Cerebral Intraparenchymal Hemorrhage due to Implantation of Electrodes for Deep Brain Stimulation: Insights from a Large Single-Center Retrospective Cross-Sectional Analysis.

Cerebral intraparenchymal hemorrhage due to electrode implantation (CIPHEI) is a rare but serious complication of deep brain stimulation (DBS) surgery. This study retrospectively investigated a large single-center cohort of DBS implantations to calculate the frequency of CIPHEI and identify patient- and procedure-related risk factors for CIPHEI and their potential interactions. We analyzed all DBS implantations between January 2013 and December 2021 in a generalized linear model for binomial responses using bias reduction to account for sparse sampling of CIPHEIs. As potential risk factors, we considered age, gender, history of arterial hypertension, level of invasivity, types of micro/macroelectrodes, and implanted DBS electrodes. If available, postoperative coagulation and platelet function were exploratorily assessed in CIPHEI patients. We identified 17 CIPHEI cases across 839 electrode implantations in 435 included procedures in 418 patients (3.9%). Exploration and cross-validation analyses revealed that the three-way interaction of older age (above 60 years), high invasivity (i.e., use of combined micro/macroelectrodes), and implantation of directional DBS electrodes accounted for 82.4% of the CIPHEI cases. Acquired platelet dysfunction was present only in one CIPHEI case. The findings at our center suggested implantation of directional DBS electrodes as a new potential risk factor, while known risks of older age and high invasivity were confirmed. However, CIPHEI risk is not driven by the three factors alone but by their combined presence. The contributions of the three factors to CIPHEI are hence not independent, suggesting that potentially modifiable procedural risks should be carefully evaluated when planning DBS surgery in patients at risk.

Submillimeter T1 atlas for subject-specific abnormality detection at 7T.

PURPOSE: Studies at 3T have shown that T1 relaxometry enables characterization of brain tissues at the single-subject level by comparing individual physical properties to a normative atlas. In this work, an atlas of normative T1 values at 7T is introduced with 0.6 mm isotropic resolution and its clinical potential is explored in comparison to 3T. METHODS: T1 maps were acquired in two separate healthy cohorts scanned at 3T and 7T. Using transfer learning, a template-based brain segmentation algorithm was adapted to ultra-high field imaging data. After segmenting brain tissues, volumes were normalized into a common space, and an atlas of normative T1 values was established by modeling the T1 inter-subject variability. A method for single-subject comparisons restricted to white matter and subcortical structures was developed by computing Z-scores. The comparison was applied to eight patients scanned at both field strengths for proof of concept. RESULTS: The proposed method for morphometry delivered segmentation masks without statistically significant differences from those derived with the original pipeline at 3T and achieved accurate segmentation at 7T. The established normative atlas allowed characterizing tissue alterations in single-subject comparisons at 7T, and showed greater anatomical details compared with 3T results. CONCLUSION: A high-resolution quantitative atlas with an adapted pipeline was introduced and validated. Several case studies on different clinical conditions showed the feasibility, potential and limitations of high-resolution single-subject comparisons based on quantitative MRI atlases. This method in conjunction with 7T higher resolution broadens the range of potential applications of quantitative MRI in clinical practice.

Adult-Onset Alexander Disease: New Causal Sequence Variant in the GFAP Gene.

Objectives: Alexander disease (AD) is a rare disorder of the CNS. Diagnosis is based on clinical symptoms, typical MRI findings, and mutations in the glial fibrillary acid protein (GFAP) gene. In this case study, we describe a new mutation (p.L58P) in GFAP that caused a phenotype of adult-onset AD (AOAD). Methods: In our outpatient clinic, a patient presented with cerebellar and bulbar symptoms after brain concussion. We used MRI and performed next-generation exome sequencing (NGS) to find mutations in GFAP to diagnose AD. The mutation was then transfected into HeLa cell lines to prove its pathogenicity. Results: The brain MRI finding showed typical AD alterations. The NGS found a heterozygous variant of unknown significance in GFAP (c.173T>C; p.L58P). After transfecting HeLa cell lines with this mutation, we showed that GFAP-L58P formed pathogenic clusters of cytoplasmic aggregates. Discussion: We have found a new mutation that causes AOAD. We recommend that AOAD is included in the diagnostic workup in adult patients with gait ataxia and cerebellar and bulbar symptoms in association with a traumatic head injury.

Comparative analysis of machine learning algorithms for multi-syndrome classification of neurodegenerative syndromes.

IMPORTANCE: The entry of artificial intelligence into medicine is pending. Several methods have been used for the predictions of structured neuroimaging data, yet nobody compared them in this context. OBJECTIVE: Multi-class prediction is key for building computational aid systems for differential diagnosis. We compared support vector machine, random forest, gradient boosting, and deep feed-forward neural networks for the classification of different neurodegenerative syndromes based on structural magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: Atlas-based volumetry was performed on multi-centric T1-weighted MRI data from 940 subjects, i.e., 124 healthy controls and 816 patients with ten different neurodegenerative diseases, leading to a multi-diagnostic multi-class classification task with eleven different classes. INTERVENTIONS: N.A. MAIN OUTCOMES AND MEASURES: Cohen's kappa, accuracy, and F1-score to assess model performance. RESULTS: Overall, the neural network produced both the best performance measures and the most robust results. The smaller classes however were better classified by either the ensemble learning methods or the support vector machine, while performance measures for small classes were comparatively low, as expected. Diseases with regionally specific and pronounced atrophy patterns were generally better classified than diseases with widespread and rather weak atrophy. CONCLUSIONS AND RELEVANCE: Our study furthermore underlines the necessity of larger data sets but also calls for a careful consideration of different machine learning methods that can handle the type of data and the classification task best.

