the changing scope of Multiple Sclerosis; 11.10.2015, prepared by Drs Wright and Schepel for education purposes only

Multiple Sclerosis: is a chronic inflammatory disease of the Central Nervous System. It is the most common cause of non-traumatic disability in young adults. Prevalence in New Zealand is 72100.000 and due to it chronicity most General Practitioners will see patients regularly. Multiple Sclerosis has always been a challenging disease. MS symptoms include fatigue, depression, spasticity, tremor, ataxia, pain, seizures, sleep disorders, nystagmus, sexual dysfunction, Bowel and bladder dysfunction among others. Before finally coming to a diagnosis of Multiple Sclerosis it is important for the Neurologist to rule out 'MS mimics' such as spinal tumours or bleeds or infarcts, Vasculitis, B12 deficiency, Sarcoidosis, Lupus, Hypercoagulable states, CNS lymphoma, Infection, Ischemia, Toxins and more. The wide variety of symptoms can make it difficult to diagnose and makes symptomatic treatment challenging. In recent years it has also become possible to treat the underlying auto-immune mechanisms and thus the outcome of disease progress. Multiple medications have become available and more are due. All with their own advantages and side-effects of which some serious, making choosing the right therapy at the right time demanding. Because of the complexity of the condition and its treatments specialist follow up is mandatory to make timely adjustments to achieve optimal outcome for the individual patient. Therapeutic management includes: relapse treatment, disease modifying treatment and symptomatic treatment. In general therapy should be initiated as early as possible. Indication depends on clinical course, disease stage and disease activity.



Modern treatments:

1.For acute relapses that are sufficiently disabling to warrant the risks of treatment, and if infection and fever are ruled out, then typically treatment is with IV or occasionally oral Methylprednisolone 500-1000mg daily for 5 days. This hastens recovery but probably has little impact on long term outcome.

2.Immunomodulators: Interferon-beta (Avonex, Betaferon), Glatiramer Acetate (Copaxone). There is now long experience and good safety profile. 30% reduction in Relapse Rate.

3.Natalizumab (Tysabri). Monoclonal antibody. 75% reduction in clinical relapses and perhaps 40% complete cessation of all clinical and radiological activity

4.Fingolimod.(Gilenya) Oral treatment. 50% reduction in clinical relapses.

5.Further medications will likely be available in not so distant future: Dimethyl Fumarate, Ocrelizumab, Alemtuzumab, and more.



All these new therapies will bring different benefits to different patients, but also potential dangerous side effects. Best known of these is PML (Progressive Multifocal Leukoencephalopathy), caused by JC-virus reactivation with severe and sometimes fatal outcome. To service patients best these changes dictate the need for close follow up and specialised care in order to stabilise and improve the effects of CNS inflammation, but also to protect against unwanted complications of treatment. For General Practitioners discriminating between MS symptoms and possible side effects of the new MS drugs can be a daunting task. Least experience will be with Natalizumab and Fingolimod, but these have now become standard practice (PHARMAC funding changes) in New Zealand for most patients so will be frequently encountered.



Since MS patients using Natalizumab and Fingolimod will need regularly specialist follow up, task of GP practise will be to monitor anything out of the ordinary during interval between clinic visits and refer patient back earlier if indicated or discuss with treating neurologist questions around treatment and symptoms.
Specific guidance regarding the newer agents:

1.Natalizumab: This is a monthly IV injection at a specifically-trained centre. For patients on treatment with Natalizumab ordinary UTI and respiratory infections are increased. These can be treated in a routine fashion. The risk of opportunistic infections or PML is low, however important to detect early. One of the first symptoms can be cognitive or behavioural change. Any sign of relapse while on this treatment should be looked at with suspicion since Natalizumab is very effective in most patients who fulfil criteria for treatment. Any uncertainty can be discussed with patients neurologist or clinical MS nurse. General blood tests will be followed up through MS clinic before every treatment which patients will get 4-6 weekly as an infusion in hospital. It is not recommended to become pregnant while on treatment because of insufficient data around safety. Stopping Natalizumab can cause an Immune Reconstitution Syndrome and worsening of MS disease. This should not be done unsupervised by a specialist.



