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There is a growing number of forcibly displaced persons (FDPs) worldwide. With more than 100 million people forcibly displaced today, there is an urgent mandate to understand the neurologic care needs of this population and how neurologists and other health care workers can most effectively provide that care. In this Emerging Issues in Neurology article, we attempt to (1) define the scope of the problem of providing neurologic care to FDPs, (2) highlight commonly encountered clinical challenges related to neurologic care of FDPs, and (3) provide useful clinical information for neurologists and other clinicians who deliver care to FDPs with neurologic needs. We address the terminology of forcible displacement and how terms may differ across a person's migration journey. Common challenges encountered by FDPs with neurologic needs across settings include loss of support systems, loss of personal health information, language barriers and differing expression of symptoms, differing belief systems, epidemiologic patterns of disease unfamiliar to the clinician, and patients' fear and perceived risks of engaging with health systems. Practical approaches are shared for clinicians who encounter an FDP with a neurologic presentation. Finally, the article discusses many unmet neurologic needs of FDPs, which require significant investment. These include addressing lapses in neurologic care during displacement and understanding the effects of forcible displacement on people with chronic neurologic conditions. Future research and educational resources should focus on improving epidemiologic intelligence for neurologic conditions across geographies, developing curricula for optimizing the neurologic care of FDPs, and evaluating the most appropriate and effective uses of health technologies in humanitarian settings.

Hyperactive delirium is common after subarachnoid hemorrhage (SAH). We aimed to identify risk factors for delirium and to evaluate its impact on outcome.

In patients with aneurysmal subarachnoid hemorrhage (aSAH), increased brain extracellular interleukin (IL)-6 levels measured by cerebral microdialysis (CMD) were associated with disease severity, early brain injury, delayed cerebral infarction, and axonal injury. In this study, we analyzed brain extracellular IL-6 levels of aSAH patients following parenteral diclofenac. Twenty-four mechanically ventilated poor-grade aSAH patients were included. Changes in cerebral metabolism, brain/body temperature, and CMD-IL-6 levels following intravenous diclofenac infusion (DCF; 75 mg diluted in 100 cc normal saline) were retrospectively analyzed from prospectively collected bedside data (at 1 hour before DCF = baseline; and at 2, 4, and 8 hours after DCF). Statistical analysis was performed using generalized estimating equations. Seventy-two events in 24 aSAH patients were analyzed. Median age was 60 years (interquartile range [IQR]: 52–67), admission Hunt & Hess grade was 4 (IQR: 3–5), and modified Fisher grade (mFisher) was 4 (IQR: 3–4). Higher CMD-IL-6 levels at baseline were linked to fever, higher mFisher, delayed cerebral infarction, and metabolic distress (p< 0.05). CMD-IL-6 levels at baseline were 281.4 pg/mL (IQR: 47–1866) and significantly (p< 0.001; Wald-X2= 106) decreased at 2 hours to 86.3 pg/mL (IQR: 7–1946), at 4 hours to 40.9 pg/mL (IQR: 4–1237), and at 8 hours to 53.5 pg/mL (IQR: 5–1085), independent of probe location or day after bleeding. Parenteral diclofenac may attenuate brain extracellular proinflammatory response in poor-grade aSAH patients.

Cardiac complications are common after spontaneous intracerebral hemorrhage (ICH). In this study we intended to investigate factors associated with higher alterations in heart rate and their impact on outcome.

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Background: Nosocomial infections are common in patients with spontaneous subarachnoid hemorrhage (SAH). The aim of this retrospective cohort study was to determine the incidence of infections during SAH and to evaluate the course of inflammation parameters and its implications for long term outcome. Objective: Ninety-nine consecutive coiled SAH patients were included. Laboratory and clinical parameters as well as culture positive infections were followed over the disease course. Long-term outcome was assessed at 6-month by the Glasgow Outcome score (GOS) and dichotomized in favorable (GOS>3) and unfavorable outcome (GOS≤3). Results: The most frequent infections were pulmonary (30.3%) urinary tract (25.3%), blood stream infections (20.2%) and ventriculitis (5.1%). The incidence of infections did not significantly differ between outcome groups. In contrast, patients with unfavorable outcome had a higher incidence of sepsis (46.7% versus 24.6%). C-reactive protein (CRP) and leukocytes were significantly higher in patients with unfavorable outcome. A CRP increase of 6 mg/dl or more in the first 3 days after SAH was independently associated with unfavorable outcome (OR 7.19 CI 1.7-30.52; p=0.008). Patients with an early CRP increase were more frequently treated with antimicrobial therapy in the first 3 days after admission which led to a significantly lower incidence of culture positive infections in the later course. Conclusion: A sharp CRP-increase in the acute phase of SAH could potentially aid the intensivist in the early identification of patients at high risk for neurological morbidity. Early antimicrobial treatment reduces the rate of patients showing culture positive infections in the course of the disease.

