A 35 year old female patient has been diagnosed with an acute exacerbation of multiple sclerosis (MS). Women make up 70% of the MS population but this gender preference remains unexplained. Thus, this patient is naturally more susceptible to getting MS as the patient is a female and falls into the 20-40 year old age bracket. In Scotland, 1 in 500 people have MS with women almost twice more likely than men to get the disease in general1,2. Also, about 1800 to 3400 people are newly diagnosed with MS each year in Wales and England which has accumulated to the present day total of 52,000 to 62,000 people3. MS is a relatively mild disease in most where the myelin sheath that covers each nerve fibre and the axons themselves in the central nervous system (CNS) are slowly lost. In MS, unfortunate patients might slowly develop certain disabilities. According to the natural history data, it takes about fourteen years to reach such a critical level of disability that almost nothing can be performed without prior assistance from the onset of the disease17. Myelin is crucial for impulses to travel quickly along the spine and brain for responses to stimuli and also environmental sensations to take place appropriately.
The symptoms that MS exhibit depends on the position of the demyelination process along the CNS4. This is so as different areas of the CNS carry out different information of the body. For example, a common early symptom called unilateral optic neuritis, where there is a sharp pain in the eye during movements or haziness in detecting colours and others, is caused by demyelination and inflammation of the optic nerves4. Optic neuritis may help in early diagnosis if the physician can detect any history of temporary blindness for a week or so, as this is very characteristic of MS1. Other common early symptoms include numbness, double vision, paraparesis, monoparesis, with paresis meaning a loss of movement, bladder control problems, ataxia which is a lacking in muscle coordination or tremors. Common ongoing symptoms include those just mentioned, vertigo which is a type of dizziness, increasing spasticity with spasticity meaning the incidence of muscle spasms, depression, emotional lability, gait abnormalities where the style of walking becomes abnormalk, fatigue, dysarthria, quadriparesis, constipation, fatigue, and pain6. Plaques are most frequently discovered in the areas surrounding the ventricles of the white matter in the cerebrum, the brain stem, the cerebellum, the spinal cord and as previously discussed, the optic nerves7.
Acute episodes of neurological symptoms are thought to be secondary to an episode of demyelination which is caused by inflammation, and therefore most treatments that affect the inflammatory process and immune system are used. Nowadays, there are three ways to treat MS, one being a disease modifying treatment which involves immunosuppressive agents such as azathioprine, and cyclophosphamide, beta-interferons and others, while secondly involving usage of drugs to treat symptoms exhibited by MD patients such as depression, fatigue and spasms and finally corticosteroids to treat relapses6. These treatments on a holistic note are to achieve a few crucial goals, which are to speed up recovery from the neurologic deficits due to the new area of inflammatory demyelination, to ease the severity of the attack and minimise possibly long lasting deficits whether physiological or mental7.
Our patient came in with an acute exacerbation of the disease, which is defined as “episodes of neurological dysfunction that occur spontaneously and are not on the basis of an alternative etiology”. Although we do not know if it is a relapse or it is the first time an exacerbation is occurring, we should treat it with identical treatment steps8. The only drugs that can be used for an acute exacerbation are corticosteroids (CS) which should be started immediately with an option to infuse 500mg-1g methylprednisolone intravenously daily for between 3 and 5 days or to give a high-dose oral methylprednisolone of 500 mg-2 g strength daily for between 3 and 5 days also8. These treatments suggested by the National Institute for Health and Clinical Excellence (NICE) will reduce the possible relapses that might occur but the prognosis will remain unchanged1.
CS work by effectively potentiating the inhibition and suppression of inflammation which is the body's response to pathogens and other immunological factors. Because of their anti-inflammatory and immunomodulating characteristics, these agents have been in the frontline to treat MS6. CS has pretty much replaced adrenocorticotropine hormone (ACTH) as 1st line treatment since it was introduce in 1970. This is because ACTH is theoretically supposed to hasten recovery from an exacerbation by stimulating the production of endogenous glucocorticosteroids (GCS) which will then suppress neuroinflammatory activities but this stimulation is highly variable and inconsistent9.
High IV doses of CS for a short term has been proven by many well-regarded clinical studies to provide symptomatic relief, improve motor function and promote faster recovery of clinical attacks5. This was evident in a meta analysis conducted in 2000, where the recovery of patients that had an acute episode based on the Expanded Disability Status Scale score (EDSS) showed that the recovery rate of the patients who were on the high dose regimen of over 500mg day proved to be statistically significantly higher than patients on the low dose 48mg maximum daily regimen10. However, long term usage of corticosteroid may not be beneficial in controlling further relapses as inflammatory agents such as Interleukin-10 (1L-10) and Chemokine Ligand 12 are only reduced during short-term treatments and are not affected in the long term11. IL-12 may not even be influenced by steroid treatment11.