2.Fingolimod: the greatest advantage is that it is an oral treatment. It is relatively new on the market and the long term safety profile is not completely defined at this point in time. Patients will receive the first dose in hospital under monitoring of heart rate, since bradycardia at start up is common. This is usually transient. Also QTc interval has to be < 500msec. It is recommended to repeat first dose observation in hospital if patient discontinues treatment within the first month or pauses treatment for >2 weeks after first month. Patients on Fingolimod should not use medications that prolong QT interval, eg antiarrhytmics, betablockers or other heart-rate lowering medication (calcium channel blockers, digoxin, pilocarpine etc). Other risk factors for QT prolongation are Hypokalemia and Hypomagnesemia. Fingolimod is not recommended for patients with cardiovascular risk factors. Macular oedema is infrequently seen usually in first 3-4 months with or without symptoms and because of this all patients will get a baseline OCT (Ocular Coherence Tomography) which can be repeated in case of symptoms of blurry vision or reduced visual acuity and therefor important that GP's refer patients back urgently in case of visual disturbances. It is more common in diabetics or those with inflammatory eye diseases. Fingolimod is immunosuppressive. Although memory T cells remain in circulation and should protect against locally invading pathogens, the peripheral lymphocyte count is decreased and infection risk especially for lower respiratory tract, bronchitis, pneumonia and Herpes Zoster seems to be increased. Treatment has to be interrupted if serious infection occurs or lymphocyte count markedly reduced while having infection (lymphocyte count >30% lower compared to baseline value). Concomitant use of corticosteroid therapy (for other diseases or for MS relapse) requires individual risk-benefit assessment. Vaccinations may be less effective during and for up to 2 months after treatment with Fingolimod. Attenuated vaccines may carry risk of infection and should be avoided. If patients with recurrent herpes simplex, history of shingles, hepatitis B or C or cancer should be started on treatment has to be assessed by neurology team. Patients with respiratory disease have to be treated with caution and respiratory function has to be monitored. A baseline lung function test can be useful. Hepatic transaminases and full blood count have to be monitored regularly. Three monthly first year. Longer interval thereafter. Patients who develop symptoms suggestive of hepatic dysfunction as nausea, vomiting, abdominal pain, fatigue, anorexia, jaundice or dark urine should have liver enzymes checked and Fingolimod discontinued if liver injury confirmed (Hepatic transaminases >3x ULN). Fingolimod and pregnancy: Women receiving Fingolimod should not become pregnant or breast-feed (for at least 2 months following discontinuation) In animal studies Fingolimod was found teratogenic. Effective contraception is needed.



3.Fampridine (Fampyra) 4-aminopyridine is symptomatic treatment for MS patients with spinal cord lesions. It has some potential to improve gait. It is a non-selective potassium channel blocker believed to restore neural conduction over demyelinated nerves. It does not prolong QTc interval. It is currently not funded. It should not be used with renal impairment or seizures



4.High dose Biotin or vitamin B7 treatment has recently emerged as possible therapy for progressive Multiple Sclerosis. High dose Biotin (300mg daily) possibly promotes myelination through enhanced myelin formation in oligodendrocytes as well as replenishing ATP in hypoxic neurons. We are currently waiting for results from the extension phase of the French trial to confirm impact of Biotin on long term disability progression. Biotin is available in lower doses in health shops (10.000 micrograms). And patients can also discuss this with MS Society Waikato. It can be purchased at 100mg tds at huge cost ($780/month) in Auckland at present, and on 12.03.2016 a patient of ours let us know they found Biotin 300mg a day can apparently be sourced for USD $130/month at http://multiplesupplements.com/collections/all-products. We trust the price will rapidly come down for this simple product vets feed to large farm animals for their hooves.








 

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