Wen, P. Y., & Huse, J. T. (2017). 2016 World Health Organization Classification of Central Nervous System Tumors. Continuum (Minneapolis, Minn.), 23(6, Neuro–oncology), 1531–1547. https://doi.org/10.1212/CON.0000000000000536
The 2016 WHO update introduces important changes to the classification of gliomas, the most common type of malignant primary brain tumor. Diffusely infiltrating gliomas of astrocytic and oligodendroglial lineage are now classified largely based on two highly recurrent molecular alterations (IDH mutation and 1p/19q codeletion) in addition to more conventional histopathologic parameters.
Multiple large retrospective analyses have now shown that in the setting of molecular stratification, conventional histopathologic parameters designating the WHO grade II to WHO grade III transition in diffuse glioma do not correlate well with disease prognosis. So diffuse astrocytomas (WHO grade II) and anaplastic astrocytomas (grade III) are now divided into three categories: IDH-mutant, IDH wildtype, and NOS. Most astrocytomas are IDH-mutant and, by definition, have intact 1p/19q (no codeletion of 1p/19q).
The diagnoses of oligodendroglioma (WHO grade II) and anaplastic oligodendroglioma (WHO grade III) have traditionally been made based on characteristic histologic appearances (fried egg) but now also require the presence of IDH mutation and 1p/19q codeletion. The 2016 WHO CNS classification strongly discourages the diagnosis of oligoastrocytoma.
In the 2016 WHO classification, glioblastomas (WHO grade IV) are divided into glioblastoma, IDH-wildtype; glioblastoma, IDH-mutant; and glioblastoma, NOS. Glioblastoma, IDH wildtype accounts for approximately 90% of glioblastomas and corresponds to primary glioblastomas that typically present after the age of 55.
Glioblastoma, IDH-mutant accounts for 10% of cases and typically occurs in younger patients. They usually correspond to secondary glioblastomas that arise from preexisting lower-grade gliomas and are usually associated with a better prognosis than wildtype glioblastomas.
The entity gliomatosis cerebri has been deleted from the 2016 WHO CNS Classification, and is now an imaging pattern of spread. Previously, it was considered a distinct form of glioma characterized by invasive tumor growth involving three or more cerebral lobes, often extending to both hemispheres and infratentorial structures and associated with a poor prognosis. However, histologically and genetically, it does not appear to be a distinct entity.
Cerebral ependymomas have traditionally been divided into grade II tumors (classic ependymomas) and grade III tumors (anaplastic ependymomas). However, the correlation of tumor grade to outcome is poor and of questionable utility. Much new information is available about the mutations involving ependymomas, but only one change made it into the new document: Ependymoma, RELA fusion-positive variant, which accounts for the majority of supratentorial ependymomas in children and is associated with a poor prognosis, has been accepted in the new classification as a genetically defined subtype.
The new classification also restructures embryonal tumors, with incorporation of genetically defined entities and removal of the term primitive neuroectodermal tumor.
The diagnosis of WHO grade II (atypical) meningiomas can now be made by the presence of brain invasion, given its association with a worse outcome. The inclusion of brain invasion in the diagnosis of WHO grade II (atypical) meningiomas may require neurosurgeons to collect adjacent normal tissue during the course of surgery, a change from current clinical practice.
Added into the classification is diffuse leptomeningeal disseminated glioneuronal tumor (DL-GNT) (aka disseminated oligodendroglial-like leptomeningeal tumour of childhood), a rare brain tumor that presents as a plaque-like subarachnoid tumor, commonly involving the basal cisterns and interhemispheric fissure of children but lacking intraparenchymal tumor. Histologically, the tumors are composed of sheets of monotonous rounded cells and tend to be IDH1 negative.
A multinodular and vacuolated pattern in ganglion cell tumors has also been recognized. These multinodular and vacuolated tumors of the cerebrum are low-grade lesions (see AJNR October 2017, 38 (10) 1899-1904).
Medulloblastomas have been distilled into four main groups: WNT-activated medulloblastomas, which have the best prognosis; SHH activated medulloblastomas, which occur in both infants and adults; group 3 medulloblastomas, which are associated with the worst outcome; and group 4 medulloblastomas.
