Bajtín y la voz del otro Bases teóricas aplicables en Lazarillo

Management of the MS patient begins at presentation with the first symptom,

investigation and subsequent diagnosis. This is a particularly crucial time and the key areas of management are education and support (Werring and Thompson 1998a). In

established MS, patient management can be split into four main areas;

1) Anticipation and prevention of problems 2) Symptomatic treatment

3) Therapies aimed at reducing disease activity 4) Rehabilitation and service delivery

Each of these areas will be considered briefly, in turn.

1.7.1 Anticipation and Prevention o f Problems

Maintaining good general health is of prime importance in MS, it has been suggested by Petajan and colleagues that regular aerobic exercise, when possible, increases physical

and psychological well-being (Petajan 1996). The role of diet in MS remains an area of debate. Several studies have implicated the consumption of animal fat, others propose

dairy products increase the risk of MS (Lauer 1997). A beneficial effect of increasing

intake of o)-3 and 0)-6 fatty acids has also been suggested to decrease the frequency and severity of relapses, although no effect on long term outcome has been found (Dworkin

1984, Bates 1989). However many of the epidemiological studies have been inconsistent

and no definite relationship between MS and dietary intake has been elucidated. General dietary advice to patients is to decrease animal fat and increase both vegetable fat and

seafood intake (Lauer 1997).

As relapses may be precipitated by intercurrent infections, these should be treated

promptly and more importantly prevented if possible, particularly in relation to the

urinary and respiratory tracts. Large residual urinary volumes or poor intermittent self

catheterisation techniques are often responsible for precipitating urinary tract infections.

With regular assessments and training these can be avoided. In the respiratory tract early

signs of aspiration should be noted and a speech therapist involved early for advice on practical management.

The question of whether patients with MS should receive vaccinations has been long debated, but recent work (Miller A 1997) suggests that the influenza vaccination does not

increase the risk of disease exacerbation and thus should not be contra-indicated in MS. The risk of other vaccines have not been studied in MS however the risk to benefit ratio of these immunisations is probably low when used in ‘at risk’ patients and should always

be offered (Panitch 1997).

Spasticity and weakness can also lead to problems with abnormal posture and gait. This can put excessive strain on the back and result in mechanical problems with considerable

pain. Untreated spasticity can also lead to contractures with consequent increasing

disability and permanent loss of function.

In the past patients were often advised not to become pregnant as this was associated with

disease exacerbation, however the relationship between pregnancy and MS has become

clearer more recently. Prospective studies have suggested that the relapse rate is decreased during pregnancy but raised during the three month puerperium, giving little

difference in the overall relapse rate over the pregnancy year, or in the long term disability of the patient (Confavreux 1998). It is generally felt that patients wishing to

start a family should not be discouraged from doing so.

1.7.2 Symptomatic Treatment

Realistically, the recent advent of new immunosuppressant treatments will have little

impact on existing problems and disability; consequently much of the management of a

patient with MS relates to control of a vast array of symptoms (Thompson 1998a, Clanet 1997). Much can be done for the patient in all areas. A combination of education,

physiotherapy and drug therapy is usually required but occasionally there is a place for more invasive treatments such as intrathecal baclofen administration for severe spasticity,

thalamic surgery for cerebellar tremor or intravesical capsaicin for severe detrusor hyper- reflexia.

Acute relapses which are significantly affecting a patients function can be treated with a short (three day) course of intravenous steroids, this has been shown to accelerate recovery although has no effect on long term outcome (Thompson 1989, Miller 1992).

1.7.3 Therapies Aimed at Reduction o f Disease Activity

In recent years considerable progress has been made in the understanding of the complex

immunopathological mechanisms underlying MS, many of these discoveries have led to the investigation of new therapeutic strategies (see table 1.1). Beta interferons (la and lb)

are now licensed worldwide and Glatiramer acetate (copaxone) is in use in the United States and Israel. Many others drugs are undergoing pivotal trials (Stevenson 1998b).

Interferons. There are three forms of beta interferon now available, interferon beta-lb (IFNB-lb, Betaseron in North America, Betaferon in Europe) given as a subcutaneous

injections every other day, at a dose of 300 micrigrams or 9.6 million lU, interferon beta- la (IFNB-la, Avonex) as a once weekly intramuscular injection at a dose of 6 million lU

(30 micrograms) and interferon beta-la (IFNB-la, Rebif) given as a subcutaneous

injection three times a week at a dose of 6 million lU (22 micrograms). Common side

effects include injection site reactions and flu-like symptoms including fever, chills and muscle aches. Considering the results of the pivotal trials in RR MS, all three interferons

demonstrated a reduction of the relapse rate in the order of one third (Paty 1993, IFNB

