Bibani, Rashid Hamid
(2013)
Exploring the neuroprotective and alerting effects of modafinil in multiple sclerosis and experimental autoimmune encephalomyelitis.
PhD thesis, University of Nottingham.
Abstract
Multiple sclerosis (MS) is the most common demyelinating disease. It is characterised by a great variety of neurological deficits, which most commonly present initially in a relapsing remitting fashion and then take on a gradually progressive course. MS is incurable, since present medications do not counteract progression of the disease. Therefore, an additional strategy aims to focus on prevention of the neuronal loss in an attempt to stop or slow down the progression of the disease.
In this thesis the neuroprotective potential of modafinil is tested in MS in a retrospective study. The ability of modafinil to reduce neurological dysfunction in the MS animal model is also investigated.
In retrospective study the expanded disability status scale (EDSS) progression of thirty patients with MS who received modafinil for the treatment of MS-related fatigue for an uninterrupted period of 3 years or more was compared with ninety matched patients not treated with modafinil, followed up for a matching period of time. We found that the EDSS increase in patients not treated with modafinil was greater than in those treated with modafinil in both relapsing/remitting and progressive MS.
In another experiment, we evaluated the effect of two treatment doses (low dose and high dose) of modafinil on the level of disability in experimental autoimmune encephalomyelitis (EAE) in a placebo controlled study. Modafinil decreased the severity of EAE at both treatment doses and the effect was greater in high dose.
The study in chapter 4 was aimed to explore the anti-fatigue and alerting effects of modafinil in MS in an attempt to link these with the potential neuroprotective effects of modafinil. This was a detailed reanalysis of a prospective placebo controlled study (based on prospectively collected data), in which we examined whether there is any difference between MS patients with fatigue, MS patients without fatigue, and healthy controls on measures of alertness and autonomic function. We found that MS patients with fatigue, compared with healthy controls, had reduced level of alertness on all the tests used, MS patients with fatigue had a reduced level of autonomic function compared to the other two groups. Furthermore, we found that Modafinil displayed alerting and sympathomimetic effects in all three groups of subjects.
In Chapter 5, we assessed a problem relevant to the progression of MS. We take advantage of the methods and data used in the chapter 2 to apply the same retrospective study methodology and statistical retrospective modeling of EDSS progression using the linear regression model to look at the role of oligoclonal band (OCB) positivity or negativity in EDSS progression. Unlike previous studies in smaller cohorts, we did not find that OCB negative patients have a more benign course of disease.
The meta-analysis study in chapter 6 was designed to generate some knowledge regarding the central mechanism of fatigue in general and fatigue related to MS, using a novel functional magnetic resonance imaging (fMRI) meta-analysis method developed by CR Tench in our group. The study has also aimed to explore the brain areas which could be activated by modafinil treatment. The conclusion of this study was that the thalamus and striate are central and relevant nodes for the pathogenesis of fatigue in MS. The study has not detected the specific brain area to be activated by modafinil and showed multiple brain activations.
With regard to the promising findings in our previous experiments, the protocol of a prospective phase II clinical trial was designed and detailed in appendix 10 using radiological primary and clinical secondary outcome measures.
In conclusion, modafinil may slow down the progression of disability in patients with MS and decrease disease severity in EAE. Modafinil can display alerting and sympathomimetic effects in MS patients as well as in healthy subjects. The thalamus and striate are central and relevant nodes for the pathogenesis of fatigue in MS. These are also areas affected by the MS gray matter pathology and may be targets for neuroprotection by modafinil in MS. Finally, we have not reported a significant difference in disease progression measured by EDSS and MSSS between OCB negative and OCB positive in our patients with MS.
This seemingly heterogeneous group of experiments, primarily centred on modafinil’s potential as mechanistic therapy in MS, bring, I hope, new knowledge of aspects of disease progression and pharmacological neuroprotection in a stage of the disease where therapeutic options are currently limited and the need for new treatments is great.
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