Hemangiopericytomas are rare tumors that resemble meningiomas. For tumors outside the CNS, the term hemangiopericytoma has largely been replaced by its incorporation into the family of solitary fibrous tumors as solitary fibrous tumor/ hemangiopericytoma. Both solitary fibrous tumors and hemangiopericytomas share mutations which fuse the STAT6 gene with the NAB2 gene, leading to STAT6 nuclear expression that can be detected with immunohistochemistry.
One significant change occurred to the classification of nerve sheath tumors: Since melanotic schwannomas have clinical and genetic behavior that is distinct from conventional schwannomas, they are now classified as a separate entity rather than a variant. Approximately 50% of individuals with psammomatous melanotic schwannomas have Carney complex with autosomal dominant inheritance (Carney complex is a rare genetic disorder characterized by multiple benign tumors such as myxomas, most often affecting the heart, skin and endocrine system and abnormalities in skin pigmentation). Carney complex is due to mutations of the PRKAR1A gene.
7 Figures and 4 Tables.
Acker, G., Fekonja, L., & Vajkoczy, P. (2018). Surgical Management of Moyamoya Disease. Stroke, 49(2), 476–482. https://doi.org/10.1161/STROKEAHA.117.018563
Excellent review on the varied surgical approaches to this disease.
Moyamoya disease (MMD) is a rare cerebrovascular disease which is characterized by bilateral progressive steno-occlusion of basal cerebral arteries with emergence of coexisting abnormal net-like vessels. MMD is most frequent in Asian countries but an increase in incidence has been reported in non-Asian countries with some ethnic differences in disease characteristics. MMD shows worldwide a bimodal age distribution with a peak each in childhood and adulthood; thus, it is one of the leading causes of stroke in children and young adults. The most frequent initial symptom of MMD adults in Asians and whites is intracranial hemorrhage because of fragile blood vessels and ischemic events, respectively. Children with MMD worldwide frequently experience ischemic events.
Historically, disease severity has been classified by the angiography-based Suzuki classification. This classification, however, neither correlates with disease severity nor allows therapeutic risk stratification and thus, has not been applied in routine clinical setting. As a consequence, the Berlin Moyamoya Grading has been established using standard diagnostic tools: magnetic resonance imaging and functional cerebrovascular assessment of hemodynamic impairment. This novel grading system correlates with disease severity and more importantly, allows to stratify the individual risk of surgical therapy (Czabanka M, et al. Proposal for a new grading of moyamoya disease in adult patients. Cerebrovasc Dis. 2011;32:41–50).
Revascularization surgery is the most effective treatment for hemorrhagic MMD as demonstrated by an RCT and most likely the most effective treatment for ischemic MMD. However, in the latter case, RCT data is still lacking. The primary aims of revascularization are to restore the blood supply to stabilize cerebrovascular hemodynamics and to regress the fragile moyamoya vessels to prevent bleeding. In surgical practice, 3 different revascularization strategies are applied: indirect, direct, and combined revascularization. Currently, there is still no consensus about the best type of revascularization surgery.
STA-MCA bypass has been the most common direct revascularization procedure
that mainly addresses the MCA territory but also supports the anterior cerebral artery (ACA) territory via leptomeningeal anastomoses. However, if needed, there are also other direct bypass procedures to address ACA or posterior cerebral artery (PCA) territories specifically, such as STA-ACA, STA-PCA, and occipital artery-PCA anastomosis, respectively. In cases where STA is not suitable or after failed STA-MCA bypass, large caliber grafts might provide a fallback strategy. A saphenous vein graft for high-flow bypass or radial artery graft for intermediate-flow bypass have been used. The major limitation for direct bypass is the demanding surgical technique and the requirement of sufficient donor and recipient vessels.
Indirect revascularization relies on neovascularization of the cortical surface via angiogenic mechanisms from pedicle base grafts (ie, pial synangiosis). In the past, a wide variety of different techniques and tissues have been used as vascularized grafts. Because these techniques do not rely on a direct vessel anastomosis but on the ingrowth of new blood vessels, they have been termed indirect revascularization techniques. In general, indirect techniques are easier to perform, but the cerebral revascularization, and thus hemodynamic protection of the brain, may take months to develop and is less predictable in hemodynamic outcome.
