Multiple sclerosis: the disease and its treatment

By Ahmed Toosy, MRCP, MA (Cantab) and Alan Thompson, FRCP, FRCPI

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating condition of the central nervous system. It is the commonest cause of neurological disability in young adults, with a female to male preponderance of two to one. It has a lifetime prevalence of 2 per 1,000 in the United Kingdom and an annual incidence of 8 in 100,000.¹

The aetiology has not been fully defined but is thought to involve a combination of genetic and environmental factors.^2,3
A viral infection early in life may initiate an autoimmune disease process in a genetically susceptible group of individuals.^4,5
Myelin basic protein has been implicated as a potential target for the autoimmune process.
MS is usually characterised by a relapsing-remitting course in the early stages, with full or nearly full recovery, initially. Over time the disease enters an irreversible progressive phase of neurological deficit.⁶
Acute relapses are caused by inflammatory demyelination,⁷
while disease progression is thought to result from axonal loss.⁸

The disease process affects myelinated fibre tracts, such as the optic nerves and the white matter tracts of the brain and spinal cord. This may lead to a variety of symptoms (see Panel 1).
The therapies used to treat MS are targeted at different aspects of the disease and can be categorised into disease modifying therapies, drugs used in acute exacerbations and drugs used to treat disease complications.

Panel 1: Symptoms of MS

• Visual disturbances
• Bladder, bowel or sexual dysfunction
• Motor symptoms (eg, weakness and spasticity)
• Sensory symptoms (eg, numbness, dysaesthesia [disagreeable sensation], paraesthesia)
• Cerebellar symptoms (eg, tremor and ataxia)
• Other symptoms (eg, fatigue, cognitive impairment and psychiatric complications)

Disease modifying therapies

Several disease modifying therapies have been developed over the past 15 years. These predominantly influence the immune system and target the inflammatory processes that are involved in the disease pathology. Only the beta interferons are presently licensed in the United Kingdom. However, glatiramer acetate (Copaxone) and mitozantrone have been licensed in the United States.

Interferon beta
The introduction of interferon beta has had a significant impact on the treatment of MS. Interferon beta occurs naturally and, although its precise mechanism of action is unclear, it is known to have immunomodulatory effects.⁹
These include inhibition of leucocyte proliferation and antigen presentation, inhibition of T-cell migration across the blood-brain barrier and modulation of cytokine production to produce an anti-inflammatory environment.¹⁰

There are three preparations in use – Avonex and Rebif (interferon beta-1a) and Betaferon (interferon beta-1b). Interferon beta-1a is a glycosylated mammalian cell product with an identical amino acid sequence to natural interferon beta. Interferon beta-1b is a non-glycosylated bacterial cell product with a slightly altered amino acid sequence to the natural product.
Interferon beta reduces relapse rates in MS patients by approximately one-third. However, the effect on disease progression has not yet been firmly established. Interferon beta can only be prescribed by a consultant neurologist and its use is restricted to patients with relapsing-remitting MS who have had two relapses in the past two years and are able to walk 100 metres unaided (ie, are ambulant).¹¹

Avonex is given by intramuscular injection at a dose of 30µg (6 million IU) once a week. Betaferon is administered subcutaneously at a dose of 0.25mg (8 million IU) on alternate days. The available doses for Rebif are 22µg (6 million IU) and 44µg (12 million IU). It is given subcutaneously three times a week.
The most common adverse effect is a ’flu-like syndrome, which in some cases can be severe. The symptoms are generally most prominent at the start of therapy and then wear off with continued treatment. Non-steroidal anti-inflammatory agents are recommended prophylactically before each interferon dose to alleviate the symptoms. Subcutaneous administration may cause skin reactions in over 50 per cent of cases but these are usually mild. Injection site necrosis has been reported although it is rare.
In addition, neutralising antibodies may develop in 10-50 per cent of patients, usually within the first two years of treatment, and can be associated with a reduction in clinical efficacy of the drug.
Laboratory monitoring is mandatory prior to treatment and then every three months and includes full blood count, urea and electrolytes, liver function tests and neutralising antibody assays.

