Wilkinson RJ, Rohlwink U, Misra UK, et al. Tuberculous meningitis. Nat Rev Neurol. 2017;13(10):581-598. doi:10.1038/nrneurol.2017.120.
Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis, for which more than 100,000 new cases are estimated to occur per year. In adults, the best-documented risk factor for tuberculous meningitis is HIV‑1 co‑infection. Among HIV-infected individuals who live in areas where tuberculosis is highly endemic, the proportion of HIV‑1‑associated meningitis cases attributable to Mycobacterium tuberculosis can exceed 50%. Individuals with tuberculous meningitis and a HIV‑1 co‑infection have a twofold to threefold increase in relative risk of death from any cause with overall mortality around 40%, even in those individuals prescribed antiretroviral therapy. Drug-resistant tuberculous meningitis in people co‑infected with HIV‑1 has a particularly poor prognosis, approaching 100% mortality.
Bacterial replication must occur in the CNS for tuberculous meningitis pathogenesis to proceed. However, the bacillary load in the CSF rarely exceeds 100–1000 bacterial colonies per milliliter, and viable bacilli are difficult to detect in the majority of individuals. Early studies in experimental animal models showed that the meningitis syndrome and even death of tuberculin-sensitized animals could be induced by meningeal inoculation with dead bacilli. Much of the tissue damage is therefore attributed to a dysregulated host inflammatory response. Once bacilli have traversed the blood–brain barrier, they are taken up by microglia and can also replicate in these cells, leading to the induction of microglial cytokine and chemokine production.
The importance of infarction to long-term outcomes has led to interest in cranial vessel imaging. CTA has been used to define lesions in the anterior and posterior cerebral circulation, and has demonstrated that the supraclinoid portion of the internal carotid artery and proximal portions of the anterior cerebral and middle cerebral arteries are most commonly affected in tuberculous meningitis. MRA has demonstrated vascular lesions, which are related to hydrocephalus, infarction and poor outcome, in around 50% of patients with tuberculous meningitis. A normal MRA result at disease presentation strongly predicts an infarct-free disease course. Brain imaging has long been part of the diagnostic assessment of TBM. Numerous case series have described the common radiographic appearances of basal meningeal exudates, hydrocephalus, infarcts and tuberculomas. However, few studies have defined the diagnostic performance of these features.
Various objective criteria for post-contrast CT basal enhancement have been proposed, most of which are specific (in the 90% range) but lack sensitivity (0–30%). The main limitation of CT and MR imaging is that around 30% of individuals at an early stage in the tuberculous meningitis disease course have normal brain CT scans, and around 15% have normal brain MRI scans. Additionally, age and HIV‑1 co‑infection status influence the appearance of the brain on imaging. Children with tuberculous meningitis are more likely to exhibit hydrocephalus than are adults with tuberculous meningitis, and basal enhancement is often less prominent in people co-infected with HIV‑1, especially those with very low CD4+ cell counts.
3 Tables, 2 Figures.
Park MS, Albuquerque FC, Mulholland CB, Mcdougall CG. Changing Paradigms in the Endovascular Management of Ruptured Anterior Communicating Artery Aneurysms. Neurosurgery. 2017;81(4):581-584. doi:10.1093/neuros/nyw051.
Endovascular treatment of anterior communicating artery (ACoA) aneurysms has evolved dramatically over the past decade. The Barrow Ruptured Aneurysm Trial (BRAT), a large-scale prospective randomized trial, compared microsurgical clip occlusion with endovascular coil embolization to determine the relative safety and efficacy of these treatments for acutely ruptured cerebral aneurysms. The trial included 130 ACoA patients; 91 (70%) of the patients’ aneurysms were clipped and 39 (30%) were coiled. Twenty-two of the 61 ACoA patients who were initially randomized to coiling crossed over to clipping after evaluation (17% of all 130 ACoA patients). No patient crossed over from clipping to coiling. The most common reasons that ruptured ACoA aneurysms were not treated with endovascular techniques were that the aneurysms were too small (<5 mm) for coils available at the time of the trial or that they had an unfavorable (<2) dome-to-neck ratio. The authors wanted to compare patients treated by coil embolization for ruptured ACoA aneurysms during the trial to those treated after the trial to determine whether advances in endovascular techniques have allowed for effective treatment of these lesions.
