1. Law LY, Riminton DS, Nguyen M, et al. The spectrum of immune-mediated and inflammatory lesions of the brainstem. Neurology 2019;93(9):390–405, 10.1212/WNL.0000000000008015

This review is aimed at highlighting clinical, MRI, and other investigative findings useful to differentiate among the various inflammatory diseases in which brainstem lesions occur, including MS, NMOSD, neuro-Behçet disease (NBD)(pronounced Beh-chet), CLIPPERS, neurosarcoidosis (NS), Susac syndrome (SS), and the histiocytic disorders. Typical MRI features are described including unique lesion characteristics within and outside the brainstem, with comparisons frequently made to MS, a prototypic inflammatory demyelinating disease in which brainstem lesions can occur.

MS lesions are usually situated in the periphery of the brainstem; classically the anterior pons or the trigeminal entry zone, or ventral to the periaqueductal gray matter, whereas chronic small vessel disease affects the territory of a perforating artery (e.g., central pons) and is associated with other sequelae of vasculopathy (lacunar infarcts, microhemorrhage). Unlike NMOSD, MS lesions are well-defined, more likely to occur in the pons than medulla, and occur in both the dorsal and ventral brainstem.

Brainstem involvement appears to be more common in AQP4-IgG-seropositive NMOSD, and the medulla is most commonly affected.  Although not entirely specific, there are lesions that favor NMOSD over MS. These include linear lesions of the dorsal medulla, adjacent to the fourth ventricle, which can be contiguous with cervical transverse myelitis. These lesions are associated with intractable hiccups and nausea and vomiting (area postrema syndrome). Diencephalic lesions circumscribing the third ventricle and rostral midbrain are also considered characteristic of NMOSD.

Behçet disease (BD) is a vasculocentric inflammatory disease most prevalent among populations extending from East Asia to the Mediterranean along the ancient Silk Road. The most common MRI finding during an acute attack is an isolated, large, asymmetric, confluent upper brainstem lesion, which may extend into the basal ganglia traversing the diencephalon. In contrast to MS, NBD lesions have blurred margins and appear crenulated. The lesion is often accompanied by edema and enhancement.

MRI in CLIPPERS (not strictly a diagnosis but an imaging pattern) a shows distinctive T2 and FLAIR lesions with a homogenous or curvilinear pattern of gadolinium enhancement (<3 mm) that “pepper” the pons.  Lesions are not associated with restricted diffusion on diffusion-weighted imaging (DWI) sequences, and mass effect is atypical. The T2 signal abnormality should not be substantially larger than the enhanced lesion. Involvement of cerebellar peduncles, medulla, midbrain, and cerebellar and cerebral hemispheres occurs with a descending gradient of lesion density from the pons.

Full evaluation for other causes of enhancing brainstem lesions is of critical importance.  Patients with suspected CLIPPERS especially need to be evaluated and serially monitored for the development of CNS lymphoma, and both CNS lymphoma and CNS tuberculosis can be responsive to corticosteroids in the early stages, leading to potential misdiagnosis. 

4 figures, 2 tables

2. Blennow K, Diaz-Lucena D, Zetterberg H, et al. CSF neurogranin as a neuronal damage marker in CJD: a comparative study with AD. J Neurol Neurosurg Psychiatry 2019;90(8):846–53, 10.1136/jnnp-2018-320155

Background: Sporadic Creutzfeldt- Jakob disease (CJD) is the most prevalent human prion disease characterized by rapidly progressive dementia and short disease duration. The most prevalent subtypes are CJDMM1/CJDMV1 (60%–70% of the cases) with predominant cortical affection and, CJD VV2 (~16% of the cases), with prominent cerebellar involvement. See Neurosurgical focus article (DOI: 10.3171/2015.8.FOCUS15328) for nice table defining types of CJD.

