INTRODUCTION:

Multiple sclerosis is a chronic immune and demyelinating disease that attacks the central nervous system, which occurs due to the destruction in myelin sheath of the nerve fibres. The destruction causes distortion in normal transmission of nerve impulses leading to symptoms like psychiatric, cognitive abnormalities, and physical problems and its clinical manifestations vary from one person to another¹. It begins in early adulthood, and females are more susceptible to disease than males in the ratio of 2:1². The cause of the disease is unknown. It appears to involve both genetic involvement and non-genetic trigger such as environmental factors, virus or metabolism which result in self-sustaining autoimmune disease leading to recurrent attack of immune system on CNS³. The major symptoms seen in MS patients are spasticity, weakness, tremor, vertigo and dizziness, bladder dysfunction, bowel dysfunction, sleep disorders, fatigue, depression⁴. According to symptoms and progression of the disease, MS is broadly classified into four major categories. They are: Relapsing Remitting Multiple Sclerosis (RRMS): It is the commonest type of multiple sclerosis, affecting about 85% of the person with this disease⁵, Secondary Progressive Multiple Sclerosis (SPMS): It occurs due to progression from RRMS, with or without occasional relapses. 80% of the people with RRMS sooner or later get SPMS, Primary Progressive Multiple Sclerosis (PPMS): It develops in almost 10% of the MS patients. It occurs due to continuous worsening of symptoms without any relapses or remissions, Progressive Relapsing Multiple Sclerosis (PRMS): It is a rare form of MS, affecting fewer than 5% of the patients. Remission does not occur in this case^3,6

The diagnostic tests widely used are MRI Scan, CNS Imaging, Sensory Evoked Potential Testing, CSF Analysis, Serologic Testing⁷. Currently, there are 10 approved disease modifying therapies available for MS. The approved disease modifying therapies (DMT) available are: teriflunomide, fingolimod, interferons (interferon-1a, interferon-1b) glatiramer acetate, natalizumab⁸. Only few studies were reported from South India on the clinical pattern and an increased prevalence due to the modern investigative facilities and increased awareness. Hence, we thought of conducting a hospital-based study to find the number of reported cases, its features and treatment pattern^9,10,11. In present study we studied the clinical profile and treatment pattern of patients with multiple sclerosis.

METHODOLOGY:

This is a Retrospective observational study. This study was conducted in the department of Neurology, Amrita Institute of Medical Science and Research Centre (AIMS), which is a 1400 bedded tertiary care, super specialty teaching hospital located in huge health campus at Ponekkara, Kochi, India, between July 2017 to May 2018 with a data collection period of 7 months. The Study was approved by the institutional ethics committee AIMS.

The list of patients with MS attended neurology department during JAN 2005 to JUN 2017 was obtained from AHIS support team of AIMS on requisition. Amrita Health Information System (AHIS) and medical record was used to obtain the relevant data. Relevant data including: Clinical investigations (MRI studies, CSF patterns), Treatment details (drugs, dose), Demographic data, MS related medical history (antecedent event, age and time of onset, type of MS). Relevant history and all other relevant information ‘were collected and entered in a pre-designed data collection form.

INCLUSION CRITERIA:

1. People of all age group diagnosed with Multiple sclerosis based on McDonald’s criteria.

2. Minimum of 1 year of follow up.

EXCLUSION CRITERIA:

1. With incomplete data or information’s.

2. When diagnosis is not definite.

3. Evidence of causes other than inflammatory demyelination on radiological, biochemical and microbiological tests.

4. Neuromyelitis Optica (NMO)

STUDY POPULATION:

The patients with multiple sclerosis of different types who attended the neurology department at AIMS during the period of JAN 2005 to JUNE 2017 and who satisfied the inclusion and exclusion criteria were included and the minimum sample size of our study was found to be 38.

