Long-term follow-up of patients with multiple sclerosis treated with a cost-effective protocol from a rural medical center in India: a retrospective case series

Sadanandavalli Retnaswami Chandra , Nitin Ramanujam Chakravarthula, Thomas Gregor Issac, Mariamma Philip

1 Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

2 Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

3 Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

4 Department of Biostatistics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India

Abstract

Key words: atorvastatin; azathioprine; methotrexate; multiple sclerosis; oral penicillin; relapsing-remitting multiple sclerosis

INTRODUCTION

Multiple sclerosis (MS) is a recurrent demyelinating disease of white matter of the central nervous system, a medical curiosity in the 19thcentury and recognized as one of the common disease of young people which starts with episodic symptoms and signs and later becomes progressive (Murray, 2006; Schultz et al., 2019; Yu et al., 2019). Patients usually become dependent for activities of daily living (ADL) after 15 years of illness. Diagnosis can be made with 100% certainty only by histopathology. The McDonald Criteria was first established in 2001 and revised in 2010 (Polman et al., 2011). If two lesions are evident in first attack, it indicates dissemination in both time and space and qualifies for initiation of disease-modifying therapies. The Schumacher Criteria (1965) formulated clinical criteria. The Poser Criteria (1983) standardized the use of diagnostic tests such as evoked potentials and a spinal tap. The signs and symptoms depend on the location of the pathology and severity. MS affects the people aged between 15 and 60 years. Women have a twofold risk of developing MS compared with men. A family history further increases the risk. Virus infections are linked to MS such as Epstein-Barr virus (EBV). White people, particularly those of Northern European descent, are at highest risk of developing MS (Kingwell et al., 2013). People living in temperate climate and Asian, African or Native American descent have the lowest risk. It presents as relapsing-remitting type, primary progressive type, secondary progressive type and progressive relapsing type. There is a need to carefully exclude the differential diagnosis which includes vasculitis, secondary demyelination, infections and leukoencephalopathy associated with metabolic diseases. Treatment options are both disease modifying and symptom oriented. Most patients are forced to discontinue the standard recommendations due to unaffordability as duration of treatment is several years to lifetime (Goldberg et al., 2009). In this pilot study, we reported the efficacy of a cheap oral protocol we prescribed to patients based on level three recommendations in literature for azathioprine, methotrexate clubbed with atorvastatin for its role in neurogenic inflammation. Oral penicillin 800 mg a day was added based on our previous observation that even bacterial infections can precipitate a relapse by elevated antistreptolysin O titers found in our patients during relapse (Gray et al., 2004; Casetta et al., 2007; Noyes et al., 2011; Wang et al., 2011).

SUBJECTS AND METHODS

Study design

This is a retrospective case series study. It was conducted at the National Institute of Mental Health and Neurosciences (NIMHANS) in Karnataka, India. Institutional review board approval was not obtained as these data were generated from a large sample of patients who opted for this regime based on literature evidence as they could not afford the usual drugs (Additional file 1). Informed consent of the study procedure was obtained from all patients (Additional file 2).

Subjects

The data was obtained from patients who were diagnosed with multiple sclerosis according to the modified Mc Donald's criteria (Polman et al., 2011). After providing informed consent, the patients who were willing to participate in this study were given the new regimen as maintenance treatment for prevention of MS relapses with either azathioprine for patients who showed a relapsing trend or methotrexate for patients who had a progressive course (Goldberg et al., 2009) after detailed discussion with patients and their caregivers.

Sample size and follow-up

The need for prevention of factors like infections, need for sunlight exposure, stopping smoking, shifting to plant based diet, antioxidant rich foods, and trauma was explained to the included patients (Sibley et al, 1985; Hayes et al., 1997; Martinelli, 2000; Jafari et al., 2009). Though the treatment protocol had been practiced for three decades in more than 250 patients spreading over several medical colleges in Kerala state government, in this study, we only included the results of 23 consecutive patients who came for follow-up in the last 3 months in the NIMHANS from October 1, 2018 to December 31, 2018 and whose complete data was available as a pilot report on long-term effects.

