Multiple sclerosis medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [15]
Overview
Medical Therapy
Disease-modifying treatment of relapsing-remitting multiple sclerosis:
Relapsing-remitting type of MS can be treated with disease modifying therapy (DMT) in order to reduce the rate of attack and disease progression.[1][2]
Infusion therapy:
- Natalizumab: This drug works as an antibody against alpha 4 subunit of integrin. As a result of Blood brain barrier disruption, inflammatory cells like lymphocytes and monocytes can access brain parenchyma and start the process of inflammation and destruction. Integrin 4 is on the surface of these inflammatory cells and helps their adhesion to vascular endothelium. Based on some studies using this drug can reduce signs, symptoms and relapses of the disease.[3][4][5][6]
- Alemtuzumab: This drug is a monoclonal antibody and can cause reduction in CD52-expressing T cells, B cells, natural killer cells and monocytes. The side effects of this drug includes: infection, autoimmune disorders and infusion reaction.[7][8][9]
- Ocrelizumab: Ocrelizumab is a monoclonal antibody against CD20 causing B cells depletion.[10] It can reduce gadolinium-enhancing brain lesions on MRI of MS patients.[11]
- Mitoxantrone: This drug has some serious side effects including cardiac toxicity, so it’s more like a reserve drug for patients who don’t respond to other therapies.[12]
Injectable therapies:
- Interferons: 1/ Interferon beta-1b: This drug is a cytokine that can affect immune system and modulates it and cause reduction in the progression of the disease.[13][14] 2/ Interferon beta-1a: Both Intramuscular and Subcutaneous interferon beta-1a can reduce disease progression, MRI lesions and acute attacks.[15][16]
- Glatiramer: Glatiramer is made from 4 amino acids and structurally similar to myelin basic protein. It binds to major histocompatibility complex molecules and competes with myelin antigens for T cell presentation.[17] this drug can reduce relapse rate of the disease.[18]
- Daclizumab: It is a monoclonal antibody against alpha chain of interleukin 2 receptor. It can reduce the relapses in MS patients.[19]
Oral therapies:
- Dimethyl fumarate: Fumarates is a neuroprotective and immunomodulatory drug which can reduce acute attacks and progression of multiple sclerosis.[20][21][22]
- Teriflunomide: This drug inhibits the biosynthesis of pyrimidines and reduce the interaction between antigen presenting cells and T cells.[23] teriflunomide can reduce relapse rate and disability progression of MS disease.[24][25] The most common side effects of this drug are nausea, diarrhea and elevated aminotransferase level.[24][26][27]
- Fingolimod:
Management of Acute Attacks
During symptomatic attacks administration of high doses of intravenous corticosteroids, such as methylprednisolone,[28][29] is the routine therapy for acute relapses.The aim of this kind of treatment is to end the attack sooner and leave fewer lasting deficits in the patient. Although generally effective in the short term for relieving symptoms, corticosteroid treatments do not appear to have a significant impact on long-term recovery.[30] Potential side effects include osteoporosis[31] and impaired memory, being the latter reversible[32]
Medical management of few individual symptoms and/or signs is as follows :-
Bladder
Treatment objectives are alleviation of symptoms of urinary dysfunction, treatment of urinary infections, reduction of complicating factors and preservation of renal function. Treatments can be classified in two main subtypes: pharmacological and non pharmacological.
Pharmacological treatments vary greatly depending on the origin or type of dysfunction; however some examples of the medications used are:[33] alfuzosin for retention,[34] trospium and flavoxate for urgency and incontinency,[35][36] or desmopressin for nocturia.[37][38]
Non pharmacological treatments involve the use of pelvic floor muscle training, stimulation biofeedback, pessaries, bladder training, and sometimes intermittent catheterization.[39]
Cognition
Interferons have demonstrated that can help to reduce cognitive limitations in multiple sclerosis.[40]Anticholinesterase drugs such as donepezil commonly used in alzheimer disease; although not approved yet for multiple sclerosis; have also shown efficacy in different clinical trials.[41][42][43]
Fatigue
There are also different medications used to treat fatigue; such as amantadine,[44][45] or pemoline [46][47] as well as psychological interventions of energy conservation;[48][49] but the effects of all of them are small. For this reason fatigue is a very difficult symptom to manage.
