Developing Effective Curative Treatments for Progressive Multiple Sclerosis (PMS)

Introduction

Many people diagnosed with Multiple Sclerosis experience chronic symptoms that hinder their daily lives, like muscle spasms, painful skin sensations, and sharp, burning neuropathic pain (Frischer, 2009). While these symptoms can be managed with current treatments, it is not uncommon for MS to suddenly flare up and leave afflicted people disabled and potentially bedridden. Additionally, the symptomatic nature of many of these treatments fails to address the disease’s pathophysiology, ultimately resulting in individuals with MS being unable to recover from the disease’s primary effects. Despite decades of intensive research to better understand its pathological mechanisms and develop disease-modifying therapies (DMTs), there has been little progress in developing curative and preventative interventions. Various studies have been conducted on MS and different findings and recommendations have been conducted; however, there has never been an exact answer to a specific cause for MS (Feinstein et al., 2015). Therefore, through analysis of various studies which have found the cause of MS to be a combination of environmental and genetic factors, there is a research gap which requires an intensive and in-depth overview of the PMS to enhance a critical and effective curative treatment option for patients suffering from PMS.

Multiple Sclerosis Background

Multiple Sclerosis is classified as a neurological disorder which affects the central nervous system. The central nervous system consists of the brain and spinal code, among other critical system of the body. The affected area is covered in tissues with Sclerosis. This condition is characterized by inflammation and damage to the sheath that covers the fibre cells (Feinstein et al., 2015). There are various causes and risk factors for multiple Sclerosis. These causes and risk factors are environmental factors, autoimmune reactions and genetic predisposition.

Environmental factors

Environmental factors such as smoking cigarettes and bhang have been identified as risk factors for Multiple Sclerosis. The sun is the primary source of vitamin D when the body lacks vitamin D there is high chances of multiple sclerosis, and lastly, viral infections, where the majority of the population suffers from multiple sclerosis (Luzzio 2023). These are environmental factors that increase the opportunities and risks of MS.

Autoimmune reactions

For quite some time in the sphere of medicine, the specific cause of Multiple Sclerosis has not been determined yet. However, scientists believe the particular cause is a combination of both environmental factors and genetic factors (Feinstein et al., 2015). Due to this combination, the immune system reacts, thereby damaging the cells protecting the nervous fibres, leading to their damage, and this often results in multiple Sclerosis.

Genetic predisposition

Genetic conditions occur when there is a history of MS in a family, which means they have a gene component that runs in the family. This family is at higher risk of MS due to their gene component and family history.

Moreover, there are different types of Multiple Sclerosis, which are Progressive-Relapsing MS (PRMS), Relapsing-Remitting MS (RRMS) and Primary Progressive MS (PPMS) and Secondary Progressive MS (SPMS) (Faissner et al., 2019). However, for this research, the focus will be specifically on Progressive Multiple Sclerosis.

Known Mechanism

Multiple sclerosis (MS) is managed through various therapeutic modalities that gear towards modification of the immune system in a bid to reduce its inclination in attacking the central nervous system. For instance, compounds such as ocrelizumab, alemtuzumab, and cladribine have presented efficacy limits against disease progression under some forms of MS (Mahad et al., 2015). Proper medication is also applied to the patients who are genetically affected by Multiple sclerosis.

Methodology

To further explore the developments in Multiple Sclerosis treatments, primary research was conducted. In general, interviews were found to be the most appropriate form considering that the research study centered on a systematic review of clinical treatment options and advances in understanding disease etiology. Since there are already many scientific papers published about Multiple Sclerosis research, it seemed that it would be more beneficial to learn about the perspectives of the clinical and medical research communities on MS treatments by interviewing professionals in these fields. In difference, surveys and non-participant observations would not have provided the same depth of useful information for my research topic. Prior to conducting the interviews, the study was IRB approved and CITI Online Training was completed.

