Claudio L. Bassetti

Practice Parameter: Prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: To systematically review outcomes in comatose survivors after cardiac arrest and cardiopulmonary resuscitation (CPR). Methods: The authors analyzed studies (1966 to 2006) that explored predictors of death or unconsciousness after 1 month or unconsciousness or severe disability after 6 months. Results: The authors identified four class I studies, three class II studies, and five class III studies on clinical findings and circumstances. The indicators of poor outcome after CPR are absent pupillary light response or corneal reflexes, and extensor or no motor response to pain after 3 days of observation (level A), and myoclonus status epilepticus (level B). Prognosis cannot be based on circumstances of CPR (level B) or elevated body temperature (level C). The authors identified one class I, one class II, and nine class III studies on electrophysiology. Bilateral absent cortical responses on somatosensory evoked potential studies recorded 3 days after CPR predicted poor outcome (level B). Burst suppression or generalized epileptiform discharges on EEG predicted poor outcomes but with insufficient prognostic accuracy (level C). The authors identified one class I, 11 class III, and three class IV studies on biochemical markers. Serum neuron-specific enolase higher than 33 μg/L predicted poor outcome (level B). Ten class IV studies on brain monitoring and neuroimaging did not provide data to support or refute usefulness in prognostication (level U). Conclusion: Pupillary light response, corneal reflexes, motor responses to pain, myoclonus status epilepticus, serum neuron-specific enolase, and somatosensory evoked potential studies can reliably assist in accurately predicting poor outcome in comatose patients after cardiopulmonary resuscitation for cardiac arrest.

Sleep-Disordered Breathing and Acute Ischemic Stroke: Diagnosis, Risk Factors, Treatment, Evolution, and Long-Term Clinical Outcome

Background and Purpose— Sleep-disordered breathing (SDB) is frequent in stroke patients. Risk factors, treatment response, short-term and long-term outcome of SDB in stroke patients are poorly known. Methods— We prospectively studied 152 patients (mean age 56±13 years) with acute ischemic stroke. Cardiovascular risk factors, Epworth sleepiness score (ESS), stroke severity/etiology, and time of stroke onset were assessed. The apnea-hypopnea index (AHI) was determined 3±2 days after stroke onset and 6 months later (subacute phase). Continuous positive airway pressure (CPAP) treatment was started acutely in patients with SDB (AHI ≥15 or AHI ≥10+ESS >10). CPAP compliance, incidence of vascular events, and stroke outcome were assessed 60±16 months later (chronic phase). Results— Initial AHI was 18±16 (≥10 in 58%, ≥30 in 17% of patients) and decreased in the subacute phase (P<0.001). Age, diabetes, and nighttime stroke onset were independent predictors of AHI (r2=0.34). In patients with AHI ≥30, age, male gender, body mass index, diabetes, hypertension, coronary heart disease, ESS, and macroangiopathic etiology of stroke were significantly higher/more common than in patients with AHI <10. Long-term incidence of vascular events and stroke outcome were similar in both groups. CPAP was started in 51% and continued chronically in 15% of SDB pts. Long-term stroke mortality was associated with initial AHI, age, hypertension, diabetes, and coronary heart disease. Conclusions— SDB is common particularly in elderly stroke male patients with diabetes, nighttime stroke onset, and macroangiopathy as cause of stroke; it improves after the acute phase, is associated with an increased poststroke mortality, and can be treated with CPAP in a small percentage of patients.

Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2012

This paper is meant to provide guidance to anyone wishing to write a neurological guideline for diagnosis or treatment, and is directed at the Scientist Panels and task forces of the European Federation of Neurological Societies (EFNS). It substitutes the previous guidance paper from 2004. It contains several new aspects: the guidance is now based on a change of the grading system for evidence and for the resulting recommendations, and has adopted The Grading of Recommendations, Assessment, Development and Evaluation system (GRADE). The process of grading the quality of evidence and strength of recommendations can now be improved and made more transparent. The task forces embarking on the development of a guideline must now make clearer and more transparent choices about outcomes considered most relevant when searching the literature and evaluating their findings. Thus, the outcomes chosen will be more critical, more patient‐oriented and easier to translate into simple recommendations. This paper also provides updated practical recommendations for planning a guideline task force within the framework of the EFNS. Finally, this paper hopes to find the approval also by the relevant bodies of our future organization, the European Academy of Neurology.