Neurogranin is a calmodulin-binding protein abundantly expressed in the soma and dendrites of neurons of the telencephalon involved in synaptic plasticity and long-term potentiation. Neurogranin has been suggested to be a specific cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker, since its concentration is increased in AD, but not in other neurodegenerative diseases (ie, frontotemporal dementia, Lewy body dementia, Parkinson’s disease, progressive supranuclear palsy). In this study, CSF neurogranin, total tau, neurofilament light (NFL) and 14-3-3 protein were measured in neurological controls (NCs, n=64), AD (n=46) and CJD (n=81). The accuracy of neurogranin discriminating the three diagnostic groups was evaluated. Correlations between neurogranin and neurodegeneration biomarkers, demographic, genetic and clinical data were assessed.

Compared with controls, CSF neurogranin concentrations were increased in CJD (4.75 times of NC; area under curve (AUC) 0.96) and AD (1.94 times of NC; AUC 0.73), and were able to differentiate CJD from AD.

CJD-MM1/MV1 cases displayed higher neurogranin levels than sporadic CJD (VV2 cases). Neurogranin was increased at early CJD disease stages and was a good prognostic marker of survival time in CJD. In brain tissue, neurogranin was detected in the cytoplasm, membrane and postsynaptic density fractions of neurons, with reduced levels in AD, and more significantly in CJD.

In total, this study evaluates for the first time the diagnostic and prognostic value of CSF neurogranin in CJD in comparison to AD. They show a striking correlation between brain and CSF findings regarding different diseases (CJD vs AD) and CJD subtypes (MM1/MV1 vs VV2). This strongly supports the usefulness of comparative analysis between brain and biological fluids to comprehensively understand the molecular mechanisms underlying neurodegenerative dementias and the associate value of their study as diagnostic and prognostic markers for these conditions.

3. Yu J-X, Hong T, Krings T, et al. Natural history of spinal cord arteriovenous shunts: an observational study. Brain 2019;142(8):2265–75, 10.1093/brain/awz153

Spinal cord arteriovenous shunts (SCAVSs) are pathological connections between spinal cord arteries and veins without a normal intervening capillary network. They can be subclassified into intramedullary spinal arteriovenous malformations (SAVMs), perimedullary arteriovenous fistulas (PMAVFs) and spinal metameric arteriovenous malformations (SMAVMs).

The authors performed an observational study in a consecutive patient cohort with symptomatic intradural spinal cord arteriovenous shunts who were admitted to three institutes to investigate the clinical course of this complex disease, which would provide valuable evidence to inform clinical decision-making.

Patients with spinal epidural vascular malformations, spinal dural arteriovenous fistulas, spinal radicular arteriovenous fistulas, filum terminale arteriovenous fistulas, spinal cavernous malformations or paravertebral spinal shunts were not included in this study.

The clinical course of patients with symptomatic intradural spinal cord arteriovenous shunts from initial presentation to occurrence of clinical deterioration, initiation of treatment, or last follow-up was analyzed. Patients with at least 1 month of observation were included in this study. Clinical onset and deterioration patterns were divided into acute and gradual. Annual and cumulative rates of clinical deterioration as well as their risk factors were analyzed using Kaplan-Meier life table analysis and Cox proportional hazards model. To assess risks and benefits of treatment, post-treatment clinical courses were further assessed.

Four hundred and sixty-six patients with a mean observational period of 36.9 ±  58.8 months were included; 56.7% of patients presented with acute onset, of whom 77.3% experienced spontaneous recovery. Age of onset older than 28 years, mid-thoracic lesions and non-ventral lesions were independent predictors of failure for spontaneous recovery. The annual risk of general, acute and gradual clinical deterioration after onset was 30.7%, 9.9% and 17.7%, respectively. Risk of deterioration was highest in the early period after initial onset. Acute onset was the only independent risk factor of acute deterioration and gradual onset was the strongest predictor of the gradual deterioration among all the stratifying factors. After invasive treatment, complete obliteration was achieved in 37.9% of patients (138 of 364) and improved or stable clinical status was noted in 80.8% of patients. Forty-two patients (11.5%) experienced permanent complications. Overall post-treatment deterioration rate was 8.4%/year, and 5.3%/year if permanent complications were excluded. They conclude that the natural history of symptomatic spinal cord arteriovenous shunts is poor, especially in the early period after onset, and early intervention is thus recommended.

