1. Benjamini D, Priemer DS, Perl DP, Brody DL, Basser PJ. Mapping astrogliosis in the individual human brain using multidimensional MRI. Brain. Published online August 12, 2022:5-6. doi:10.1093/brain/awac298
There are currently no noninvasive imaging methods available for astrogliosis assessment or mapping in the central nervous system despite its essential role in the response to many disease states, such as infarcts, neurodegenerative conditions, traumatic brain injury, and infection. Multidimensional MRI is an increasingly employed imaging modality that maximizes the amount of encoded chemical and microstructural information by probing relaxation (T1 and T2) and diffusion mechanisms simultaneously. The authors use the exquisite sensitivity of this modality to derive a signature of astrogliosis and disentangle it from normative brain at the individual level using machine learning. They investigated ex vivo cerebral cortical tissue specimens derived from seven subjects who sustained blast induced injuries, which resulted in scar-border forming astrogliosis without being accompanied by other types of neuropathologic abnormality, and from seven control brain donors. By performing a combined postmortem radiology and histopathology correlation study they found that astrogliosis induces microstructural and chemical changes that are detected with multidimensional MRI, and which can be attributed to astrogliosis because no axonal damage, demyelination, or tauopathy were histologically observed in any of the cases in the study. Importantly, they showed that no one-dimensional T1, T2, or diffusion MRI measurement can disentangle the microscopic alterations caused by this neuropathology. Based on these finding, they developed a within-subject anomaly detection procedure that generates MRI-based astrogliosis biomarker maps ex vivo, which were significantly and strongly correlated with co-registered histological images of increased glial fibrillary acidic protein deposition. The findings elucidate the underpinning of MRI signal response from astrogliosis, and the demonstrated high spatial sensitivity and specificity in detecting reactive astrocytes at the individual level, and if reproduced in vivo, will significantly impact neuroimaging studies of injury, disease, repair, and aging.
7 figures, 1 table
2. Salih M, Enriquez-Marulanda A, Khorasanizadeh M, Moore J, Prabhu VC, Ogilvy CS. Cerebrospinal Fluid Shunting for Idiopathic Intracranial Hypertension: A Systematic Review, Meta-Analysis, and Implications for a Modern Management Protocol. Neurosurgery. 2022;91(4):529-540. doi:10.1227/neu.0000000000002086
This systematic review and meta-analysis assessed the outcome after CSF shunting for IIH by analyzing the published literature on the topic over a period of approximately 21 years. Although these are largely retrospective observational studies with some heterogeneity, a total of 372 patients from 15 studies were available for analysis. They selected the 3 cardinal and most disabling symptoms for this review; although other symptoms such as diplopia due to a sixth nerve palsy and pulsatile tinnitus may be noted, they are not consistently reported. They focused on headache, papilledema, and visual impairment for meta-analysis because most studies reported outcomes for these 3 symptoms and physical signs. The results of this study indicate that the most significant improvement was seen in papilledema; almost 96% of patients were noted to have an improvement in papilledema with CSF shunting. Headache also showed substantial improvement, with a 91% rate of improvement. Improvement of visual symptoms was noted in 85%.
Procedural complications and long-term durability of CSF shunting was also assessed. Intraprocedural complications and periprocedural infection or hemorrhage were not reported in any study. 12 studies reported periprocedural low-pressure headache due to CSF overdrainage. In most cases, original headache of patients improved for a short period of time after shunting, and they subsequently developed a headache that was related to body position. The overall occurrence rate of low-pressure headache was 20%. This may also be related to the relatively high rate of LP shunt placement that was observed in this analysis. There were no reports of malpositioned catheters or intracranial complications noted on cranial computed tomography (CT) in these patients. Overall, the most common reason for revision was catheter obstruction with recurrence of symptoms and signs of increased intracranial pressure. Other reasons for revision included abdominal catheter migration and infection.
Current management protocols were also discussed. Neuroimaging evaluation includes a high-quality MR and signs suggestive of IIH include flattening of the posterior scleral margins, widening of the peri-optic CSF space, tortuosity of the optic nerves, “empty-sella,” cerebellar tonsillar descent, and very small or slit-like ventricles. This is complemented by an MRV study to assess the status of the intracranial venous sinus pathways and look for any focal stenosis, atresia, or other venous abnormalities that may predispose an individual to developing IIH. If no contraindications exist, this is followed by a lumbar puncture (LP) to assess the opening CSF pressure and also allow removal of CSF from the lumbar subarachnoid cistern to ascertain any therapeutic benefit from CSF drainage. Routine CSF studies are also performed, and the patient is followed in clinic in 1 to 2 weeks to assess the response to CSF drainage. The diagnosis of IIH is confirmed by this collation of clinical symptomatology, neurological and ophthalmological evaluations, LP, and neuroimaging studies.