The post-BRAT cohort included 93 patients who were significantly older (mean age, 59.5 vs 52.8 yr) than the BRAT cohort; there were no significant cohort differences in sex, Hunt and Hess grade, or mean aneurysm size. The use of balloon remodeling was significantly higher in the post-BRAT cohort (31.2% vs 5.1%), as was the proportion of wide-necked aneurysms treated (66.7% vs 30.8%). There was no significant difference in clinical outcome or retreatment rate between the 2 cohorts. They conclude that ACoA lesions thought unamenable to endovascular therapy in an earlier randomized trial are now successfully coiled with increased use of adjunctive techniques, without sacrificing patient outcome or treatment durability.
Asken BM, Sullan MJ, Dekosky ST, Jaffee MS, Bauer RM. Research Gaps and Controversies in Chronic Traumatic Encephalopathy A Review. JAMA Neurol. 2017;74(10):1255-1262. doi:10.1001/jamaneurol.2017.2396.
Chronic traumatic encephalopathy (CTE) cannot currently be diagnosed prior to autopsy. This is technically true of other diseases such as Alzheimer disease (AD), although the degree of certainty with which AD can be presumptively diagnosed through clinical presentation and positive biomarkers is substantially higher than seen in chronic traumatic encephalopathy. Pathological diagnostic criteria now exist for chronic traumatic encephalopathy; the pathognomonic signature being a dot-like distribution of phosphorylated tau (p-tau) aggregated in neurons, astrocytes, and cell processes in perivascular spaces within the depths of cortical sulci. Consensus panel findings suggest that the unique distribution differentiates chronic traumatic encephalopathy from other tauopathies.
Quantification of the true risk of developing chronic traumatic encephalopathy is complex. Media headlines indicate a risk that almost certainly overestimates prevalence owing to sampling bias. Brains evaluated for chronic traumatic encephalopathy at autopsy have almost exclusively included individuals brought to chronic traumatic encephalopathy research centers because of an extensive history of repetitive brain trauma (RBT) coupled with a history of troublesome clinical symptoms. The few exceptions to biased sampling include one study which analyzed a larger brain bank and found chronic traumatic encephalopathy pathological findings in 21 of 66 brains (31.8%) of individuals with a documented history of repetitive brain trauma, and no evidence of chronic traumatic encephalopathy among 198 brains without a documented history of repetitive brain trauma.
Available data suggest that CTE is associated with a combination of mild TBI (mTBI) or concussion and repetitive subclinical brain trauma, often referred to as “subconcussive blows.” However, it is not known whether single-event TBI can lead to chronic traumatic encephalopathy in individual cases. One study found no evidence of chronic traumatic encephalopathy in 33 brains of individuals with a history of single-event trauma. However, within the broader literature examining single-event TBI as a risk factor for neurodegenerative disease, mention or evaluation of chronic traumatic encephalopathy has been rare.
