Devon Conway

Combination therapy in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the CNS. It is the most common non-traumatic cause of neurological disability among young adults in western Europe and North America. Existing MS therapies are partly effective in halting ongoing inflammatory tissue damage and clinical progression. MS pathogenesis is complex and probably heterogeneous among patients, suggesting that combination therapy strategies that target a range of disease mechanisms might be more effective than medications used as monotherapy. Potential regimens include the combination of interferons and glatiramer acetate with each other or with approved second-line drugs such as natalizumab and mitoxantrone. Disease-modifying therapies have also been used in combination with drugs approved for other indications, such as corticosteroids, methotrexate, azathioprine, and cyclophosphamide. Many preliminary studies have provided favourable results for various combination regimens. However, several subsequent large, randomised, controlled trials have had negative or conflicting results. Therefore, the usefulness of combination therapy in MS remains uncertain.

Long term benefit of multiple sclerosis treatment: an investigation using a novel data collection technique

Background: The Knowledge Program (KP) is an initiative to collect self-reported patient data and objective clinician assessments electronically at each outpatient clinical encounter. Available outcomes include the EuroQoL-5D (EQ5D), Patient Health Questionnaire-9 (PHQ9), Multiple Sclerosis Performance Scales (MSPS), and the timed 25-foot walk (T25FW). Objective: This study was designed to use the KP to investigate the long-term benefits of early treatment (ET) in multiple sclerosis (MS). Methods: The KP was queried for patients with relapsing–remitting MS or secondary progressive MS who were ≥5 years from symptom onset. ET was defined as treatment with an approved agent for ≥3 of the first five years after symptom onset. Propensity scores for ET were calculated based on early clinical characteristics. Patients were divided into propensity score quintiles and linear regression models were constructed to determine the treatment effect sizes and confidence intervals. Results: From the 1082 patients that met entry criteria, 453 patients (41.9%) received ET. Those patients receiving ET showed significantly better scores on the EQ5D index, PHQ9, and MSPS, but only in the upper three propensity quintiles. For the T25FW, ET did not result in significantly better times in any quintile. Conclusions: These results suggest that ET of MS is beneficial but the effect appears modest.

Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course

Background: Comorbidities are known to affect multiple sclerosis (MS) patients in a number of ways, including delaying time to diagnosis and reducing health-related quality of life. Objective: To determine the impact of hypertension, hyperlipidemia, diabetes mellitus, and obstructive lung disease on disease course in MS patients. Methods: The Knowledge Program is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through Knowledge Program query and chart review, we identified all relapsing-remitting MS patients seen between 1 January 2010 and 29 May 2012 and acquired their magnetic resonance imaging (MRI) results and comorbidities. Linear and logistic regression models with adjustment for important covariates were used to determine whether the comorbidities affected outcomes over a 3-year period. Results: Hypertension, diabetes, and obstructive lung disease, but not hyperlipidemia, impacted clinical outcomes, including walking speed, self-reported disability, and depression. Hypertension had the greatest effect. The presence of multiple comorbidities had a cumulative effect on clinical outcomes. MRI outcomes were unaffected by comorbidities. Conclusion: This 3-year longitudinal study revealed that all comorbidities tested except hyperlipidemia impacted clinical outcomes and a cumulative effect with multiple comorbidities was observed. Consideration of comorbid conditions is essential in MS patient care.

Emerging Oral Therapies in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The seven therapies currently approved by regulatory agencies are administered by subcutaneous or intramuscular injection or intravenous infusion. Many phase 2 trials involving oral MS therapeutics were recently completed, as were two phase 3 trials of fingolimod and one phase 3 trial of cladribine. Numerous other oral treatments are being investigated in ongoing phase 3 trials. Although an oral route of administration is attractive, these medications also present new challenges in balancing convenience, efficacy, and safety. In this review, we examine the safety and efficacy data from emerging oral therapies in an attempt to clarify their potential future role in the treatment of MS patients.

The Stepping Test: A Step Back In History

The stepping test is a valuable part of the neurological examination that is used to localize labyrinthine pathology. The test is known by two eponyms: the “Fukuda Test” in the United States and Asia and the “Unterberger Test” in Europe. Some controversy exists as to which name is correct. Siegfried Unterberger was an Austrian otolaryngologist who initially described the test in 1939. It was modified in 1959 by Tadashi Fukuda, a Japanese otolaryngologist, who introduced a method to better quantify the test results. Thus, the test should be called the “Unterberger Test,” unless Fukudas methods for measurement are used.