Background: Fever is common in neurocritical care patients and is associated with poor outcome. Targeted temperature management (TTM), i.e. therapeutic hypothermia or controlled normothermia, after acute brain injury has been studied as a neuroprotectant for several decades. In contrast to pharmacological agents with specific targets TTM affects multiple pathophysiological mechanisms and is primarily thought to attenuate secondary brain injury. Most promising results have been obtained from experimental studies on cerebral ischemia or traumatic brain injury showing beneficial effects of hypothermia on structural and functional outcome. Objective: The aim of this systematic review of the literature is to provide an overview on preclinical and clinical data on the use of TTM for intracerebral hemorrhage (ICH). The impact of TTM on structural changes and functional outcome after induced and spontaneous ICH will be summarized. Results and Discussion: A positive influence of hypothermia has been observed in animal models of spontaneous ICH improving, among others, perihematomal edema, blood-brain barrier integrity, inflammation and thrombin-induced injury. However, results regarding functional outcome are conflicting. Little data is available on the effect of TTM after spontaneous ICH in humans. Single-center observational studies have shown reduced perihematomal edema under mild hypothermia and an association with favorable outcome. However, these beneficial effects on mortality and functional outcome have not been confirmed in randomized studies so far. Thus, results from ongoing, prospective randomized-controlled trials are highly anticipated.

Introduction: Animal data suggest an association between neuroinflammation and secondary brain injury including axonal injury after aneurysmal subarachnoid hemorrhage (aSAH). We sought to study the association between brain extracellular interleukin (IL)-6 and TAU-protein levels as a surrogate marker for neuroinflammation and axonal injury in patients with poor grade aSAH. Methods: Prospectively collected data from 26 consecutive poor-grade aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD) were retrospectively analyzed. IL-6 and TAU-protein levels were analyzed using ELISA from a single CMD-sample every 24 hours and correlated with brain metabolic and hemodynamic parameters. Patients were dichotomized to highgrade (N=10) or low-grade (N=16) neuroinflammation according to their median CMD-IL-6 levels. Data were analyzed using generalized estimating equations to account for multiple within-subject measurements. Results: Perilesional probe location (P=0.02) and aSAH related intracerebral hemorrhage (aICH) volume (P=0.003) at admission were associated with high-grade neuroinflammation. Brain extracellular TAU-protein levels (P=0.001), metabolic distress and delayed cerebral infarction (DCI; P=0.001) were linked to high-grade neuroinflammation. Relative or absolute phosphor-TAU levels were not correlated with CMD-IL-6 levels. High-grade neuroinflammation was a predictor for worse outcome three months after ictus, independently from probe location, initial Hunt grade and age (P=0.01). Conclusion: Neuroinflammation after aSAH is associated with intraparenchymal bleeding, deranged cerebral metabolism and TAU-protein release. The impact of potential anti-inflammatory treatment strategies on secondary brain injury after aSAH has to be investigated in future studies.

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The impact of therapeutic hypothermia (TH) on long-term neurological outcome is still controversial. Data on the effects of TH on brain homeostasis are mostly derived from experimental research. Invasive multimodal neuromonitoring techniques may provide additional insight into pathophysiological changes associated with primary or secondary brain injury in humans. In this study we describe the principles of multimodal neuromonitoring and its potential in the clinical setting of TH. We call for more research using multimodal neuromonitoring techniques in patients undergoing TH to optimize cooling and rewarming strategies.