Internuclear Ophthalmoplegia
Different drugs as well as optic compensatory systems and prisms can be used to improve this symptoms.[50][51][52][53] Surgery can also be used in some cases for this problem.[54]
Optic Neuritis
Systemic intravenous treatment with corticosteroids, which may quicken the healing of the optic nerve, prevent complete loss of vision, and delay the onset of other symptoms, is often recommended.
Trigeminal Neuralgia
Usually it's successfully treated with anticonvulsants such as carbamazepine[55] or phenytoin[56] but others such as gabapentin[57] can be used. [58]
Lhermittes's Sign and Dysesthesias
Both Lhermitte's sign and painful dysesthesias usually respond well to treatment with carbamazepine, clonazepam or amitriptyline.[59][60][61]
Spasticity
There is evidence, albeit limited, of the clinical effectiveness of baclofen,[62] dantrolene,[63] diazepam,[64] and tizanidine.[65][66][67] In the most complicated cases intrathecal injections of baclofen can be used.[68]
Transverse Myelitis
Treatment is usually symptomatic only, corticosteroids being used with limited success.
Tremor and Ataxia
In the treatment of tremor many medications have been proposed; however their efficacy is very limited. Medications that have been reported to provide some relief are isoniazid,[69][70][71][72] carbamazepine,[73] propranolol,[74][75][76] and gluthetimide,[77] but published evidence of effectiveness is very limited.[78]
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Chemical structure of alemtuzumab
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Disease-modifying treatments are expensive and require frequent injections.
References
- ↑ Capra R, Cordioli C, Rasia S, Gallo F, Signori A, Sormani MP (November 2017). "Assessing long-term prognosis improvement as a consequence of treatment pattern changes in MS". Mult. Scler. 23 (13): 1757–1761. doi:10.1177/1352458516687402. PMID 28080255.
- ↑ Lizak N, Lugaresi A, Alroughani R, Lechner-Scott J, Slee M, Havrdova E, Horakova D, Trojano M, Izquierdo G, Duquette P, Girard M, Prat A, Grammond P, Hupperts R, Grand'Maison F, Sola P, Pucci E, Bergamaschi R, Oreja-Guevara C, Van Pesch V, Ramo C, Spitaleri D, Iuliano G, Boz C, Granella F, Olascoaga J, Verheul F, Rozsa C, Cristiano E, Flechter S, Hodgkinson S, Amato MP, Deri N, Jokubaitis V, Spelman T, Butzkueven H, Kalincik T (March 2017). "Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis". J. Neurol. Neurosurg. Psychiatry. 88 (3): 196–203. doi:10.1136/jnnp-2016-313976. PMID 27683916.
- ↑ Rice GP, Hartung HP, Calabresi PA (April 2005). "Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale". Neurology. 64 (8): 1336–42. doi:10.1212/01.WNL.0000158329.30470.D0. PMID 15851719.
- ↑ Hynes RO (February 1987). "Integrins: a family of cell surface receptors". Cell. 48 (4): 549–54. PMID 3028640.
- ↑ Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F, Steinman L, Karin N (March 1992). "Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin". Nature. 356 (6364): 63–6. doi:10.1038/356063a0. PMID 1538783.
- ↑ Kent SJ, Karlik SJ, Cannon C, Hines DK, Yednock TA, Fritz LC, Horner HC (April 1995). "A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis". J. Neuroimmunol. 58 (1): 1–10. PMID 7730443.
- ↑ Ruck T, Bittner S, Wiendl H, Meuth SG (July 2015). "Alemtuzumab in Multiple Sclerosis: Mechanism of Action and Beyond". Int J Mol Sci. 16 (7): 16414–39. doi:10.3390/ijms160716414. PMC 4519957. PMID 26204829.
- ↑ Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK (October 2008). "Alemtuzumab vs. interferon beta-1a in early multiple sclerosis". N. Engl. J. Med. 359 (17): 1786–801. doi:10.1056/NEJMoa0802670. PMID 18946064.
- ↑ Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA (November 2012). "Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial". Lancet. 380 (9856): 1819–28. doi:10.1016/S0140-6736(12)61769-3. PMID 23122652.
- ↑ Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L (January 2017). "Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis". N. Engl. J. Med. 376 (3): 221–234. doi:10.1056/NEJMoa1601277. PMID 28002679.