STATISTICAL ANALYSIS:

The collected data was recorded and compiled using Microsoft Excel Worksheet. Statistical analysis was done using IBM SPSS 20. (SPSS Inc, Chicago, USA). Continuous variables are expressed using mean and standard deviation and categorical variables are presented using frequency and percentage. The results are presented in form of tables and graphs.

RESULT AND DISCUSSION:

In this retrospective observational study, 43 multiple sclerosis patients who satisfied the inclusion and exclusion were included

AGE DISTRIBUTION OF PATIENTS:

The mean age of the patients in this study was 33.14±11.7 year with a minimum age of 9 years and a maximum of 56 years. The age distribution of patients is shown in the below Fig. 1

Fig .1: Age distribution of patients

GENDER DISTRIBUTION OF PATIENTS:

In this study, females are more in numbers than male. The male to female ratio of the study sample was 1:2.3. The gender distribution of patients is shown below in Fig. 2.

Fig .2: Gender distribution of patients

COMORBIDITY OF PATIENTS:

The major co morbidities seen in our study population was Type 2 Diabetes, Dyslipidaemia, Hypertension, Hypothyroidism and Asthma. In this study, 8(18.6%) were having Type 2 DM, 5 (11.62%) of them had DLP, 2 (4.65%) of them had HTN and 1 patient had hypothyroidism and 1patient had asthma. Majority of patients (60.46%) were not having any co morbidities. Fig.3

Fig. 3: Comorbidity of patients

SYMPTOMS OF MULTIPLE SCLEROSIS PATIENTS:

In the present study muscular issues 69.8% (30) and sensory disturbance 67.4% (29) was found to be the most predominant symptoms seen among MS patients. Other main symptoms showed by the patient during illness include visual disturbance (21 patients), bladder issues (13 patients), cognitive problems (6 patients). Headache, walking difficulty, ataxia, and balance disorder was the least common symptoms showed by the patients. A study on clinical profile of MS in Kashmir by Bashir Ahmad Sanaie et al showed that visual involvement was seen in (40%), weakness of limbs (35%), sphincter involvement (20%), sensory symptoms (10%) and trigeminal neuralgia (10%) were the most common presenting symptoms, which were slightly similar to our study¹².

Fig.4: Symptoms of multiple sclerosis patients

TYPES OF MULTIPLE SCLEROSIS IN PATIENTS:

In this study we found that 33(76.74%) patients had relapsing remitting MS, 7(16.3%) patients had secondary progressive, 2 patients had primary progressive and 1 patient had progressive relapsing MS. The minimum age of onset of MS was found as 6 and maximum as 56. The mean age of onset in female 28.35±12.97 and in male 31.70±8.78. An institutional study conducted by Rohit Bhatia in New Delhi was similar to our study that is, among 101 patients having MS, relapsing remitting type was found to be more in patients (68%) followed by secondary progressive MS for 17% and primary progressive MS for 15% of cases¹³_.

Fig.5: Types of multiple sclerosis in patients

NUMBER OF RELAPSES OBSERVED IN OUR STUDY POPULATION

It is evident from the figure that in the present study majority patients 41.86% (18) had single relapses and 1 patient had 5 relapses. Fig.6

Fig.6: Number of relapses observed in our study population

SITE OF LESIONS:

In our study, the most lesions are seen at periventricular white matter in which out of 43 patients, 21(41.8%) had lesion at this site. 8 male patients out of 13 and 13 out of 30 female patients had lesion at this site. Some of the other sites in which patients experienced lesions are Brain (6 patients(14%)), Brain stem (7 patients(16.3%)), Periventricular white matter and spinal cord (1 patient), Periventricular white matter and corona radiate (3 patients (7%) ), Spinal cord (3 patients(7%)), Spinal cord and brain stem (1 patient(2.3%)).The presence of periventricular lesions on MRI scan is a part of the revised McDonald multiple sclerosis diagnostic criteria¹⁴. Brain steminvolvements are seen in small vessel disease and located peripherally. Typical spinal cord lesions in MS are relatively small and peripherally located. They are most often found in the cervical cord and are usually less than 2 vertebral segments in length¹⁵.