In combined revascularization techniques, the direct bypass aims at immediate hemodynamic improvement, and the indirect bypass serves as a way to further improve the result midterm and to serve as a fallback strategy in case the direct bypass fails. Combined procedures have been increasingly applied. However, a quantitative assessment of bypass flow revealed a reciprocal revascularization development for these techniques, suggesting that 1 plus 1 will not necessarily result in 2 and that the final hemodynamic net result remains unpredictable.
4 figures.
Thakar, S., Sivaraju, L., Jacob, K. S., Arun, A. A., Aryan, S., Mohan, D., Hegde, A. S. (2018). A points-based algorithm for prognosticating clinical outcome of with syringomyelia: results from a predictive model analysis of 82 surgically managed adult patients. Journal of Neurosurgery: Spine, 28(1), 23–32. https://doi.org/10.3171/2017.5.SPINE17264
The objective of this study was to generate an algorithm from a predictive analysis of a large number of clinical and radiological variables to prognosticate postoperative improvement in a multifactorial outcome measure in a subset of Chiari malformation Type I (CMI) patients.
Data from the clinical records of 82 symptomatic adult patients with CMI and altered hindbrain CSF flow who were managed with foramen magnum decompression, C-1 laminectomy, and duraplasty over an 8-year period were collected and analyzed. Various preoperative clinical and radiological variables in the 57 patients who formed the study cohort were assessed in a bivariate analysis to determine their ability to predict clinical outcome (as measured on the Chicago Chiari Outcome Scale [CCOS]) and the resolution of syrinx at the last follow-up. The variables that were significant in the bivariate analysis were further analyzed in a multiple linear regression analysis. The model with the best prediction of Chicago Chiari Outcome Scale was identified and internally validated in a subcohort of 25 patients.
They measured many, many different things, but the one that seems to show the most important difference was the M-line-FVV line, which I will try and explain. This is a line that extends from the most posterior point of the fourth ventricle on the sagittal view, to the most anterior aspect of the pons. The complexity comes from the angle of this line, which is made parallel to the “L” line extending from the basion to the posterior cerebellum and itself is parallel to the inferior endplate of C2. So as far as I can tell:
Draw line along inferior endplate of C2
Draw parallel line to that from basion posteriorly
Then draw parallel line to that from posterior aspect of 4th ventricle to anterior pons. Got it??
They conclude that the presence of gait imbalance and motor deficits independently predict worse clinical and radiological outcomes, respectively, after decompressive surgery for CMI with altered hindbrain CSF flow. Caudal displacement of the obex and a shorter M-line–FVV distance correlated with good Chicago Chiari Outcome Scale scores, indicating that patients with a greater degree of hindbrain pathology respond better to surgery.
Some studies have documented markers of worse hindbrain pathology in patients with CMI, such as poor CSF flow, smaller PFV as being associated with better outcomes after surgery (worse is better). The consensus of these studies is that the more severe the hindbrain CSF flow, either due to a smaller posterior fossa or ventral encroachment by an angulated odontoid, the more direct its pathoetiological role in symptomatology and the better the response to decompressive surgery. After adjusting for multiple variables, this study identified 2 novel preoperative markers—the obex position and the M-line–FVV distance—that corroborate the “worse is better” radiological paradigm in CMI. Caudal displacement of the obex (i.e., a shorter distance from the FM) can be considered a marker of disease severity in CMI. Given the fact that posterior fossa overcrowding is considered a hallmark of CMI, it can be inferred that a smaller M-line–FVV distance correlated with a smaller PFV/ICV ratio is indicative of a smaller ratio being a marker of worse anomalous hindbrain morphology.
8 Figures
Reich, D. S., Lucchinetti, C. F., & Calabresi, P. A. (2018). Multiple Sclerosis. New England Journal of Medicine, 378(2), 169–180. https://doi.org/10.1056/NEJMra1401483
Typical excellent NEJM review article (don’t forget that you can download the artwork in Powerpoint format).
The concept that MS is a disseminated plaque-like sclerosis was established 150 years ago; and the demonstration of dissemination— in space (disease-related changes in multiple regions of the CNS, including white matter, gray matter, brain stem, spinal cord, and optic nerve) and time — forms the cornerstone of diagnosis of the disease.