6 figures, 3 tables, no imaging
3. Lehrer EJ, Ahluwalia MS, Gurewitz J, et al. Imaging-defined necrosis after treatment with single-fraction stereotactic radiosurgery and immune checkpoint inhibitors and its potential association with improved outcomes in patients with brain metastases: an international multicenter study of 697 patients. J Neurosurg. Published online September 1, 2022:1-10. doi:10.3171/2022.7.JNS22752
Brain metastasis is the most common intracranial neoplasm. Conservative estimates indicate that a brain metastasis will be diagnosed in 10%–30% of cancer patients at some time during their disease course. Historically, these patients had a poor prognosis with a median overall survival (OS) of approximately 3.5 months. Treatment also consisted of a multimodal approach involving corticosteroids, resection, and whole-brain radiation therapy (WBRT). Treatment-related morbidity has markedly decreased in recent years because of the widespread adoption of stereotactic radiosurgery (SRS) and the incorporation of memantine and hippocampal avoidance in WBRT. Furthermore, improved systemic therapies, such as immune checkpoint inhibitors (ICIs), have demonstrated an improvement in OS across multiple advanced malignancies, such as non–small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC), and they are now widely used in this setting.
Multiple retrospective single-institution studies have demonstrated that OS is improved when SRS is combined with ICIs, particularly when these therapies are administered within 4 weeks of one another. A complication of SRS is the development of radiation necrosis (RN), which can be associated with significant neurological morbidity with roughly 50% of patients being symptomatic. The incidence of RN following SRS ranges from 5% to 25%, with different studies using various diagnostic criteria ranging from pathological tissue diagnosis to imaging changes. Multiple factors have demonstrated an association with RN, such as dose-volume relationships, previous WBRT, use of systemic therapies, and choice of radiosurgery platform. Furthermore, the use of ICIs has demonstrated a strong association with the development of RN.
There were 697 patients with 4536 brain metastases with a median follow-up of 13.6 months who were included in the analysis. Treatment-related imaging changes (TRICs) were diagnosed in 9.8% of patients, and MRI was the diagnostic modality in 97.1% of the patients. The median number of brain metastases per patient was 3. The median age was 66 years, and 54.1% of patients were male. Primary tumor histology was NSCLC, melanoma, and RCC in 57.3%, 36.3%, and 6.4% of cases, respectively. TRICs were classified using MRI, PET, MR spectroscopy, or biopsy findings. MRI findings, such as contrast enhancement and perilesional edema, as well as specific enhancement patterns such as a “soap bubble” and “Swiss cheese” appearance, were noted. Although PET and MR spectroscopy were used in a minority of cases, the radiotracer standardized uptake value and choline/creatinine ratios were noted for PET and MR spectroscopy imaging, respectively. A multidisciplinary consensus by local clinical providers at each participating SRS site was mandated. TRICs following ICI and SRS were associated with a median OS benefit of approximately 6 months in this retrospective multicenter study.
2 figures, 3 tables, no imaging
4. Triplett JD, Kutlubaev MA, Kermode AG, Hardy T. Posterior reversible encephalopathy syndrome (PRES): diagnosis and management. Pract Neurol. 2022;22(3):183-189. doi:10.1136/practneurol-2021-003194
PRES often presents non-specifically with symptoms manifesting over several hours or days. Encephalopathy develops in 28%–94% of patients and ranges from mild confusion and cognitive deficits to stupor and sometimes coma. Seizures affecting up to 74%–87% of patients and typically occur within 24–48 hours of presentation; in a minority (3%–17%), seizures may evolve into status epilepticus, and rarely this is the presenting symptom. Headaches develop in up to half of patients with PRES and are usually dull, diffuse, and gradual in onset. A thunderclap headache can occur in the context of PRES but should raise the suspicion of reversible cerebral vasoconstriction syndrome (RCVS). This condition occurs in the context of similar risk factors to PRES but is distinguished mainly by thunderclap headache, cerebral vasculopathy, infarction, and subarachnoid or intracranial hemorrhage.
PRES is associated with numerous conditions and iatrogenic causes, though most frequently with hypertension, renal failure, eclampsia, transplant and immunosuppressive use, sepsis, autoimmune disorders and exposure to cytotoxic medications. Rarer iatrogenic causes include linezolid, intravenous immunoglobulin and intoxication with LSD, cocaine, and even scorpion poisoning.
The typical CT and MRI features of PRES include almost symmetrical hemispheric vasogenic oedema affecting subcortical white matter and often extending to the overlying cortex, best seen on MRI with FLAIR sequences. MRI diffusion-weighted imaging usually confirms vasogenic oedema with absence of restricted diffusion. Postcontrast enhancement occurs in 38%–50% of patients in one of three patterns: a leptomeningeal pattern, a cortical pattern within regions of altered FLAIR signal or a combined pattern.