Background:The prevalence of febrile seizures (FSs) and epilepsy are often reported to be higher in sub-Saharan Africa. Furthermore, several studies describe complex features of FSs as risk factors for the development of subsequent epilepsy.Methods:During the period from 2002 to 2004 door-to-door studies with supplementary data collection were conducted in three different areas of Tanzania, examining the prevalence of FSs in 7,790 children between the age of 2 mo and 7 y at the time of the interview. The information on the presence of FSs of 14,583 children, who at the time of the interview were younger than 15 y, was collected in order to describe reported seizures, if any.Results:Overall, 160 children between 2 mo and 7 y with a prevalence rate of 20.5/1,000 (95% confidence interval: 17.5–23.9/1,000) met the criteria for FSs. The average age at onset was 2.2 (SD: 1.8) y and ~42% had complex FSs. Respiratory tract infections and malaria were the most frequent concomitant diseases.Conclusion:Our findings do not confirm the assumption of an increased prevalence of FSs in sub-Saharan Africa. However, the elevated number of complex FSs emphasizes the necessity of more reliable studies about FSs and its consequences.

We analyzed the impact of long-term endovascularly based prophylactic normothermia versus conventional temperature management on inflammatory parameters in patients with severe cerebrovascular disease.

Spontaneous subarachnoid hemorrhage (SAH) still has a high risk for poor outcome that is frequently attributable to symptomatic cerebral vasospasm (CVS). We hypothesize that cellular microparticles (MP) play a role in the pathogenesis of CVS and may serve as biomarkers for CVS.

To provide an overview of infectious intracranial complications secondary to invasive procedures or trauma in the neuro-ICU patient population. Nosocomial infections of the central nervous system are a serious complication contributing to morbidity, prolonged length of stay in the ICU and/or hospital, and mortality of neurocritical care patients.

We sought to study the effectiveness and safety of endovascular cooling to maintain prophylactic normothermia in comparison with standardized, stepwise, escalating fever management to reduce fever burden in patients with severe cerebrovascular disease.

ABSTRACTThe pharmacokinetic profile of linezolid in cerebrospinal fluid (CSF) in five neurointensive care patients with staphylococcal ventriculitis was studied. The mean area under concentration-time curve (± standard deviation) was 63 ± 18.9 mg · h/liter, with a CSF-to-plasma ratio of 0.8 ± 0.3. Times above MIC in CSF were 99.8% and 57.2% for pathogens with MICs of 2 mg/liter and 4 mg/liter, respectively.

Introduction We report the case of a patient who developed a severe post-exertional heat stroke with consecutive multiple organ dysfunction resistant to conventional antipyretic treatment, necessitating the use of a novel endovascular device to combat hyperthermia and maintain normothermia.Methods A 38-year-old male suffering from severe heat stroke with predominant signs and symptoms of encephalopathy requiring acute admission to an intensive care unit, was admitted to a ten-bed neurological intensive care unit of a tertiary care hospital. The patient developed consecutive multiple organ dysfunction with rhabdomyolysis, and hepatic and respiratory failure. Temperature elevation was resistant to conventional treatment measures. Aggressive intensive care treatment included forced diuresis and endovascular cooling to combat hyperthermia and maintain normothermia.Results Analyses of serum revealed elevation of proinflammatory cytokines (TNF alpha, IL-6), cytokines (IL-2R), anti-inflammatory cytokines (IL-4) and chemokines (IL-8) as well as signs of rhabdomyolysis and hepatic failure. Aggressive intensive care treatment as forced diuresis and endovascular cooling (CoolGard® and CoolLine®) to combat hyperthermia and maintain normothermia were used successfully to treat this severe heat stroke.Conclusion In this case of severe heat stroke, presenting with multiple organ dysfunction and elevation of cytokines and chemokines, which was resistant to conventional cooling therapies, endovascular cooling may have contributed significantly to the reduction of body temperature and, possibly, avoided a fatal result.