- ↑ Kappos L, Li D, Calabresi PA, O'Connor P, Bar-Or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J, Hauser SL (November 2011). "Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial". Lancet. 378 (9805): 1779–87. doi:10.1016/S0140-6736(11)61649-8. PMID 22047971.
- ↑ Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW (November 2003). "The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology". Neurology. 61 (10): 1332–8. PMID 14638950.
- ↑ Kasper LH, Reder AT (August 2014). "Immunomodulatory activity of interferon-beta". Ann Clin Transl Neurol. 1 (8): 622–31. doi:10.1002/acn3.84. PMC 4184564. PMID 25356432.
- ↑ "Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group". Neurology. 45 (7): 1277–85. July 1995. PMID 7617182.
- ↑ "Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group". Lancet. 352 (9139): 1498–504. November 1998. PMID 9820297.
- ↑ Clanet M, Radue EW, Kappos L, Hartung HP, Hohlfeld R, Sandberg-Wollheim M, Kooijmans-Coutinho MF, Tsao EC, Sandrock AW (November 2002). "A randomized, double-blind, dose-comparison study of weekly interferon beta-1a in relapsing MS". Neurology. 59 (10): 1507–17. PMID 12451189.
- ↑ Arnon R, Aharoni R (October 2004). "Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications". Proc. Natl. Acad. Sci. U.S.A. 101 Suppl 2: 14593–8. doi:10.1073/pnas.0404887101. PMC 521994. PMID 15371592.
- ↑ Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (July 1995). "Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group". Neurology. 45 (7): 1268–76. PMID 7617181.
- ↑ Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, Stefoski D, Robinson R, Riester K, Rana J, Elkins J, O'Neill G (June 2013). "Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial". Lancet. 381 (9884): 2167–75. doi:10.1016/S0140-6736(12)62190-4. PMID 23562009.
- ↑ Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT (September 2012). "Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis". N. Engl. J. Med. 367 (12): 1087–97. doi:10.1056/NEJMoa1206328. PMID 22992072.
- ↑ Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (September 2012). "Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis". N. Engl. J. Med. 367 (12): 1098–107. doi:10.1056/NEJMoa1114287. PMID 22992073.
- ↑ Xu Z, Zhang F, Sun F, Gu K, Dong S, He D (April 2015). "Dimethyl fumarate for multiple sclerosis". Cochrane Database Syst Rev (4): CD011076. doi:10.1002/14651858.CD011076.pub2. PMID 25900414.
- ↑ Zeyda M, Poglitsch M, Geyeregger R, Smolen JS, Zlabinger GJ, Hörl WH, Waldhäusl W, Stulnig TM, Säemann MD (September 2005). "Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation". Arthritis Rheum. 52 (9): 2730–9. doi:10.1002/art.21255. PMID 16142756.
- ↑ 24.0 24.1 O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, Benzerdjeb H, Truffinet P, Wang L, Miller A, Freedman MS (October 2011). "Randomized trial of oral teriflunomide for relapsing multiple sclerosis". N. Engl. J. Med. 365 (14): 1293–303. doi:10.1056/NEJMoa1014656. PMID 21991951.
- ↑ He D, Zhang C, Zhao X, Zhang Y, Dai Q, Li Y, Chu L (March 2016). "Teriflunomide for multiple sclerosis". Cochrane Database Syst Rev. 3: CD009882. doi:10.1002/14651858.CD009882.pub3. PMID 27003123.
- ↑ O'Connor PW, Li D, Freedman MS, Bar-Or A, Rice GP, Confavreux C, Paty DW, Stewart JA, Scheyer R (March 2006). "A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses". Neurology. 66 (6): 894–900. doi:10.1212/01.wnl.0000203121.04509.31. PMID 16567708.
- ↑ O'Connor P, Comi G, Freedman MS, Miller AE, Kappos L, Bouchard JP, Lebrun-Frenay C, Mares J, Benamor M, Thangavelu K, Liang J, Truffinet P, Lawson VJ, Wolinsky JS (March 2016). "Long-term safety and efficacy of teriflunomide: Nine-year follow-up of the randomized TEMSO study". Neurology. 86 (10): 920–30. doi:10.1212/WNL.0000000000002441. PMC 4782117. PMID 26865517.
- ↑ Methylprednisolone Oral. US National Library of Medicine (Medline) (2003-04-01). Retrieved on2007-09-01.
- ↑ Methylprednisolone Sodium Succinate Injection. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-09-01.