Panel 2: Clinical trial evidence for interferon beta

Avonex

A double-blind, placebo controlled trial was conducted on 301 patients with relapsing-remitting MS and mild neurological impairment. The primary outcome variable measured was the time to onset of irreversible worsening in disability. This was defined as a deterioration from baseline of at least one point on the EDSS (see Panel 3). The results of the study were analysed early when 172 patients had completed two years of treatment. They demonstrated a significant delay in EDSS progression as well as a reduction in the relapse rate in the treatment group by about one-third.¹²
There was no significant change in the total MRI lesion load, although a significant reduction in gadolinium enhancement (ie, a reduced number of actively inflamed areas) was shown.¹³

Panel 3: The Edss scale

The expanded disability status scale (EDSS) is a quantitative clinical scale of neurological impairment ranging from 0 to 10. Increasing numbers represent increasing disability.

Betaferon

A multicentre North American trial involved 372 patients with relapsing-remitting MS and mild to moderate disability. High dose Betaferon (8 million IU) was compared with low dose Betaferon (1.5 million IU) and placebo. High dose treatment reduced the relapse rate by 31 per cent compared with placebo. It also increased the time to first relapse and the proportion of patients who were relapse-free.^14,15
There was no significant difference in neurological disability between treatment groups. A European trial of 718 patients with secondary progressive MS was recently completed. This showed a delay in disability progression of nine to 12 months over two to three years.¹⁶
There were also favourable effects on relapse rate and MRI parameters.¹⁷
A further trial of secondary progressive MS has been completed in the United States and publication of the results are awaited.

Rebif

In a recent large study, 560 patients with relapsing-remitting disease and mild to moderate disability were randomised to Rebif 22µg (6 million IU), Rebif 44µg (12 million IU) or placebo. They were treated for two years.
A significant reduction in relapse rate (by 27 per cent for the lower dose and 33 per cent for the higher dose) was shown with Rebif. The time interval between relapses was also increased and the relapse severity was reduced. In addition, a delay in progression of disability was also demonstrated.¹⁸
However, the results of a further trial examining Rebif in secondary progressive MS were presented last year and showed no significant delay in disease progression.
These results were in abstract form only and full publication of the data is awaited.

Glatiramer acetate (Copaxone)
This is a mixture of polypeptides that have been synthesised randomly from a pool of four amino acids – L-glutamic acid, L-alanine, L-lysine and L-tyrosine. Glatiramer acetate was originally designed to mimic myelin basic protein. Its mode of action has not been defined, although it is thought to involve inhibition of lymphocyte migration¹⁹
and suppression of T cell activation.²⁰
It may exert its effects by competing with myelin basic protein and perhaps other myelin autoantigens for binding to MHC class II molecules expressed on antigen presenting cells.²¹

A two-year study demonstrated a 29 per cent reduction in relapse rate in patients with relapsing-remitting MS.^22,23
In addition, a recently presented magnetic resonance imaging (MRI) study has demonstrated that treatment with glatiramer acetate decreases lesion activity in patients with relapsing-remitting MS.
Glatiramer acetate is given daily at a dose of 20mg subcutaneously. It is generally well tolerated, with the most common adverse experience being injection-site reaction. In addition, about 15 per cent of patients may experience brief episodes (30 seconds to 30 minutes) of facial flushing and chest tightness, sometimes with palpitations, anxiety and dyspnoea.

Mitozantrone
Mitozantrone is a cytotoxic agent with potent immunosuppressant effects. These include suppression of B cell immunity and reduction of T cell numbers. The drug is likely to obtain a licence in the United States shortly for clinically worsening secondary progressive and relapsing-remitting MS. The recommended dose is 12mg/m2 administered by intravenous infusion every three months. The total recommended cumulative dose should not exceed 140mg.
A placebo-controlled trial of mitozantrone (by intravenous infusion every month) involving 51 patients showed a significant reduction in relapse rate but not in MRI lesion load or progression of disability.²⁴
Another small trial compared the effect of treatment with methylprednisolone to both methylprednisolone and mitozantrone combined over six months in 42 patients with MS.²⁵
It showed a significant reduction in the relapse frequency and in the number of actively inflamed lesions on MRI and a significant improvement in changes in disability score in the mitozantrone group. In a further placebo-controlled trial, 194 patients were randomised to receive either 12mg/m2, 5mg/m2 or placebo intravenously every three months for two years. Mitozantrone significantly reduced the annual relapse rate by approximately 60 per cent, delayed the time to first exacerbation and slowed progression.²⁶

The most frequent adverse effects of mitozantrone include nausea, alopecia, leucopenia and amenorrhoea. Cardiotoxicity is a well recognised side effect, which is seen more at higher doses but which was not a major problem in the studies described above. Regular monitoring of cardiac function by echocardiography and blood counts is advisable.