1995, Jacobs 1995, Jacobs 1996, PRISMS 1998). In the Betaferon study there was no

significant difference between the treated and placebo groups when considering progression of disability, both the Rebif and Avonex studies of IFNB-la suggested lower rates of progression in the treated groups compared to the placebo groups. The Rebif

study reported a reduction in total lesion load seen on T2 weighted MRI, the Betaferon a stabilisation of T2 lesion load and the Avonex study no effect. All three studies described a striking reduction of new gadolinium enhancing lesions as compared to the placebo controls. More recently a European multicentre study of IFNB-lb for SP MS has

been completed, this demonstrated again a reduction in relapse rate by one third but more

importantly a significant difference between the treated and placebo groups in time to confirmed disability progression and time to reach defined disability end-points

(becoming wheel chair bound) (European study group on Interferon p-lb in secondary

progressive MS 1998). These differences were in the order of 20-32% and were independent of baseline disability or superimposed relapses (Miller 1998a and 1998b).

This study demonstrated for the first time that IFNB has an effect not only on the relapses

of MS but also slows the insidious disease progression probably responsible for the majority of disability in MS.

Table 1.1: Therapeutic agents in multiple sclerosis.

Licensed Treatment for Relapsing-Remitting MS

-Interferon beta-lb (betaferon) -Interferon beta-la (avonex, rebif) -Glatiramer acetate (copaxone)

Drugs Undergoing Pivotal Trials

-Interferon beta-lb (SP MS and clinically isolated syndromes)

-Interferon beta-la (SP and PP MS, and clinically isolated syndromes) -Intravenous immunoglobulin

Other Drugs Investigated

-Mitoxantrone (effective in RR MS and ‘active’ MS) -Cladribine (of no proven benefit)

-Methotrexate (effective in small study of progressive patients) -Oral tolerance: ingested myelin (negative study)

-Sulfasalazine (of no proven benefit)

-Linomide (adverse effect: ischaemic heart disease) -Hyperbaric oxygen (of no proven benefit)

-Deoxyspergualine (of no proven benefit)

-Total lymphoid irradiation (of no proven benefit) -Ginkolide B (of no proven benefit)

-Acyclovir (non significant reduction in relapse rate) -Anti- CD4 (of no proven benefit)

Future Therapies

-Monoclonal antibodies (Campath -IH) -Adhesion molecule therapies

Further studies with the interferons are ongoing, they include, IFNB-la (Rebif) for SP

MS and IFNB-la (Avonex) for RR, SP and PP MS (Leary 1997). Both Rebif and Avonex

are also being studied in patients with clinically isolated syndromes (monosymptomatic)

to detect if the time to conversion to MS can be delayed.

Glatiramer Acetate (Copaxone). This is a mixture of several polypeptides (L-alanine,

L-glutamic acid, L-lysine and L-tyrosine) in a specific ratio. Its therapeutic effect is

thought to involve inhibition of the immune response to myelin basic protein. In 1991 a pivotal trial showed a reduction in relapse rate of 29% in the treated group (Johnson

1995, Wolinsky 1995). There was no difference in progression to disability and a very limited MRI study did not show any treatment effect on total T2 lesion load or in the

number of new enhancing lesions (Cohen 1995). It is given as a daily subcutaneous injection. Side effects are rare but include injection site reactions and a rare transient systemic reaction consisting of flushing, chest tightness, shortness of breath and anxiety,

lasting between 30 seconds and 30 minutes.

Intravenous Immunoglobulin. The mechanism of action of intravenous immunoglobulin (IVIG) in MS is unknown but is thought to be a combination of T cell

receptor blockade, modulation of cytokine activity and induction of antigen specific

supressor cells. Animal studies have suggested that it might promote remyelination. A recent double-blind, placebo controlled study of monthly IVIG infusions in 150 patients

for two years showed that IVIG treatment had a beneficial effect on the course of clinical disability (Fazekas 1997). It is well tolerated with very few side effects.

1.7,4 Rehabilitation and Service Delivery

A multi-disciplinary approach is required to deal with the wide range of disabling and

interacting symptoms seen in MS. Multi-disciplinary team assessments identify areas of

potential functional improvement and patient-centred, goal-orientated rehabilitation

programmes are initiated (Thompson 1996).

Short periods of intensive inpatient rehabilitation have been shown to reduce levels of disability and handicap (Freeman 1997), the benefit persisting for at least six months

(Freeman 1999).

Ideally the patient with MS and their carers should be managed in a comprehensive,

flexible, community based service with close links to a neuroscience centre. This is usually achieved by ensuring a link worker or community care co-ordinator is established

to deal with both the purchaser and provider. Their role should ideally also include the continuation of education and training for both the patients and health professionals

(Thompson 1997a).