LABORATORY INVESTIGATIONS

Most commonly used laboratory investigation were MRI brain, MRI spine, CSF. In our study 88.4% of the patients received MRI brain, 41.9% received MRI spine, 30.2% had CSF analysis. Other lab investigations received by our patients are visual evoked potential test (7%) and Blood Smear analysis (9.3%). Fig.7

Fig.7: Laboratory investigations

Magnetic resonance imaging (MRI) is the preferred imaging technique for the diagnosis of MS lesions and to monitor the course of the disease. MRI helps to visualize and understand much more about the underlying pathology of the disease. The MRI brain images can be classified based on Neuro-Fuzzy Classifier (NFC), is used to detect the abnormalities in new MR images for head/brain injury. The time required for the computation is less than another approaches¹⁶.

Cerebro Spinal Fluid (CSF) is obtained by doing a lumbar puncture or “spinal tap”. The CSF in MS people usually contains high level of IgG antibodies, and the presence of oligoclonal bands it is highly sensitive and specific for MS. Additional molecules of CSF can help to support the diagnosis of MS, improve the differential diagnosis of MS subtypes and predict the course of the disease, thus selecting the optimal treatment¹⁷.Visual Evoked Potential (VEP) test is used to measure the electrical activity of the brain in response to the stimulation of specific sensory nerve pathways. Using evoked potentials, the level of initial delay or block can be determined,it provides an evidence of optic nerve lesion which may not be visible on MRI scan^18.

TYPE OF LESIONS:

MS lesions are oriented around both brain and spinal cord. In our study 10 patients evidently shown T2 FLAIR and Hyper intense lesions in periventricular white matter predominantly. There is a depiction of demyelinating plaques in 4 patients with MS. And T2 hyper intense, hyper intense and demyelinating plaques and hypo intense, hyper intense and T2 FLAIR lesions were showed in only 2 patients in each type. There was minimum involvement of lesions were seen in other patients. No relevant MRI data were provided for 11 patients from collected data.

MEDICATIONS RECIEVED BY MS PATIENTS

Table.1: Medications received by MS patients

Drug	Received	No. of Patients (n=43)	Percentage (%)
Prednisolone	Yes	33	76.7%
Prednisolone	No	10	23.3%
Calcium	Yes	23	53.5%
Calcium	No	20	46.5%
Inj.methyl prednisolone	Yes	16	37.2%
Inj.methyl prednisolone	No	27	62.8
Vit b complex	Yes	5	11.6%
Vit b complex	No	38	88.4%
Vitamin d	Yes	8	18.6%
Vitamin d	No	35	81.4%
Interferon beta 1 a	Yes	8	18.6%
Interferon beta 1 a	No	35	81.4%
Topiramate	Yes	4	9.3%
Topiramate	No	49	90.7%
Azathioprine	Yes	4	9.3%
Azathioprine	No	39	90.7%
Selenium	Yes	3	7.0%
Selenium	No	40	93%
Piracetam	Yes	2	4.7%
Piracetam	No	41	95.3%

Table.1 illustrates the treatment details of our patients. Overall, 33 patients (76.4%) took oral prednisolone at some point during their disease. The maximum dose of oral steroid received by patients was considered 60mg, which is followed by the tapered doses up to a minimum of 5mg with 2-3 weeks of duration⁸.