- ↑ Brusaferri F, Candelise L (2000). "Steroids for multiple sclerosis and optic neuritis: a meta-analysis of randomized controlled clinical trials". J. Neurol. 247 (6): 435–42. PMID 10929272.
- ↑ Dovio A, Perazzolo L, Osella G; et al. (2004). "Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis". J. Clin. Endocrinol. Metab. 89 (10): 4923–8. doi:10.1210/jc.2004-0164. PMID 15472186.
- ↑ Uttner I, Müller S, Zinser C; et al. (2005). "Reversible impaired memory induced by pulsed methylprednisolone in patients with MS". Neurology. 64 (11): 1971–3. doi:10.1212/01.WNL.0000163804.94163.91. PMID 15955958.
- ↑ Ayuso-Peralta L, de Andrés C (2002). "[Symptomatic treatment of multiple sclerosis]". Revista de neurologia (in Spanish; Castilian). 35 (12): 1141–53. PMID 12497297.
- ↑ Information from the USA National library of medicine on alfuzosin[1]
- ↑ Information from the USA National library of medicine on trospium[2]
- ↑ Information from the USA National library of medicine on flavoxate [3]
- ↑ Bosma R, Wynia K, Havlíková E, De Keyser J, Middel B (2005). "Efficacy of desmopressin in patients with multiple sclerosis suffering from bladder dysfunction: a meta-analysis". Acta Neurol. Scand. 112 (1): 1–5. doi:10.1111/j.1600-0404.2005.00431.x. PMID 15932348.
- ↑ Information from the USA National library of medicine on desmopressin[4]
- ↑ Frances M Diro (2006) "Urological Management in Neurological Disease". [5]
- ↑ Montalban X, Rio J (2006). "Interferons and cognition". J Neurol Sci. 245 (1–2): 137–40. PMID 16626757.
- ↑ Christodoulou C, Melville P, Scherl W, Macallister W, Elkins L, Krupp L (2006). "Effects of donepezil on memory and cognition in multiple sclerosis". J Neurol Sci. 245 (1–2): 127–36. PMID 16626752.
- ↑ Porcel J, Montalban X (2006). "Anticholinesterasics in the treatment of cognitive impairment in multiple sclerosis". J Neurol Sci. 245 (1–2): 177–81. PMID 16674980.
- ↑ Information from the USA National library of medicine on donepezil[6]
- ↑ Pucci E, Branãs P, D'Amico R, Giuliani G, Solari A, Taus C (2007). "Amantadine for fatigue in multiple sclerosis". Cochrane database of systematic reviews (Online) (1): CD002818. doi:10.1002/14651858.CD002818.pub2. PMID 17253480.
- ↑ Amantadine. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-10-07.
- ↑ Weinshenker BG, Penman M, Bass B, Ebers GC, Rice GP (1992). "A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis". Neurology. 42 (8): 1468–71. PMID 1641137.
- ↑ Pemoline. US National Library of Medicine (Medline) (2006-01-01). Retrieved on 2007-10-07.
- ↑ Mathiowetz VG, Finlayson ML, Matuska KM, Chen HY, Luo P (2005). "Randomized controlled trial of an energy conservation course for persons with multiple sclerosis". Mult. Scler. 11 (5): 592–601. PMID 16193899.
- ↑ Matuska K, Mathiowetz V, Finlayson M (2007). "Use and perceived effectiveness of energy conservation strategies for managing multiple sclerosis fatigue". The American journal of occupational therapy. : official publication of the American Occupational Therapy Association. 61 (1): 62–9. PMID 17302106.
- ↑ Leigh RJ, Averbuch-Heller L, Tomsak RL, Remler BF, Yaniglos SS, Dell'Osso LF (1994). "Treatment of abnormal eye movements that impair vision: strategies based on current concepts of physiology and pharmacology". Ann. Neurol. 36 (2): 129–41. PMID 8053648.
- ↑ Starck M, Albrecht H, Pöllmann W, Straube A, Dieterich M (1997). "Drug therapy for acquired pendular nystagmus in multiple sclerosis". J. Neurol. 244 (1): 9–16. PMID 9007739.
- ↑ Clanet MG, Brassat D (2000). "The management of multiple sclerosis patients". Curr. Opin. Neurol. 13 (3): 263–70. PMID 10871249.