The minimum necessary exposure to repetitive brain trauma for significant risk of chronic traumatic encephalopathy is thus unknown and is likely specific to the individual. The overlap between chronic traumatic encephalopathy – related research and the extensive literature evaluating the relative risk of neurodegenerative disease (eg, AD) due to single or isolated mild TBI is similarly unclear. Unlike most nonathlete and civilian populations, certain collision sport athletes and military personnel are uniquely exposed to repetitive brain trauma before and after isolated instances of diagnosed mild TBI. It may be the case that these population-based differences in pre-mild TBI and post-mild TBI exposure to repetitive brain trauma explain some of the inconsistencies across studies examining long-term structural changes associated with mild TBI or concussion history. An associated problem is that diagnosis of concussion remains largely dependent on self-report, which is subject to motivational and generational biases. Athletes in particular may underreport or never report symptoms so that they can return to sport sooner, but it is worth considering how risk for long term negative effects and injury cascades might be reduced if athletes or others sustaining diagnosed concussion allow for a recovery period instead of exposing themselves to intense exertion or further head impacts (subclinical or otherwise) within the so-called window of vulnerability after concussion. Generational (cohort) differences may also be important, as many aging athletes were raised in a culture that not only did not support the rapid reporting of concussion- related symptoms but also encouraged rapid return to sport after injury.
One figure which is a timeline of notable events and publications in repetitive brain trauma research.
Ding J, Sigurðsson S, Jónsson P V., et al. Large Perivascular Spaces Visible on Magnetic Resonance Imaging, Cerebral Small Vessel Disease Progression, and Risk of Dementia. JAMA Neurol. 2017;20814(9):1105-1112. doi:10.1001/jamaneurol.2017.1397.
Cerebral small vessel disease (SVD) is a major contributor to cognitive impairment in older individuals. In addition to well-established neuroimaging hallmarks of SVD, including small subcortical infarcts, white matter hyperintensities (WMHs), and microbleeds, MRI–visible perivascular spaces (PVSs) are emerging as a potential small vessel disease marker. The PVSs are fluid-filled cavities that surround small, penetrating cerebral arterioles and venules and are commonly considered to play an important role in forming a network of drainage channels for the elimination of metabolic waste and fluid from the brain. When the caliber and the number of normally microscopic PVSs increases with advancing age, PVSs appear on T2-weighted MRI as round or tubular hyperintensities in the basal ganglia and white matter. Whether large perivascular spaces (L-PVSs) (>3mmin diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown.
This was a prospective, population-based study from the Age, Gene/Environment Susceptibility–Reykjavik Study which assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points.
To distinguish PVSs from subcortical infarcts, L-PVSs were evaluated separately and defined as round or tubular defects with a short axis larger than 3mm in the subcortical area, without a rim or area of high signal intensity on the axial FLAIR and without evidence of hemosiderin in its wall on the axial T2*-weighted gradient-echo.
The associations of L-PVSs with a greater decline in processing speed and higher risk of vascular dementia were independent of MRI markers of cerebrovascular disease, suggesting that they were not simply attributable to confounding by other vascular mechanisms. The associations remained significant for L-PVSs in basal ganglia. So the authors findings are consistent with the hypothesis that SVD contributes to a profile of vascular related cognitive impairment and suggest that L-PVS may be part of the pathologic spectrum that links hypertension and arteriosclerosis to vascular dementia. To summarize, large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.
1 Figure, 3 Tables
Centeno M, Tierney TM, Perani S, et al. Combined electroencephalography–functional magnetic resonance imaging and electrical source imaging improves localization of pediatric focal epilepsy. Ann Neurol. 2017;82(2):278-287. doi:10.1002/ana.25003.
The authors report the use of simultaneous electroencephalography–functional magnetic resonance imaging (EEG-fMRI) data to derive EEG-fMRI and electrical source imaging (ESI) maps. Their yield and their individual and combined ability to (1) localize the epileptogenic zone and (2) predict seizure outcome were then evaluated.
