Multiple sclerosis

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A devastating and protean disease, diagnosis of which cannot nowadays be deliberately delayed, given MRI



This is a disease characterised by inflammation and damage to myelin resulting in the appearance of plaques of gliosis throughout the brain and spinal cord. It tends to affect young adults but cases also occur in the elderly. The fear is often severe disability but most will lead a fairly normal life. Modern imaging has meant that the diagnosis is easier and milder cases found.

Info bulb.pngMRI is not universally accepted as being the last word. Disease which is clinically MS is likely to be MS and MRI may add less to certainty than is generally thought.[1]


Many agents have been suggested, viral, environmental and genetic. There is an apparent unexplained proclivity for MS occurring more frequently in higher latitudes (above 40 degrees). There is some immunological and epidemiological evidence for a latency phase after an initiating event that may occur more than 10 years before clinical manifestations. Increased genetic risk is associated with[2]:

  • HLA-DRA at 6p21 which is a very strong association perhaps mainly contributed to by DRB1 alleles but also HLA-C gene variations.[3]
  • Interleukin-2 receptor α (IL2RA) gene variants on chromosome 10 coding for CD25 (as expected if daclizumab is to work[4] !)
  • Interleukin-7 receptor α (IL7RA) gene variants on chromosome 5 possibly affecting homeostasis of the memory T-cell pool[5][6].


Disease involving

  • Optic nerve
    • Optic neuritis
    • Retrobulbar neuritis
  • Spinal Cord
    • Spastic paraparesis
    • Spastic bladder
    • Lhermitte's sign
  • Cerebellum
    • Nystagmus
    • Ataxia
    • Dysdiadochokiesia
    • Past pointing
    • Scanning speech
  • Brainstem
    • Cranial Nerve lesions
    • Diplopia
    • Spastic weakess
    • Dysarthria
    • Ataxic nystagmus


  • Benign multiple sclerosis may show no progression for 20 years and occurs in about 15%.
  • Relapsing–remitting multiple sclerosis is the presentation in 85% of Western patients with episodic, often reversible neurologic dysfunction
  • Secondary–progressive multiple sclerosis develops in 75% with progressive and irreversible worsening of neurological state
  • Fulminant multiple sclerosis is the development of severe disability within 5 years of onset and is rare



  1. Two demyelinating episodes
  2. Appearance of new, typical lesions on MRI or unequivocal evidence of one or more previous demyelinating episodes[7]


  • MRI

Demyelination of periventricular areas.


Presently reserved for flare ups in relapsing–remitting multiple sclerosis.

  • Interferon-beta (IFN-beta) is likely to be beneficial in slowing disease progression[9]. There is evidence for a small benefit in those treated at first event[10]. The main issue is cost effectiveness compared with symptom management alone[11].
  • Glatiramer acetate (copolymer 1) is of unknown effectiveness even if it reduces demylination burden[12]
  • IV Methylprednisolone is advocated by some. It shortens flare ups but overall long term effects are uncertain as there is little RCT evidence
  • α4-integrin antagonists such as natalizumab noting the feared side effect of progressive multifocal leukoencephalopathy.
  • In development drugs such as daclizumab[13] and alemtuzumab which phase 3 trials indicate may be superior to interferon beta-1a[14].
  • There is some preliminary evidence for optic nerve remyelination with clemastine at high dose[15]. Benzatropine might have similar properties[16].

Ineffectual treatment

This includes a rather long list of medications including pulse long term steroids[17] and simvastatin[18].


The lesions of multiple sclerosis have demyelination associated with mononuclear leukocyte infiltrates. Animal models have implicated the interaction between α4β1 integrin (very late activation antigen - (VLA)-4) on T cells and counter-receptors on the vascular endothelium.[19]. This lead to clinical trials of α4-integrin antagonists.