Multiple sclerosis lesions can appear throughout the CNS and are most easily recognized in the white matter as focal areas of demyelination, inflammation, and glial reaction. Evidence from MRI and pathological assessment (biopsies and autopsies) indicates that the earliest stages of white-matter demyelination are heterogeneous and evolve over the course of months. Regardless of the particular immunologic pattern of early demyelination, analysis of active lesions, over both time and space, suggests that a single immune-effector mechanism dominates in each person.
Myelin is not exclusive to white matter, and demyelination in multiple sclerosis also involves gray matter. Approximately half of cortical lesions are perivascular. In some cortical lesions, the inflamed vessel may be located near the leukocortical junction, in which case demyelination also affects the juxtacortical white matter. Sometimes, a small penetrating cortical vein is involved, and only central cortical layers are affected. Cortical lesions are less inflammatory than their white-matter counterparts and have substantially less permeability of the blood–brain barrier.
Spinal cord lesions are a major source of clinical disability. Perivascular and circumferential demyelination is often highly inflammatory and can involve gray matter. Spinal cord atrophy results from focal inflammatory demyelination and remote neuroaxonal degeneration. It is detectable by MRI, and the cross-sectional area of the spinal cord is therefore a promising outcome measure for clinical trials.
It is not known whether multiple sclerosis has single or multiple causes, and rarely (if ever) has a specific etiologic trigger been identified. Nonetheless, various genetic and environmental risk factors have been found. For unknown reasons, approximately three quarters of people with multiple sclerosis are women, as is common in diseases that are considered autoimmune. People with an affected first-degree relative have a 2 to 4% risk of multiple sclerosis (as compared with approximately 0.1% risk in the general population), and concordance in monozygotic twins is 30 to 50%. Genome wide association studies, based on samples assembled from thousands of patients with multiple sclerosis and matched controls, have identified more than 200 gene variants that raise the risk of the disease, of which the most significant remains the HLA DRB1*1501 haplotype (with an odds ratio of approximately 3). Most risk alleles are associated with immune-pathway genes, a finding consistent with the notion that autoimmune mechanisms are paramount in the development of clinical multiple sclerosis.
Gory, B., Lapergue, B., Blanc, R., Labreuche, J., Ben Machaa, M., Duhamel, A., … Piotin, M. (2018). Contact Aspiration Versus Stent Retriever in Patients With Acute Ischemic Stroke With M2 Occlusion in the ASTER Randomized Trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization). Stroke, 49(2), 461–464. https://doi.org/10.1161/STROKEAHA.117.019598
Middle cerebral artery M2-segment occlusions represent an important subgroup of patients with acute stroke with large-vessel occlusion. The safety of mechanical thrombectomy, especially contact aspiration (CA), in such distal intracranial occlusions is still under debate. The safety of MT in M2 occlusions remains a concern, and stent retriever (SR) may be more difficult to maneuver in the distal arteries.
The authors compared reperfusion, adverse events, neurological recovery, and functional outcome of patients with isolated M2 occlusions according to the first-line strategy mechanical thrombectomy devices via a post hoc analysis of the ASTER trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization). The primary outcome was successful reperfusion at the end of all endovascular procedures, defined as modified Thrombolysis in Cerebral Infarction (mTICI) scores 2b/3.
Seventy-nine patients were included: 48 were allocated to the CA group and 31 to the SR group. There were no significant differences between CA and SR groups in reperfusion after all endovascular procedures regarding mTICI 2b/3 (89.6% versus 83.9%), mTICI 2c/3 (54.2% versus 54.8%), and mTICI 3 (35.4% versus 41.9%) rates.
They conclude that first-line mechanical thrombectomy with CA compared with SR did not result in an increased successful revascularization rate in patients with acute stroke with isolated M2 occlusion. Effectiveness and safety should not be an argument in the choice of the first-line strategy for MT of isolated M2 occlusions because they observed no significant differences.
Dudli, S., Liebenberg, E., Magnitsky, S., Lu, B., Lauricella, M., & Lotz, J. C. (2017). Modic type 1 change is an autoimmune response that requires a pro-inflammatory milieu provided by the “modic disc”. The Spine Journal. https://doi.org/10.1016/j.spinee.2017.12.004
In-vitro cell co-culture study plus in-vivo experiments in rat caudal vertebrae which aimed to test whether bone marrow has an autoimmune response to NP cells that is amplified by an inflammatory milieu, and ultimately leads to MC development in vivo. They hypothesized that an inflammatory co-stimulus is required for bone marrow/NP crosstalk to stimulate MC.