Previous EEG-fMRI studies in adults have shown that fMRI can map the epileptogenic zone using interictal and ictal events. Compared to clinical EEG alone, EEG-fMRI has been shown to provide a more accurate localization of the epileptogenic zone in up to two thirds of cases, to have a good degree of correlation with invasive EEG findings, and to be predictive of good surgical outcome. However, EEG-fMRI maps often show multiple regions of activity that, although consistent with the idea that epilepsy is a network disease, complicate interpretation where a single spatial target is typically required for surgery to proceed. Previous studies have often used the statistic global maxima (GM), or have constrained the search area to the spike field or to the clinically defined epileptic focus to obtain a localization. These approaches can have low sensitivity (in the case of GM) or are dependent on subjective interpretation if they use a clinically defined focus or are based on the interictal epileptiform discharge (IED) field. In a pediatric cohort, clinical EEG is often less localizing and repeat surgery relatively common, and therefore the use of IED fields may be problematic. Recently, EEG-fMRI was shown to be feasible in children from 6 to 18 years old without sedation and to possibly have a higher yield compared with adults in a selected population. New methodological developments (topographic voltage correlation analysis) allow EEG-fMRI maps to be obtained without interictal epileptiform discharges.
Electrical source imaging has been shown to localize the epileptogenic zone with high sensitivity and specificity in a mixed group of adults and children using high-density (>32 channel) EEG and has shown promise in a pediatric cohort. Electrical source imaging has a limited spatial accuracy and can have limitations in cases with deep sources, previous surgery, or where interictal epileptiform discharges are not typical discrete events.
Fifty-three children with drug-resistant epilepsy underwent EEG-fMRI. Interictal discharges were mapped using both EEG-fMRI hemodynamic responses and electrical source imaging. A single localization was derived from each individual test (EEG-fMRI global maxima [GM]/ESI maximum) and from the combination of both maps (EEG-fMRI/ESI spatial intersection). To determine the localization accuracy and its predictive performance, the individual and combined test localizations were compared to the presumed EZ and to the postsurgical outcome.
Fifty-two of 53 patients had significant maps: 47 of 53 for EEG-fMRI, 44 of 53 for ESI, and 34 of 53 for both. The EZ was well characterized in 29 patients; 26 had an EEG-fMRI global maxima localization that was correct in 11, 22 patients had ESI localization that was correct in 17, and 12 patients had combined EEG-fMRI and ESI that was correct in 11. Seizure outcome following resection was correctly predicted by EEG-fMRI global maxima in 8 of 20 patients, and by the ESI maximum in 13 of 16. The combined EEG-fMRI/ESI region entirely predicted outcome in 9 of 9 patients, including 3 with no lesion visible on MRI.
The yield of EEG-fMRI alone was 89%, ESI alone 73%, and combined EEG-fMRI/ESI 43%. Low yield has been highlighted as a limiting factor for the clinical use of EEG-fMRI. Studies report significant findings in 27 to 76% of cases. The improvement in the yield in this study may be explained by the population of pediatric patients studied, who typically have frequent interictal epileptiform discharges, and the use of topographic correlation analysis (which allowed a localization to be achieved in the cases without IEDs).
3 Figures, 1 Table
Baek J-H, Kim BM, Yoo J, et al. Predictive Value of Computed Tomography Angiography–Determined Occlusion Type in Stent Retriever Thrombectomy. Stroke. 2017;48(10):2746-2752. doi:10.1161/STROKEAHA.117.018096.
238 consecutive patients with stroke who underwent CTA and then endovascular treatment for intracranial large artery occlusion were retrospectively reviewed. CTA-determined occlusion type was classified into truncal-type occlusion or branching-site occlusion and compared with digital subtraction angiography–determined occlusion type during endovascular treatment.
When the relevant bifurcation site was clearly observed on CTA, the case was assigned as truncal-type occlusion. Conversely, for patients whose bifurcation site was not observed or vague, the occlusion was assigned as branching-site occlusion.
Three rapidly- and readily-assessable pre-procedural findings (CTA-determined occlusion type, atrial fibrillation, and hyperdense artery sign), which may infer occlusion pathomechanism (embolic versus nonembolic) before endovascular treatment, were evaluated for association with stent retriever success along with stroke risk factors and laboratory results. In addition, the predictive power of the 3 pre-procedural findings for stent retriever success was compared with ROC curve analyses.
