David M. Greer

Evidence-based guideline update: Determining brain death in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology

Objective: To provide an update of the 1995 American Academy of Neurology guideline with regard to the following questions: Are there patients who fulfill the clinical criteria of brain death who recover neurologic function? What is an adequate observation period to ensure that cessation of neurologic function is permanent? Are complex motor movements that falsely suggest retained brain function sometimes observed in brain death? What is the comparative safety of techniques for determining apnea? Are there new ancillary tests that accurately identify patients with brain death? Methods: A systematic literature search was conducted and included a review of MEDLINE and EMBASE from January 1996 to May 2009. Studies were limited to adults. Results and recommendations: In adults, there are no published reports of recovery of neurologic function after a diagnosis of brain death using the criteria reviewed in the 1995 American Academy of Neurology practice parameter. Complex-spontaneous motor movements and false-positive triggering of the ventilator may occur in patients who are brain dead. There is insufficient evidence to determine the minimally acceptable observation period to ensure that neurologic functions have ceased irreversibly. Apneic oxygenation diffusion to determine apnea is safe, but there is insufficient evidence to determine the comparative safety of techniques used for apnea testing. There is insufficient evidence to determine if newer ancillary tests accurately confirm the cessation of function of the entire brain.

Impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive meta-analysis.

Background and Purpose— Many studies associate fever with poor outcome in patients with neurological injury, but this relationship is blurred by divergence in populations and outcome measures. We sought to incorporate all recent scholarship addressing fever in brain-injured patients into a comprehensive meta-analysis to evaluate disparate clinical findings. Methods— We conducted a Medline search for articles since January 1, 1995 (in English with abstracts, in humans) and hand searches of references in bibliographies and review articles. Search terms covered stroke, neurological injury, thermoregulation, fever, and cooling. A total of 1139 citations were identified; we retained 39 studies with 67 tested hypotheses contrasting outcomes of fever/higher body temperature and normothermia/lower body temperature in patients with neurological injury covering 14 431 subjects. A separate meta-analysis was performed for each of 7 outcome measures. Significance was evaluated with Zc developed from probability values or t values. Correlational effect size, r(es), was calculated for each study and used to derive Cohen’s d unbiased combined effect size and relative risk. Results— Fever or higher body temperature was significantly associated with worse outcome in every measure studied. Relative risk of worse outcome with fever was: mortality, 1.5; Glasgow Outcome Scale, 1.3; Barthel Index, 1.9; modified Rankin Scale, 2.2; Canadian Stroke Scale, 1.4; intensive care length of stay, 2.8; and hospital length of stay, 3.2. Conclusions— In the pooled analyses covering 14 431 patients with stroke and other brain injuries, fever is consistently associated with worse outcomes across multiple outcome measures.

Collateral vessels on CT angiography predict outcome in acute ischemic stroke.

Background and Purpose— Despite the abundance of emerging multimodal imaging techniques in the field of stroke, there is a paucity of data demonstrating a strong correlation between imaging findings and clinical outcome. This study explored how proximal arterial occlusions alter flow in collateral vessels and whether occlusion or extent of collaterals correlates with prehospital symptoms of fluctuation and worsening since onset or predict in-hospital worsening. Methods— Among 741 patients enrolled in a prospective cohort study involving CT angiographic imaging in acute stroke, 134 cases with proximal middle cerebral artery occlusion and 235 control subjects with no occlusions were identified. CT angiography was used to identify occlusions and grade the extent of collateral vessels in the sylvian fissure and leptomeningeal convexity. History of symptom fluctuation or progressive worsening was obtained on admission. Results— Prehospital symptoms were unrelated to occlusion or collateral status. In cases, 37.5% imaged within 1 hour were found to have diminished collaterals versus 12.1% imaged at 12 to 24 hours (P=0.047). No difference in worsening was seen between cases and control subjects with adequate collaterals, but cases with diminished sylvian and leptomeningeal collaterals experienced greater risk of worsening compared with control subjects measured either by admission to discharge National Institutes of Health Stroke Scale increase ≥1 (55.6% versus 16.6%, P=0.001) or ≥4 (44.4% versus 6.4%, P<0.001). Conclusion— Most patients with proximal middle cerebral artery occlusion rapidly recruit sufficient collaterals and follow a clinical course similar to patients with no occlusions, but a subset with diminished collaterals is at high risk for worsening.