Functional connectivity in the default network during resting state is preserved in a vegetative but not in a brain dead patient

Recent studies on spontaneous fluctuations in the functional MRI blood oxygen level‐dependent (BOLD) signal in awake healthy subjects showed the presence of coherent fluctuations among functionally defined neuroanatomical networks. However, the functional significance of these spontaneous BOLD fluctuations remains poorly understood. By means of 3 T functional MRI, we demonstrate absent cortico‐thalamic BOLD functional connectivity (i.e. between posterior cingulate/precuneal cortex and medial thalamus), but preserved cortico‐cortical connectivity within the default network in a case of vegetative state (VS) studied 2.5 years following cardio‐respiratory arrest, as documented by extensive behavioral and paraclinical assessments. In the VS patient, as in age‐matched controls, anticorrelations could also be observed between posterior cingulate/precuneus and a previously identified task‐positive cortical network. Both correlations and anticorrelations were significantly reduced in VS as compared to controls. A similar approach in a brain dead patient did not show any such long‐distance functional connectivity. We conclude that some slow coherent BOLD fluctuations previously identified in healthy awake human brain can be found in alive but unaware patients, and are thus unlikely to be uniquely due to ongoing modifications of conscious thoughts. Future studies are needed to give a full characterization of default network connectivity in the VS patients population. Hum Brain Mapp, 2009.

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.

Sleep apnea in patients with transient ischemic attack and stroke A prospective study of 59 patients

Although sleep apnea (SA) appears to be a cardiovascular risk factor, little is known about its frequency in patients with transient ischemic attack (TIA) and stroke.We prospectively studied 59 subjects (26 women and 33 men; mean age, 62 years) with stroke (n = 36) or TIA (n = 23) with the use of a standard protocol that included assessment of snoring and daytime sleepiness (Epworth Sleepiness Score [ESS]), a validated SA score (Sleep Disorders Questionnaire [SDQ-SA]), and a severity of stroke score (Scandinavian Stroke Scale [SSS]). SA was considered clinically probable (P-SA) when habitual snoring was associated with an ESS of >10 or when SDQ-SA score was >or=to32 in women and >or=to36 in men. Polysomnography (PSG) was obtained in 36 subjects (group 1) a mean of 12 days after TIA or stroke. In 23 subjects (group 2), PSG was not available (n = 11), refused (n = 10), or inadequate (n = 2). Clinical and PSG data were compared with those obtained in 19 age- and gender-matched control subjects. Groups 1 and 2 were similar in mean age (61 versus 64 years), type of event (36% versus 44% TIA), reported habitual snoring (58% versus 52%), and P-SA (58% versus 50%). PSG showed SA (Apnea-Hypopnea Index [AHI], >or=to10) in 25 of 36 subjects (69%). The proportion of subjects with SA was similar in the TIA and stroke groups (69% versus 70%) and was well above the frequency found in our control group (15%). An AHI of >or=to20 and a minimal oxygen saturation of <85% were each found in 20 of 36 subjects (55%). Gender and age did not correlate with severity of SA. Subjects with habitual snoring, P-SA, or severe stroke (SSS of <30) had a significantly higher AHI (p < 0.05). The sensitivity of P-SA for SA was 64%, and the specificity was 67%. We conclude that SA has a high frequency in patients in the acute phase of TIA and stroke and SA cannot be predicted reliably on clinical grounds alone but is more likely in patients with habitual snoring, abnormal SDQ-SA, or severe stroke. NEUROLOGY 1996;47: 1167-1173

SPECT during sleepwalking

Sleepwalking is a dissociation between body sleep and mind sleep. We report single photon emission computed tomography (SPECT) in a man with a history of sleepwalking. Our findings suggest that this dissociation arises from activation of thalamocingulate pathways and persisting deactivation of other thalamocortical arousal systems.

Early prognosis in coma after cardiac arrest: a prospective clinical, electrophysiological, and biochemical study of 60 patients.

