Christian R. Baumann

CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions

Objective: To determine the role of CSF hypocretin-1 in narcolepsy with and without cataplexy, Kleine-Levin syndrome (KLS), idiopathic and other hypersomnias, and several neurological conditions. Patients: 26 narcoleptic patients with cataplexy, 9 narcoleptic patients without cataplexy, 2 patients with abnormal REM-sleep-associated hypersomnia, 7 patients with idiopathic hypersomnia, 2 patients with post-traumatic hypersomnia, 4 patients with KLS, and 88 patients with other neurological disorders. Results: 23 patients with narcolepsy-cataplexy had low CSF hypocretin-1 levels, while one patient had a normal hypocretin level (HLA-DQB1*0602 negative) and the other two had intermediate levels (familial forms). One narcoleptic patient without cataplexy had a low hypocretin level. One patient affected with post-traumatic hypersomnia had intermediate hypocretin levels. The KLS patients had normal hypocretin levels while asymptomatic, but one KLS patient (also affected with Prader-Willi syndrome) showed a twofold decrease in hypocretin levels during a symptomatic episode. Among the patients without hypersomnia, two patients with normal pressure hydrocephalus and one with unclear central vertigo had intermediate levels. Conclusion: Low CSF hypocretin-1 is highly specific (99.1%) and sensitive (88.5%) for narcolepsy with cataplexy. Hypocretin ligand deficiency appears not to be the major cause for other hypersomnias, with a possible continuum in the pathophysiology of narcolepsy without cataplexy and idiopathic hypersomnia. However, partial hypocretin lesions without low CSF hypocretin-1 consequences cannot be definitely excluded in those disorders. The existence of normal hypocretin levels in narcoleptic patients and intermediate levels in other rare aetiologies needs further investigation, especially for KLS, to establish the functional significance of hypocretin neurotransmission alterations.

Comparison of Intraarterial and Intravenous Thrombolysis for Ischemic Stroke With Hyperdense Middle Cerebral Artery Sign

Background and Purpose— It is unclear whether intraarterial (IAT) or intravenous (IVT) thrombolysis is more effective for ischemic stroke with hyperdense middle cerebral artery sign (HMCAS) on computed tomography (CT). The aim of this study was to compare IAT and IVT in stroke patients with HMCAS. Methods— Comparison of data from 2 stroke units with similar management of stroke associated with HMCAS, except that 1 unit performed IAT with urokinase and the other IVT with plasminogen activator. Time to treatment was up to 6 hours for IAT and up to 3 hours for IVT. Outcome was measured by mortality and the modified Rankin Scale (mRS), dichotomized at 3 months into favorable (mRS 0 to 2) and unfavorable (mRS 3 to 6). Results— One hundred twelve patients exhibited a HMCAS, 55 of 268 patients treated with IAT and 57 of 249 patients who underwent IVT. Stroke severity at baseline and patient age were similar in both groups. Mean time to treatment was longer in the IAT group (244±63 minutes) than in the IVT group (156±21 minutes; P=0.0001). However, favorable outcome was more frequent after IAT (n=29, 53%) than after IVT (n=13, 23%; P=0.001), and mortality was lower after IAT (n=4, 7%) than after IVT (n=13, 23%; P=0.022). After multiple regression analysis IAT was associated with a more favorable outcome than IVT (P=0.003) but similar mortality (P=0.192). Conclusion— In this observational study intraarterial thrombolysis was more beneficial than IVT in the specific group of stroke patients presenting with HMCAS on CT, even though IAT was started later. Our results indicate that a randomized trial comparing both thrombolytic treatments in patients with middle cerebral artery occlusion is warranted.

Hypocretin-1 (orexin A) deficiency in acute traumatic brain injury

Hypocretin-1 is involved in the regulation of the sleep-wake cycle. The authors prospectively assessed CSF hypocretin-1 levels in 44 consecutive patients with acute traumatic brain injury (TBI). Compared with controls, hypocretin-1 levels were abnormally lower in 95% of patients with moderate to severe TBI and in 97% of patients with posttraumatic brain CT changes. Hypocretin-1 deficiency after TBI may reflect hypothalamic damage and be linked with the frequent development of posttraumatic sleep-wake disorders.