The calcium supplementation contributes to the development of improved treatment options for patients with MS by modulating calcium channels. It is helpful for the management of deficit motor, sensory, cognitive functions. In our study, 23 patients (53.5%) with Multiple Sclerosis had received calcium supplements and 20 patients (46.5%) hadn’t received. 500 mg tablets were administered twicedaily¹⁹.Disabling relapses may be treated with high doses of Intravenous corticosteroids (methylprednisolone 1g/day for 3days). This corticosteroid having great role in treating various inflammatory conditions and they provide a quick symptomatic relief²⁰. The statins have an agreeable safety profile in treating MS together with interferon beta²¹. In our study out of 43 patients, 16 patients (37.2%) had received intravenous corticosteroids. Intravenous corticosteroids are given during hospitalisation in large doses as pulse therapy for 3-5 days and usually followed by oral steroid loading dose. Oral corticosteroids were also given at maximum dose of 48 mg followed by tapering the dose up to minimum dose of 4 mg for a duration of 30days²². Vitamin B complex is an anti- inflammatory &remyelinating agent available alone or in combination with other agents in the prevention or reversal of symptoms and for the improvement of the quality of life in MS patients. Vitamin B complex contains thiamine (B1), riboflavin (B2), niacinamide (B3), pantothenic acid (B5), pyridoxine (B6), cyanocobalamin (B12) in it, which is administered at a maximum dose of 1000 mg/day. It can also be classified into energy releasing, hematopoietic, or other²³.It is found to relieve MS symptoms. In our study, Vitamin B complex was received only by 5 patients (11.6%). It is administered in once daily dose. Vitamin D (calcitriol) is a risk factor for infectious and chronic inflammatory diseases, such as MS especially peoples who were in higher latitudes. In our study, 8 patients (18.6%) received Vitamin D regularly for 30 days and 35 patients (81.4%) did not receive. Inj. Vitamin D were also administered in the dose range of 44 mcg Subcutaneous twice weekly. Doctors prefer the dose of 2000-5000 IU with the aim to get safest level of vitamin D in MS patients. Adding high doses of vitamin D to the treatment regimen to those with RRMS having interferon beta injection, reduced the number of new lesions over 48 weeks^19,24. DMT focuses on the long-term management of the disease with the aim to reduce relapse rates, lessen severity, and to slow the progression of disability and cognitive decline. Interferons belong to the class of glycoproteins known as cytokines. They activate immune cells such as natural killer cells and macrophages²⁵. Interferon beta 1a has efficacy on RRMS, and it reduces the relapses rate and significant effect on MRI lesion include black hole formation, progression, cognitive loss and it is a neuroprotective agent. In our study,8 patients (18.6%) were subjected to DMT and other 35 patients (81.4%) switched to other therapies. IFN beta 1a administered via intra muscularly at ahigh dose of 44 mcg alone or with intravenous corticosteroids therapy during hospitalization for multiple sclerosis²⁶. Oral Interferon 1a available in 22 mcg formulation. Topiramate is effective on the dysaesthetic pain (neuropathic pain) in patients with multiple sclerosis. Here also4 patients (9.3%) patients received topiramate in minimum dose of 25 mg twice a day and 39 patients (90.7%) were not. Maximum dose of 150 mg/day is effective for the treatment of dysaesthetic pain in lower limb²⁷.Azathioprine is the most widely used immunosuppressive treatment in multiple sclerosis. It is an alternative to interferon beta for treating MS because it is less expensive. 4 patients (9.3%) patients in our study had received this immunosuppressive therapy and 39 patients (90.7%) were not. Cumulative doses of 600 g should not be exceeded in relation to a possible increased risk of malignancy²⁸.Selenium is a mineral as well as an antioxidantmay influence the course of MS by decreasing oxidative injury and play a major role in preventing cell damage²⁹. Other antioxidant regimens used to treat the symptoms of MS are Ginkgo biloba, Alpha-lipoic acid, Vitamin E, Essential fatty acids³⁰. 3 patients (7.0%) out of 43 had received selenium. Piracetam improves the cognitive deficit associated with traumatic brain injuries. It is a nootropic drug. It is also effective in lowering the depression and anxiety. 2 patients (4.7%) out of 43 patients had received piracetam³¹.