This is further supported by one systematic review which included four placebo controlled Randomised Clinical Trials (RCT) comparing the effects of ACTH, prednisolone and methylprednisolone given for 9-18 months, one Controlled Clinical Trial and six RCTs which concluded that there were no significant effect on long-term functional improvements or on relapse occurrence12. However, there were numerous side effects commonly associated with CS treatment reported such as herpes simplex, herpes zoster, severe pedal oedema, acute anxiety and severe depression reported12.Two RCTs conducted in a hospital compared the efficacy of oral and IV methylprednisolone and it showed significant results in they both are equally good12. Both routes cost roughly the same over a 5 day period that is needed to treat MS exacerbation at about 50 pounds and is the most cost-effective available currently18.
Other drugs which are given for MS are largely for rehabilitation after an acute episode. There are no good, safe preventive treatments with those with primary progressive MS1. Immunosuppressive agents are one such an example in MS treatments and the most widely used drug currently is an anti-proliferative agent, Azathioprine (AZA)13. Its high usage is probably due to it costing about 10 pounds/week/patient which is much cheaper than other immunomodulators such as interferons rather than its efficacy profile1. AZAis a purine analogue that is metabolized rapidly to the cytotoxic and immunosuppressant derivatives 6-mercaptopurine and thioinosine acid, the latter competing with DNA nucleotides14. AZA has been included in only a few clinical trials as it has lost its patent protection and hence has no resource to fund expensive and high quality clinical trials14. Its usage is certainly controversial as it causes frequent side-effects and thus is generally regarded as a 2nd-line drug13.
Most of the clinical trials showed AZA has no significant beneficial effect to MS patients even though one RCT did state that MRI scans of the brain showed smaller lesions after long term treatment12. However, the patients involved in that trial did not show any symptomatic improvements and this possibly might show us that that there is only a weak link between MS and brain lesions. There is one very good systematic review of a meta-analysis which did prove there was a significant beneficiary effect on MS symptoms15. A study done on 739 MS patients with AZA which was published in The Lancet showed there were slight but significantly more freedom from relapses over a three year span16. Side-effects are mostly dose related and can be possibly be avoided with proper adjuvant drug prescribing15. However, a review found that one in ten patients will suffer from intolerable vomiting and compliance can be a serious problem12.
Interferon Beta (IB) is licensed to use in relapsing, remitting MS however is not recommended by the NHS in England and Wales18. IB is available as its 1a and 1b variant form in the market18. It is also terribly expensive and costs around 200 pounds per week to treat a patient1. Interferon Alpha will not be discussed here as out of the seven RCTs ever done on IA, none reported beneficial effects on MS symptoms and only reported adverse side-effects12. IB is an endogenous natural cytokine that acts through high affinity cell-surface receptors to mobilise transcription factors that modify gene expression. The proteins coded by these IFN beta-regulated genes exhibit anti-viral, anti-proliferative, and anti-inflammatory actions19. It is also possible that the efficacy of IFN beta products is mediated by multiple mechanisms that regulate various components of the inflammatory process in MS19. A paper published on The Lancet, found that out of the 350 MS patients given IB-1a in a Randomised double-blind placebo-controlled study, statistically significantly more of them had reduced number of active lesions, delayed progression in disability and relapse-free periods compared to the 150 MS patient who were on placebo20.
Since MS is a T cell-mediated inflammatory demyelinating disease, it theoretically should makes perfect sense that an IB is administered as it significantly reduces T-cell levels in the body, which then inhibits activation of macrophages that inflame the CNS21. However, even though all the findings above does conclusively show that IB does prevent relapse to a significantly good extent, but if the cost factor has to be taken into account, for example, if the cost for the potential hospitalisation due to a relapse is to be compared to a patient's medication cost for a year, the exorbitant cost needed for a slight increase in the quality of life of a patient, which a cheap drug such as AZA can quite easily provide, does not make this form of treatment very feasible22. IB should not be used in patients with severe depressive illness and those have suicidal ideation18. Patients with liver diseases should especially refrain from using this drug18. Even if a patient has a healthy liver, liver function tests are to be conducted in order to monitor for possible hepatic injuries18.
Glatiramer acetate (GA) consists of 4 amino acids mimicking the myelin basic protein which inhibits T-cell response to several natural myelin antigens23. Thus it is another immunomodulating drug like IB. The advantage with GA is that beyond its anti-inflammatory actions, it is also a neuroprotective agent. This is because GA-specific T-cells obtained from MS patients could express and secret the neurotrophic factor Brain Derived Neurotrophic Factors (BDNF) which promotes tissue repair in the CNS. It is licensed for usage in ambulatory patients with relapse-remitting MS but this is not recommended by the NHS in England and Wales18. There is a strict range of diagnostic guidelines which have to be followed by a specialist in order to initiate a patient on GA12. For example, the patient must be able to walk 100 metres or more without assistance and also should have had at least two clinically significant relapses in the past two years12.
