1. Multiple Sclerosis Short synopsis Ross Bills 11/2/06

2. Pathology  Demyelination (loss of white matter) within CNS/Spinal Cord  Myelin sheath degenerates, fat-granule cells and lymphocytes in perivascular spaces, sclerotic plaque later (shrunken, greyish to naked eye)  Single/multiple lesions  Multiple sites present confusing clinical picture  Clinical findings dependant on sites

3. Aetiology  Complex  Geography - temperate climates more than tropical, but if people move regardless of genetic background they carry the risk of where they grow up  Familial - familial - 5%  Precipitants - complex, infection including influenza, pregnancy puerperium and lactation, allergy, surgery, trauma  Biochemical - Myelin 75% lipids, 25% proteins, enzymes that break down the protein have been found at edges of plaques, low dietary intake of polyunsaturated fats in areas where incidence is higher?  Immunological - demyelinating antibody found in plaque which acts on glial cells?  Viral - increased incidence of high antibody titres to measles, mumps, vaccinia and herpes simplex  Allergic - some animal studies showed similar pathology.

4. Presentation  Age 20-40 years at onset (12-60 not unheard of)  1:2000 in England and Wales  19,000+ patients in Australia  No sex bias  One of the commonest neurological conditions

5. Types of MS  Relapsing Remitting  Progressive Relapsing  Secondary Progressive  These terms describe the pattern of the disease over time.

6. Clinical  Two presentations  Single or several focal lesions worsening over a short time - settling over 1 to 2 weeks  Visual changes (optic neuritis)  Numbness or weakness of a limb, face  Bladder symptoms  Insidious onset slowly progressive, classically weakness of one or both lower limbs  Remission may see signs improve or vanish

7. Symptoms  There is no set pattern to MS and everyone with MS has a different set of symptoms, which vary from time to time and can change in severity and duration, even in the same person.  The systems commonly affected include:  vision  co-ordination  Strength  sensation  speech and swallowing  bladder control  sexuality  cognitive function  Fatigue  http://www.msif.org/en/symptoms_treatments/index.htm l

8. Value of the history  Because of the variability of signs and symptoms the history is all important - there may be NO clinical signs  Only later after several attacks may the signs become more permanent  More acute onset:  Pallor of the optic disc (unilateral)  Slight unilateral nystagmus  Slight intention tremor  Changes in abdominal or tendon reflexes, extensor plantar response (Babinski)  Insidious onset:  Predominantly spinal signs  Spastic paraplegia  Sensory including vibration sense changes, position sense changes  Spastic or ataxic gait

9. Investigation 1  Investigate to exclude other causes:  Differential Diagnosis  Spinal Cord Compression  Cervical Spondylosis  Hereditary Ataxias  Tabes Dorsalis  Vitamin Deficiency (B12)  Psychological/Psychiatric Disorders  Others

10. Investigation 2  Old: Lumbar puncture looking for abnormal proteins, monoclonal bands (oligoclonal IgG)  Ongoing: Visual evoked responses, (2/3 of people with clinical MS and no visual symptoms had abnormal VER) Auditory evoked responses, (May show changes in brainstem lesions)  Best: MRI Scan defines demyelinated lesions very well

11. Prognosis  Such a variable course  The prognosis becomes clear only after observing the patient over time  Rapidly Progressive versus Exacerbations with remissions of variable time (up to 20 years and more)

12. Treatment 1  In the absence of curative treatment patient education and support is vital  Bladder disorders are common  Probanthine improves bladder control  Fatigue and tiredness are common  Exercise and activity within achievable levels has been shown to be beneficial  Muscle spasm and spasticity  Baclofen may help, physiotherapy, exercise  Specific Dietary Measures may be of little value  Avoidance of animal fat led to reduction in polyunsaturated fatty acids, B12 injections only useful if there is a deficiency

13. Treatment 2  Does anything help?  In the past IV methylprednisolone infusions over five days showed some benefits in reducing length of exacerbations and severity - still used.  Dexamethasone also used  Oral steroids may also be useful (Prednisolone)  No real benefits with long term steroids  Azothioprine and other immunosuppressants showed little value in relatively benign cases, where side effects outweighed benefits  Psychological Support may be beneficial in terms of CBT to assist in coping strategies, and also in the treatment of the often present co-morbid depression of chronic disease

14. Treatment 3  Newer Options:  Interferon has been shown to reduce recurrences and degree of disability in people who have the exacerbation/remission pattern of MS  Side effects can be severe - injection site reactions, flu like symptoms, fatigue, headache, muscle and joint pains  Interferon beta-1a (Avonex)  Interferon beta-1b (Rebif)  Interferon beta-1b (Betaferon)

15. Treatment 4  Newer Options:  Methotrexate may have some benefits, but these need to be weighed against the serious side effects  The benefits found were not statistically significant.  This raises an obvious evidence based medicine question? Refer to Cochrane database.

16. Treatment 5  Newest:  Mitoxantrone (MX) [Immunosupressive drug]  Has shown benefits in short term treatment of MS  Side effects are significant, and limit its use to those with evidence for significantly worsening disability  Amennorhea, nausea, vomiting, alopecia, UTI’s, transitory leucopenia in the short term  Cardiotoxicity, therapy related acute leukaemias in the longer term  Copaxone (glatiramer acetate)  Hippocrates: “First do no harm!”  Bills: “If the cure is worse than the disease, then let the patient decide to have the disease!”

17. Treatment 6  Alternative Therapies  Supplements and vitamins - no scientific support  Fatty Acids - may have a modest effect in slowing progression, reducing severity and duration of exacerbations  Diets - a balanced diet may do no good, but will do no harm. No evidence for value of “fad diets”  Removal of old “mercury amalgam” fillings - no evidence  Acupuncture - may have psychological benefits, no influence on course of disease. Relief of pain and muscle spasm nay be a real benefit though.  Yoga/Meditation - again, psychological benefits, no influence on course of disease  Hyperbaric Oxygen - no effect on course of disease

18. Limitations  We don’t understand the cause, we have limited treatment options, and the things we do have an enormous potential to make the patient’s life worse  More than ever this is the sort of case where we should educate and involve the patient in the clinical decision making process  In general practice it is necessary to remember the need to consider all the other aspects of the patient’s life about which we can do things.  If there is a teaching point in this sort of case, it is that Humility is far better than Hubris