1. Absinta, M., Ha, S.-K., Nair, G., Sati, P., Luciano, N. J., Palisoc, M., … Reich, D. S. (2017). Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. ELife, 6, 1–15. https://doi.org/10.7554/eLife.29738
Previous investigators have described the existence of a network of true lymphatic vessels within the mammalian dura that runs alongside blood vessels, such as the superior sagittal and transverse sinuses. The dural lymphatic vessels display typical immuno-histochemical markers that identify lymphatic vessels elsewhere in the body. They provide an alternate conduit for drainage of immune cells and CSF from the brain, beyond previously described pathways of flow: via arachnoid granulations into the dural venous sinuses, and via the cribriform plate into the ethmoid region. Recent studies which are based on injections of fluorescent tracers and in vivo microscopy, indicate that the dural system may be substantially more important for drainage of macromolecules and immune cells than previously realized.
The authors, using high-resolution T2-FLAIR and T1-weighted black-blood MRI images, obtained after the intravenous injection of gadobutrol, were able to visualize the collection of interstitial gadolinium within dural lymphatic vessels (maximum apparent diameter ~1 mm) in 5/5 human healthy volunteers and 3/3 common marmoset monkeys. Their results suggest that in the dura, similar to many other organs throughout the body, small intravascular molecules extravasate into the interstitium and then, under a hydrostatic pressure gradient, collect into lymphatic capillaries through a loose lymphatic endothelium.
Meningeal lymphatics were also assessed using a second gadolinium-based contrast agent, gadofosveset (trade names Vasovist, Ablavar), a blood-pool contrast agent. Gadofosveset binds reversibly to serum albumin, increasing its molecular weight from 0.9 to 67 kDa. Under physiological conditions, albumin has a low transcapillary exchange rate into the interstitial compartment, estimated to be on the order of 5% per hour, which explains the propensity of gadofosveset to remain within blood vessels. In both species, gadofosveset did not reveal dural lymphatics, especially on T1-black blood images. As expected, on T1-weighted MPRAGE images, gadofosveset provided superior intravascular enhancement, in both meningeal and parenchymal blood vessels, compared to gadobutrol.
The authors further investigated the existence and topography of lymphatics in coronal and longitudinal sections of human and marmoset dura. They tested a variety of putative lymphatic endothelial markers and found that selective double immunostaining for D2-40 podoplanin/CD31 and for PROX1/CD31 was the most effective strategy in discriminating lymphatic vs. venous blood vessels in dura samples. This is a challenging task since lymphatics sprout from transdifferentiation of venous endothelium.
Differently from experiments implementing injections of tracers within brain structures, here the authors aimed primarily to image dural lymphatic vessels in human and nonhuman primates, but could not prove whether dural lymphatic vessels drain immune cells, CSF, or other substances from the brain to deep cervical lymph nodes, nor could they assess any link with the glymphatic system.
4 figures including high quality MRI images.
2. Opoku-Darko, M., Lang, S. T., Artindale, J., Cairncross, J. G., Sevick, R. J., & Kelly, J. J. P. (2018). Surgical management of incidentally discovered diffusely infiltrating low-grade glioma. Journal of Neurosurgery, 129(1), 19–26. https://doi.org/10.3171/2017.3.JNS17159
All cases of LGG surgically treated between 2004 and 2016 at the authors’ institution were analyzed to identify those that were discovered incidentally. An “incidental” finding was defined as an abnormality on imaging that was obtained for a reason not attributable to the glioma, such as trauma, headache, screening, or research participation. Kaplan-Meier analysis was performed to determine actuarial rates of overall survival, progression-free survival, and malignant progression–free survival.
In 34 (6.8%) of 501 adult patients who underwent surgery for LGG, the tumors were discovered incidentally. Headache (26%, n = 9) and screening (21%, n = 7) were the most common indications for brain imaging in this group. Four of these 34 patients had initial biopsy after the tumor was identified on imaging. In 5 cases, the patients opted for immediate resection; the remaining cases were managed with a “watch-and-wait” approach, with intervention undertaken only after radiological or clinical evidence of disease progression. The mean duration of follow-up for all 34 cases was 5 years. Twelve patients (35.3%) had disease progression, with an average time to progression of 43.8 months. There were 5 cases (14.7%) of malignant progression and 4 deaths (11.8%). Oligodendroglioma was diagnosed in 16 cases (47%) and astrocytoma in 15 (44%).