Brain imaging shows bilateral cortical–subcortical vasogenic oedema that falls into three anatomical patterns seen in about 70% of patients: a dominant parieto-occipital pattern (22%), a holohemispheric watershed pattern (23%); and superior frontal sulcus pattern (27%). A central-variant (brainstem) pattern has also been identified, affecting the brainstem, basal ganglia, posterior limb of the internal capsule, cerebellum and periventricular regions, but has no cortical or subcortical involvement.
Intracranial hemorrhages are found on imaging in 10%–25% of cases, mostly intraparenchymal or subarachnoid. Up to 65% of patients who undergo follow-up MRI with susceptibility-weighted imaging have microhemorrhages.
PRES and RCVS are well known to overlap, and so cerebral CT or MR angiography is recommended to help to distinguish them. In RCVS, vessel wall MR angiography shows arterial wall thickening but without arterial wall enhancement, consistent with transient vasoconstriction. However, PRES occurs in 9%–38% of RCVS cases, and 87% of PRES cases have angiographic changes consistent with RCVS.
2 figures with imaging, 2 tables and an information box and keypoints
5. Baldassari LE, Wattjes MP, Cortese ICM, et al. The neuroradiology of progressive multifocal leukoencephalopathy: A clinical trial perspective. Brain. 2022;145(2):426-440. doi:10.1093/brain/awab419
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection caused by JC virus (JCV), involving an infection of white matter (principally oligodendrocytes) and neurons in the brain, and leading to irreversible demyelination and neuroaxonal damage. Despite the persistent risk of PML among patients with immunosuppressive conditions and a growing risk of PML among patients treated with immunomodulatory agents, no therapeutics are approved for the treatment of PML.
Regarding imaging of PML in routine clinical care, there is substantial experience supporting the use of T2-weighted sequences (including T2-FLAIR) for identifying and monitoring individual lesions; gadolinium enhancement for identifying PML-IRIS (albeit not reliably); DWI for determining whether a lesion is actively expanding; and potentially SWI for assessing lesion chronicity. Perfusion, magnetization transfer, spectroscopy, and PET remain research applications at this time. Quantification of atrophy and lesion volumes are emerging areas of interest in the field of PML, but only limited data are available. Techniques for brain and lesion volume quantification are now available but require further research regarding performance and clinical application. In addition, there is no evidence supporting or refuting the application of ultra-high field MRI in PML. A limited number of case reports describe PML lesion characteristics and PML lesion evolution based 7 T MRI but do not report advances in lesion detectability and characterization relative to standard MRI field strengths. With respect to therapeutic trials, imaging outcome measures should ideally be objective, quantifiable using standardized methods, specific to the disease of interest, and correlated (both cross-sectionally and longitudinally) to clinically meaningful symptoms and disability. A surrogate end point should be predictive of the true clinical end point of interest and be in the causal pathway. Imaging measures show promise in this regard, potentially as surrogates of either a clinical measure or event (e.g. survival, degree of physical disability, quality of life) or disease activity (e.g. resolution of infection). Though extent of involvement on MRI (e.g. unilobar or widespread/ multilobar, as well as lesion burden) and the presence of supratentorial versus infratentorial lesions have been shown to be associated with survival and functional outcomes in some studies of PML, these data are generally limited, heterogeneous, and confounded by other clinical features (e.g. age, underlying disease, and baseline disability) known to be associated with survival.
1 table, 4 figures with imaging
6. Sekeres MA, Taylor J. Diagnosis and Treatment of Myelodysplastic Syndromes. JAMA. 2022;328(9):872. doi:10.1001/jama.2022.14578
Myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia. MDS are associated with an increased risk of acute myeloid leukemia (AML). The yearly incidence of MDS is approximately 4 per 100 000 people in the United States. MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival. The median age at diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. Risk factors associated with MDS include older age and prior exposures to toxins such as chemotherapy or radiation therapy. MDS are more common in men compared with women (with yearly incidence rates of approximately 5.4 vs 2.9 per 100 000). MDS typically has an insidious presentation, consisting of signs and symptoms associated with anemia, thrombocytopenia, and neutropenia. MDS can be categorized into subtypes that are associated with lower or higher risk for acute myeloid leukemia transformation and that help with therapy selection. Patients with lower-risk MDS have a median survival of approximately 3 to 10 years, whereas patients with higher-risk disease have a median survival of less than 3 years. Therapy for lower-risk MDS is selected based on whether the primary clinical characteristic is anemia, thrombocytopenia, or neutropenia. Management focuses on treating symptoms and reducing the number of required transfusions in patients with low-risk disease. For patients with lower-risk MDS, erythropoiesis stimulating agents, such as recombinant humanized erythropoietin or the longer-acting erythropoietin, darbepoetin alfa, can improve anemia in 15% to 40% of patients for a median of 8 to 23 months. For those with higher-risk MDS, hypomethylating agents such as azacytidine are first-line therapy. Hematopoietic cell transplantation is considered for higher-risk patients and represents the only potential cure.