There were only 2 patients (4.7%) out of 43patients who had received drugs like Phenytoin, Carbamazepine, Dimethyl fumarate and Quetiapine. Phenytoin is usually used as an anti-epileptic agent, but also found to have an additional neuroprotection in patients with acute demyelinating optic neuritis which is a common feature of relapsing Multiple Sclerosis³².Carbamazepine is an anticonvulsant. it used for the treatment of nerve pain associated with trigeminal or glosso pharyngeal neuralgia and for the treatment of spasticity and bipolar disorder³³.Dimethyl fumarate (DMF)due to its immune-modulatory property, is used for the treatment of RRMS. The number and size of lesion as detected by MRI were also decreased in patients receiving DMF at every dosage³⁴. Quetiapine fumarate is an atypical antipsychotic drug. In multiple sclerosis. Quetiapine have remyelinating and neuroprotective properties in inflammatory and non-inflammatory models of demyelination³⁵.

Lactulose, Amitriptyline, Vitamin B 12, Leviteracetam, Pregabalin, Aspirin, Zolpidem, Tolterodin, Tramadol, Bilberry, Lacosamide were received by only 1 patient (2.3%). Lactulose is an osmotic laxative provides successful approach to managing constipation in MS patients. Amitriptyline is an antidepressant drug which is used in multiple sclerosis in lower doses for the treatment of neuropathic or nerve pain, such burning sensation and pins and needles or stabbing pain³⁶. Vitamin B 12 is a water-soluble vitamin to help maintain the myelin sheath of nerves. Leviteracetam is a second-generation anti-epileptic drug effective for reducing phasic spasticity. Aspirin (acetylsalicylic acid, ASA) has found to reduce inflammation, lessen fatigue, and promote remyelination. Most of the therapeutic uses of ASA is due to its inhibition of cyclooxygenases (COXs), enzymes that catalyse a step in the production of prostaglandins (PGs), prostacyclin, and thromboxane (TXA)³⁷. Zolpidem, a non-benzodiazepine hypnotic, acts selectively via alpha1-subunit of GABA_A receptors. Zolpidem may improve symptoms of spasticity in higher doses via affection of GABA alpha2-receptor and alpha3-receptor subunits^38,39.Tramadol comes under opioid analgesic, typically used to alleviate moderate to severe pain⁴⁰.TramadolHCl is a centrally acting synthetic analgesic, commonly prescribed to treat neuropathic pain and various disorders characterised by tender, painful and stiff muscles⁴¹.Bilberry or blueberry is an herb that is rich in antioxidants and has a potential to improve vision, reduce inflammation, and protect cognitive function⁴².Lacosamide is an anti-epileptic drug, which is a functionalized amino acid, used for the treatment of partial onset seizures in adults with focal epilepsy⁴³.

CONCLUSION:

In our study, majority of patients were in relapsing remitting form of multiple sclerosis with, one-time relapse and more than one lesion. MRI scan was most used diagnostic technique in our study. MRI showed lesions in Periventricular white matter in majority of patients and even involvement in the areas of brain stem and spinal cord was observed. Muscular weakness, sensory disturbances and cognitive problems were the common symptoms observed in our study population. Female preponderance and early onset of age was also observed among the population. Prednisolone in oral/IV form was the commonest therapy for majority of patients. Interferon beta 1a (cytokine), which are relatively newer agents in the treatment of multiple sclerosis was also prescribed to the MS patients. Since exact cause of the diseases is still unknown, treatment provided to the patients were based on their symptoms.

REFERENCES:

1. Brassington JC, Marsh NV. Neuropsychological aspects of multiple sclerosis. Neuropsychology review. 1998 Jun 1;8(2):43-77.

2. Steinman L. Multiple sclerosis: a coordinated immunological attack against myelin in the central nervous system. Cell. 1996 May 3;85(3):299-302.

3. Goldenberg MM. Multiple sclerosis review. Pharmacy and Therapeutics. 2012 Mar;37(3):175.

5. Leary SM, Porter B, Thompson AJ. Multiple sclerosis: diagnosis and the management of acute relapses. Postgraduate Medical Journal. 2005 May 1;81(955):302-8.

6. Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. Neurology. 1996 Apr 1;46(4):907-11.

7. Calabresi PA. Diagnosis and management of multiple sclerosis. American family physician. 2004 Nov 15;70(10):1935-44.

8. Adam AL, Morgan MR, Lindsey WT. A review and treatment option updates multiple Sclerosis: Alabama Pharmacy Association. Continuing Education. August 31, 2014.

9. Pandit L, Subramanya R, RaoSN. Multiple sclerosis in coastal Karnataka. Neurology India.1993;41(3):143-6.

10. Kuroiwa Y, Kurland LT (eds): Multiple Sclerosis East and West. Asian Multiple Sclerosis Workshop, Kyoto, September 1981 / Satellite Symposium Multiple Sclerosis and 12th World Congress of Neurology, Kyoto, September 1981: Proceedings. Basel, Karger, 1982, pp 31-42.

11. Mathew NT, Mathai KV, Abraham J, Taori GM. Incidence and pattern of demyelinating disease in India. Journal of the neurological sciences. 1971 May 1;13(1):27-38.

12. Sanaie BA, Zahwa B, Singh H. Clinical Profile of Multiple Sclerosis in Kashmir (India): A Tertiary Care Hospital Based Study. International Journal of Scientific Study. 2017 Feb 1;4(11):103-6.

13. Gangopadhyay G, Das SK, Sarda P, Saha SP, Gangopadhyay P, Roy TN, Maity B. Clinical profile of multiple sclerosis in Bengal. Neurology India. 1999 Jan 1;47(1):18.

14. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg‐Wollheim M. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2001 Jul;50(1):121-7.

15. BarkhofF, Smithuis R, Hazewinkel M. Multiple sclerosis. Radiology assistant. Department of Diagnostic Radiology, Vrinje Universiteit Hospital, Amsterdam, The Netherland. Available from http://www.radiologyassistant.nl/en/p4556dea65db62/multiple-sclerosis.html

16. Burje S, Rungta S, Shukla A. Detection and Classification of MRI Brain Images for Head/Brain Injury Using Soft Computing Techniques. Research Journal of Pharmacy and Technology. 2017;10(3):715-20.

17. Deisenhammer F, Zetterberg H, Fitzner B and Zettl UK. The Cerebrospinal Fluid in Multiple Sclerosis. Front. Immunol. 12 April 2019. doi: 10.3389/fimmu.2019.00726

18. Palace J. Making the diagnosis of multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry. 2001 Dec 1;71(suppl 2): ii3-8.

19. Alharbi FM. Update in vitamin D and multiple sclerosis. Neurosciences. 2015 Oct;20(4):329.

20. Gouda V, Shastry CS, Mateti UV, Subrahmanya C, Chand S. Study on Steroid Utilization Patterns in General Medicine Department. Research Journal of Pharmacy and Technology. 2019;12(10):4771-6.

21. Lekshmi RS, Shanmugasundaram P. Neuroprotective Properties of Statins. Research Journal of Pharmacy and Technology. 2018;11(8):3581-4.

22. Chabas D, Fontaine B, Lyon-Caen O. Multiple Sclerosis, Orphanet Encyclopedia. July 2004.

23. Ghosh S, Pahari S, Roy T. An updated overview on food supplement. Asian Journal of Research in Chemistry. 2018; 11(3): 691-7.

24. Subashree R, Arjunkumar R. Vitamin D Deficiency in Periodontal Health. Research Journal of Pharmacy and Technology. 2014;7(2):248-52.

25. Khokra SL, Parashar B, Dhamija HK, Bala M. Immunomodulators: Immune System Modifiers. Research Journal of Pharmacy and Technology. 2012;5(2):169-74.

26. Litvinova EV, Posilkina OV, Maslova NF. Formation of patent strategy at all stages of biosimilar development and Implementation. Research Journal of Pharmacy and Technology. 2018;11(7):3081-6.