Other potential therapies
A number of drugs have been tried for MS treatment.

Intravenous immunoglobulin
A two-year randomised controlled trial in approximately 150 patients with relapsing-remitting MS showed a favourable effect on relapse rate in the treatment group, who received IV immunoglobulin 0.15-0.2g/kg/month.²⁷
A beneficial effect has also been demonstrated on MRI activity.²⁸
Further trials are required with larger numbers of patients. The main side effects are malaise, headache, fever, rash and, rarely, aseptic meningitis, thromboembolism and transmission of infection.

Azathioprine
Meta-analyses of randomised controlled trials with azathioprine have provided some evidence for a reduction in relapse rate²⁹
and a possible effect on disease progression.³⁰

Ciclosporin
A beneficial clinical effect has been shown on disease progression with ciclosporin. However, this is considered to be outweighed by drug toxicity, especially nephrotoxicity.³¹

Methotrexate
A small trial of low dose oral methotrexate (7.5mg/week) in 60 patients with progressive MS demonstrated a reduction in the progression of upper limb dysfunction. However, there was no significant effect on ambulation, disability or MRI activity.³²

Cladribine
Cladribine is a synthetic antineoplastic agent with immunosuppressive effects. Its use is limited by significant myelosuppression. The evidence for its use in the treatment of MS is mixed. Several small trials have suggested beneficial effects on relapse rate, progression of disease and MRI activity in both relapsing and progressive disease.^33,34,35
However, a large study that investigated the effect of cladribine in 159 patients with progressive MS found no beneficial effect on disease progression.³⁶

Anti-a4 integrin (Antegren)
Anti-a4 integrin is a monoclonal antibody directed against a4 integrin, a cell adhesion molecule involved in immune cell migration. A trial of 72 patients with active relapsing-remitting or secondary progressive MS reported a significant reduction in the number of active lesions on MRI after short-term treatment with intravenous anti-a4 integrin.³⁷
However, longer term follow up demonstrated an increased relapse rate in the treatment group. Further studies are underway.

Campath-1H
A few small studies have been performed with Campath-1H, an anti-leucocyte (CD52) monoclonal antibody, which is administered as an intravenous infusion. A reduced relapse rate has been demonstrated with a concomitant decrease in the number of active inflammatory lesions on MRI. However, up to half the patients studied continued to deteriorate and this was associated with brain atrophy.³⁸
Side effects include a persistent lymphopenia (reduced number of lymphocytes), autoimmune hyperthyroidism and a transient exacerbation of neurological deficit after the first dose.

Lenercept
Tumour necrosis factor (TNF), an inflammatory mediator, is thought to contribute to the inflammatory response and to tissue injury in MS. Lenercept is a dimeric recombinant protein molecule built from two copies of the TNF receptor extracellular domain fused to a fragment of the human immunoglobulin IgG heavy chain. Its effect is to bind to and deplete TNF. It has a beneficial effect in experimental animal models of MS. However, a double-blind placebo-controlled study conducted in 168 patients with relapsing-remitting MS showed an increased relapse rate in the lenercept treatment group.³⁹
Adverse effects included headache, nausea, abdominal pain and hot flushes. Its role in the treatment of MS is consequently doubtful and further research is required.

Future possibilities
An increasing number of potential therapies are currently undergoing clinical evaluation. These include peptide therapies, T-cell vaccination, interleukin 10, matrix metalloproteinase inhibitors, plasmapheresis, vitamin D, retinoic acid, ganciclovir, valaciclovir, bone marrow transplantation and autologous stem cell transplantation.