When MRIs are conducted on MS patients, it was found that GA significantly reduces the number of T1 black holes which are areas of oedema or axonal loss caused by MS24. Also, GA-treated patients have been observed to exhibit lower brain atrophy than patients treated with placebo which could possibly mean a better prognosis of the debilitating disease24. A few Multicentre Clinical Trials of GA conducted on 405 patients revealed that in a 2 year long treatment period, relapse and progression rates were significantly reduced by almost 30%15. GA can cause side-effects such as palpitation, flushing, chest pain, tachycardia and dyspnoea which might occur immediately after administration18. A recent publication has casted doubts on the cost-effectiveness of IB and GA and the current risk-sharing scheme.12 The amount of money spent by the NHS on disease-modifying therapies , including not only the drugs themselves but all the extra resources needed to run the scheme is large. Furthermore, this scheme only affects about 15% of people with MS and many of those eventually discontinue IB due to intolerable side effects12.
Other 2nd-line drugs used to rehabilitate the patient and modify the disease are Alemtuzumab and Mitoxantrone but there are huge safety issues in its usage and there no high quality clinical trials to back its usage in MS other than perhaps a possible usage in secondary progressive MS1. Thus we will go further into drugs that can be prescribed to alleviate MS symptoms which can help patients to live well. Given the large number of impairments that may arise secondary to multiple sclerosis, the large variety of contexts that will apply to people with MS, and therefore the almost infinite number of particular situations, each being unique, it is currently very difficult to be sure that the correct drug to be given to a patient is administered, especially since there are no such guidelines available partly due to the complexity of MS symptoms12.
Baclofen, diazepam, dantrolene, gabapentin and tizanidine are licensed for use in the alleviation of chronic muscle spasm associated with MS18. If spasticity or spasms are present, then simple causative or aggravating factors such as pain and infection should be sought and treated. Spasms may create pain, interfere with mobility and activities of daily living, alter posture, interfere with sleep, lead to joint contractures and increase the risk for skin breakdown26. Out of the five, baclofen, gabapentin and dantrolene are especially recommended in MS treatment as they are the best researched upon drugs with significantly beneficial results18,26.
Currently, if spasm is diagnosed in MS patients, then gabapentin or baclofen should ideally be started upon if the aggravating factors can't be immediately spotted12. Gabapentin was designed to physically resemble gama-aminobutyric acid (GABA) neurotransmitter and hopefully work in that pathway but its true mechanism of action is unknown27. A trial showed that at a dose of 400mg orally three times a day, gabapentin may be of value of being a significantly effective anti-spasmodic26. Gabapentin rarely has any side effects26. Baclofen inhibits transmission at spinal level and also depresses the CNS making it a powerful skeletal muscle relaxant18. Three trials showed statistically significant reduction in the number and intensity of muscle spasms after they were put on Baclofen28-30. Baclofen also is less sedative than diazepam and tizanidine18. However, 25-30% of patients on Baclofen will not have satisfactory relief from spasms and other choices of drugs should be considered here26.
Dantrolene specifically acts upon the skeletal muscle and thus produces lesser central adverse effects which make it the drug of choice right after the two above have proven not to work12,18. Based on all the trials Dantrolene was put through, as per its mechanism of action, it is a very safe drug with very little side-effects but unfortunately also with a very insignificant effectiveness on reducing spasms12. All these anti-spasmodic drugs should be cautiously titrated so as to not cause any more side-effects than the patient is already suffering from18. These drugs are also fairly cheap and thus the drug that best works for a patient should be prescribed perhaps life-long so as to improve his/her quality of life18.
For my patient, i would start her on a CS treatment to immediately bring her exacerbation down. She would be given a high-dose oral methylprednisolone of 500 mg-2 g strength daily for between 3 and 5 days as it usually takes that long to treat an acute MS exacerbation. The oral dose is chosen simply because I do not want to stress up the patient even more than she already is. If she can't swallow the pills, only then would 500mg-1g methylprednisolone be infused intravenously.
To rehabilitate the patient after the relapse has been cured, AZA should be prescribed as IB is simply too expensive and GA is not recommended by the NHS18. As AZA is extremely irritant by the IV route, an oral dose of 1-3mg/kg a day should be started ideally titrating from lowest possible dose as this drug cause vomiting very often7. Initially anti-emetics should not be prescribed so as to determine the optimum lowest dose to exert good anti-inflammatory which could in turn prevent a relapse12. Once the dose is found, an anti-emetic such as 20mg Domperidone up to 4 times a day if needed should be prescribed18. Lastly, an anti-spasmodic should be prescribed if patient complains of painful and frequent spasms. Gabapentin 400mg orally three times a day or an initial low dose of Baclofen 5mg three times a day up to a max of 100 mg should be considered12. Side effects for Baclofen especially should be monitored if a high increase in dose is needed to control spasms29,18. The pharmacological and clinical evidences are as previously discussed above.
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CLINICAL PHARMACOLOGY AND PRESCRIBING