Considering the topic of the research study, medical professionals particularly familiar with Multiple Sclerosis were recruited for the interviews. To be more specific, two professionals (MS researcher and MS primary care physician) were interviewed. The primary physician recruited was an ideal interviewee due to their neuroimmunology specialization, their knowledge of how effective various treatments are, and the multidisciplinary care they provide for patients with Multiple Sclerosis. Similarly, the medical researcher recruited was found to be an ideal interviewee due to their specialization in neuroimmunology and their extensive research relating to the molecular mechanisms of Multiple Sclerosis and the effectiveness of various treatments in targeting these mechanisms. The participants responded through a designated Google Form with various open-ended questions to maximize efficiency for the primary research results.

Interview protocols were created to prepare for the email interviews. In general, the protocols were structured, meaning that a detailed list of interview questions was prepared for each interview with no follow-up questions. While both interview protocols contained questions regarding the specified participant’s education and experience, each protocol also had questions tailored to their profession. The primary physician’s interview protocol questions revolved around the efficiency of current MS treatments and the interviewee’s perspectives on how Multiple Sclerosis should be treated more efficiently. Additional questions involved their perspectives on the shortcoming of existing disease-modifying therapies and if there were any particular ones with promising results from ongoing clinical trials so far. In difference, the interview protocol for the medical researcher focused on their perspectives on how research about MS disease etiology is proceeding and how disease-modifying therapies could be improved.

Results

After Collection and analysis of the feedback provided by the interviewees the data was compiled in firm of tables as follows.

Table 2. Drugs tested in phase III clinical trials in progressive mutliple sclerosis.

SPMS

• Cladribine
• Cyclophosphamide
• Dirucotide
• Dronabinol
• Interferon-beta1a i.m. (avonex)
• Interferon-beta1a s/c (rebif)
• Interferon-beta-1b s/c (betaferon/betaseron)
• Intravenous immunoglobulin
• Lamotrigine
• Mitoxantrone

PPMS

• Dronabinol
• Glatiramer acetate
• Interferon-beta1a (avonex)
• Interferon-beta1b (betaferon/betaseron)
• Rituximab

Discussion

Progressive multiple sclerosis (MS) can present with a variety of clinical characteristics, such as cerebellar syndrome, cognitive decline, spinal cord problem with gait and bladder, bowel, and sexual abnormalities, or a combination of these. Premature disability is most commonly caused by cognitive deterioration. Furthermore, the main symptoms that adversely impact an MS patient’s quality of life include cognitive deterioration, fatigue, and depression.1,2 New approaches to rehabilitation are being developed for individuals with cerebellar illness or cognitive deficits.3. Strategies that are helpful and efficient exist for managing symptoms related to spinal cord involvement.

The goal of treatment for people with progressive MS, whether it be secondary (i.e., preceded by a relapsing-remitting course) or primary (i.e., progressive from the outset), is rehabilitation because there is still minimal potential to change the course of the disease for progressive MS. Patients with evidence of active inflammatory illness seem to respond best to ocrelizumab, the only licensed disease-modifying treatment for primary progressive disease. For secondary progressive illness, there is currently no approved treatment. As such, a clinician managing a patient with progressing multiple sclerosis needs to be knowledgeable about rehabilitation techniques (Frischer et al.,2019). The complete therapy of patients with progressive forms of MS is the main topic of this research; however, the management strategies presented also apply to individuals with relapsing-remitting MS who have similar symptoms. Gait, sexual, bowel, and bladder dysfunctions, cognitive decline, difficulty speaking and swallowing, and pressure sores are among the symptoms that are covered.

