Mingkun Yu

Efficacy of Modafinil on Fatigue and Excessive Daytime Sleepiness Associated with Neurological Disorders: A Systematic Review and Meta-Analysis

Background Modafinil is a novel wake-promoting agent approved by the FDA ameliorating excessive daytime sleepiness (EDS) in three disorders: narcolepsy, shift work sleep disorder and obstructive sleep apnea. Existing trials of modafinil for fatigue and EDS associated with neurological disorders provided inconsistent results. This meta-analysis was aimed to assess drug safety and effects of modafinil on fatigue and EDS associated with neurological disorders. Methods A comprehensive literature review was conducted in order to identify published studies assessing the effects of modafinil on fatigue and EDS associated with neurological disorders. Primary outcomes included fatigue and EDS. Secondary outcomes included depression and adverse effects. Findings Ten randomized controlled trials were identified including 4 studies of Parkinson’s disease (PD), 3 of multiple sclerosis (MS), 2 of traumatic brain injury (TBI) and 1 of post-polio syndrome (PPS). A total of 535 patients were enrolled. Our results suggested a therapeutic effect of modafinil on fatigue in TBI (MD -0.82 95% CI -1.54 - -0.11 p=0.02, I2=0%), while a beneficial effect of modafinil on fatigue was not confirmed in the pooled studies of PD or MS. Treatment results demonstrated a clear beneficial effect of modafinil on EDS in patients with PD (MD -2.45 95% CI -4.00 - -0.91 p=0.002 I2=14%), but not with MS and TBI. No difference was seen between modafinil and placebo treatments in patients with PPS. Modafinil seemed to have no therapeutic effect on depression. Adverse events were similar between modafinil and placebo groups except that more patients were found with insomnia and nausea in modafinil group. Conclusions Existing trials of modafinil for fatigue and EDS associated with PD, MS, TBI and PPS provided inconsistent results. The majority of the studies had small sample sizes. Modafinil is not yet sufficient to be recommended for these medical conditions until solid data are available.

Prognostic Influence and Magnetic Resonance Imaging Findings in Paroxysmal Sympathetic Hyperactivity after Severe Traumatic Brain Injury

Paroxysmal sympathetic hyperactivity (PSH) is a clinical syndrome affecting a subgroup of survivors of severe brain injury. In this study, the prevalence, magnetic resonance imaging (MRI) presentation, influence on the clinical course in the intensive care unit (ICU), and effect on neurological recovery of PSH were prospectively surveyed in 87 patients with severe traumatic brain injury (TBI). Cranial MRI was performed during the first 30 days after injury. The outcome was assessed according to the Glasgow Outcome Scale (GOS). PSH occurred in 18.4% of patients, with a greater incidence among younger patients and those with lower Glasgow Coma Scale (GCS) scores. Patients with PSH had more deep lesions as shown on cranial MRI, significantly longer ICU stays, and worse outcomes. PSH was shown to be common among patients with severe TBI who also had deep intraparenchymal lesions. The mechanism by which PSH influences patient outcomes has yet to be defined, but we believe that it may be mediated by diencephalic-mesencephalic dysfunction or disconnection.

Risk Factors Associated with Sleep Disturbance following Traumatic Brain Injury: Clinical Findings and Questionnaire Based Study

