous system and it produces rapid onset of limb weakness with loss of tendon reflexes and autonomic dysfunction, with variable sensory signs. In about 5% of cases the problem arises from acute axonal neuropathy. About 10% of affected people die in the acute illness phase and a further 10% have incomplete recovery and are left with severe long-term disability.

The immunological response is probably due to shared antigens on the infecting organism and the peripheral nerve tissue. In many cases, antiganglioside antibodies are present. The autoantibodies fix complement, and attract lymphocytes and then macrophages, which invade the myelin sheaths. Axonal degeneration may result from matrix metalloproteinases and toxic nitric oxide radicals released from the macrophages, and frequently results in long-term disability.

Management

There are several aspects to the management of Guillain–Barré syndrome.

Supportive treatment may be life-saving and is the cornerstone of management. For example, ventilatory support is necessary for respiratory muscle weakness or paralysis. Haemodynamic disturbance, including significant bradycardia and asystole, can result from autonomic involvement and may require cardiovascular support. Prophylaxis for deep venous thrombosis with subcutaneous heparin (Ch. 11) should be given. Pain may require analgesia, or the use of gabapentin or carbamazepine (Ch.23), and can be reduced by passive limb movement.

High-dose intravenous immunoglobulin (IgG) given within the first 2 weeks is equally effective as plasma exchange, and is now the preferred treatment. It may work by blocking macrophage receptors, inhibiting antibody production and complement binding and neutralising the pathological antibodies. Unwanted effects include malaise, chills and fever. IgG reduces the need for supported ventilation, and the time taken to recover walking.

Plasma exchange, when used within 4 weeks of the onset of symptoms, improves the long-term outcome. The benefit is probably due to removal of autoantibodies.

Corticosteroids are of no benefit, either alone or in combination with immunoglobulin.

Self-Assessment

True/false questions

1. Treatment with interferon beta is of benefit in reducing relapses in multiple sclerosis.

2. Multiple sclerosis is characterised in the early years by a steady progressive worsening of symptoms in the majority of people.

3. Glutamate can cause neuronal damage.

4. Riluzole is of benefit in motor neuron disease by blocking the release of γ-aminobutyric acid (GABA).

5. Natalizumab is used in multiple sclerosis as it enhances the action of adhesion molecules, increasing the passage of lymphocytes into the CNS.

6. Fingolimod is a produg activated by phosphorylation.

One-best-answer (OBA) question

Which of the following is the most accurate statement about the treatment of multiple sclerosis?

A Interferon beta causes influenza-like symptoms in 1% of those who receive it.

B Expert opinion does not recommend glatiramer acetate as a first-line drug for use in multiple sclerosis.

C Glatiramer acetate causes few unwanted effects following injection.

D Corticosteroid treatment is of benefit in reducing the progression of multiple sclerosis.

E Neuronal conduction is unimpaired in multiple sclerosis.

True/false answers

1. False. Interferon beta is used in multiple sclerosis and may diminish the production of inflammatory interferon-γ.

2. False. Multiple sclerosis is usually characterised by relapses and remissions over a number of years, although after about 10 years a steady decline sets in.

3. True. Glutamate is an excitatory amino acid neurotransmitter but can cause cell damage and death (excitotoxicity) by a number of mechanisms, including an uncontrolled increase in intracellular Ca²⁺.

4. False. Riluzole is the only drug that will alter the course of motor neuron disease; it inhibits glutamate release and action, thereby reducing its toxicity.

5. False. Natalizumab is an inhibitor of the α₄-integrin adhesion molecule and reduces the migration of lymphocytes into the CNS.

6. True. Fingolimod is rapidly phosphorylated by sphingosine kinases.

OBA answer

Answer B is correct.

A Incorrect. Influenza-like symptoms can occur in about 50% of people.

B Correct. The use of glatiramer acetate is usually restricted to people who cannot tolerate interferon beta, or who have developed antibodies to interferon beta.

C Incorrect. Glatiramer acetate can cause flushing, chest tightness, palpitations, anxiety and breathlessness.

D Incorrect. Corticosteroids may shorten the duration of acute attacks but have no effect on progression of multiple sclerosis.

E Incorrect. Long-term disability is due to demyelination of nerves and consequent further axonal damage. Demyelination of nerves results in disordered neuronal conduction.

Compendium: drugs used to treat multiple sclerosis, motor neuron disease and Guillain–Barré syndrome

Drug	Kinetics (half-life)	Comments
Corticosteroids	See Ch. 44	Corticosteroids such as methylprednisolone or prednisolone may be of benefit for acute relapse in people with multiple sclerosis (see Ch. 44)
Glatiramer acetate	Hydrolysed locally at the site of injection; absorbed parent compound and fragments enter the blood and lymphatic system; metabolised by proteolysis	A tetrapeptide that may act as an immunological decoy for myelin basic protein; given by subcutaneous injection to treat multiple sclerosis
Fingolimod	Prodrug with high oral bioavailability; rapidly phosphorylated to active metabolite; highly sequestered in tissues; hepatic metabolism (4–9 days)	Sphingosine analogue; phosphorylated form prevents lymphocyte egress from lymph nodes; given orally
Interferon beta	Rapid elimination due to tissue uptake and catabolism (especially in the liver); metabolised by proteolysis (2–4 h)	Anti-inflammatory cytokine given by subcutaneous or intramuscular injection for relapsing–remitting multiple sclerosis
Mitoxantrone	Metabolism and renal excretion; long terminal half-life (5–18 days)	A cytotoxic antibiotic given by intravenous infusion for the treatment of cancer (Ch. 52); not currently licensed for multiple sclerosis
Natalizumab	Protein clearance (11 days); clearance increased in the presence of natalizumab antibodies	A monoclonal antibody that blocks lymphocyte adhesion; given as an intravenous infusion for relapsing–remitting multiple sclerosis
Riluzole	High oral bioavailability (90%); hepatic metabolism (12 h)	A glutamate receptor antagonist used for motor neuron disease; given orally