For the majority of patients’ emergent open surgery is not necessary, but a specific subset of patients might benefit from this strategy.  More than 15% of acute onset patients did not spontaneously recover in the observational period of 42 months. Predictive factors for failure to recover were an initial mALS (modified Aminoff and Logue scale of disability – gait and micturation), age of onset older than 28 years, mid-thoracic and non-ventral lesions.

The risk of acute deterioration is significantly increased during the first few months after acute onset, which is similar to brain arteriovenous malformation. Therefore, although an emergent open surgery is not necessary for the majority of patients with acute onset, the authors suggest an early endovascular embolization of weak points such as intranidal aneurysms to prevent subsequent hemorrhage.

4 figures, 4 tables

4. Yogendrakumar V, Ramsay T, Fergusson D, et al. New and expanding ventricular hemorrhage predicts poor outcome in acute intracerebral hemorrhage. Neurology 2019;93(9):e879–88, 10.1212/WNL.0000000000008007

Intraventricular hemorrhage (IVH) is a well-established predictor of poor clinical outcome. The concurrent presence of IVH is associated with a mortality rate as high as 50% to 75%. The mechanisms of IVH-related brain injury vary and may involve the exertion of mass effect on brain structures, development of obstructive hydrocephalus, and global dysfunction secondary to the contamination of CSF with blood.

Questions remain as to what degree of IVH expansion affects clinical outcome. The presence of new IVH on successive imaging appears to be associated with poor outcome yet attempts to validate this finding have led to conflicting results.

They performed the study in 2 stages using data from 2 prospectively collected ICH observational cohorts. In the first stage, they modeled a relationship between IVH expansion and long-term outcome. They then used the resultant probability distribution to select clinically relevant thresholds that could be practically applied by clinicians at the bedside. They subsequently validated the findings in the second stage of the study. The primary exposure was IVH expansion (including development of new IVH) at 24 hours, calculated as the difference in IVH volume between the 24-hour CT followup and the baseline CT. Repeat imaging was standardized in the PREDICT study (derivation cohort), and all study participants received follow-up imaging at 24 hours.

They assessed hematoma volumes in a blinded fashion at a central laboratory using computerized planimetry software validated for ICH measurements.

Of the 256 patients from PREDICT study, 127 (49.6%) had an mRS score of 4 to 6. Twenty-four-hour IVH volume change and poor outcome fit a nonlinear relationship, in which minimal increases in IVH were associated with a high probability of an mRS score of 4 to 6. IVH expansion ≥1 mL and development of any new IVH strongly predicted poor outcome at 90 days.

The authors conclude that IVH expansion as small as 1 mL or any new IVH is strongly predictive of poor outcome.

3 figures, 4 tables

5. Huang WY, Saver JL, Wu YL, et al. Frequency of intracranial hemorrhage with low-dose aspirin in individuals without symptomatic cardiovascular disease: a systematic review and meta-analysis. JAMA Neurol 2019;76(8):906–14, 10.1001/jamaneurol.2019.1120

The benefits of low-dose aspirin for secondary prevention of myocardial infarction and ischemic stroke are well established, with prevention of recurrent ischemic events outweighing the risk of hemorrhage. However, the value of aspirin for primary prevention of symptomatic cardiovascular disease is controversial because the risk of cardiovascular events among event-free individuals is typically lower than that of patients with symptomatic atherosclerotic disease, and the increased risk of bleeding may offset the overall benefit of aspirin use.  Of the various major bleeding events related to the use of aspirin, intracranial hemorrhage is a special concern because it is strongly associated with a high risk of mortality and poorer health over a lifetime.

Published meta-analyses have provided conflicting findings regarding whether the use of aspirin for primary prevention of symptomatic cardiovascular disease increases the risk of intracranial hemorrhage. Furthermore, the link between aspirin use for primary prevention and specific subtypes of intracranial hemorrhage, such as intracerebral hemorrhage or subdural hemorrhage, was not investigated in published meta-analyses.