Apoptosis plays an essential role in the cascade of CNS cell degeneration after traumatic brain injury. However, the underlying mechanisms are poorly understood. The authors examined the temporal profile and cell subtype distribution of the proapoptotic protein Bid from 6 hours to 7 days after cortical impact injury in the rat. Increased protein levels of tBid were seen in the cortex ipsilateral to the injury site from 6 hours to 3 days after trauma. Immunohistologic examinations revealed expression of tBid in neurons, astrocytes, and oligodendrocytes from 6 hours to 3 days after impact injury, and concurrent assessment of DNA damage using TUNEL identified tBid-immunopositive cells with apoptoticlike morphology in the traumatized cortex. Moreover, Bid cleavage and activation of caspase-8 and caspase-9 occurred at similar time points and in similar brain regions (i.e., cortical layers 2 to 5) after impact injury. In contrast, there was no evidence of caspase-8 or caspase-9 processing or Bid cleavage in the ipsilateral hippocampus, contralateral cortex, and hippocampus up to 7 days after the injury. The results provide the first evidence of Bid cleavage in the traumatized cortex after experimental traumatic brain injury in vivo,and demonstrate that tBid is expressed in neurons and glial cells. Further, findings indicate that cleavage of Bid may be associated with the activation of the initiator caspase-8 and caspase-9. Finally, these data support the hypothesis that cleavage of Bid contributes to the apoptotic degeneration of different CNS cells in the injured cortex.

Apoptotic cell death plays an important role in the cascade of neuronal degeneration after traumatic brain injury (TBI), but the underlying mechanisms are not fully understood. However, increasing evidence suggests that expression of Fas and its ligand (FasL) could play a major role in mediating apoptotic cell death in acute and chronic neurologic disorders. To further investigate the temporal pattern of Fas and FasL expression after experimental TBI in the rat, male Sprague Dawley rats were subjected to unilateral cortical impact injury. The animals were killed and examined for Fas and FasL protein expression and for immunohistologic analysis at intervals from 15 minutes to 14 days after injury. Increased Fas and FasL immunoreactivity was seen in the cortex ipsilateral to the injury site from 15 minutes to 72 hours after the trauma, respectively. Immunohistologic investigation demonstrated a differential pattern of Fas and FasL expression in the cortex, respectively: increased Fas immunoreactivity was seen in cortical astrocytes and neurons from 15 minutes to 72 hours after the injury. In contrast, increased expression of FasL was seen in cortical neurons, astrocytes, and microglia from 15 minutes to 72 hours after impact injury. Concurrent double-labeling examinations using terminal deoxynucleotidyl tranferase-mediated deoxyuridine-biotin nick end labeling identified Fas- and FasL-immunopostive cells with high frequency in the cortex ipsilateral to the injury site. In contrast, there was no evidence of Fas- and FasL-immunopositive cells in the hippocampus ipsilateral to the injury site up to 14 days after the trauma. Further, Fas and FasL immunoreactivity was absent in the contralateral cortex and hippocampus at all time points investigated. These results reveal induction of Fas and FasL expression in the cortex after TBI in the rat. Further, these data implicate an involvement of Fas and FasL in the pathophysiologic mechanism of apoptotic neurodegeneration after TBI. Last, these data suggest that strategies aimed to repress posttraumatic Fas- and FasL-induced apoptosis may open new perspectives for the treatment of TBI.

Epileptic seizures and epilepsy in urban settings of low-income and middle-income countries (LMIC) are largely under-researched, but their prevalence is necessary for good healthcare planning. This study aimed to determine the lifetime prevalence of epileptic seizures and epilepsy in urban Dar es Salaam.

• In a 3-year period, 110 patients with central nervous system infections of various causes were examined serially by means of transcranial Doppler sonography. In viral-induced infections, no changes of flow velocity in basal cerebral arteries were seen, whereas in bacterial meningitis, a significant increase of blood flow velocity in the middle cerebral artery was recorded. Its extent was mainly associated with the type of the infectious agent, most frequently observed in pneumococcal meningitis (77%). The increase was up to 100% of the baseline values and was reversible in all cases. All patients were offered full-scale neurointensive care, and all subjects with bacterial meningitis were fully heparinized.

Le « nodding syndrome » (NS) est une encéphalopathie épileptique pédiatrique décrite pour la première fois en Tanzanie, avec des épidémies récentes au Sud-Soudan (SS) et en Ouganda (OUG : 2000–2013). Les épidémies de NS ont coïncidé avec des conflits civils au cours desquels les populations ont été déplacées dans des camps surpeuplés où les maladies infectieuses étaient fréquentes et la qualité de la nourriture médiocre. Des conférences internationales en OUG 2012 et 2015 ont examiné l’épidémiologie, l’étiologie, la classification, les caractéristiques et le traitement du NS.

