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Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8 + T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8 + T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8 + T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8 + T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.

In 2016, the Bárány Society defined new diagnostic criteria for the neurovascular compression syndrome of the eighth nerve, called "vestibular paroxysmia" (VP), differentiating between definite (dVP) and probable (pVP) forms. The aim of this study was (1) to describe clinical symptoms and laboratory findings in a well-diagnosed large patient cohort according to those criteria, and (2) to evaluate the long-term course over years in dVP. We identified 146 patients (73 dVP, 73 pVP) from our tertiary dizziness center registry. Data of structured history-taking, clinical neurological, neuro-ophthalmological/-otological examinations as well as MRI imaging were extracted for analyses. Overall, attack frequency ranged between 5 and 30 attacks per day; spinning vertigo was the most frequent type. In two-thirds of patients, attacks occurred spontaneously; in one-quarter, they were triggered by head movements. The majority (approximately 70%) reported no accompanying symptoms; in those with symptoms, mild unilateral cochlear symptoms prevailed. One-third of patients initially showed hyperventilation-induced nystagmus without specific direction, and a deviation of the subjective visual vertical between 3° and 6°. Complete loss of peripheral vestibular function was never evident. dVP and pVP significantly differed concerning the vertigo type, e.g., spinning vertigo was more frequent in dVP. Fortunately, three-quarters of dVP patients remained attack-free during follow-up (mean 4.8 years, standardized questionnaire), more than half of them even without any medication. Patients with ongoing attacks showed significantly higher attack frequency at baseline, but reported persistent frequency reduction. Overall, the long-term prognosis of VP appears favorable, not necessarily requiring ongoing treatment., (© 2022. The Author(s).)

Objectives: Recently, a novel clearing system for interstitial solutes of the brain was described as a perivascular pathway named the glymphatic system. Furthermore, lymphatic vessels were found in the meninges to drain interstitial fluids. It is hypothesized that interstitial solutes, such as amyloid β, are firstly processed through the brain by the glymphatic system and secondly drained out of the brain by lymphatic vessels (glymphatic-lymphatic fluid transport system [GLS]). Since then, various neurological disorders, such as Alzheimer disease, have been associated with a dysfunction of the GLS. In the current study, we aimed to establish a clinical magnetic resonance imaging (MRI) study protocol for visualizing lymphatic vessels as part of the GLS in humans. More importantly, we aimed to describe the dynamic changes of a contrast agent in these lymphatic vessels over time., Materials and Methods: Twenty volunteers with an unremarkable neurological/psychiatric history were included in this 3T MRI study. Serial MRI sequence blocks were performed at 3 predefined time points (TPs): TP 1, precontrast MRI before administration of a gadolinium-based contrast agent (GBCA); TP 2, immediately post-GBCA (early ce-MRI); and TP 3, 60 minutes post-GBCA (late ce-MRI). Each MRI block contained the following sequences obtained in the same order: whole-brain 3D T1-MPRAGE, whole-brain 3D T2-FLAIR, focused 2D T2-FLAIR, and whole-brain 3D T1-SPACE. Signal intensity (SI) in compartments of the GLS adjacent to the superior sagittal sinus, gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) was calculated by manually placed regions of interest. The time course of the signal intensities was examined by generalized linear mixed models. The data were adjusted for age, cognitive function (Montreal-Cognitive-Assessment test), and sleep quality (Pittsburgh Sleep Quality Index questionnaire)., Results: The GLS was best visualized in the 2D T2-FLAIR