Background Sleep disturbance is very common following traumatic brain injury (TBI), which may initiate or exacerbate a variety of co-morbidities and negatively impact rehabilitative treatments. To date, there are paradoxical reports regarding the associations between inherent characteristics of TBI and sleep disturbance in TBI population. The current study was designed to explore the relationship between the presence of sleep disturbance and characteristics of TBI and identify the factors which are closely related to the presence of sleep disturbance in TBI population. Methods 98 TBI patients (72 males, mean age ± SD, 47 ± 13 years, range 18-70) were recruited. Severity of TBI was evaluated based on Glasgow Coma Scale (GCS). All participants performed cranial computed tomography and were examined on self-reported sleep quality, anxiety, and depression. Results TBI was mild in 69 (70%), moderate in 15 (15%) and severe in 14 (15%) patients. 37 of 98 patients (38%) reported sleep disturbance following TBI. Insomnia was diagnosed in 28 patients (29%) and post-traumatic hypersomnia in 9 patients (9%). In TBI with insomnia group, 5 patients (18%) complained of difficulty falling asleep only, 8 patients (29%) had difficulty maintaining sleep without difficulty in initial sleep and 15 patients (53%) presented both difficulty falling asleep and difficulty maintaining sleep. Risk factors associated with insomnia were headache and/or dizziness and more symptoms of anxiety and depression rather than GCS. In contrast, GCS was independently associated with the presence of hypersomnia following TBI. Furthermore, there was no evidence of an association between locations of brain injury and the presence of sleep disturbance after TBI. Conclusion Our data support and contribute to a growing body of evidence which indicates that TBI patients with insomnia are prone to suffer from concomitant headache and/or dizziness, report more symptoms of anxiety and depression and severe TBI patients are likely to experience hypersomnia.

Clinical treatment of traumatic brain injury complicated by cranial nerve injury

OBJECTIVE To discuss the epidemiology, diagnosis and surgical treatment of cranial nerve injury following traumatic brain injury (TBI) for the sake of raising the clinical treatment of this special category of TBI. PATIENTS AND METHODS A retrospective analysis was made of 312 patients with cranial nerve injury among 3417 TBI patients, who were admitted for treatment in this hospital. RESULTS A total of 312 patients (9.1%) involving either a single nerve or multiple nerves among the 12 pairs of cranial nerves were observed. The extent of nerve injury varied and involved the olfactory nerve (66 cases), optic nerve (78 cases), oculomotor nerve (56 cases), trochlear nerve (8 cases), trigeminal nerve (4 cases), abducent nerve (12 cases), facial nerve (48 cases), acoustic nerve (10 cases), glossopharyngeal nerve (8 cases), vagus nerve (6 cases), accessory nerve (10 cases) and hypoglossal nerve (6 cases). Imaging examination revealed skull fracture in 217 cases, complicated brain contusion in 232 cases, epidural haematoma in 194 cases, subarachnoid haemorrhage in 32 cases, nasal cerebrospinal fluid (CSF) leakage in 76 cases and ear CSF leakage in 8 cases. Of the 312 patients, 46 patients died; the mortality rate associated with low cranial nerve injury was as high as 73.3%. Among the 266 surviving patients, 199 patients received conservative therapy and 67 patients received surgical therapy; the curative rates among these two groups were 61.3% (122 patients) and 86.6% (58 patients), respectively. CONCLUSION TBI-complicated cranial nerve injury is subject to a high incidence rate, a high mortality rate and a high disability rate. Our findings suggest that the chance of recovery may be increased in cases where injuries are amenable to surgical decompression. It is necessary to study all 12 pairs of cranial nerves systematically. Clinically, it is necessary to standardise surgical indications, operation timing, surgical approaches and methods for the treatment of TBI-complicated cranial nerve injury.

Clinical features and functional recovery of traumatic isolated oculomotor nerve palsy in mild head injury with sphenoid fracture