3 tables, 1 graphic
7. Martín-Aguilar L, Lleixà C, Pascual-Goñi E. Autoimmune nodopathies, an emerging diagnostic category. Curr Opin Neurol. 2022; 579-585. doi:10.1097/wco.0000000000001107
The recent discovery of pathogenic antibodies against the nodes of Ranvier has led to the recognition of a new group of antibody-mediated neuropathies with well established clinical features and disease mechanisms that differ from classical inflammatory neuropathies. The nodes of Ranvier are small regions located at periodic interruptions of the myelin sheath in myelinated nerve fibers. Complex axoglial interactions configure their organization in a series of domains: the nodes, paranodes and juxtaparanodes. This organization is essential for the ability of myelinated fibers to conduct nerve impulses by saltatory conduction, a much faster and more energy-efficient mechanism of impulse propagation than that observed in unmyelinated fibers. Nodal/paranodal antibodies targeting cell adhesion molecules (CAMs) of the paranodal and nodal axo-glial junctions including contactin 1 (CNTN1), contactin-associated protein 1 (Caspr1), neurofascin 155 (NF115) and pan-neurofascin (panNF) were initially reported in 5–10% of patients that meet the clinical and electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP).
Clinical spectrum of autoimmune nodopathy includes acute, subacute or chronic onset sensory-motor neuropathies mimicking Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy but may differ in their response to IVIG. Neurophysiologically they overlap with acquired demyelinating neuropathies, but ultrastructural studies and animal models demonstrated antibody-mediated pathology restricted to the node.
1 table, no imaging
8. Shah VA, Thompson RE, Yenokyan G, et al. One-Year Outcome Trajectories and Factors Associated with Functional Recovery among Survivors of Intracerebral and Intraventricular Hemorrhage with Initial Severe Disability. JAMA Neurol. 2022;21287. doi:10.1001/jamaneurol.2022.1991
In this post hoc analysis (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 trial (CLEAR-III) and the Minimally Invasive Surgery Plus Alteplase for Intracerebral Hemorrhage Evacuation (MISTIE-III) phase 3 trial) of patients with ICH and IVH and initial severe disability, more than 40% of patients recovered to good outcome by 1 year. Prediction of long-term functional recovery was significantly associated with improvement after inclusion of more granular baseline characteristics (ie, diabetes, leukoaraiosis, IVH volume, and pineal shift) and hospital events, including cerebral hypoperfusion, ischemic stroke, sepsis, persistent hydrocephalus, need for supportive interventions (mechanical ventilation and gastrostomy), and hematoma evolution. Significant reduction in hematoma and IVH volumes in the first month were strongly associated with long-term functional recovery, highlighting the importance of minimally invasive interventions to reduce blood volume. The combined cohort experienced higher rates of good 1-year outcome than previously reported, despite the inclusion of only patients with high-severity ICH and IVH. Outcomes from these clinical trials may be biased by rigid exclusion criteria, including baseline Glasgow Coma Scale score less than 4, fixed pupils, infratentorial extension, and baseline mRS greater than 1, limiting generalizability. However, outcomes were less impacted by early withdrawal of life-sustaining treatment, which occurred in only 88 of 999 patients (8.8%) in the first month, compared with 20% to 30%in prior studies. Patients with ICH who are maximally treated have favorable outcomes at a similar rate, highlighting the possible negative impact of early pessimistic prognostication on future recovery.
3 figures, 2 tables, no imaging
9. Selim MH. Time for a New Perspective on Intracerebral Hemorrhage. JAMA Neurol. 2022;79(9):844. doi:10.1001/jamaneurol.2022.1988
The recovery of patients with ICH takes a long time; many patients who have severe disability during hospitalization can achieve significant recovery over the following months to year. Accurate prognostication requires longer periods of evaluation after treatment. Most patients with ICH who die in the hospital do so after decisions are made to withdraw life-sustaining measures because of perceived high likelihood of poor long-term outcomes. These new findings give us an opportunity to pause and rethink how we approach ICH. The current American Heart Association/ American Stroke Association guidelines for the treatment of patients with spontaneous ICH recommend aggressive guideline-concordant care for all patients with ICH, unless they have previously documented their desire to limit these treatments before the onset of their ICH, including the postponement of new do-not-attempt-resuscitation and/or intubation orders or the withdrawal of medical support until at least the second full day of hospitalization. The author would argue that a much longer period is needed to promote maximal treatment for these patients. It is time for new evidence supported perspective on ICH.
The American Society of Neuroradiology is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Visit the ASNR Education Connection website to claim CME credit for this podcast.