  1. Whiting P et al. "Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis: systematic review". doi 10.1136/bmj.38771.583796.7C This is an early paper and requires further evaluation.
  2. Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ. Risk alleles for multiple sclerosis identified by a genomewide study. The New England journal of medicine. 2007 Aug 30; 357(9):851-62.(Link to article – subscription may be required.)
  3. Yeo TW, De Jager PL, Gregory SG, Barcellos LF, Walton A, Goris A, Fenoglio C, Ban M, Taylor CJ, Goodman RS, Walsh E, Wolfish CS, Horton R, Traherne J, Beck S, Trowsdale J, Caillier SJ, Ivinson AJ, Green T, Pobywajlo S, Lander ES, Pericak-Vance MA, Haines JL, Daly MJ, Oksenberg JR, Hauser SL, Compston A, Hafler DA, Rioux JD, Sawcer S. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Annals of neurology. 2007 Mar; 61(3):228-36.(Link to article – subscription may be required.)
  4. Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG. Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Neurology. 2007 Aug 21; 69(8):785-9.(Link to article – subscription may be required.)
  5. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL. Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature genetics. 2007 Sep; 39(9):1083-91.(Link to article – subscription may be required.)
  6. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Salter H, Olsson T, Hillert J. Variation in interleukin 7 receptor alpha chain (IL7R) influences risk of multiple sclerosis. Nature genetics. 2007 Sep; 39(9):1108-13.(Link to article – subscription may be required.)
  7. Swanton JK, Fernando K, Dalton CM, Miszkiel KA, Thompson AJ, Plant GT, et al. Modification of MRI criteria for multiple sclerosis in patients with clinically isolated syndromes. Journal of neurology, neurosurgery, and psychiatry 2006;77(7):830-3. (Direct link – subscription may be required.)
  8. Kuhle J, Pohl C, Mehling M, Edan G, Freedman MS, Hartung HP, et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. The New England journal of medicine 2007;356(4):371-8. (Direct link – subscription may be required.)
  9. Clerico M, Contessa G, Durelli L. Interferon-beta1a for the treatment of multiple sclerosis. Expert opinion on biological therapy 2007;7(4):535-42. (Direct link – subscription may be required.)
  10. Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalbán X, Barkhof F, Radü EW, Bauer L, Dahms S, Lanius V, Pohl C, Sandbrink R. Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study. Lancet. 2007 Aug 4; 370(9585):389-97.(Link to article – subscription may be required.)
  11. Bell C, Graham J, Earnshaw S, Oleen-Burkey M, Castelli-Haley J, Johnson K. Cost-effectiveness of four immunomodulatory therapies for relapsing-remitting multiple sclerosis: a Markov model based on long-term clinical data. Journal of managed care pharmacy : JMCP 2007;13(3):245-61.
  12. Munari L, Lovati R, Boiko A. Therapy with glatiramer acetate for multiple sclerosis. Cochrane database of systematic reviews (Online) 2004;(1):CD004678. (Direct link – subscription may be required.)
  13. Wynn D, Kaufman M, Montalban X, Vollmer T, Simon J, Elkins J, O'Neill G, Neyer L, Sheridan J, Wang C, Fong A, Rose JW. Daclizumab in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, add-on trial with interferon beta. Lancet neurology. 2010 Apr; 9(4):381-90.(Link to article – subscription may be required.)
  14. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Bass AD, Wynn DR, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston DA. Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes. Lancet neurology. 2011 Apr; 10(4):338-48.(Link to article – subscription may be required.)
  15. Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Büdingen HC, Henry RG, Hauser SL, Chan JR. Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial. Lancet (London, England). 2017 Oct.(Print-Electronic) (Link to article – subscription may be required.)
  16. Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, Padmanabhan K, Swoboda JG, Ahmad I, Kondo T, Gage FH, Theofilopoulos AN, Lawson BR, Schultz PG, Lairson LL. A regenerative approach to the treatment of multiple sclerosis. Nature. 2013 Oct; 502(7471):327-332.(Print-Electronic) (Link to article – subscription may be required.)
  17. Ravnborg M, Sørensen PS, Andersson M, Celius EG, Jongen PJ, Elovaara I, Bartholomé E, Constantinescu CS, Beer K, Garde E, Sperling B. Methylprednisolone in combination with interferon beta-1a for relapsing-remitting multiple sclerosis (MECOMBIN study): a multicentre, double-blind, randomised, placebo-controlled, parallel-group trial. Lancet neurology. 2010 Jul; 9(7):672-80.(Link to article – subscription may be required.)
  18. Sorensen PS, Lycke J, Erälinna JP, Edland A, Wu X, Frederiksen JL, Oturai A, Malmeström C, Stenager E, Sellebjerg F, Sondergaard HB. Simvastatin as add-on therapy to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet neurology. 2011 Jul 8.(Epub ahead of print) (Link to article – subscription may be required.)
  19. Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 2005;64(8):1336-42. (Direct link – subscription may be required.)
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