Sleep–wake disturbances 3 years after traumatic brain injury

Background 6 months after traumatic brain injury (TBI), almost three out of four patients suffer from sleep–wake disturbances (SWD) such as post-traumatic hypersomnia (increased sleep need of ≥2 h compared with before injury), excessive daytime sleepiness (EDS), fatigue and insomnia. The long-term course of post-traumatic SWD, however, is unknown. Objectives To assess the prevalence and characteristics of post-traumatic SWD 3 years after trauma. Design Prospective longitudinal clinical study in 51 consecutive TBI patients (43 males, eight females, mean age 40±16 years). Main outcome measures EDS (as assessed by the Epworth sleepiness scale), fatigue (fatigue severity scale), post-traumatic hypersomnia (sleep length per 24 h), insomnia, depression and anxiety. Results Post-traumatic SWD were found in 34 patients (67%): post-traumatic hypersomnia in 14 (27%), EDS in six (12%), fatigue in 18 patients (35%) and insomnia in five patients (10%). SWD were not associated with severity or localisation of, or time interval since, TBI. Insomnia was linked to depressive symptoms. Conclusions This prospective study shows that 3 years after TBI, two out of three patients suffer from residual SWD, particularly fatigue and post-traumatic hypersomnia. In 45% of TBI patients, SWD appear directly related to the trauma itself.

Hypocretins (orexins) and sleep–wake disorders

Since their discovery in 1998, the hypocretins (orexins)-peptides that are produced by a group of neurons situated in the posterolateral hypothalamus--have been shown to excite many CNS areas including many neuronal systems that regulate sleep and wakefulness. Animal studies indicate that hypocretins play a part in the regulation of various functions including arousal, muscle tone, locomotion, regulation of feeding behaviour, and neuroendocrine and autonomic functions. A link between hypocretin deficiency and narcoleptic symptoms was first shown in canine and rodent models of narcolepsy. Hypocretin deficiency, as shown by low or absent concentrations in CSF, was subsequently found in 90% of patients with sporadic narcolepsy-cataplexy, and less commonly in familial narcolepsy. In most other sleep-wake and neurological disorders, hypocretin concentrations are normal. Low concentrations were also found in hypothalamic disorders, acute traumatic brain injury, and a few other disorders. The exact function of the hypocretin system in sleep-wake regulation and its pathophysiological role in hypocretin-deficient and non-deficient narcolepsy as well as in non-narcoleptic, hypocretin-deficiency syndromes remain unclear.

Seizure outcome after resection of cavernous malformations is better when surrounding hemosiderin-stained brain also is removed.

Summary:  Purpose: Considering the epileptogenic effect of cavernoma‐surrounding hemosiderin, assumptions are made that resection only of the cavernoma itself may not be sufficient as treatment of symptomatic epilepsy in patients with cavernous malformations. The purpose of this study was to test the hypothesis whether seizure outcome after removal of cavernous malformations may be related to the extent of resection of surrounding hemosiderin‐stained brain tissue.

Loss of hypocretin (orexin) neurons with traumatic brain injury

Chronic, daytime sleepiness is a major, disabling symptom for many patients with traumatic brain injury (TBI), but thus far, its etiology is not well understood. Extensive loss of the hypothalamic neurons that produce the wake‐promoting neuropeptide hypocretin (orexin) causes the severe sleepiness of narcolepsy, and partial loss of these cells may contribute to the sleepiness of Parkinson disease and other disorders. We have found that the number of hypocretin neurons is significantly reduced in patients with severe TBI. This observation highlights the often overlooked hypothalamic injury in TBI and provides new insights into the causes of chronic sleepiness in patients with TBI. Ann Neurol 2009;66:555–559

Parkinsonism with excessive daytime sleepiness--a narcolepsy-like disorder?