Gait Problems and Spasticity

A number of cerebellar or sensory mechanisms, such as weakness, spasticity, ataxia, or, more frequently, a combination of these, can affect gait. Tizanidine, baclofen, and diazepam are three oral medications that are effective in treating spasticity. It is crucial to thoroughly explain to the patient that the goals of treatment are to improve gait and relieve discomfort associated with spasticity and spasms. A velocity-dependent rise in tone does not need to be treated unless it is causing symptoms. To give yourself enough time to gauge your response, begin baclofen at a modest dose (e.g., 5 mg three times per day) and titrate to an effective dose by adding 5 mg per dose every three to five days (Cree et al.,2021). BIf nausea occurs, which is an unusual side effect, take Baclofen with meals. Patients need to be aware that the ideal dose is dependent on their response and might range from being very low to very high (e.g., >100 mg/day). The patient should be ready for the possibility of weakness as the dose is titrated upward. If weakness does develop, lower the dosage to a level that is easier to handle (Mahad et al.,2019). Additional side effects include drowsiness that goes away on a steady dose after a day or two, and worsening of cognitive problems, especially at larger doses.

Tizanidine, like baclofen, has a short half-life and is likewise administered multiple times daily. Depending on the patient’s reaction to the drug, the initial dose of 2 mg is administered at bedtime and titrated to 4 mg to 8 mg given three times a day. Tizanidine’s primary side effect is drowsiness, which frequently prevents use throughout the day. Rarely, orthostatic hypotension may develop at larger dosages (Sorensen et al.,2020). Due to its extended half-life, diazepam is a great antispasticity medication that can be used for nocturnal spasticity. Typically, 2 to 4 mg before bed is sufficient, and patients frequently report—much to their surprise—less fatigue during the day due to better-quality sleep. On the highest dosages of oral medications that are tolerated, some patients may continue to have spasticity. For these patients, intrathecal baclofen (ITB) should be taken into consideration. If a patient is not responding to a 50 mcg intrathecal test dose, 100 mcg may be used to see if this therapy modality is suitable for them. Patients who have the baclofen pump implanted should start with a low dose (≤25 mcg/day by simple continuous flow), particularly if they can walk around (Luzzio, 2023). Before the ideal dosage is reached, it could take many weeks. ITB dosage can be adjusted to meet the individual needs of the patient (e.g., increased dose during the night and lowered dose during the day).

Regardless of the underlying cause, dalfampridine can improve aberrant gait in MS patients. It is unclear if this is due to effects on spasticity or other factors. Ten milligrams should be taken twice a day, roughly twelve hours apart. Patients with a creatine clearance of less than 60 milliliters per minute or those with a history of epilepsy or seizures should not be taken dalacrimperidine. When therapy first starts, there are a lot of possible side effects, such as sleeplessness, nausea, imbalanced gait, and dizziness. These usually go away after a week, however insomnia could linger. The easiest way to deal with dalfampridine-induced insomnia is to take the first dose early in the morning (for example, 4:00 am) and go back to sleep, and then take the second dose about 4:00 pm (Feinstein et al.,2015). It may take many weeks following the start of treatment for patients to fully realize the benefits. Regretfully, there is no assurance of a response; over 60% of patients report no discernible improvement.

Rehabilitative Treatment

Before submitting a patient for necessary physical therapy (PT), it is crucial to establish appropriate medical management of gait and spasticity symptoms in order to prevent wasting valuable therapeutic resources from PT. A patient who is in immediate danger of falling is an exception to this rule. Programs with prior experience meeting the unique PT requirements of MS patients may yield superior results and higher patient satisfaction scores than those without. The PT specialist is also most qualified to assess whether gait aids (such as a brace, cane, or walker) are required and to determine how to use them safely and effectively. It is best to provide a prescription for PT at the same time as one for a gait assistance (Faissner et al.,2019). An ankle-foot orthosis (AFO) should be evaluated for any patient exhibiting toe drag.. A An AFO can be worn all the time or only when necessary, particularly if the patient plans to walk for extended periods of time (eg, hiking, traveling). Using a brace does not result in reliance, despite what many patients believe to be false. When patients require wheelchairs (manual and motorized) as alternatives to walking, direct them to reliable suppliers for their particular requirements, particularly if a customized item is needed. Because most insurance companies need a wheelchair to be suitable for at least five years, wheelchair design must be carefully considered. As a result, the design needs to account for future needs or at the very least be flexible (Macaron and Ontaneda, 2019). Encourage all patients to engage in physical activity appropriate to their level of motor proficiency and overall health. Frequent exercise, particularly cardiovascular exercise, improves wellbeing and may help MS patients with a variety of symptoms, such as depression and fatigue.