Treatments used in acute exacerbations

Acute deterioration in the neurological status of a patient with MS may be due to an episode of inflammatory demyelination (relapse). However, other conditions may also cause acute deterioration. These include intercurrent infection (especially urinary tract infection), electrolyte imbalance, fever or drug intoxication. In a relapse, neurological deterioration normally occurs over several days and recovery takes weeks to months. ACTH (adrenocorticotrophic hormone) was administered in the past to treat relapses but is no longer routinely available.⁴⁰
Steroids are now normally used in treating relapses. They help to speed the rate of recovery but do not affect the eventual degree of recovery.⁴¹
They are thought to work by reducing oedema and inflammation and consequently resolving conduction block.
Steroids may be given intravenously or orally and several studies have compared these routes of administration. No conclusion has been reached as to which is definitely superior.^42,43,44
The most popular choice is intravenous methylprednisolone.⁴⁵

Intravenous methylprednisolone
The usual regime for administration of methylprednisolone is to give 1g by intravenous infusion per day for three days.⁴⁵
Alternatively, 500mg daily for five days is sometimes given. Before prescribing this therapy, infection (especially urinary tract infection) should be excluded as a cause for the acute deterioration. Steroids have an immunosuppressant action and may exacerbate the infection, which, in some cases, may lead to septicaemia.
Side effects of steroids include restlessness, anxiety and insomnia. Depression, psychosis or euphoria may also arise. Long-term complications of steroids are generally rare with intermittent therapy, but osteoporosis or aseptic necrosis can occur.

Oral steroids
Oral prednisolone may be effective in shortening acute attacks of MS and tends to be used in the community in preference to intravenous steroids when relapses are not severe. The dose begins at 60mg daily, gradually reduced over three to four weeks. Concurrent anti-ulcer therapy may be needed.
Dexamethasone is not routinely used but has been shown in small studies to be as effective as intravenous methylprednisolone in promoting recovery from a relapse.^46,47

Plasma exchange
Therapeutic plasma exchange has been shown in one small study to benefit patients with severe relapses that have not responded to intravenous corticosteroids.⁴⁸
Associated adverse effects include anaemia and, less commonly, heparin-associated thrombocytopenia syndrome.

Drugs used to treat disease complications

So far, no disease modifying therapy has been found that halts disease progression or improves neurological status. For this reason, the mainstay of MS treatment remains symptomatic management.⁴⁹

Spasticity

Spasticity is a common symptom in MS.⁵⁰
Patients may complain of difficulty in walking, stiffness, clonus (alternating muscle contraction and relaxation), spasms, pain or impaired balance. Later on they may develop pressure sores and contractures. Several drugs may be used to treat spasticity.

Baclofen
Baclofen is the drug of choice. It is an analogue of GABA (gamma aminobutyric acid) and is thought to inhibit monosynaptic and polysynaptic transmission at the spinal level and also to depress the CNS. It is advisable to start treatment at low doses and then slowly increase to a therapeutic level or until intolerable side effects occur. Maximising the bedtime dose, usually the time of greatest spasticity, can also be helpful. Most patients will require 40 to 80mg per day in three or four divided doses. A daily dose in excess of 100mg is not recommended unless the patient is under close supervision. Baclofen should not be stopped abruptly because of the risk of seizures, psychosis, confusion, tachycardia and temporary aggravation of spasticity.
Adverse effects, such as weakness and sedation occur predominantly with initial treatment, with large doses, after increasing the dose too quickly or in the elderly.

Tizanidine
Tizanidine is an alternative to baclofen, particularly when the latter is limited by muscle weakness. It is an a2-adrenergic receptor agonist which acts both at supra-spinal and spinal levels. It inhibits spinal polysynaptic reflex activity. Tizanidine has no direct effect on skeletal muscle.^51,52
Treatment is started at a dose of 2mg daily, increasing by 2mg increments at no less than half-weekly intervals. The effect of tizanidine on spasticity is maximal within two to three hours and it has a relatively short duration of action. It is usually given in three or four divided doses and the total daily dose should not exceed 36mg. Tizanidine may cause reversible increases in hepatic transaminases in 5 per cent of patients. Consequently, it is recommended that liver functions tests should be monitored monthly for the first four months of treatment.

Benzodiazepines
Diazepam and clonazepam are effective at relieving spasticity but their use is limited by sedation, depression and dependency. They are especially useful at night when sedation may be beneficial. Diazepam is usually given at a dose of 10mg nocte. The dose for clonazepam is normally 0.5 to 1mg daily, although it can be as high as 2mg daily.