BackgroundParkinsonian patients with excessive daytime sleepiness (EDS), hallucinations, REM sleep behavior disorder (RBD), short mean sleep latencies, and sleep-onset REM periods (SOREMP) on multiple sleep latency tests (MSLT) have been reported. In these patients a narcolepsy-like pathophysiology of sleep-wake disturbances has been suggested.Patients and methodsWe studied 14 consecutive patients with Parkinsonism and EDS. Standard studies included assessment of duration and severity of Parkinsonism (Hoehn & Yahr score), Epworth sleepiness score (ESS), history of “REM-symptoms” (RBD/hallucinations/sleep paralysis/cataplexy-like episodes), polysomnography (PSG),MSLT, and measurement of cerebrospinal fluid (CSF) levels of hypocretin-1 (orexin A).ResultsThere were 12 men and 2 women (mean age 69 years; range 54–82). The mean duration and the Hoehn & Yahr score were 6.3 years and 2.2, respectively. Diagnoses included idiopathic Parkinson’s disease (IPD, n=10), dementia with diffuse Lewy bodies (n=3), and multisystem atrophy (n=1). The ESS was ≥10 in all patients (mean 12; range 10–18). “REM-symptoms” were reported by all but two patients (hallucinations: n=9; RBD: n=9).None of the patients reported cataplexy-like symptoms or sleep paralysis. On PSG sleep apnea (apnea hypopnea index > 10/h, n=7), periodic limb movements during sleep (PLMS-index > 10/h, n=6), and features of RBD (n=5) were found. On MSLT mean sleep latency was < 5 minutes in 10 patients, and SOREMP were found in two patients. When compared with controls (n=20, mean 497 pg/ml; range 350–603), CSF hypocretin-1 levels were normal in 8 patients and low in 2 patients (221 and 307 pg/ml, respectively).ConclusionThese findings do not support the hypothesis of a “final common pathway” in the pathophysiology of narcolepsy and Parkinsonism with EDS. Sleep apnea and PLMS may play a so-far underestimated role in the pathogenesis of EDS in Parkinsonian patients.

Seizure Outcome after Resection of Supratentorial Cavernous Malformations: A Study of 168 Patients

Summary:  Purpose: The optimal management of cerebral cavernous malformations (CCMs) with epileptic seizures is still a matter of debate. The aim of our study was to examine seizure outcome in the largest published series of surgically treated patients with epilepsy due to a supratentorial CCM, and to define predictors for good surgical outcome.

Modafinil ameliorates excessive daytime sleepiness after traumatic brain injury.

Background: Excessive daytime sleepiness (EDS) and fatigue are common symptoms after traumatic brain injury (TBI), but there is no specific treatment for affected patients. With this pilot study, we aimed at studying the effect of daily modafinil on posttraumatic EDS and fatigue. Methods: We conducted a prospective, double-blind, randomized, placebo-controlled pilot study in 20 patients with TBI who had fatigue or EDS or both. After baseline examinations (questionnaires including the Epworth Sleepiness Scale to assess EDS and the Fatigue Severity Scale to assess fatigue, actigraphy, polysomnography, maintenance of wakefulness test, and psychomotor vigilance test), 10 patients received 100 to 200 mg modafinil every morning, and 10 patients were treated with placebo. After a 6-week treatment period, all examinations were repeated. Results: EDS improved significantly in patients with TBI who were treated with modafinil, compared with the placebo group. Similarly, the ability to stay awake on the maintenance of wakefulness test improved only in the modafinil group. Modafinil, however, had no impact on posttraumatic fatigue. Clinically relevant side effects were not observed. Conclusion: This study indicates that modafinil is effective and well tolerated in the treatment of posttraumatic EDS but not of fatigue. Classification of evidence: This study provides Class I evidence that modafinil (100–200 mg daily) improves posttraumatic EDS compared with placebo. This study provides Class I evidence that modafinil (100–200 mg daily) does not improve posttraumatic fatigue compared with placebo.