OBJECT The aim of this study was to provide information about long-term functional outcome in patients with isolated oculomotor nerve palsy following minor head injury and to discuss surgical treatment of these patients, especially those with accompanying sphenoid fracture. METHODS A retrospective analysis was made of 26 patients with traumatic isolated oculomotor nerve palsy. The severity of oculomotor nerve palsy and the functional recovery were evaluated based on extraocular muscle movement, eyelid movement, and pupil size. On average, patients were evaluated 3.6 days after the initial injury, and the average follow-up period was 14.2 months (range 3 months-2 years). RESULTS Twenty men and six women were enrolled in this study. The most common cause of trauma was motor vehicle accident in 17 (65.4%) of 26. Among all the recorded symptoms, internal ophthalmoplegia was most frequently seen. The recovery rates of ptosis, external ophthalmoplegia, and internal ophthalmoplegia were 95% (19 of 20 patients), 83.3% (15 of 18 patients), and 50% (13 of 26 patients), respectively. The 6 patients with sphenoid fracture underwent surgical decompression of the superior orbital fissure, after which all patients experienced recovery from ptosis and external ophthalmoplegia and 66.7% (4 of 6 patients) recovered from internal ophthalmoplegia. CONCLUSIONS Limited eye movement may be a major factor that negatively affects functional recovery after mild head injury. Sphenoid fracture might be one of the potential mechanisms involved in traumatic isolated oculomotor nerve palsy after mild head injury. Surgical decompression should be considered when there is evidence of bone compression of the superior orbital fissure.

Risk factors related to dysautonomia after severe traumatic brain injury.

BACKGROUND Dysautonomia after severe traumatic brain injury (TBI) is a clinical syndrome affecting a subgroup of survivors and is characterized by episodes of autonomic dysregulation and muscle overactivity. The purpose of this study was to determine the incidence of dysautonomia after severe TBI in an intensive care unit setting and analyze the risk factors for developing dysautonomia. METHODS A consecutive series of 101 patients with severe TBI admitted in a major trauma hospital during a 2-year period were prospectively observed to determine the effects of age, sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, admission Glasgow Coma Scale (GCS) score, injury severity score, emergency craniotomy, sedation or analgesia, diffuse axonal injury (DAI), magnetic resonance imaging (MRI) scales, and hydrocephalus on the development of dysautonomia. Risk factors for dysautonomia were evaluated by using logistic regression analysis. RESULTS Seventy-nine of the 101 patients met inclusion criteria, and dysautonomia was observed in 16 (20.3%) of these patients. Univariate analysis revealed significant correlations between the occurrence of dysautonomia and patient age, admission GCS score, DAI, MRI scales, and hydrocephalus. Sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, injury severity score, sedation or analgesia, and emergency craniotomy did not influence the development of dysautonomia. Multivariate logistic regression revealed that patient age and DAI were two independent predictors of dysautonomia. There was no independent association between dysautonomia and admission GCS score, MRI scales, or hydrocephalus. CONCLUSIONS Dysautonomia frequently occurs in patients with severe TBI. A younger age and DAI could be risk factors for facilitating the development of dysautonomia.

Hyperbaric Oxygen Therapy in the Management of Paroxysmal Sympathetic Hyperactivity After Severe Traumatic Brain Injury: A Report of 6 Cases

Paroxysmal sympathetic hyperactivity (PSH) after severe brain injury is detrimental to the recovery of patients. Pharmacologic management of PSH is difficult and efficacy is unpredictable or incomplete. This report presents 6 cases of PSH after extremely severe traumatic brain injury in which hyperbaric oxygen therapy (HBOT) controlled paroxysmal autonomic changes and posturing in the early subacute phase after limited success with conventional medication regimens. Thus, HBOT may present an option for the management of PSH in addition to pharmacologic therapy. Potential mechanisms for these effects are discussed.

Vascular endothelial growth factor is neuroprotective against ischemic brain injury by inhibiting scavenger receptor A expression on microglia

Vascular endothelial growth factor (VEGF) is a secreted mitogen associated with angiogenesis. VEGF has long been thought to be a potent neurotrophic factor for the survival of spinal cord neurons. However, the role of VEGF in the regulation of ischemic brain injury remains unclear. In this study, rats were subjected to MCAO (middle cerebral artery occlusion) followed by intraperitoneal injection of VEGF165 (10 mg/kg) immediately after surgery and once daily until the day 10. The expression of target genes was assayed using qPCR, western blot and immunofluorescence to investigate the role of VEGF165 in regulating ischemic brain injury. We found that VEGF165 significantly inhibited MCAO‐induced up‐regulation of Scavenger receptor class A (SR‐A) on microglia in a VEGFR1‐dependent manner. VEGF165 inhibited lipopolysaccharide (LPS)‐induced expression of proinflammatory cytokines IL‐1β, tumor necrosis factor alpha (TNF‐α) and iNOS in microglia. More importantly, the role of VEGF165 in inhibiting neuroinflammation is partially abolished by SR‐A over‐expression. SR‐A further reduced the protective effect of VEGF165 in ischemic brain injury. These data suggest that VEGF165 suppresses neuroinflammation and ischemic brain injury by inhibiting SR‐A expression, thus offering a new target for prevention of ischemic brain injury.