ABSTRACTIntraventricular application of vancomycin is an effective therapeutic regimen for the treatment of shunt-associated staphylococcal ventriculitis. We examined the in vitro activity of vancomycin at high concentrations against Staphylococcus aureusATCC 25923 and Staphylococcus epidermidisATCC 12228 in human cerebrospinal fluid samples. Time-kill curves revealed equal efficacies for concentrations of 10, 100, and 300 μg/ml, and incubation times of 24 to 48 h were needed to achieve a 3 log10reduction of viable bacteria. A concentration of 5 μg/ml showed a slightly lower activity, but this difference was not significant. In an infant who was successfully treated for shunt-associated ventriculitis due to S. epidermidisby once-daily local administration of vancomycin (3 mg for 2 days and 5 mg for 4 days [0.5 to 0.8 mg/kg of body weight]) the in vivo kill kinetics were similar to those for the in vitro results. These results support time-dose regimens that provide trough vancomycin levels of 5 to 10 μg/ml.

ABSTRACTA newly developed enzyme immunoassay (EIA) was used to detect the presence of pneumococcal teichoic and lipoteichoic acids in cerebrospinal fluid (CSF) from patients with Streptococcus pneumoniaemeningitis who were being treated with antibiotics. All initial CSF samples, which on culture grew S. pneumoniae, were positive in the EIA. A total of 14 subsequent culture-negative samples gave clear signals in the EIA up to day 15 after the onset of antibiotic treatment. For 11 CSF specimens, culture, microscopy, and latex agglutination were negative while the EIA detected pneumococcal antigens. The EIA did not react either with CSF of patients with meningitis caused by bacteria other than S. pneumoniaeor by viral pathogens. In conclusion, this EIA can be a valuable tool for the diagnosis of S. pneumoniaemeningitis from CSF samples in cases in which prior antimicrobial therapy minimizes the usefulness of culture or other antigen detection tests.

&lt;it>Objective&lt;/it>: The present study was performed to test the ability of fosfomycin to penetrate into the CSF of neurointensive care patients with ventriculostomy-associated ventriculitis. &lt;it>Patients and methods&lt;/it>: Six patients requiring neurointensive care monitoring, including extraventricular drainage due to secondary obstructive hydrocephalus, were enrolled into the study. All patients received 8 g of fosfomycin intravenously three times a day over a period of at least 5 days. Concentrations of fosfomycin in the CSF and plasma were measured after single-dose administration and at steady state. &lt;it>Results&lt;/it>: Mean values of the fosfomycin area under the time–concentration curves for the dosing interval of 8 h (AUC&lt;inf>8&lt;/inf>) were 929 ± 280 and 225 ± 131 mg·h/L for plasma and CSF after single-dose administration, respectively (&lt;it>P&lt;/it> &lt; 0.03). The ratios of the AUC&lt;inf>8&lt;/inf> for CSF to the AUC&lt;inf>8&lt;/inf> for plasma were 0.23 ± 0.07 after a single dose and 0.27 ± 0.08 following multiple doses (&lt;it>P&lt;/it> > 0.05, not significant). Additional &lt;it>in vitro&lt;/it> experiments have shown that fosfomycin exerts non-concentration-dependent microbial growth inhibition. At steady state, the time above MIC (&lt;it>t&lt;/it> > MIC) values were 98&percnt;, 92&percnt; and 61&percnt; for pathogens with MIC values of 8, 16 and 32 mg/L, respectively. &lt;it>Conclusion&lt;/it>: The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. Thus, the co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible pathogens.

IN REPLY Responding to Goldman's comment, we, indeed, assume that heparinization was one strategy for favorable outcome in our patients.1 Both bacterial and venous cerebrovascular complications account for still high mortality rates and long-term sequelae in bacterial meningitis, in particular in pneumococcal meningitis.2,3 Our data point to an obstructive process of the basal cerebral blood vessels with highest risk of developing brain ischemia throughout the first 5 days. There is strong evidence that these hemodynamic changes reflect secondary vasculitis4; additionally, following initial inflammatory damage of endothelium, the endogenous coagulation cascade might be activated, converting prothrombin into thrombin. Heparin as a thrombin antagonist should, thus, counteract possible development of local thrombosis, which—in addition to narrowing of the blood vessel—could lead to cerebral ischemia or even infarction.However, anticoagulant therapy is associated with some risk due to well-known side effects. Heparin causes transient mild thrombocytopenia in up to 25%