Data collection and analysis

The included participants were followed up regularly over a period of 10 years from 2008 to 2018 at the NIMHANS. The illness was also confirmed radiologically by characterization of the lesion patterns and identification of lesion load and the location of lesions. Cerebrospinal fluid (CSF) was also collected to confirm the markers specific for MS. CSF anti-aquaporin-4 antibody assessment was also done to rule out cases of neuromyelitis optica. Clinical, radiological and serological data which were obtained were input into Excel sheet and analyzed by SPSS 21.0 software (IBM, Armonk, NY, USA).

RESULTS

Twenty-three patients were identified during the period of data collection. The mean age of the study population was 34.74 ± 10.76 years (range, 17-55 years). The mean duration of illness was 6.8 ± 5.23 years and the mean duration of remission was 4.09 ± 3.5 years respectively. Vasculitis examination (to rule out secondary demyelination) results were negative in all patients. Among these 23 participants, 61% were females and 39% were males. 43.5% of the patients had associated pyramidal symptoms and none of the patients had extra pyramidal symptoms. Cerebellar symptoms and signs were present in 14 patients (61%), Lhermitte's sign in 19 patients (83%). Cranial nerve involvement was present in 15 patients (65%). Cognitive decline was seen only in 2 patients (9%) and the remaining 21 patients (91%) had no features clinically suggestive of cognitive impairment. Cerebellar signs were present in 83% of included participants and cord signs appeared in ＞ 90% of the population. CSF oligoclonal bands were positive in 20 patients (87%) and CSF neuromyelitis optica was negative in all patients except for one patient who had weakly positive titers of anti-neuromyelitis optica antibody in addition.

Magnetic resonance imaging was done for patients (56.5%) with cerebellar signal change and patients (91%) with spinal cord signal changes. About 25% (6) patients had parenchymal loss in brain imaging (black holes) prior to the initiation of treatment. 43.5% of the included patients did not suffer from any relapse during the treatment with the novel regimen, 26.7% of them having a single relapse which was managed with parenteral methylprednisolone 1 g daily for 5 days, and all of them recovered uneventfully. Multiple relapses (2 or more) were observed in only about 30% of the population. The provisional diagnosis of MS subtype made for the patients is depicted in the histogram below (Figure 1).

There were 19 patients in the azathioprine group (82.6%) and 4 patients in the methotrexate group (17.4%). Expanded Disability Status scale (EDSS) was applied prior to and after treatment initiation and the difference in EDSS score between prior to and after treatment initiation was compared using Wilcoxon Sign Rank test as the sample size was relatively small. There was significant difference in disability rating between prior to and after treatment initiation (P ＜ 0.001). The mean EDSS score was 3.83 ± 0.78 and 1.15 ± 0.5 prior to and after treatment initiation, respectively. This suggests an improvement from moderate disability in one functional system to no disability with minimal signs in one functional system. The patients treated with azathioprine regimen showed significant improvement compared with that in patients receiving methotrexate regimen (P ＜ 0.001). There was also significant difference in the disability scores measured by EDSS between patients who had no relapses and those who had relapses (P = 0.005). Patients having no relapses showed a better outcome with lesser disability compared with those having relapses. About 45% of patients had no relapses after receiving the new regimen during the follow up period studied. The magnetic resonance imaging evidence of lesion load reduction was seen in all patients at the end of 1 year and 3 years. But complete resolution of lesions was not seen even in patients who were clinically in good remission (see Figure 2 for typical cases). None of the patients in this group had bone marrow suppression or tumors.

Figure 1: Percentage of MS subtypes.