and 3D T1-SPACE sequences, enabling further SI measurement. In precontrast (TP 1), the SI within the GLS was significantly higher than in CSF and significantly lower than in GM and WM. In post-GBCA, a significant increase (TP 2) and decrease (TP 3), respectively, of the GLS SI values were noted (86.3 ± 25.2% increase and subsequent decrease by 25.4 ± 9% in the 3D T1-SPACE sequence). The SI values of CSF, GM, and WM did not change significantly between the 3 TPs., Conclusions: A clinical MRI study protocol was established for the visualization of lymphatic vessels as an important part of the GLS and therefore the brain's clearing mechanism of interstitial solutes. Furthermore, dynamic changes in the GLS were described over time, possibly reflecting the clearing function of the GLS. This might constitute the basis for evaluating the GLS function in manifold neurological pathologies in the future., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Symptomatic and asymptomatic delayed non-ischemic cerebral enhancing (NICE) lesions in magnetic resonance imaging (MRI) have been reported as a rare complication after endovascular therapy (EVT) in recent years with incidence rates between 0.05% and 0.9% in most studies. Information on long-term clinical course and immunotherapies is scarce or has not been reported in detail in the literature. Objective: Aims of our study were to assess the incidence of NICE lesions in patients after cerebral EVT over a period of more than 12 years, describe clinical and EVT characteristics, and immunotherapies applied., Methods: A retrospective chart review of all patients treated by endovascular therapy for symptomatic or asymptomatic aneurysms at the University Hospital of Augsburg from May 1, 2008 to December 31, 2020 was performed. Patients were identified retrospectively and followed-up prospectively where appropriate. In addition, one case treated at another institution was included., Results: Five out of 746 patients, 0.67%, developed NICE lesions after EVT, all with non-ruptured aneurysms and all symptomatic upon detection of NICE lesions by MRI. In total, the disease course of 6 female patients is reported. Symptoms occurred after a mean time of 15 days (±13.42, SD) after EVT with headache (6/6 patients), focal neurological signs (6/6 patients), epileptic seizures (2/6 patients) and cognitive deficits (3/6 patients). All 6 patients received glucocorticosteroids (GCS), 1/6 azathioprine (AZA), 4/6 mycophenolate mofetil (MMF), 1/6 methotrexate (MTX), 1/6 rituximab (RTX), 2/6 cyclophosphamide (CYC) and 3/6 tocilizumab (TCZ). A treatment response could be observed for GCS, TCZ and MMF (in two of four cases), RTX and AZA did not result in disease stabilization., Conclusions: Delayed NICE lesions are a rare complication after EVT, requiring immunotherapies in all patients reported here. Physicians should be aware of this disorder in case of new symptoms or contrast enhancing lesions after EVT., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Antonios Bayas: received personal compensation from Merck Serono, Biogen, Novartis, TEVA, Roche, Sanofi/Genzyme and Celgene; he received grants for congress travel and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono and Celgene. None related to this manuscript. Ansgar Berlis: received within last three years proctor fees from Microvention and Stryker, lecture fees from Phenox, Penumbra, Stryker and CEC fee from Phenox. None related to this manuscript. Michael Ertl: received personal compensation from Bayer Healthcare, Daiichi-Sankyo and Boehringer Ingelheim; he received grants for congress travel and participation from Daiichi-Sankyo. None related to this manuscript. Christoph Maurer received an educational grant from Microvention and Stryker, none related to this manuscript. Monika Christ: no conflict of interests. Markus Naumann: no conflict of interests. Felix Joachimski: no conflict of interests. Mona Müller no conflict of interests. Julia Welzel: no conflict of interests. Lisa Ann Gerdes: no conflict of interests. Klaus Seelos: no conflict of interests., (© The Author(s), 2022.)