Recommendations for the Management of Cerebral and Cerebellar Infarction With Swelling A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association

Background and Purpose— There are uncertainties surrounding the optimal management of patients with brain swelling after an ischemic stroke. Guidelines are needed on how to manage this major complication, how to provide the best comprehensive neurological and medical care, and how to best inform families facing complex decisions on surgical intervention in deteriorating patients. This scientific statement addresses the early approach to the patient with a swollen ischemic stroke in a cerebral or cerebellar hemisphere. Methods— The writing group used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. The panel reviewed the most relevant articles on adults through computerized searches of the medical literature using MEDLINE, EMBASE, and Web of Science through March 2013. The evidence is organized within the context of the American Heart Association framework and is classified according to the joint American Heart Association/American College of Cardiology Foundation and supplementary American Heart Association Stroke Council methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive American Heart Association internal peer review. Results— Clinical criteria are available for hemispheric (involving the entire middle cerebral artery territory or more) and cerebellar (involving the posterior inferior cerebellar artery or superior cerebellar artery) swelling caused by ischemic infarction. Clinical signs that signify deterioration in swollen supratentorial hemispheric ischemic stroke include new or further impairment of consciousness, cerebral ptosis, and changes in pupillary size. In swollen cerebellar infarction, a decrease in level of consciousness occurs as a result of brainstem compression and therefore may include early loss of corneal reflexes and the development of miosis. Standardized definitions should be established to facilitate multicenter and population-based studies of incidence, prevalence, risk factors, and outcomes. Identification of patients at high risk for brain swelling should include clinical and neuroimaging data. If a full resuscitative status is warranted in a patient with a large territorial stroke, admission to a unit with neurological monitoring capabilities is needed. These patients are best admitted to intensive care or stroke units attended by skilled and experienced physicians such as neurointensivists or vascular neurologists. Complex medical care includes airway management and mechanical ventilation, blood pressure control, fluid management, and glucose and temperature control. In swollen supratentorial hemispheric ischemic stroke, routine intracranial pressure monitoring or cerebrospinal fluid diversion is not indicated, but decompressive craniectomy with dural expansion should be considered in patients who continue to deteriorate neurologically. There is uncertainty about the efficacy of decompressive craniectomy in patients ≥60 years of age. In swollen cerebellar stroke, suboccipital craniectomy with dural expansion should be performed in patients who deteriorate neurologically. Ventriculostomy to relieve obstructive hydrocephalus after a cerebellar infarct should be accompanied by decompressive suboccipital craniectomy to avoid deterioration from upward cerebellar displacement. In swollen hemispheric supratentorial infarcts, outcome can be satisfactory, but one should anticipate that one third of patients will be severely disabled and fully dependent on care even after decompressive craniectomy. Surgery after a cerebellar infarct leads to acceptable functional outcome in most patients. Conclusions— Swollen cerebral and cerebellar infarcts are critical conditions that warrant immediate, specialized neurointensive care and often neurosurgical intervention. Decompressive craniectomy is a necessary option in many patients. Selected patients may benefit greatly from such an approach, and although disabled, they may be functionally independent.

Hypoxic-ischemic brain injury: pathophysiology, neuropathology and mechanisms.

Hypoxic-ischemic brain injury is a well known consequence of cardiac arrest. Variable injuries can occur with purely hypoxic or histotoxic insults such as asphyxiation and carbon monoxide poisoning. The injury may happen at the time of the insult, but there may also be continued damage after circulation and oxygenation are reestablished. The nature and extent of the damage appears to depend on the severity, time course and duration of the oxygen deprivation and lack of blood supply, as well as on the underlying mechanism. This review describes the pathophysiological and molecular basis of hypoxic ischemic brain injury, and differentiates between the mechanisms of injury by cardiac arrest, pure respiratory arrest, and arrest secondary to cytotoxicity (e.g. carbon monoxide poisoning).

Comatose Patients with Cardiac Arrest: Predicting Clinical Outcome with Diffusion-weighted MR Imaging

PURPOSE To examine whether the severity and spatial distribution of reductions in apparent diffusion coefficient (ADC) are associated with clinical outcomes in patients who become comatose after cardiac arrest. MATERIALS AND METHODS This was an institutional review board-approved, HIPAA-compliant retrospective study of 80 comatose patients with cardiac arrest who underwent diffusion-weighted magnetic resonance imaging. The need to obtain informed consent was waived except when follow-up phone calls were required; in those cases, informed consent was obtained from the families. Mean patient age was 57 years +/- 16 (standard deviation); 31 (39%) patients were women. ADC maps were semiautomatically segmented into the following regions: subcortical white matter; cerebellum; insula; frontal, occipital, parietal, and temporal lobes; caudate nucleus; putamen; and thalamus. Median ADCs were measured in these regions and in the whole brain and were compared (with a two-tailed Wilcoxon test) as a function of clinical outcome. Outcome was defined by both early eye opening in the 1st week after arrest (either spontaneously or in response to external stimuli) and 6-month modified Rankin scale score. RESULTS Whole-brain median ADC was a significant predictor of poor outcome as measured by no eye opening (specificity, 100% [95% confidence interval {CI}: 86%, 100%]; sensitivity, 30% [95% CI: 18%, 45%]) or 6-month modified Rankin scale score greater than 3 (specificity, 100% [95% CI: 73%, 100%]; sensitivity, 41% [95% CI: 29%, 54%]), with patients with poor outcomes having significantly lower ADCs for both outcome measures (P <or= .001). Differences in ADC between patients with good and those with poor outcomes varied according to brain region, involving predominantly the occipital and parietal lobes and the putamen, and were dependent on the timing of imaging. CONCLUSION Spatial and temporal differences in ADCs may provide insight into mechanisms of hypoxic-ischemic brain injury and, hence, recovery.