- ↑ Menon GJ, Thaller VT (2002). "Therapeutic external ophthalmoplegia with bilateral retrobulbar botulinum toxin- an effective treatment for acquired nystagmus with oscillopsia". Eye (London, England). 16 (6): 804–6. PMID 12439689.
- ↑ Jain S, Proudlock F, Constantinescu CS, Gottlob I (2002). "Combined pharmacologic and surgical approach to acquired nystagmus due to multiple sclerosis". Am. J. Ophthalmol. 134 (5): 780–2. PMID 12429265.
- ↑ Information from the USA National library of medicine on carbamazepine[7]
- ↑ Information from the USA National library of medicine on phenytoin[8]
- ↑ Information from the USA National library of medicine on gabapentin[9]
- ↑ Solaro C, Messmer Uccelli M, Uccelli A, Leandri M, Mancardi GL (2000). "Low-dose gabapentin combined with either lamotrigine or carbamazepine can be useful therapies for trigeminal neuralgia in multiple sclerosis". Eur. Neurol. 44 (1): 45–8. PMID 10894995.
- ↑ Information from the USA National library of medicine on clonazepam[10]
- ↑ Information from the USA National library of medicine on amitriptyline[11]
- ↑ Moulin DE, Foley KM, Ebers GC (1988). "Pain syndromes in multiple sclerosis". Neurology. 38 (12): 1830–4. PMID 2973568.
- ↑ ;Baclofen oral. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-10-17.
- ↑ Dantrolene oral. US National Library of Medicine (Medline) (2003-04-01). Retrieved on 2007-10-17.
- ↑ Diazepam. US National Library of Medicine (Medline) (2005-07-01). Retrieved on 2007-10-17.
- ↑ Tizanidine. US National Library of Medicine (Medline) (2005-07-01). Retrieved on 2007-10-17.
- ↑ Beard S, Hunn A, Wight J (2003). "Treatments for spasticity and pain in multiple sclerosis: a systematic review". Health technology assessment (Winchester, England). 7 (40): iii, ix–x, 1–111. PMID 14636486.
- ↑ Paisley S, Beard S, Hunn A, Wight J (2002). "Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review". Mult. Scler. 8 (4): 319–29. PMID 12166503.
- ↑ Becker WJ, Harris CJ, Long ML, Ablett DP, Klein GM, DeForge DA (1995). "Long-term intrathecal baclofen therapy in patients with intractable spasticity". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. 22 (3): 208–17. PMID 8529173.
- ↑ Bozek CB, Kastrukoff LF, Wright JM, Perry TL, Larsen TA (1987). "A controlled trial of isoniazid therapy for action tremor in multiple sclerosis". J. Neurol. 234 (1): 36–9. PMID 3546605.
- ↑ Duquette P, Pleines J, du Souich P (1985). "Isoniazid for tremor in multiple sclerosis: a controlled trial". Neurology. 35 (12): 1772–5. PMID 3906430.
- ↑ Hallett M, Lindsey JW, Adelstein BD, Riley PO (1985). "Controlled trial of isoniazid therapy for severe postural cerebellar tremor in multiple sclerosis". Neurology. 35 (9): 1374–7. PMID 3895037.
- ↑ Information from the USA National library of medicine on Isoniazid [12]
- ↑ Information from the USA National library of medicine on carbamazepine [13]
- ↑ Koller WC (1984). "Pharmacologic trials in the treatment of cerebellar tremor". Arch. Neurol. 41 (3): 280–1. PMID 6365047.
- ↑ Sechi GP, Zuddas M, Piredda M, Agnetti V, Sau G, Piras ML, Tanca S, Rosati G (1989). "Treatment of cerebellar tremors with carbamazepine: a controlled trial with long-term follow-up". Neurology. 39 (8): 1113–5. PMID 2668787.
- ↑ Information from the USA National library of medicine on propanolol[14]
- ↑ Aisen ML, Holzer M, Rosen M, Dietz M, McDowell F (1991). "Glutethimide treatment of disabling action tremor in patients with multiple sclerosis and traumatic brain injury". Arch. Neurol. 48 (5): 513–5. PMID 2021365.
- ↑ Mills RJ, Yap L, Young CA (2007). "Treatment for ataxia in multiple sclerosis". Cochrane database of systematic reviews (Online) (1): CD005029. doi:10.1002/14651858.CD005029.pub2. PMID 17253537.