The search identified 13 randomized clinical trials of low-dose aspirin use for primary prevention, enrolling 134,446 patients. Pooling the results from the random-effects model showed that low-dose aspirin, compared with control, was associated with an increased risk of any intracranial bleeding (8 trials; relative risk, 1.37; 2 additional intracranial hemorrhages in 1000 people), with potentially the greatest relative risk increase for subdural or extradural hemorrhage (4 trials; relative risk, 1.53) and less for intracerebral hemorrhage and subarachnoid hemorrhage. Patient baseline features associated with heightened risk of intracerebral hemorrhage with low-dose aspirin, compared with control, were Asian race/ethnicity and low body mass index.

They conclude that among people without symptomatic cardiovascular disease, use of low-dose aspirin was associated with an overall increased risk of intracranial hemorrhage, and heightened risk of intracerebral hemorrhage for those of Asian race/ethnicity or people with a low body mass index.

1 table, 2 figures with forest plots

6. Yamaki VN, Solla DJF, Ribeiro RR, et al. Papillary tumor of the pineal region: systematic review and analysis of prognostic factors. Neurosurgery 2019;85(3):E420–29, 10.1093/neuros/nyz062

Tumors in the pineal region are rare, representing less than 1% of all intracranial tumors in adults. Nearly 17 histological tumor types have been described for pineal tumors, each with different oncologic behaviors. The papillary tumor of the pineal region (PTPR) is the most recently identified type of pineal tumor. Due to the recent identification of PTPRs, no valid histologic grading system or standard treatment options exist for this type of tumor. In previous series, only gross total resection (GTR) resulted in longer overall survival. In addition, the role of adjuvant treatments has not yet been determined.

The authors performed a comprehensive patient-level analysis of all PTPR cases and identify their clinical features, treatment options, and prognostic factors. The initial search yielded 1164 studies, of which 71 were included (60 case reports and 11 case series), containing 177 patients (mean age 33.0 ± 15.3 yr and 53.2% male). Intracranial hypertension and hydrocephalus prevailed as the clinical picture. Surgery was performed on 82.0% and gross total resection (GTR) was achieved on 71.4%. A total of 56.8% recurred after a median 29 mo. The 36-mo survival rate was 83.5%. Good functional outcomes (Glasgow Outcome Scale 4/5) were observed in 60.0%. The variables of interest were inconsistently reported and the multivariable analysis final sample was 133 patients. Tumor size and surgery are associated with improvement in 36-mo survival. They did not observe any significant benefits from GTR or adjuvant treatments.

PTPR present as well-circumscribed masses and tend to be larger than other pineal tumors. On MRI, it has variable T1 and T2 signal intensities with heterogeneous contrast enhancement. A cystic component or the presence of multiple cysts was described, as well as hyperintense foci in T1-weighted images representing inclusions of proteins. The authors results found those features in more than 80% of PTPRs.

7. Wu X, Matouk CC, Mangla R, et al. Cost-effectiveness of computed tomography angiography in management of tiny unruptured intracranial aneurysms in the United States. Stroke 2019;50(9):2396–2403, 10.1161/STROKEAHA.119.025600

Unruptured intracranial aneurysms (UIAs) are relatively common and a significant proportion (up to 87.6%) of incidentally discovered UIAs are small, measuring <3 to 4 mm. The natural history of UIAs remains poorly understood. Only a small percentage eventually rupture, especially the tiny and small aneurysms, contributing to uncertainty about their optimal management.

Patients with no prior history of SAH and harboring aneurysms ≤7 mm are often followed-up conservatively using cross-sectional imaging to assess change in size/morphology, which may increase the risk of rupture. The American Heart Association/American Stroke Association guidelines recommend radiographic follow-up with magnetic resonance imaging or computed tomography angiography (CTA) at regular intervals. However, the interval and duration of recommended follow-up are uncertain.

A Markov decision model was constructed from a societal perspective starting with patients 30, 40-, or 50-year-old, with incidental detection of unruptured intracranial aneurysm ≤3 mm and no prior history of subarachnoid hemorrhage. Five different management strategies were assessed (1) annual CTA surveillance, (2) biennial CTA, (3) CTA follow-up every 5 years, (4) coiling and subsequent magnetic resonance imaging follow-up, and (5) annual CTA surveillance for the first 2 years, followed by every 5-year CTA follow-up. Probabilistic, 1-way, and 2-way sensitivity analyses were performed.