They conclude that resection can be safely performed without significant consequence to patient performance status and should be favored over a “watch and wait” approach. Both early and delayed postoperative seizures occur frequently in patients with iLGGs and may be a consequence of treatment or may simply reflect the natural history of LGG (16 [47%] of 34) patients experienced postoperative seizures. In 6 of these patients, the seizures occurred during the early postoperative period (< 3 months after surgery) and in 10 they developed during the late postoperative period (> 3 months after surgery).
The majority of iLGGs harbor IDH1 mutation, leading to delayed disease progression, longer time before malignant transformation, and improved OS.
4 tables and 4 figures (including KM plots)
3. ter Telgte, A., van Leijsen, E. M. C., Wiegertjes, K., Klijn, C. J. M., Tuladhar, A. M., & de Leeuw, F.-E. (2018). Cerebral small vessel disease: from a focal to a global perspective. Nature Reviews Neurology, 14(7), 387–398. https://doi.org/10.1038/s41582-018-0014-y
Typical thorough Nature review article which I will not try and summarize. But let’s spend a moment on the different types of SVD:
There are thought to be six types of SVD. The most prevalent type of SVD comprises a set of pathological changes under the influence of age and vascular risk factors — especially hypertension — that mainly affect the perforating arterioles. This type is characterized by arteriolar wall thickening (mainly due to deposition of collagen, plasma proteins and inflammatory cells in the vessel wall), loss of smooth muscle cells involved in the regulation of arterial pressure and blood flow and leakage of plasma proteins into the perivascular tissue. Arteriolosclerosis represents an early stage of the disease, whereas lipohyalinosis and fibrinoid necrosis are observed at later stages — although these early and late stages can occur simultaneously in one vessel.
The second most common type of SVD is cerebral amyloid angiopathy (CAA), which is characterized by the deposition of amyloid- β in the walls of small arteries, arterioles and, infrequently, capillaries and venules, predominantly in the cerebral cortex and leptomeninges. In addition, vasculopathic changes observed in CAA include vessel wall thickening, loss of smooth muscle cells, fibrinoid necrosis and exudation of blood breakdown products into perivascular tissue. In both of these types of SVD, the described vessel wall alterations are associated with enlarged perivascular spaces. Occlusion or rupture of the blood vessel can occur, which leads to infarction or hemorrhage, although CAA is typically associated with lobar hemorrhages. Microatheroma and microaneurysms are sometimes formed, which can also cause an infarct or hemorrhage.
The remaining four types of SVD result from rare causes and consist of hereditary forms of SVD (such as CADASIL), inflammatory and immunologically mediated SVD, venous collagenosis and, finally, a category of other causes of SVD (such as post-radiation angiopathy).
I had not heard of venous collagenosis before, so I will put a link to a relevant paper in the show notes on the AJNR blog.
J Neuropathol Exp Neurol. Vol. 76, No. 4, April 2017, pp. 299–312
doi: 10.1093/jnen/nlx009
3 Figures
4. Respondek, G., Levin, J., & Höglinger, G. U. (2018). Progressive supranuclear palsy and multiple system atrophy. Current Opinion in Neurology, 31(4), 1. https://doi.org/10.1097/WCO.0000000000000581
Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are pathologically defined neurodegenerative diseases, characterized by cerebral aggregation of the proteins tau and a-synuclein, respectively. Clinically, PSP and MSA belong to the group of atypical parkinsonian syndromes. They typically present with hypokinetic rigid syndromes with additional features that differentiate them from idiopathic Parkinson disease.
Richardson syndrome, the typical clinical manifestation of PSP, presents with vertical supranuclear gaze palsy, slowing of vertical saccades, and early postural instability. These signs constitute the core diagnostic features of previous diagnostic criteria. However, in the first 3 years, patients with non-Richardson syndrome PSP phenotypes make up probably about two-thirds of all PSP patients and frequently lack these features.
The presence of postural instability and supranuclear gaze palsy is no longer crucial for the clinical diagnosis of PSP. Clinical diagnosis is rather based on combinations of signs in four functional domains: oculomotor dysfunction, postural instability, akinesia, and cognitive dysfunction.
MSA: Clinicopathological correlations in autopsy-proven MSA cases also showed that the spectrum of symptoms is broader than reflected in the current consensus criteria. Occurrence of cognitive dysfunction in up to 30% of patients was reported, particularly affecting processing speed and attention. In late stages, with MSA disease affecting the temporal lobe, patients can show frank dementia with memory disturbances. In cognitively impaired MSA patients, focal volume reduction in cortical areas has been shown.