National Institutes of Health Stroke Scale Score Is Poorly Predictive of Proximal Occlusion in Acute Cerebral Ischemia

Background and Purpose— Multimodal imaging is gaining an important role in acute stroke. The benefit of obtaining additional clinically relevant information must be weighed against the detriment of increased cost, delaying time to treatment, and adverse events such as contrast-induced nephropathy. Use of National Institutes of Health Stroke Scale (NIHSS) score to predict a proximal arterial occlusion (PO) is suggested by several case series as a viable method of selecting cases appropriate for multimodal imaging. Methods— Six hundred ninety-nine patients enrolled in a prospective cohort study involving CT angiographic imaging in acute stroke were dichotomized according to the presence of a PO, including a subgroup of 177 subjects with middle cerebral artery M1 occlusion. Results— The median NIHSS score of patients found to have a PO was higher than the overall median (9 versus 5, P<0.0001). The median NIHSS score of patients with middle cerebral artery M1 occlusion was 14. NIHSS score ≥10 had 81% positive predictive value for PO but only 48% sensitivity with the majority of subjects with PO presenting with lower NIHSS scores. All patients with NIHSS score ≥2 would need to undergo angiographic imaging to detect 90% of PO. Conclusions— High NIHSS score correlates with the presence of a proximal arterial occlusion in patients presenting with acute cerebral ischemia. No NIHSS score threshold can be applied to select a subgroup of patients for angiographic imaging without failing to capture the majority of cases with clinically important occlusive lesions. The finding of minimal clinical deficits should not deter urgent angiographic imaging in otherwise appropriate patients suspected of acute stroke.

Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders.

Abstract The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

Wake-Up Stroke: Clinical and Neuroimaging Characteristics

Background: Approximately 25% of ischemic stroke patients awaken with neurological deficits. In these patients, in whom the time from symptom onset is uncertain, brain imaging is a potential strategy to characterize the ischemia duration and the presence of salvageable brain tissue. Methods: We prospectively evaluated consecutive patients with acute ischemic stroke. CT angiography and CT perfusion (CTP) were performed in patients within 24 h of symptom onset. The patients were classified into ‘known onset’, ‘indefinite onset but not on awakening’ and ‘wake-up stroke’ groups. Results: Of 676 patients evaluated, 420 had known-onset strokes, 131 wake-up strokes and 125 strokes with an indefinite time of symptom onset. Ischemic lesion volumes were higher in patients with indefinite-onset strokes (p = 0.04). The frequencies of CTP mismatch and of large-vessel intracranial occlusions were similar among the groups (p = 0.9 and p = 0.2, respectively). Conclusion: The considerable prevalence of CTP mismatch and of intracranial artery occlusions in our patients with wake-up strokes suggests that arterial and perfusion imaging might be particularly important in this population. Revised indications for thrombolysis by using imaging-based protocols might offer these patients the prospect of receiving acute stroke treatment even without a clear time of symptom onset.

Feasibility and safety of combined percutaneous coronary intervention and therapeutic hypothermia following cardiac arrest

REVIEW Mild therapeautic hypothermia (MTH) has been associated with cardiac dysrhythmias, coagulopathy and infection. After restoration of spontaneous circulation (ROSC), many cardiac arrest patients undergo percutaneous coronary intervention (PCI). The safety and feasibility of combined MTH and PCI remains unclear. This is the first study to evaluate whether PCI increases cardiac risk or compromises functional outcomes in comatose cardiac arrest patients who undergo MTH. METHODS Ninety patients within a 6-h window following cardiac arrest and ROSC were included. Twenty subjects (23%) who underwent PCI following MTH induction were compared to 70 control patients who underwent MTH without PCI. The primary endpoint was the rate of dysrhythmias; secondary endpoints were time-to-MTH induction, rates of adverse events (dysrhythmia, coagulopathy, hypotension and infection) and mortality. RESULTS Patients who underwent PCI plus MTH suffered no statistical increase in adverse events (P=.054). No significant difference was found in the rates of dysrhythmias (P=.27), infection (P=.90), coagulopathy (P=.90) or hypotension (P=.08). The PCI plus MTH group achieved similar neurological outcomes (modified Rankin Scale (mRS) <or=3 (P=.42) and survival rates (P=.40). PCI did not affect the speed of MTH induction; the target temperature was reached in both groups without a significant time difference (P=.29). CONCLUSION Percutaneous coronary intervention seems to be feasible when combined with MTH, and is not associated with increased cardiac or neurological risk.