Follow-up every 5 years would be optimal when the rupture risk is <57.4% in growing aneurysms, which is not even close to the low rupture rates reported in patients with tiny aneurysms. In this model, they used 4.17% from the study by Villablanca et al. The sensitivity analysis shows that follow-up every 5 years is better when the rupture risk in nongrowing aneurysms is <2.66% per year. When the risk is higher, coiling would become the optimal strategy. The reported rupture risk in the literature is much smaller.

This study reveals that every 5-year CTA imaging surveillance is the cost-effective strategy in patients with aneurysms ≤3mm, resulting in better health outcomes and lower healthcare spending. Although associated with ionizing radiation, the risks associated with CTA use do not impact the conclusions, given the higher risk for aneurysmal rupture and associated costs/complications. More aggressive management strategies might be appropriate in selected high-risk patients.

4 figures, 2 tables, no imaging

8. Trivelato FP, Abud DG, Ulhôa AC, et al. Derivo embolization device for the treatment of intracranial aneurysms. Stroke 2019;50(9):2351–58, 10.1161/STROKEAHA.119.025407

The Derivo Embolization Device (DED) (a rather unfortunate abbreviation) is a second-generation FDD with a novel surface finishing that might lead to reduced friction and low thrombogenicity. Only 3 small series with short-term angiographic results have been published. Therefore, clinical and angiographic data are scarce. The objective of this registry was to report a nationwide experience with the DED for the treatment of intracranial aneurysms. The authors prospectively evaluated a multicenter series to establish the safety and efficacy of the DED and to identify predictors of occlusion and complications.

BRAIDED (Brazilian Registry of Aneurysms Assigned to Intervention With the Derivo Embolization Device) is a multicenter, prospective, interventional, single-arm trial of the Derivo Embolization Device for the treatment of intracranial aneurysms. The primary effectiveness end point was total aneurysm occlusion at 6- and 12-month angiographies. The secondary safety end point was the absence of serious adverse events during follow-up.

Between December 2016 and October 2018, 146 patients harboring 183 intracranial aneurysms were treated in 151 interventions at 7 centers. Derivo Embolization Device placement was technically successful in all patients. Most aneurysms (86.9%) were located at the internal carotid artery, and the mean diameter was 6.7 mm. At 6 months, 113 of 140 (80.7%) aneurysms met the study’s primary end point, and 74 of 83 (89.2%) met the study’s primary end point at 12 months. Saccular morphology of the aneurysm and the presence of a branch arising from the sac predicted persistence. A long duration of follow-up predicted total occlusion. Of the 146 enrolled patients, 138 (94.5%) were treated without serious adverse events during follow-up.

Based on good results regarding the treatment of large-to-giant saccular internal carotid aneurysms located at a sidewall, the indications for FDD expanded, including aneurysms with different shapes, locations, and sizes. The present series reflects the greater heterogeneity of treated aneurysms, including 25 (13.7%) nonsaccular aneurysms, 17 (9.3%) located in the posterior circulation, 9 (4.9%) located at or beyond the circle of Willis, 6 (3.3%) located at bifurcations, and only 31 (16.9%) were large or giant aneurysms. Only 18 (9.3%) aneurysms would be eligible according to the criteria of the PUFs trial (Pipeline for Uncoilable or Failed Aneurysms).

Among the 11 patients who experienced periprocedural complications, 4 had improper DED expansion. All of them included the proximal opening of the device, with a fish mouth configuration in 2 patients. Entering the device with a balloon can be challenging. Nevertheless, angioplasty was performed in 2 patients, and device removal and substitution were performed in the remaining patients. The patients had an uneventful recovery. Four (2.7%) patients presented with thromboembolic complications during the procedure, and 1 patient presented with thrombotic complication 4 days after the intervention. These events resulted in 1 death and 1 major stroke. Ruptured lesions, small aneurysm diameter, and balloon angioplasty were identified in the multivariable analysis as risk factors for periprocedural complications.

5 tables, 1 figure including angiograms