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.

Chronic Cerebrospinal Venous Insufficiency as a Cause of Multiple Sclerosis: Controversy and Reality

Opinion statementMultiple sclerosis (MS) is a relapsing and progressive disorder of the central nervous system. It is characterized most commonly by episodes of clinical worsening, followed by clinical improvement. Pathologically, MS is associated with focal areas of myelin destruction, inflammation, and axonal transection (“demyelinating plaques”) in the brain and spinal cord. Traditionally, MS has been considered an autoimmune disorder, with the primary pathophysiology arising from an errant immune system. Recent work has raised the possibility that MS is not caused primarily by an immune abnormality but may instead arise from venous anomalies affecting the jugular and/or azygos venous systems. This condition has been called chronic cerebrospinal venous insufficiency (CCSVI). It has been proposed that CCSVI may be pathogenic in MS, causing venous back pressure and iron deposition, with a secondary immune response. Some investigators have proceeded to unblinded nonrandomized angioplasty and stenting procedures in patients with CCSVI, with anecdotal reports of symptom improvement. Because of conflicting data on the presence of CCSVI and the absence of controlled trials of CCSVI intervention, the current standard of clinical care is neither to evaluate multiple sclerosis (MS) patients for CCSVI anomalies, nor to intervene with procedures to alter such anomalies. There is intense interest and ongoing work to evaluate the presence of venous anomalies in MS patients as well as in normal controls and patients with other neurologic conditions; to characterize such anomalies, if present; and to further understand whether the concept of a “backpressure” pathology is borne out by the evidence. If CCSVI is indeed a pathogenic mechanism for some subset of the MS population, this would dramatically change the focus of attention for therapeutic endeavors and monitoring for this population and would bring MS therapeutics firmly into the area of vascular intervention. On the other hand, the history of MS research contains many novel and potentially paradigm-shifting ideas that were later disproved by other investigators.

Multiple sclerosis: Mechanisms of disability accumulation in multiple sclerosis

Natural history studies have identified numerous features of disability progression in patients with multiple sclerosis (MS), and have provided valuable insight into the underlying pathology of the disease that could assist the development of new treatment strategies. A new study indicates that disability progression occurs in two stages in patients with MS.

Factors associated with clinically significant increased walking time in multiple sclerosis: Results of a survival analysis of short-term follow-up data from a clinical database

Background: Because multiple sclerosis (MS) is variable and unpredictable, if symptom worsening could be predicted, patients may feel better prepared to manage changes in function. Objective: The objective of this paper is to study the prediction of walking impairment in MS. Methods: We retrieved data for all MS patients at our center (2008–2009), including baseline and follow-up timed 25-foot walk (T25FW) times. We assessed the incidence of ≥20% worsening in T25FW by developing two survival models: (1) disease course and (2) Multiple Sclerosis Performance Scales (MSPS) score. The outcome was days until ≥20% worsening in T25FW. Covariates were disease subtype, years since diagnosis, Patient Health Questionnaire-9 (PHQ-9) score, and demographics. Data were interval censored; missing data were handled with multiple imputation. Results: Of 1544 patients, 309 (20%) experienced ≥20% worsening T25FW. For disease course, time to worsening was significantly shorter for secondary progressive vs. relapsing–remitting disease (p < 0.001). For MSPS, patients with lower baseline MSPS scores progressed more slowly (p = 0.001). In both models, sex, baseline T25W, and time since diagnosis were significantly associated with worsening. In the disease course model, PHQ 9 score may be related to worsening (p = 0.07). Conclusion: These findings suggest factors associated with worsening in T25FW and a potential approach to establishing indicators associated with clinically significant change.

COL4A1 gene mutation – beyond a vascular syndrome

COL4A1 mutations have been associated with a variety of vascular abnormalities and disease manifestations, including porencephaly, infantile hemiparesis, intracerebral hemorrhage in neonates and children, intracerebral hemorrhage and cerebral small vessel disease in adulthood, intracranial aneurysms, and retinal arteriolar tortuosities [1]. The gene encodes for type IV collagen a1 that forms the vascular basement membrane in heterotrimer triple helix collagen. Seizures have been described with COL4A1 mutation, the reasons for which are unknown. We present a patient with COL4A1 mutation who developed status epilepticus, and offer a hypothesis generating explanation for seizures in this monogenic cerebral small vessel disease.