PSP: A key role of the protein tau in the pathophysiology of PSP is well established, relating intracellular tau aggregation to neurodegeneration. Newer evidence from cell culture and animal models suggests transneuronal spreading of tau disease in a prion-like manner.
MSA: Also in MSA, prion-like spreading of a-synuclein disease is of research interest. Injection of human brain-derived a-synuclein specimen into brains of transgenic mice expressing mutated human a-synuclein transmitted a-synuclein disease. Transmission was even possible from formalin fixed tissue, demonstrating the resistance of transmissible a-synuclein specimen to denaturation. Thus, it was argued that clinicians should be cautious whenever working with human MSA specimen containing a-synuclein aggregates.
Several abnormalities on MRI have been proposed in the past as possible markers to differentiate parkinsonian syndromes. However, their sensitivity and specificity are still controversial. In a large retrospective multicenter cohort, manual planimetry of the midsagittal midbrain and pons areas discriminated well between PSP, MSA, and Parkinson disease. Specifically, best individual markers for PSP and MSA were the midsagittal midbrain area and the midsagittal pons area, respectively. The midbrain/ pons planimetric ratio was the best differentiator between PSP and MSA.
5. Kopjar, B., Bohm, P. E., Arnold, J. H., Fehlings, M. G., Tetreault, L. A., & Arnold, P. M. (2018). Outcomes of Surgical Decompression in Patients With Very Severe Degenerative Cervical Myelopathy. SPINE, 43(16), 1102–1109. https://doi.org/10.1097/BRS.0000000000002602
Postoperative outcomes of 60 patients with very severe degenerative cervical myelopathy (DCM) (modified Japanese Orthopaedic Association [mJOA] score less than or equal to 8) were compared to outcomes of 188 patients with severe DCM (mJOA 9–11).
Both cohorts improved in mJOA, and multiple other scores. Despite the substantial postoperative improvements, patients in both cohorts had considerable residual symptoms. Two-thirds of the patients in the very severe cohort had severe (mJOA less than or equal to 11) or moderate (mJOA <14) myelopathy symptoms at 24 months follow-up. Longer duration of disease was associated with poorer treatment response.
Although the extent of improvement is substantial, the patients with very severe disease endure significant residual symptoms and disability. Surgical treatment, although the most effective treatment modality, is not the cure of advanced DCM. Only about 1 in 10 patients were symptom-free.
5 Tables, 1 Figure (no imaging).
6. Pihlasviita, S., Mattila, O. S., Ritvonen, J., Sibolt, G., Curtze, S., Strbian, D., … Lindsberg, P. J. (2018). Diagnosing cerebral ischemia with door-to-thrombolysis times below 20 minutes. Neurology, 91(6), e498–e508. https://doi.org/10.1212/WNL.0000000000005954
Accuracy of admission diagnostics was studied in an observational cohort of 1,015 stroke-code patients arriving by ambulance as candidates for recanalization therapy between May 2013 and November 2015. Immediate admission evaluation was performed by a stroke neurologist or a neurology resident with dedicated stroke training, primarily utilizing CT-based imaging.
Of the 150 (14.8%) misdiagnosed patients, 135 (90.0%) had no acute findings on initial imaging and 100 (67.6%) presented with NIH Stroke Scale score 0 to 2. Misdiagnosis altered medical management in 70 cases, including administration of unnecessary treatments (thrombolysis n = 13, other n = 24), omission of thrombolysis (n = 5), delays to specific treatments of stroke mimics (n = 13, median 56 hours), and delays to antiplatelet medication (n = 14, median 1 day). Misdiagnosis extended emergency department stay (median 6.6 vs 5.8 hours) and led to unnecessary stroke unit stay (n = 10). Detailed review revealed 8 cases (0.8%) in which misdiagnosis was possible or likely to have worsened outcomes, but no death occurred as a result of misdiagnosis. Of the 59 misdiagnosed patients with acute cerebral ischemia, 5 (8.5%) were eligible for thrombolysis, but it was withheld because of an uncertain or incorrect admission diagnosis and relative contraindications.