In-vitro: bone marrow mononuclear cells (BMNCs) and NP cells (NPC) from rats were co-cultured with and without IL-1α stimulation. Cell viability (n=3) of BMNCs and NPCs and gene expression (n=7) was analyzed. In-vivo: pro-inflammatory (LPS) and control disc nucleus surrogates (NP micromass pellets) 11 were generated in-vitro from rat NPCs and implanted into rat tail vertebrae, and the response was 12 compared to sham surgery (n=12 each).
BMNC / NPC co-culture significantly increased lymphocyte viability (42% to 69%) and reduced NPC viability (96% to 88%), indicating immunogenicity of NPC. However, IL-1α was required to cause significant transcriptional up-regulation of IL-1, IL-6, IL-10, and TrkA. Therefore, an inflammatory activation is required to amplify the immune response.
NP cells are immunogenic but cannot trigger MC without an additional pro-inflammatory stimulus. Their data suggests that MC require endplate defects that allow marrow/NPC co-mingling plus an adjacent inflammatory ‘MC disc’ that can amplify the immune response.
5 Figures
Duperron, M.-G., Tzourio, C., Sargurupremraj, M., Mazoyer, B., Soumaré, A., Schilling, S., Debette, S. (2018). Burden of Dilated Perivascular Spaces, an Emerging Marker of Cerebral Small Vessel Disease, Is Highly Heritable. Stroke, 49(2), 282–287. https://doi.org/10.1161/STROKEAHA.117.019309
The genetic contribution to dilated perivascular space (dPVS) burden—an emerging MRI marker of cerebral small vessel disease—is unknown. The authors measured the heritability of dilated perivascular space burden and its shared heritability with other MRI markers of cerebral small vessel disease.
The study sample comprised 1597 participants from the population-based Three City (3C) Dijon Study, with brain MRI and genome-wide genotyping.
Dilated perivascular space burden was significantly correlated with white matter hyperintensity volume and lacunar brain infarcts, the strongest correlation being found between white matter hyperintensity volume and dilated perivascular space in basal ganglia. Heritability estimates were h2=0.59 for dilated perivascular space burden, h2=0.54 for white matter hyperintensity volume, and h2=0.48 for lacunar brain infarcts.
The conclude that the data provide evidence for important genetic contribution to dilated perivascular space burden in older community-dwelling people, some of which may be shared with white matter hyperintensity volume. Differential heritability patterns for dilated perivascular space in white matter and basal ganglia suggest at least partly distinct underlying biological processes.
Teunissen, F. R., Verbeek, B. M., Cha, T. D., & Schwab, J. H. (2017). Spinal cord injury after traumatic spine fracture in patients with ankylosing spinal disorders. J Neurosurg Spine, 27(December), 1–8. https://doi.org/10.3171/2017.5.SPINE1722
The study included all patients older than 18 years of age with AS or DISH who presented to two affiliated tertiary care centers between January 1, 1990, and January 1, 2016, and had a traumatic fracture of the spine. Factors associated with SCI after traumatic fracture were compared using Fisher’s exact tests. Logistic regression was used for the analysis of predictive factors for SCI. One hundred seventy-two patients with a traumatic fracture of an ankylosed spine were included. Fifty-seven patients (34.1%) had an SCI associated with the fracture. The cervical spine was the most fractured region for patients both with (77.2%) and without (51.4%) SCI. A cervical fracture (odds ratio [OR] 2.70) and a spinal epidural hematoma (SEH) after fracture (OR 2.69) were predictive of SCI.
Early and late complication rates were significantly higher and hospital stay was significantly longer in patients with SCI. The probability of survival was significantly lower in the SCI group compared with the non-SCI group. They conclude that the incidence of SCI was high after fracture of the spine in patients with AS and DISH. Predictive factors for SCI after fracture were a fracture in the cervical spine and an SEH following fracture.
Strangely, they do not describe any of the imaging parameters….plain film, CT, MR….used to make the diagnosis. You would think that would change dramatically over the time scale of the study.