27. Siniscalchi A, Gallelli L, De Sarro G. Effects of topiramate on dysaesthetic pain in a patient with multiple sclerosis. Clinical drug investigation. 2013 Feb 1;33(2):151-4.

28. Casetta I, Iuliano G, Filippini G. Azathioprine for multiple sclerosis. Cochrane Database of Systematic Reviews. 2007(4).

29. Clausen J, Jensen GE, Nielsen SA. Selenium in chronic neurologic diseases. In Selenium 1988 (pp. 179-203). Humana Press.

30. Patel VK, Kpatel C, Patel HU, Patel CN. Vitamins, Minerals and Carotenoids as a Antioxidants. Asian Journal of Research in Chemistry. 2010;3(2):255-60.

31. Popova NF, Kamchatnov PR, Riabukhina OV, Batysheva TT, Zaĭtsev KA, Boĭko AN. Omaron in the complex treatment of patients with multiple sclerosis. Zhurnal nevrologii i psikhiatrii imeni SS Korsakova. 2010;110(11 Pt 1):17-20.

32. Asadi-Pooya AA. Phenytoin for neuroprotection. The Lancet Neurology. Available from: www.thelancet.com/neurology. August 2016;15(9)

33. Marabathuni VJ, Bhavani M, Lavanya M, Padmaja K, Madhavi N, Babu P, Rao CM. Formulation and evaluation of mouth dissolving Tablets of carbamazepine. Asian Journal of Pharmacy and Technology. 2017;7(3):137-43

34. Bomprezzi R. Dimethyl fumarate in the treatment of relapsing–remitting multiple sclerosis: an overview. Therapeutic advances in neurological disorders. 2015 Jan;8(1):20-30.

35. Zhornitsky S, Wee Yong V, Koch MW, Mackie A, Potvin S, Patten SB, Metz LM. Quetiapine fumarate for the treatment of multiple sclerosis: focus on myelin repair. CNS neuroscience & therapeutics. 2013 Oct;19(10):737-44.

36. Kopsky DJ, Liebregts R, Keppel Hesselink JM. Central neuropathic pain in a patient with multiple sclerosis treated successfully with topical amitriptyline. Case reports in medicine. 2012;2012.

37. Tsau S, Emerson MR, Lynch SG, LeVine SM. Aspirin and multiple sclerosis. BMC medicine. 2015 Dec;13(1):153.

38. Damm J, Eser D, Moeller HJ, Rupprecht R. Severe dependency on zolpidem in a patient with multiple sclerosis suffering from paraspasticity.The World Journal of Biological Psychiatry. 2010 Mar1;11(2-2):516-8.

39. Kesselring J, Beer S. Symptomatic therapy and neurorehabilitation in multiple sclerosis. The Lancet Neurology. 2005 Oct 1;4(10):643-52.

40. Khan N, Smith MT. Multiple sclerosis-induced neuropathic pain: pharmacological management and pathophysiological insights from rodent EAE models. Inflammopharmacology. 2014 Feb 1;22(1):1-22.

41. Khochage SR, Bhutkar MA, Mali SD, Todkar SB. Formulation and Evaluation of Pulsincap of Tramadol HCl for the Treatment of Rheumatoid arthritis. Research Journal of Pharmacy and Technology. 2013;6(10):1137-40.

42. Bagur MJ, Murcia MA, Jiménez-Monreal AM, Tur JA, Bibiloni MM, Alonso GL, Martínez-Tomé M. Influence of diet in multiple sclerosis: a systematic review. Advances in nutrition. 2017 May;8(3):463-72.

43. Cawello W, Stockis A, Andreas JO, Dimova S. Advances in epilepsy treatment: Lacosamide Pharmacokinetic Profile. Annals of the New York Academy of Sciences. 2014 Nov;1329(1):18-32.

Received on 11.02.2020 Modified on 06.03.2020

Research J. Pharm. and Tech. 2020; 13(12):6066-6072.

DOI: 10.5958/0974-360X.2020.01057.4