Conclusion

Progressive multiple sclerosis (MS) presents with various clinical characteristics, including cerebellar syndrome, cognitive decline, spinal cord problems, gait and bladder, bowel, and sexual abnormalities. Premature disability is most commonly caused by cognitive deterioration, and symptoms adversely impact an MS patient’s quality of life include cognitive deterioration, fatigue, and depression. New approaches to rehabilitation are being developed for individuals with cerebellar illness or cognitive deficits. The goal of treatment for people with progressive MS is rehabilitation, as there is still minimal potential to change the course of the disease. Patients with active inflammatory illness respond best to ocrelizumab, the only licensed disease-modifying treatment for primary progressive disease. For secondary progressive illness, there is currently no approved treatment. A clinician managing a patient with progressing multiple sclerosis needs to be knowledgeable about rehabilitation techniques. Gait problems and spasticity can be treated using oral medications like Tizanidine, baclofen, and diazepam. The ideal dose depends on the patient’s response and may range from very low to very high. Tizanidine has a short half-life and is administered multiple times daily. Diazepam is a great antispasticity medication that can be used for nocturnal spasticity. Dalfampridine can improve aberrant gait in MS patients, but there is no assurance of a response. Rehabilitative treatment involves establishing appropriate medical management of gait and spasticity symptoms before submitting a patient for physical therapy (PT). Programs with prior experience meeting the unique PT requirements of MS patients may yield superior results and higher patient satisfaction scores than those without. An ankle-foot orthosis (AFO) should be evaluated for any patient exhibiting toe drag. When patients require wheelchairs, design must be carefully considered and account for future needs. Encourage all patients to engage in physical activity appropriate to their level of motor proficiency and overall health.

References

Cree, B. A., Arnold, D. L., Chataway, J., Chitnis, T., Fox, R. J., Pozo Ramajo, A., … & Lassmann, H. (2021). Secondary progressive multiple sclerosis: new insights. Neurology, 97(8), 378-388.

Faissner, S., Plemel, J. R., Gold, R., & Yong, V. W. (2019). Progressive multiple Sclerosis: From pathophysiology to therapeutic strategies. Nature Reviews Drug Discovery, 18(12), 905–922.

Feinstein, A., Freeman, J., & Lo, A. C. (2015). Treatment of progressive multiple Sclerosis: What works, what does not, and what is needed. The Lancet Neurology, 14(2), 194–207.

Frischer, J. M., Bramow, S., Dal-Bianco, A., Lucchinetti, C. F., Rauschka, H., Schmidbauer, M., Laursen, H., Sorensen, P. S., & Lassmann, H. (2009). The relation between inflammation and neurodegeneration in multiple sclerosis brains.

Hauser, S. L., & Cree, B. A. (2020). Treatment of multiple sclerosis: a review. The American journal of medicine, 133(12), 1380-1390.

Luzzio, C. (2023, June 30). Multiple Sclerosis. Practice Essentials, Background, Pathophysiology.

Macaron, G., & Ontaneda, D. (2019). Diagnosis and management of progressive multiple sclerosis. Biomedicines, 7(3), 56.

Mahad, D. H., Trapp, B. D., & Lassmann, H. (2015). Pathological mechanisms in progressive multiple sclerosis. The Lancet Neurology, 14(2), 183-193.

Sorensen, P. S., Fox, R. J., & Comi, G. (2020). The window of opportunity for treatment of progressive multiple sclerosis. Current opinion in neurology, 33(3), 262-270.