DISCUSSION

In this pilot report, we analyzed the data of 23 patients who came for follow up with the mean illness duration of 6.8 ± 5.23 years and the mean remission duration of 4.09 ± 3.5 years respectively. There was significant reduction in EDSS scores. Statistical data rejected the null hypothesis with a significance level of 0.5. The cost of the regime is approximately 5000 INR (Indian Rupees) per year. Azathioprine used at 1 mg/kg had no side effects in any of the included patients. Statins interfere with production of several proinflammatory mediators including inducible nitric oxide synthase, tumor necrosis factor alpha (TNFα), and inducible major histocompatibility complex (interferon gamma) (Weber et al., 2005). MHC class II genes are concerned with susceptibility to MS being at the core of the destructive cascade (Chow, 2009). Statins bind to lymphocyte functional antigen (LFA-1), inhibit mevolonate pathway, and exhibit neuroprotective effects in the long run (Stalker et al., 2001; Schramm et al., 2007; van der Most et al., 2009). Azathioprine inhibits cell proliferation by inhibiting purine synthesis (Yudkin et al., 1991). It has been tried alone or in combination with other therapies with variable results. Methotrexate inhibiting dihydrofolate reductase in rapidly multiplying cells and the underlying benefits were reported in studies in patients with progressive multiple sclerosis (Goodkin et al., 1996; Billups et al., 2000). Cost is an important factor in patients receiving long term treatment and it has to be taken into consideration in countries where there is no uniform insurance coverage and patients have to spend for treatment when their role as active breadwinners is hampered by disease. This is all the more relevant when the popular regimes are also able to give only partial protection against relapses and progression (Leppert et al., 1996).

There are limitations in this study. Even though a large number of patients are successfully treated in this regime, this pilot report included only patients who came for follow up in the last 3 months of 2018 due to practical problems as this is a non-funded study and has no personnel to support the evaluation. The patients who were on other regimes were not used as controls.

Taken together, this pilot report of patients who were randomly recruited for evaluation reveals the combination of azathioprine 1 mg/kg, atorvastatin 10 mg/day, and oral penicillin 800 mg/day used in patients with relapsing-remitting multiple sclerosis significantly reduced clinical disability at a very cost-effective way that is most suited for resource limited nations. Methotrexate 7.5 mg/week was used in place of azathioprine in patients with progressive course with good results with reference to relapses, disability, and safety. Radiological reduction of lesion load at 1-year and 3-year follow-up was partial. There were no serious side effects in any patient. The regime is relatively safe during pregnancy as most patients are young females. This regime should be tried in low income patients with confidence as no regime currently available either completely prevents relapses or lesion load in imaging.

Additional files

Additional file 1: IRB Approval.

Additional file 2: Model consent form.

Acknowledgements

We express our gratitude to the patient and families for the faith they kept in us.

Author contributions

Study conception: SRC, MP. Study design: NRC. Definition of intellectual content, clinical and experimental studies, and guarantor: SRC. Literature retrieval: SRC, TGI. Data acquisition: NRC, TGI, MP. Data analysis, statistical analysis, manuscript preparation, editing, and review: TGI, MP. All authors approved the final manuscript for publication.

Figure 2: Magnetic resonance images of a 25-year-old male patient (A) and a 29-year-old female patient (B) at onset of multiple sclerosis (A1, B1) and 3 years after treatment (A2, B2).

Conflicts of interest

The authors have no conflicts of interest to declare.

Financial support

None.

Institutional review board statement

Institutional review board approval was not obtained as these data were generated from a large sample of patients who opted for this regime based on literature evidence as they could not afford the usual drugs. This study was performed according to the Declaration of Helsinki, and informed consent of the study procedure was obtained from all participants.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the forms, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.

Reporting statement

This study followed the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) statement.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of National Institute of Mental Health And Neurosciences (NIMHANS), India.

Copyright license agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, and tables), will be available upon request. Data will be available immediately following publication, no end date for anyone who wishes to access the data. In order to gain access, data requestors will need to sign a data access agreement. Proposals should be directed to drchandrasasi@yahoo.com.

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Peer review

Externally peer reviewed.

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