For example, one patient that was missed giving thrombolysis had a clinical fluctuation with NIHSS score 2–6, alcohol intoxication, no findings on CT, CTA, or perfusion imaging but ended up have acute ischemia (no data whether this was a tiny DWI finding, or a real imaging miss).
They conclude that the findings support the safety of highly optimized door-to-needle times, built on thorough training in a large-volume, centralized stroke service with long-standing experience.
Ton of presented data with 6 tables.
7. Tsivgoulis, G., Geisler, F., Katsanos, A. H., Kõrv, J., Kunz, A., Mikulik, R., … Audebert, H. J. (2018). Ultraearly Intravenous Thrombolysis for Acute Ischemic Stroke in Mobile Stroke Unit and Hospital Settings. Stroke, 49, 1996–1999. https://doi.org/10.1161/STROKEAHA.118.021536
They identified 117 MSU-GH (38.4% of 305 mobile stroke unit (MSU)-treated patients) and 136 hospital setting (HS) golden hour (GH) eligible patients without prestroke disability. Between the two groups, no significant differences were documented in the rates of favorable functional outcome (51.3% versus 46.2%) and mortality (7.7% versus 9.9%) at 3 months, or in the distribution of 3-month modified Rankin Scale scores. In multivariable logistic regression analyses, adjusting for potential confounders, MSU treatment was not associated with a significantly different likelihood of favorable functional outcome or mortality at 3 months.
They conclude that there is no evidence that safety and efficacy of ultraearly intravenous thrombolysis for AIS differs when used in MSUs or in HS.
Considering that the vast proportion of the population does not have access to a stroke center within 60 minutes after stroke onset MSUs emerge as the only reliable option that can target the critical GH window with swift tPA administration and transfer to the nearest comprehensive stroke center for subsequent EVT in case of large vessel occlusion. The present study provides reassurance that the outcomes of ultraearly IVT in MSU are comparable to those of tPA delivery in HS.
1 Figure, 1 Table (no images).
8. Wijburg, M. T., Kleerekooper, I., Lissenberg-Witte, B. I., de Vos, M., Warnke, C., Uitdehaag, B. M. J., … Wattjes, M. P. (2018). Association of Progressive Multifocal Leukoencephalopathy Lesion Volume With JC Virus Polymerase Chain Reaction Results in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis. JAMA Neurology, 75(7), 827–833. https://doi.org/10.1001/jamaneurol.2018.0094
Early diagnosis of PML leads to improved survival and functional outcome. Because brain MRI may reveal PML lesions months before the onset of symptoms, MRI has been introduced as a screening tool in patients treated with natalizumab (NTZ) classified as having high risk of developing PML. However, JCV DNA can be undetectable by PCR in CSF of patients with PML and the authors hypothesize that rigorous pharmacovigilance may lead to detection of patients with smaller lesions and more frequently negative PCR results. There have been no studies investigating an association between PML imaging findings and CSF JCV PCR results in patients with NTZ-PML.
They defined inclusion criteria as a diagnosis of PML, meeting 1 of the following conditions:
1. According to the consensus statement from the AAN Neuroinfectious Disease Section (definite or probable PML [ie, a positive PCR and MRI findings suggestive of PML, with or without PML symptoms]);
or
2. In the absence of a positive PCR, the presence of all 4 of the following features: 1) high risk of PML development [ie, positive anti-JCV serostatus and NTZ treatment duration greater than 12 months]; 2) no MS disease activity prior to PML suspicion; 3) MRI lesions highly suggestive of PML, with lesion characteristics as previously reported and absence of lesion characteristics suggestive of other diseases, as judged by an experienced neuroradiologist; 4) lesion evolution on follow-up MRI scans suggestive of PML including development of immune reconstitution inflammatory syndrome.
In this cross-sectional study that included 56 patients, patients with small progressive multifocal leukoencephalopathy lesion volumes had a significantly higher probability for undetectable JC virus DNA or low JC virus copy numbers in cerebrospinal fluid.
Patients with smaller PML lesion volumes are more likely to have undetectable JCV DNA, and PML can thus not reliably be excluded based on a negative PCR result. The intense pharmacovigilance by MRI of NTZ-treated patients with MS leads to detection of smaller and asymptomatic lesions suggestive of PML and thus more PCR-negative CSF results, which can lead to uncertainty about the diagnosis and clinical treatment. In these patients, meticulous clinical and MRI follow-up in combination with repeated CSF JCV PCR testing is warranted.
2 figures, 2 tables