CTA-determined occlusion type corresponded adequately with digital subtraction angiography–determined occlusion type. Atrial fibrillation and CTA-determined branching-site occlusion were independent predictors for SR success. For predicting SR success, the area under the ROC curve value for CTA-determined branching-site occlusion was significantly greater than atrial fibrillation and the hyperdense artery sign.
They conclude that the determination of occlusion type using CTA might increase the possibility of recanalization and shorten puncture-to recanalization time by determining the optimal endovascular treatment strategy before starting the treatment.
3 Figures, 3 Tables
Thomalla G, Boutitie F, Fiebach JB, et al. Effect of informed consent on patient characteristics in a stroke thrombolysis trial. Neurology. 2017;89(13):1400-1407. doi:10.1212/WNL.0000000000004414.
The authors wanted to determine whether the manner of consent, i.e., informed consent by patients themselves or informed consent by proxy, affects clinical characteristics of samples of acute stroke patients enrolled in clinical trials.
They analyzed the manner of obtaining informed consent in the first 1,005 patients from WAKE-UP, an investigator-initiated, randomized, placebo-controlled trial of MRI-based thrombolysis in stroke patients with unknown time of symptom onset running in 6 European countries. Patients providing informed consent by themselves were compared with patients enrolled by proxy consent. Baseline clinical measures were compared between groups.
In 359 (35.7%) patients, informed consent was by proxy. Patients with proxy consent were older and had a higher frequency of arterial hypertension. They showed higher scores on the NIH Stroke Scale and more frequently aphasia. The rate of proxy consent varied among countries ranging from 77.1% in Spain to 1.2% in Denmark.
The authors conclude that the manner of informed consent affects the clinical characteristics of patients, and the manner of informed consent differed significantly among countries. These findings illustrate the importance of identifying strategies for the inclusion of incapable patients in acute stroke trials. As of yet, reperfusion treatment is the only effective treatment strategy for acute stroke, and it is still only available for a limited subgroup of stroke patients. Further clinical trials improving treatment of acute stroke and testing new treatment approaches are urgently needed. Differences in national regulations and diverging practice to informed consent may hamper trial success. More harmonized interpretation and implementation of international regulations into national practice is required to enable comparable practice including all different manners of consent in an emergency setting among different countries.
Aydın Y, Çavuşoğlu H, Yüce İ, Özdilmaç A, Kahyaoğlu O. A Prospective Study of Interbody Fat Graft Application With the Anterior Contralateral Cervical Microdiscectomy to Preserve Segmental Mobility. Neurosurgery. 2017;81(4):627-637. doi:10.1093/neuros/nyx056.
The authors describe a “minimally invasive” technique (anterior cervical discectomy!) in which they use interbody fat graft placement and show good results and effectiveness, especially in patients who were suffering from cervical paramedian disc herniation. The evaluated 432 patients were observed from 2000 to 2013. All these consecutive patients had paramedian disc herniation. The initial 239 patients (group 1) underwent microdiscectomy without graft placement, whereas the remaining 193 patients (group 2) had a microdiscectomy with interbody fat graft insertion. The Neck Disability Index (NDI) and Short Form-36 (SF-36) were used to evaluate clinical outcomes. Patients were followed up for 5.3 years (range 2-13 years).
Spontaneous radiological fusion was noticed in 12% of group 1 patients and none of the group 2 patients. It has been observed that the mean overall cervical curvature (C2-7) angles and segmental lordosis did not change significantly in late follow-up findings.
The accompanying comment on this paper notes: This manuscript details a novel procedure for motion preservation in the cervical spine by use of free autologous fat grafts in the disc space. Although the mechanism underlying bone growth inhibition is unknown, there is some limited support for this principle in the literature. Further studies are required to directly compare this technique to cervical disc arthroplasty, anterior cervical discectomy and fusion, and posterior cervical foraminotomy and discectomy, for treatment of cervical radiculopathy.
Somewhat strange, but interesting.
4 Figures, 3 Tables