BACKGROUND: The univariate study of clinical, electrophysiological, or biochemical variables has been shown to predict the outcome in postanoxic coma in about 50% of patients for each type of variable. Previous studies did not, however, consider the prognostic accuracy of a multivariate approach. METHODS: Sixty patients in coma for more than six hours after cardiac arrest were prospectively examined by means of repeated clinical examinations (including Glasgow coma score (GCS)), EEG, and medianus nerve somatosensory evoked potentials (SEPs). In 16 patients, the early concentrations of serum neuron specific enolase and ionised calcium were also measured. RESULTS: Within the first year after cardiac arrest, 20% of patients made a good neurological recovery; 80% remained in a vegetative state or died. Clinical examination correctly predicted outcome in 58% of patients, SEP in 59%, and EEG in 41%. The combination of clinical examination, SEP, and EEG raised the percentage of correct predictions to 82%, without false pessimistic predictions. Concentrations of serum neuron specific enolase and ionised calcium were of no additional prognostic help. Multivariate regression analysis identified the association of GCS < 8 at 48 hours with abnormal or absent early cortical SEPs as highly predictive of a bad outcome (risk = 97%, 95% confidence interval = 86-99%). CONCLUSION: The combination of GCS at 48 hours, SEP, and if these are non-conclusive, EEG, permits a more reliable prediction of outcome in postanoxic coma than clinical examination alone.

Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt pathways

Apart from its hematopoietic function, erythropoietin (Epo) exerts neuroprotective functions in brain hypoxia and ischemia. To examine the mechanisms mediating Epos neuroprotective activity in vivo, we made use of our transgenic mouse line tg21 that constitutively expresses human Epo in brain without inducing excessive erythrocytosis. We show that human Epo is expressed in tg21 brains and that cortical and striatal neurons carry the Epo receptor. After middle cerebral artery occlusion, human Epo potently protected brains of tg21 mice against ischemic injury, both when severe (90 min) and mild (30 min) ischemia was imposed. Histochemical studies revealed that Epo induced an activation of JAK‐2, ERK‐1/‐2, and Akt pathways in the ischemic brain. This activation was associated with elevated Bcl‐XL and decreased NO synthase‐1 and ‐2 levels in neurons. Intracerebroventricular injections of selective inhibitors of ERK‐1/‐2 (PD98059) or Akt (wortmannin) pathways revealed that both ERK‐1/‐2 and Akt were required for Epos neuroprotective function, antagonization of either pathway completely abolishing tissue protection. On the other hand, ERK‐1/‐2 and Akt blockade did not reverse the neuronal NO synthase‐1/‐2 inhibition, indicating that Epo down‐regulates these NO synthases in an ERK‐1/‐2 and Akt independent manner. On the basis of our data, the dual activation of ERK‐1/‐2 and Akt is crucial for Epos neuroprotective activity.

The phosphatidylinositol-3 kinase/Akt pathway mediates VEGF’s neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia

Based on its trophic influence on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for stroke treatment. VEGFs survival‐promoting effects are purchased at the expense of an increased blood brain barrier permeability, which potentially compromises tissue survival. The mechanisms via which VEGF protects the brain against ischemia remained unknown. We examined signaling pathways underlying VEGFs neuroprotective activity in our transgenic mouse line, which expresses human VEGF165 under a neuron‐specific enolase (NSE) promoter. We show that VEGF receptor‐2 (Flk‐1) is expressed on ischemic neurons and astrocytes and is activated by VEGF. Following 90‐min episodes of middle cerebral artery occlusion, VEGF increased phosphorylated (but not total) Akt and ERK‐1/‐2 and reduced phosphorylated mitogen activated protein kinase/p38 and c‐Jun NH2‐terminal kinase (JNK)‐1/‐2 levels, at the same time decreasing inducible NO synthase expression in ischemic neurons. Inhibition of Akt with Wortmannin reversed VEGFs neuroprotective properties, diminished brain swelling, and restored the vascular permeability induced by VEGF to below levels in WT animals. The aggravation of brain injury by Wortmannin was associated with the restitution of p38, but not of JNK‐1/‐2, ERK‐1/‐2, or inducible NOS (iNOS). Our data demonstrate that VEGF mediates both neuroprotection and blood brain barrier permeability via the phosphatidylinositol‐3 kinase (PI3K)/Akt pathway. Based on our observation that VEGF neuroprotection and vascular leakage depend on PI3K/Akt, which is putatively regulated by VEGF receptor‐2, we predict that it may not easily be possible to make use of VEGFs neuroprotective function without accepting its unfavorable consequence, the increased vascular permeability.—Kilic, E., Kilic, Ü., Wang, Y., Bassetti, C. L., Marti, H. H., Hermann, D. M. The phosphatidylinositol‐3 kinase/Akt pathway mediates VEGFs neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. FASEB J. 20, E307–E314 (2006)