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Purpose: Crossing pathologies of the corticospinal tract (CST) are rare and often associated with genetic disorders. However, they can be present in healthy humans and lead to ipsilateral motor deficits when a lesion to motor areas occurs. Here, we review historical and current literature of CST crossing pathologies and present a rare case of asymmetric crossing of the CST., Methods: Description of the case and systematic review of the literature were based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed database was searched for peer-reviewed articles in English since 1950. All articles on ipsilateral stroke, uncrossed CST, and associated neurologic disorders were screened. Furthermore, a literature review between the years 1850 and 1980 including articles in other languages, books, opinions, and case studies was conducted., Results: Only a few descriptions of CST crossing pathologies exist in healthy humans, whereas they seem to be more common in genetic disorders such as horizontal gaze palsy with progressive scoliosis or congenital mirror movements. Our patient presented with aphasia and left-sided hemiparesis. Computed tomographic (CT) scan revealed a perfusion deficit in the left middle cerebral artery territory, which was confirmed by diffusion-weighted magnetic resonance imaging (MRI), so that thrombolysis was administered. Diffusion tensor imaging with fibre tracking revealed an asymmetric CST crossing., Conclusions: The knowledge of CST crossing pathologies is essential if a motor deficit occurs ipsilateral to the lesion side. An ipsilateral deficit should not lead to exclusion or delay of therapeutic options in patients with suspected stroke. Here, a combined evaluation of CT perfusion imaging and MRI diffusion imaging may be of advantage., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Clinical, neuroimaging, and genetic characterization of 3 patients with LINS1 -associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits., Methods: Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clinic. General and neurologic examination, expert dysmorphology examination, and 3T brain MRI were performed. Whole-exome sequencing was performed for the 3 affected brothers, followed by Sanger sequencing in all available family members., Results: The index patient and his 2 affected brothers presented a complex neurologic syndrome with similar features but marked intrafamilial phenotypical variability, including varying degrees of cognitive impairment, speech impairment, dystonia, abnormal eye movements, and dysmorphic features. All 3 affected brothers are homozygous for a novel, pathogenic frameshift mutation in LINS1 , c.1672_1679del, and p.Gly558Pro fs *22, whereas both parents and healthy siblings are heterozygous for the mutation. No major brain malformations were evident in 3T brain MRI of the affected brothers., Conclusion: This consanguineous family with a novel mutation expands the spectrum of LINS1 -associated disorder to include developmental regression, oculomotor signs, and dystonia, previously not described in the published 9 cases of this rare disorder. The 3T-MRI data from our 3 patients and review of the neuroimaging data in the literature showed unspecific brain MRI changes. LINS1 protein is a known modulating factor of the Wnt signaling pathway, with important roles in organogenesis including of the cerebral cortex. More research is warranted to disentangle the underlying pathophysiologic mechanisms, leading to cognitive impairment and the complex phenotype of LINS1 -associated disorder., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Human encephalitis can originate from a variety of different aetiologies, of which infection is the most common one. The diagnostic work-up is specifically challenging in patients with travel history since a broader spectrum of unfamiliar additional infectious agents, e. g. tropical disease pathogens, needs to be considered. Here we present a case of encephalitis of unclear aetiology in a female traveller returning from Africa, who in addition developed an atypical herpes simplex virus (HSV) encephalitis in close temporal relation with high-dose steroid treatment., Case Presentation: A previously healthy 48-year-old female presented with confusion syndrome and impaired vigilance which had developed during a six-day trip to The Gambia. The condition rapidly worsened to a comatose state. Extensive search for infectious agents including a variety of tropical disease pathogens was unsuccessful. As encephalitic signs persisted despite of calculated antimicrobial and antiviral therapy, high-dose corticosteroids were applied intravenously based on the working diagnosis of an autoimmune encephalitis. The treatment did, however, not improve the patient's condition. Four days later, bihemispheric signal amplification in the insular and frontobasal cortex was observed on magnetic resonance imaging (MRI). The intracranial pressure rapidly increased and could not be controlled by conservative treatment. The patient died due to tonsillar herniation 21 days after onset of symptoms. Histological examination of postmortem brain tissue demonstrated a generalized lymphocytic meningoencephalitis. Immunohistochemical reactions against HSV-1/2 indicated an atypical manifestation of herpesviral encephalitis in brain tissue. Moreover, HSV-1 DNA was detected by a next-generation sequencing (NGS) metagenomics approach. Retrospective analysis of cerebrospinal fluid (CSF) and serum samples revealed HSV-1 DNA only in specimens one day ante mortem., Conclusions: This case shows that standard high-dose steroid therapy can contribute to or possibly even trigger fulminant cerebral HSV reactivation in a critically ill patient. Thus, even if extensive laboratory diagnostics including wide-ranging search for infectious pathogens has been performed before and remained without results, continuous re-evaluation of potential differential diagnoses especially regarding opportunistic infections or reactivation of latent infections is of utmost importance, particularly if new symptoms occur.