The Development of Posttraumatic Stress Disorder after Mild TraumaticBrain Injury in Civilian Populations: A Meta-Analysis

Background: Posttraumatic stress disorder (PTSD) is an anxiety disorder following exposure to a traumatic event. Recent studies demonstrate that mild traumatic brain injury (mTBI) is strongly associated with PTSD among soldiers returning from Iraq. However, the effect of mTBI on development of PTSD in civilian populations is quite controversial. The study is aimed at identifying whether mTBI contributes to an increased risk of PTSD in civilian populations as it happens in the service members. Methods: A comprehensive search of literature was undertaken in order to identify published studies on PTSD associated with mTBI. mTBI was defined according to the American Congress of Rehabilitation Medicine (ACRM). PTSD was operationalized as the presence of symptoms consistent with those defined by the Diagnostic and Statistical Manual of Mental Disorders. The effect of mTBI on the development of PTSD was assessed with odds ratio (OR) with 95% confidence intervals (CIs). Results: The pooled data consisted of 1222 mTBI patients and 1468 general trauma participants. 14% of mTBI patients reported PTSD, and 9% of general trauma patients developed PTSD. Or of the pooled studies indicates a 61% increase in the prevalence of PTSD, suggesting that mTBI might increase the risk of development of PTSD in civilian settings (or 1.61, 95% CI 1.25-2.06. p=0.0002, I2=0%). The occurrence of PTSD was not significantly different among 3-months, 6-months and 12-months follow up subgroups (p=0.28). A sensitivity analysis shows the results are affected by sequential exclusion of study reported by Bryant et al. (2010). When Bryant et al. data were removed, OR of the other six studies demonstrates that the prevalence of PTSD in mTBI and general trauma groups doesn’t significantly differ (OR 1.30, 95% CI 0.88-1.93. p=0.19, I2=0%). The study from Bryant et al contributed 57% of patients to overall data, which was derived from four levels I trauma centers across three states in Australia. Conclusion: Our data indicate that mTBI patients are more prone to develop PTSD than general trauma patients without mTBI in civilian settings.

Endoscopic transmaxillary transMüller's muscle approach for decompression of superior orbital fissure: A cadaveric study with illustrative case

BACKGROUND In an effort to avoid the damage and inconvenience associated with transcranial approaches, we developed an endoscopic transmaxillary transMüllers muscle approach for decompression of the superior orbital fissure (SOF). METHODS The endoscopic transmaxillary transMüllers muscle route was performed in ten cadaveric heads. We measured important anatomic landmarks, and angles radiographically. This approach was initially attempted in one patient with traumatic superior orbital fissure syndrome (tSOFS). RESULTS A maxillary antrostomy was carried out with a buccal sulcus incision. The sinus ostium and the course of infraorbital nerve were used as endoscopic anatomic landmarks. Then the inferior orbital fissure was drilled out, followed by separating the Müllers muscle. The periorbita were peeled off from the lateral wall, followed by the endoscope going along the periorbital space, until the lateral aspect of the SOF could be visualized. Decompression was successfully performed in all specimens. The initial clinical application justified this approach. The patient had an uneventful postoperative course and satisfactory recovery. CONCLUSION This approach offers sufficient endoscopic visualization and reliable decompression of SOF. It avoids the need for brain retraction, temporalis muscle manipulation, or any external incision, and appears to be able to deliver satisfying aesthetic results as well as favourable functional recovery.