Innovations In Clinical Neuroscience

MAR-APR 2018

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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21 ICNS INNOVATIONS IN CLINICAL NEUROSCIENCE March-April 2018 • Volume 15 • Number 3–4 R E V I E W substantial enough to cause four patients with BDS and five patients with MS to drop out before the end of the study. Data were collected from each group at baseline (T0), after three months of modafinil therapy (T1), and after one month of washout (T2). Improvement of fatigue severity (FAI score) was seen among the entire modafinil treatment cohort (p=0.006), but this was only significant in the MS and BDS groups and not the CS group. Good responders (patients with improved FAI scores) were significantly more common in the MS group (58.3%) than in the CS group (11.1% patients; p=0.04). This difference was also seen when comparing the BDS group (70%) to the CS group (11.1%; p=0.04). The authors concluded that modafinil appeared to adequately ameliorate fatigue in patients with BDS or MS and in patients who suffered a stroke and had lesions on certain areas of the brain. This led the authors to speculate that the location of the TBI might play a substantial role in determining medication selection. Additionally, patients reported improvements in daily quality of life. 24 Case report . Tcheremissine and Rachal 25 presented a case report of a patient with TBI who experienced benefit from using modafinil as evidenced by significant improvements in depressive symptoms and greater ability to participate in all activities of daily living. A 58-year old man who was five years post- TBI presented to the clinic with difficulty functioning in his daily routine. He reported low energy, feelings of hopelessness due to difficulty in concentration, depression, and inability to hold a job or enjoy life. His past medication history included paroxetine 30mg at bedtime, bupropion XL 300mg daily, dextroamphetamine and amphetamine (Adderall XR) 20mg daily, and zolpidem 10mg at bedtime. He reported minimal improvement from all these medications. At that time, the patient was placed on modafinil initiated at 100mg once daily and titrated to 300mg daily. The patient reported a more than 50-percent increase in his ability to participate in daily activities, with major improvements in his depressive symptoms. He was able to tolerate modafinil and did not report any side effects. The authors stated that their case provides more evidence that modafinil is a safe and efficacious adjunctive therapy for patients with TBI. Systematic review . A systematic review and meta-analysis conducted by Sheng et al 6 compiled 10 randomized, controlled trials (RCTs) describing the efficacy of modafinil as a treatment for fatigue and EDS among patients with various neurological disorders. The RCTs included four on Parkinson's disease (PD), three on MS, two on TBI, and one on post-polio syndrome (PPS). Eight of the 10 studies collected (2 PD, 3 MS, 2 TBI, and 1 PPS) investigated the effect of modafinil on fatigue. The two PD studies showed a pooled mean FSS score of -0.22 points compared to placebo groups (p=0.66), while the three MS studies showed a pooled mean FSS score of -6.56 points compared to placebo groups (p=0.33). Neither of these findings was statistically significant. Additionally, the one PPS study showed no statistically significant difference between experiment and placebo subjects. However, the two TBI studies showed a pooled mean FSS score of -0.82 compared to placebo (p=0.02), clearly suggesting the benefit of modafinil in the setting of TBI. EDS severity was measured using ESS in four PD, two MS, two TBI, and one PPS studies. Overall mean difference between ESS scores in the four PD groups was -2.41 (p=0.004), showing clear benefit of modafinil use among patients with PD and EDS. However, ESS scores implied that modafinil was ineffective compared to placebo when treating EDS patients with either TBI or MS, or PPS (p-values not reported). Sheng et al concluded that the evidence for modafinil use in patients with PD, MS, TBI, or PPS is weak due to inconsistency of the results between trials. They noted that additional studies using larger sample sizes must be conducted and provide consistent results before a proper recommendation regarding modafinil utilization in these patient populations can be made. One TBI study by Kaiser et al 9 objectively measured sleepiness with MWT scores and found therapeutic benefit of utilizing modafinil in the treatment group (8.4±9.6; p=0.04) as compared to placebo group (0.4±6.2). Cantor et al 4 conducted a systematic review in which they collected articles that met five distinct inclusion criteria: published in English, peer-reviewed, sample size included at least 70-percent individuals with TBI, measured fatigue as a primary or secondary outcome, and involved some kind of intervention. The primary outcome of this systematic review was to identify studies that described different interventions for the management of fatigue in patients following TBI. There were only five articles that had fatigue as their primary outcome. Nineteen of the 44 articles that were fully reviewed met all the inclusion criteria. The authors found only two studies that evaluated the efficacy of modafinil in reducing fatigue and sleepiness. These two studies were also included in the meta-analysis by Sheng, et al 6 Cantor et al concluded that data concerning fatigue treatment were inconsistent among the reviewed articles, that modafinil is likely ineffective for posttraumatic brain injury fatigue (PTBIF), and that further larger-scale studies are needed to evaluate fatigue treatments among different patient populations. 4 DISCUSSION Fatigue and EDS are serious long-term complications experienced by many patients with TBI. 1,4,21 However, these symptoms are often very subjective, making discovery of an adequate treatment strategy an arduous endeavor. ESS, FSS, MSLT, and MWT tests used to assess the severity of fatigue and EDS require extensive patient participation, which is not easily obtained from those who suffer from lack of energy or motivation. Prompt treatment is often needed to minimize long-term consequences of TBI; yet evidence supporting treatment modalities that result in consistent improvement in important patient parameters, such as fatigue and EDS, is substantially lacking. The Kaiser et al 9 trial concluded that modafinil was able to improve MWT scores, thereby alleviating EDS in patients with TBI; and the study conducted by Brioschi et al 24 found that patients with BDS or MS and fatigure respond favorably to modafinil. However, Kaiser et al 9 reported an unfavorable outcome regarding post-TBI fatigue FSS scores, and Brioschi 24 reported that modafinal appeared to have no statistically significant benefit for patients with CS, as measured by ESS or FSS, compared to placebo; this implies that location of TBI might need to be determined before medication therapy can be appropriately selected, an idea supported by animal models reported by Kumar, 17 Elovic, 12 and Minzenberg and Carter. 15 The study conducted by Jha et al 21 concluded that neither EDS nor fatigue are ameliorated by the use of modafinil when compared to placebo. The lack of efficacy in the Jha et al trial is interesting because the patients were given higher dosages (up to 400mg)

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