Cerebrotendinous xanthomatosis (CTX, MIM 213700) is a rare autosomal recessive lipid storage disorder caused by CYP27A1 mutations. Treatment with chenodeoxycholic acid (CDCA) may slow the progression of the disease and reverse some symptoms in a proportion of patients. In a non-consanguineous Caucasian family, two siblings with CTX were evaluated before treatment and prospectively followed-up every 6 months after starting CDCA therapy, using systematic clinical examination, neuropsychological tests, laboratory tests, electroencephalography (EEG) and brain MRI, diffusion tensor imaging (DTI) and tractography. A 30-year-old patient and her 27-year-old brother were referred for progressive spastic paraparesis. Both had epilepsy, learning difficulties, chronic diarrhoea and juvenile-onset cataracts. CTX was diagnosed by increased cholestanol levels and compound heterozygosity for CYP27A1 mutations. Therapy with CDCA led to resolution of chronic diarrhoea, normalisation of serum cholestanol and EEG, and a progressive improvement in gait, cognition and seizure control. Before treatment, conventional brain MRI showed no CTX-related abnormalities for the proband and no cerebellar abnormalities for the brother, while DTI showed reduced fractional anisotropy (FA) and tract-density in the cerebellum and widespread cerebral reductions of FA in both patients, compared to a group of 35 healthy controls. Repeated DTI after starting therapy showed progressive increases of cerebellar tract density and of cerebral FA. In patients with CTX, therapy with CDCA may lead to significant clinical improvement, with normalisation of biochemical and electrophysiological biomarkers. DTI and tractography may detect changes when the conventional MRI is unremarkable and may provide potential neuroimaging biomarkers for monitoring treatment response in CTX, while the conventional MRI remains unchanged.

Background: Prognosis and treatment of cystic craniopharyngiomas are poorly defined., Objective: To analyze progression-free survival (PFS) and safety profile of cystic craniopharyngiomas undergoing resection or minimally invasive drainage procedures. We compared further outcome measurements for cystic and solid tumors undergoing resection to elucidate the impact of the initial tumor composition on both PFS and the toxicity profile., Methods: All patients with craniopharyngiomas consecutively treated between 1999 and 2014 were included. A treatment decision in favor of microsurgery or stereotactic treatment was made interdisciplinarily. For stereotactic drainage, a catheter was implanted, allowing both permanent upstream (into ventricular spaces) and downstream (into prepontine cistern) drainage. Study endpoints were tumor progression, functional outcome, and treatment toxicity. Functional endocrinological and visual outcome analyses referred to data obtained preoperatively and 6 weeks after treatment. The Kaplan-Meier method was used for survival analysis. Prognostic factors were obtained from proportional hazard models., Results: Seventy-nine patients were included. The distribution of clinical and tumor-related data was well balanced among patients with solid (n = 35) and cystic (n = 44) tumors and those undergoing microsurgical or stereotactic treatment. Cystic tumors had shorter PFS (5-year PFS: 53.6% vs 66.8%, P = .10) and needed significantly more therapeutic interventions, which was independent of the initial treatment mode. The endocrinological deterioration rate was high for both solid and cystic tumors after microsurgery (59.4% and 85.7%, respectively), whereas it was significantly lower for cystic tumors undergoing stereotactic treatment (23.1%, P < .001)., Conclusion: Stereotactic bidirectional drainage of cystic craniopharyngiomas is effective and provides a better endocrinological outcome than conventional microsurgery., (Copyright © 2017 by the Congress of Neurological Surgeons)