Dantrolene
Dantrolene is effective in reducing spasticity but always causes muscle weakness and is poorly tolerated. It is thought to bind to the sarcoplasmic reticulum and lower the intracellular calcium concentration in skeletal muscle. Treatment should start at 25mg daily and be slowly titrated upwards in increments of 25-50mg until the desired therapeutic effect is reached. Each dosage level should be maintained for one week before the next increment. The maximum daily dose should not exceed 400mg (prescribed as 100mg four times a day). The effective dose is usually 25 to 100mg three to four times a day. Adverse effects tend to limit the use of dantrolene. Because it causes significant muscle weakness, dantrolene is contraindicated where spasticity is used to maintain an upright posture or locomotor function.

Other drugs
Gabapentin has been reported to reduce spasticity and spasm in MS.⁵³
It is a GABA analogue but its mechanism of action is unknown. The therapeutic dose is 900-1200mg daily in divided doses. Side effects are rare and it is well tolerated. Several small placebo-controlled trials of MS patients with relatively severe spasticity have demonstrated a beneficial effect with vigabatrin 2-3g/day.⁵⁴
Side effects include drowsiness, dizziness, headache, weight gain and, more rarely, neuroses and psychoses.
Cannabinoids form the active ingredients in cannabis. A questionnaire-based study suggested that cannabis may improve various symptoms of MS, including spasticity, pain and tremor.⁵⁵
A recent study has investigated the effect of cannabinoids in mice with experimental allergic encephalomyelitis (an animal model of MS). It found a clear improvement in spasticity and tremor after administration of cannabinoids.⁵⁶
A large double-blind placebo-controlled trial to investigate the effect of cannabinoids on spasticity in human subjects with MS has recently been funded.

Interventional procedures
These are usually considered when spasticity is severe and poorly responsive to oral drug therapy. Intrathecal baclofen may be given via a pump that is surgically implanted into the abdominal wall. A catheter connects the pump to the intrathecal space and is able to deliver small but effective doses of baclofen with few systemic side effects.^57,58,59
The main complications include pump malfunction, catheter-related problems (kinking, breaking, displacement), local inflammation and, rarely, spinal meningitis. Respiratory depression has also been reported secondary to overdosing.
Phenol injection may be administered into a peripheral nerve or intrathecally. When injected intrathecally it may cause sphincter dysfunction. It is useful for severe disability, especially when anal and/or bladder sphincter function has already been compromised.
Botulinum toxin given as intramuscular injections provides temporary relief for distal muscle spasticity.^60,61
It is a neurotoxin derived from Clostridium botulinum, which blocks cholinergic transport at the neuromuscular junction by preventing the release of acetylcholine.
Rhizotomy is a neurosurgical procedure sometimes used for MS that interrupts the muscle stretch reflex. Anterior rhizotomy produces irreversible weakness but spares sensory loss and urinary retention. Tendon-lengthening procedures provide relief for fixed contractures but are rarely used in MS.

Tremor

About 70 per cent of patients experience cerebellar intention tremor (ie, one which is only apparent during intentional movement) or ataxia at some time during their illness.⁶²
Tremor is a very difficult symptom to treat, with tremor of the head and trunk being particularly resistant to therapy. Minor tremor may respond to weighting of the affected limb. Many drugs have been tried to treat tremor. A few are listed below.

Isoniazid
A small benefit has been shown with the use of isoniazid but high doses are normally required (600-1,200mg daily).^63,64
It is given with pyridoxine 100mg a day to prevent peripheral neuropathy. Side effects occur more commonly in slow acetylators. They include fever, peripheral neuropathy, optic neuritis, lupoid syndrome, haematological abnormalities, gynaecomastia and liver dysfunction.

Clonazepam
Clonazepam sometimes has a beneficial effect but its use may be limited by side effects.

Ondansetron
A beneficial effect was demonstrated with the intravenous form of ondansetron.⁶⁵
However, a more recent trial which investigated the effect of oral ondansetron was negative.⁶⁶
Severe constipation and high drug costs limit its use. Other side effects include headache, flushing, and hiccups.

