Multiple sclerosis in Pakistan: Current status and future perspective.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) which commonly leads to disability. We reviewed articles on MS from Pakistan using PubMed, Google Scholar and Pak Medinet to present different aspects of the disease and the status of disease modifying treatments in Pakistan and South Asia. MS is not as uncommon in Pakistan as it has been previously thought to be. Estimated prevalence of MS in Pakistan may be 10 per 100,000 population. Data suggests that most features of MS found in Pakistan are similar to those found in the West. These features include a female preponderance, mean age of onset in the third decade of life and similar risk factors including viral infections, smoking, and vitamin D deficiency, as well as genetic risk factors. Relapsing-remitting multiple sclerosis (RRMS) is the most common disease pattern seen in Pakistan which is also consistent with data from other regions. Treatment modalities in Pakistan include immunomodulatory and immunosuppressive drugs. In order to improve care for MS patients in Pakistan, it is extremely important to obtain a population-based prevalence of MS in the country and a national MS registry, along with implementing programs for patients' awareness and the training of doctors, especially internists. There are many disease modifying therapies (DMT) available in Pakistan but no data is available on the utilization and impact of these DMTs.

Achieving effective patient and public involvement in international clinical trials in neurology.

There is a growing need for patient and public involvement (PPI) to inform the way that research is developed and performed. International randomized controlled trials are particularly likely to benefit from PPI, but guidance is lacking on how or when it should be incorporated. In this article, we describe the PPI process that occurred during the design and initiation of an international treatment clinical trial in MS. PPI was incorporated using a structured approach, aiming to minimize bias and achieve equivalence in study design, implementation, and interpretation. Methods included PPI representation within the study research team, and the use of focus groups, analyzed using thematic framework analysis. We report the outcomes of PPI and make recommendations on its use in other neurology clinical trials. By sharing our model for PPI, we aim to maximize effectiveness of future public involvement and to allow its effect to be better evaluated.

Determining the effectiveness of early intensive versus escalation approaches for the treatment of relapsing-remitting multiple sclerosis: The DELIVER-MS study protocol.

Multiple Sclerosis (MS) is a common cause of neurological disability among young adults and has a high economic burden. Currently there are 18 disease modifying agents for relapsing MS, which were tested in clinical trials versus placebo or an active comparator in a pairwise manner. However, there is currently no consensus on the fundamental principles of treatment approach and initial therapy selection. These factors result in variable use of disease modifying therapies. Here we describe the study protocol for Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the Treatment of Relapsing-remitting Multiple Sclerosis (DELIVER-MS). The main objective of the study is to determine whether an early highly effective treatment approach, defined as use of one of four monoclonal antibodies as initial therapy, is more effective than an escalation treatment approach (any other approved medication as initial therapy with subsequent escalation to higher efficacy treatments guided by radiological and clinical evaluation). The primary endpoint of the study is reduction in normalized brain volume loss from baseline visit to month 36 visit using MRI. Brain volume loss was selected as the best short-term predictor of long-term clinical disability. A total of 400 participants will be randomized 1:1 using minimization to account for age and sex by site, and 400 will be enrolled into a parallel observational cohort. The study results will help guide overall treatment philosophy and will have important implications for patient choice, clinical practice, and treatment access.

Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis.

Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.

Rates of Adverse Events and Outcomes among Stroke Patients Admitted to Primary Stroke Centers.

BACKGROUND AND PURPOSE: To identify the beneficial effects of primary stroke centers (PSCs) certification by Joint Commission (JC), we compared the rates of in-hospital adverse events and discharge outcomes among ischemic stroke patients admitted to PSCs and those admitted to non-PSC hospitals in the United States. METHODS: We obtained the data from the Nationwide Inpatient Sample from 2010 and 2011. The analysis was limited to states that publicly reported hospital identity. PSCs were identified by matching the Nationwide Inpatient Sample hospital files with the list provided by JC. The analysis was limited to patients (age ≥18 years) discharged with a principal diagnosis of ischemic stroke (International Classification of Disease, 9th Revision, codes 433.x1, 434.x1). RESULTS: We identified a total of 123,131 ischemic stroke patients from 28 states. A total of 72,982 (59.3%) patients were admitted to PSCs. After adjusting for age, gender, race or ethnicity, comorbidities, All Patients Refined Diagnosis Related Groups (APR-DRG)-based disease severity, and hospital teaching status, patients admitted to PSCs were at lower risk of in-hospital adverse events complications: pneumonia (odds ratio [OR], .8; 95% confidence interval [CI], .7-.8) and sepsis (OR, .7; 95% CI, .6-.8). Patients admitted to PSCs were more likely to receive thrombolysis (OR, 1.6; 95% CI, 1.5-1.7). The mean cost of hospitalization (95% CI) of the patients was significantly higher in patients admitted at PSCs compared with those admitted at non PSC hospitals $47621 (47099-48144) vs. $35229 (34803-35654), P < .0001). The patients admitted to PSCs had lower inpatient mortality (OR, .8; 95% CI, .8-.9) and were more likely to be discharged with none to minimal disability (OR, 1.1; 95% CI, 1.0-1.1). CONCLUSIONS: Compared with non-PSC admissions, patients admitted to PSCs are less likely to experience hospital adverse events and more likely to experience better discharge outcomes.

Reversible cerebral vasoconstriction syndrome associated with interferon beta-1a use for multiple sclerosis.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) has been associated with multiple medications, cocaine, pregnancy, migraine, and other conditions. OBJECTIVES: RCVS associated with interferon beta use has never before been described. METHODS: We describe the case of a 20-year-old female who developed acute onset severe headache and was found to have subarachnoid hemorrhage 2 months after initiating Rebif (Interferon beta-1a) for multiple sclerosis (MS). Cerebral angiography showed multiple areas of distal stenosis and dilatation with radiographic resolution 1 month later. RESULTS/CONCLUSIONS: This is the first case report of RCVS in an MS patient treated with Rebif.

Thoracolumbar Arteriovenous Malformations Presenting with Intracranial Subarachnoid Hemorrhage: Case Series and Review of Literature.

OBJECTIVE: Cryptogenic intracranial subarachnoid hemorrhage accounts for approximately 15% of all subarachnoid hemorrhage cases. Diagnostic workup after negative cerebral digital subtraction angiogram typically includes magnetic resonance imaging of the brain and cervical spine for arteriovenous malformations, tumors, and fistulae. Only a few cases of thoracolumbar spinal vascular malformations have been associated with intracranial subarachnoid hemorrhage. METHODS: Case series and review of the literature. RESULTS: We found 3 patients at our institution who had nontraumatic, nonaneurysmal intracranial subarachnoid hemorrhage with isolated spinal vascular malformation in the thoracolumbar region. Including our 3 cases, we found a total of 15 similar cases in the literature. Most of the patients were younger, most having concurrent spinal cord symptoms of radiculopathy (27%), myelopathy (20%), or bladder bowel involvement (20%). Most of the spinal vascular malformations were intramedullary or conus medullaris type. Locations of intracranial subarachnoid hemorrhage were mostly isolated to the perimesencephalic area and posterior fossa. CONCLUSIONS: In younger populations presenting with nonaneurysmal intracranial subarachnoid hemorrhage and symptoms related to the spinal cord, evaluation for thoracolumbar spinal vascular malformations must be included in the initial workup.