Other drugs
Propranolol (40mg to 160mg daily) may be of benefit if there is an additional diagnosis of essential tremor. Other potentially useful drugs include lorazepam and carbamazepine.⁶⁷

Surgical treatment
Stereotactic thalamotomy, in which a small part of the thalamus is ablated, may reduce contralateral tremor but there are significant risks of hemiparesis and dysarthria.^68,69
Deep brain stimulation through an electrode implanted in the thalamus (thalamic stimulation) has been developed as an alternative to thalamotomy. It has been found to be equally effective but has fewer adverse effects.⁷⁰
Surgical treatments are usually considered as a last resort and require a careful selection process.

Pain

Shooting or lancinating pains are common features of MS.⁷¹
Trigeminal neuralgia, due to plaques in the posterior root entry zone, occurs in about 2 per cent of patients.⁷²
Most bilateral trigeminal neuralgia is caused by MS. The common drugs used to treat neuropathic pain are described below.

Carbamazepine
Carbamazepine is a dibenzazepine derivative with antiepileptic, neurotropic and psychotropic properties. It is known to block voltage gated sodium channels but may have additional modes of action. It is given orally in two or three divided doses. Treatment should start at 100mg to 200mg daily and be slowly titrated upwards until a satisfactory clinical response is obtained. Some patients may require up to 1600mg daily.
Carbamazepine is a hepatic enzyme inducer and may increase the metabolism of other drugs. It is recommended that a full blood count and serum biochemistry, including liver function tests, are carried out before commencing treatment.

Phenytoin
Phenytoin is normally used as an anticonvulsant but can be effective in treating neuropathic pain. It has several known modes of action. It reduces sodium conductance, enhances GABA-mediated inhibition post-synaptically and can reduce calcium entry through its pre-synaptic actions. A satisfactory maintenance dose would be 200mg to 500mg daily in single or divided doses. Phenytoin is hydroxylated in the liver by an enzyme system which is saturable. Therefore, small incremental doses may produce substantial increases in serum levels in the upper range of therapeutic concentrations. Monitoring of plasma concentrations may assist dosage adjustment.

Tricyclic antidepressants
Drugs such as amitriptyline and imipramine may improve uncomfortable sensations or burning pains of the extremities. They are well established drugs but their use can be limited by their antimuscarinic or cardiac side effects. The usual dose for amitriptyline is initially 10-25mg daily, increasing to 75mg daily. Imipramine is usually effective in the dose range of 25-100mg per day. Tricyclics are usually taken at night because of their sedating effect.
Arrhythmias and heart block occasionally follow the use of tricyclics. The drugs are also sometimes associated with convulsions (they lower the seizure threshold in epilepsy). Hepatic and haematological reactions have been reported.

Other drugs
These include misoprostol,⁷³
lamotrigine,⁷⁴
sodium valproate, baclofen and gabapentin.⁷⁵
They have been shown to have beneficial effects to varying degrees but are not often used to treat pain in MS.

Bladder dysfunction

Urinary disturbances are very common in MS. and usually consist of urgency, frequency, incomplete emptying and sometimes incontinence.⁷⁶
The cause may be urinary tract infection, which should be excluded, especially if symptoms are new or have worsened. Several drugs that may be helpful for urinary symptoms are described below.

Anticholinergic agents
Oxybutynin is an anticholinergic agent, which also exerts a direct antispasmodic effect on smooth muscle, thus inhibiting bladder contraction. The usual dose is 5mg two to three times a day. This may be increased to a maximum of 5mg four times a day if side effects are tolerable.
Tolterodine is a competitive cholinergic receptor antagonist with a selectivity for the bladder. The recommended dose is 2mg twice a day, except in patients with impaired liver function for whom it is 1mg twice a day. Both tolterodine and oxybutynin are contraindicated in patients with glaucoma, urinary retention, myasthenia, severe ulcerative colitis and previous hypersensitivity.

Desmopressin
Desmopressin is especially useful in patients with nocturnal enuresis.⁷⁷
It may be taken in tablet form or as nasal spray. It is an analogue of antidiuretic hormone and temporarily reduces urine volume and frequency. The tablet form (DDAVP) is given at a dose of 0.2mg at bedtime, increasing to 0.4mg if necessary. The nasal spray administers metered doses of 10µg, and 20µg at bedtime is the recommended dose (one spray per nostril), increasing to 40µg, if necessary. Occasional side effects include headache, stomach pain and nausea. Hyponatraemia and fluid retention may also occur and so care must be taken with elderly patients. The nasal spray is associated with nasal congestion, rhinitis and epistaxis.

Other therapies
Suprapubic bladder neck vibration systems have recently been introduced and can improve bladder emptying in ambulant patients.⁷⁸
In severe cases, chemical denervation of the detrusor muscle with intravesicular capsaicin may be necessary.⁷⁹
In some cases urinary diversion procedures have been performed in patients with uncontrollable sphincter incompetence.

Bowel dysfunction

Constipation is the most common symptom of bowel dysfunction in MS. Diarrhoea may also occur and is more distressing.
Management of constipation should include a high-fibre diet combined with high fluid intake, maintaining an active life and establishing a bowel programme. Glycerin suppositories may be used to maintain a regular bowel habit. Stimulating laxatives such as lactulose or senna and softeners such as docusate are also commonly used.
Diarrhoea can be managed with a bulk-forming agent and a regular bowel habit. Loperamide may also be useful.

Sexual dysfunction

Sexual dysfunction may be a pathological or psychological problem. It is present in a high proportion of MS patients. Symptoms include hypo-orgasmia/anorgasmia, decreased vaginal secretion and reduced libido in women, and erectile dysfunction, ejaculatory and/or orgasmic dysfunction and reduced libido in men. Erectile impotence is the commonest complaint in males with MS. This may be helped by intracavernosal injections or by oral sildenafil.

Fatigue

Fatigue is a common complaint and affects up to 90 per cent of patients. Fatigue management plans are normally advised where patients learn to make behavioural changes and to develop strategies to improve their efficiency. The following drugs have been used to treat fatigue.

Amantadine
Amantadine has been used to treat Parkinson’s disease, herpes zoster and influenza A but has also been found to improve fatigue levels in MS.⁸⁰
Approximately 40 per cent of patients respond to amantadine 100mg twice a day. The doses should be given in the morning and early afternoon.

4-Aminopyridine
4-Aminopyridine is not licensed in the UK. It is a potassium channel blocker which improves nerve conduction and, along with 3,4-diaminopyridine, has been found to improve fatigue but its use is limited by side effects.^81,82

Other drugs
Fluoxetine has been used to treat fatigue with mixed results. It is given at a dose of 10-40mg daily. Pemoline,⁸³
a stimulant, is no longer available in the UK. It can cause liver toxicity and psychosis.

Vertigo and dizziness

When vertigo is severe it may be accompanied by nausea and vomiting. Antiemetic agents, such as prochlorperazine or ondansetron may be useful in treating acute or severe vertigo.
Vertigo may also respond to benzodiazepines such as diazepam, clonazepam and lorazepam.

Mood disorders

Depression is the most common mood disorder in patients with MS.⁸⁴
It usually responds to standard antidepressant therapies (eg, sertraline, fluoxetine). The lifetime incidence of major depression in patients with MS is 36 to 54 per cent. Several drugs commonly used to treat MS have been associated with depression, although the evidence is not compelling. These include interferon beta, corticosteroids, benzodiazepines and baclofen.
Sedating tricyclic antidepressants, such as amitriptyline, are especially useful in patients suffering from dysaesthesia or insomnia. Hypomania and psychosis can also occur in MS and are managed with standard psychiatric therapy.

Conclusion

Symptomatic therapy is an important aspect of MS treatment. Along with supportive measures and rehabilitation therapies,^85,86
which have not been discussed in this review, it forms the cornerstone of the management of MS. Therapies have begun to emerge that are able to modify disease activity, although they do not affect its progression. Active research into disease-modifying therapies is ongoing and many potential therapies are being investigated. In the next few years it is hoped that more effective disease-modifying treatments will be found to help patients with MS.

Dr Toosy is a research fellow and Professor Thompson is professor of clinical neurology and neurorehabilitation at the Institute of Neurology, University College, London

Credit for Learning: 1

The Pharmaceutical Journal Vol 264 No 7095p694-700 May 6, 2000 Continuing education

This article forms the basis of questions under the PJ/College of Pharmacy Practice Credit for Learning scheme