Electrode placement for SEEG: Combining stereotactic technique with latest generation planning software for intraoperative visualization and postoperative evaluation of accuracy and accuracy predictors.

BACKGROUND: Intracranial recordings with stereoelectroencephalography (SEEG) aims at defining the epileptogenic zone in patients with pharmacoresistant epilepsy. Currently used techniques for depth electrode implantation include stereotactic frame-based and navigated frameless applications, both either conventional or robot-assisted. Safety and diagnostic effectiveness depend on accuracy of implantation. OBJECTIVE: To evaluate the planning experience, accuracy of stereotactic electrode placement as well as accuracy predictors with the use of latest generation planning software. METHODS: Retrospective study of 15 consecutive patients who received depth electrodes using the Leksell stereotactic frame, after planning with Elements (Brainlab, Munich, Germany). For each electrode, we calculated the entry point error (EPE) as lateral deviation and target point error (TPE) both as lateral deviation and distance to tip. Multivariate regression analysis and computation of 95% confidence intervals using the bootstrap method were applied for statistical analysis and evaluation of accuracy predictors. RESULTS: The mean EPE, lateral deviation at TP and distance to tip at TP were 0.6 ±0.5 mm, 1.1 ±0.7 mm and 1.5 ±0.8 mm respectively. Order of implantation (1-6 vs. >6) is predictor for distance to tip at TP and length of electrode predictor for the lateral deviation at TP. Localization of electrode generally did not correlate to error, but insular electrodes were significantly less accurate than lobar ones. CONCLUSION: Combination of frame-based stereotaxy with latest generation planning software may offer a better planning and implantation experience. Accuracy predictors should be analyzed and be considered for the improvement of accuracy and safety of SEEG implantation methods.

Diffusion tensor imaging in unclear intramedullary tumor-suspected lesions allows separating tumors from inflammation.

DESIGN: Prospective diagnostic study. OBJECTIVES: Primary imaging-based diagnosis of spinal cord tumor-suspected lesions is often challenging. The identification of the definite entity is crucial for dedicated treatment and therefore reduction of morbidity. The aim of this trial was to investigate specific quantitative signal patterns to differentiate unclear intramedullary tumor-suspected lesions based on diffusion tensor imaging (DTI). SETTING: Medical Center - University of Freiburg, Germany. METHODS: Forty patients with an unclear tumor-suspected lesion of the spinal cord prospectively underwent DTI. Primary diagnosis was determined by histological or clinical work-up or remained indeterminate with follow-up. DTI metrics (FA/ADC) were evaluated at the central lesion area, lesion margin, edema, and normal spinal cord and compared between different diagnostic groups (ependymomas, other spinal cord tumors, inflammations). RESULTS: Mean DTI metrics for all spinal cord tumors (n = 18) showed significantly reduced FA and increased ADC values compared to inflammatory lesions (n = 8) at the lesion margin (p < 0.001, p = 0.001) and reduced FA at the central lesion area (p < 0.001). There were no significant differences comparing the neoplastic subgroups of ependymomas (n = 10) and other spinal cord tumors (n = 8), but remaining differences for both compared to the inflammation subgroup. We found significant higher ADC (p = 0.040) and a trend to decreased FA (p = 0.081) for ependymomas compared to inflammations at the edema. CONCLUSION: Even if distinct differentiation of ependymomas from other spinal cord neoplasms was not possible based on quantitative DTI metrics, FA and ADC were feasible to separate inflammatory lesions. This may avoid unnecessary surgery in patients with unclear intramedullary tumor-suspected lesions.

3D X-ray based visualization of directional deep brain stimulation lead orientation.

Knowing the orientation of directional deep brain stimulation electrodes enables imaging-based adjustment of the stimulation settings. A rotational X-ray based examination was developed to determine the electrodes orientation. By identifying the patient´s 0° axis and the electrode´s rotation using the "iron sights"-sign, the exact orientation of the electrode in relation to the ACPC-line is given. The presented imaging approach offers a reliable diagnostic tool for visualization of the implanted DBS electrode orientation in clinical routine.

Hippocampus-Avoidance Whole-Brain Radiation Therapy Is Efficient in the Long-Term Preservation of Hippocampal Volume.

BACKGROUND AND PURPOSE: With improved life expectancy, preventing neurocognitive decline after cerebral radiotherapy is gaining more importance. Hippocampal damage has been considered the main culprit for cognitive deficits following conventional whole-brain radiation therapy (WBRT). Here, we aimed to determine to which extent hippocampus-avoidance WBRT (HA-WBRT) can prevent hippocampal atrophy compared to conventional WBRT. METHODS AND MATERIALS: Thirty-five HA-WBRT and 48 WBRT patients were retrospectively selected, comprising a total of 544 contrast-enhanced T1-weighted magnetic resonance imaging studies, longitudinally acquired within 24 months before and 48 months after radiotherapy. HA-WBRT patients were treated analogously to the ongoing HIPPORAD-trial (DRKS00004598) protocol with 30 Gy in 12 fractions and dose to 98% of the hippocampus ≤ 9 Gy and to 2% ≤ 17 Gy. WBRT was mainly performed with 35 Gy in 14 fractions or 30 Gy in 10 fractions. Anatomical images were segmented and the hippocampal volume was quantified using the Computational Anatomy Toolbox (CAT), including neuroradiological expert review of the segmentations. RESULTS: After statistically controlling for confounding variables such as age, gender, and total intracranial volume, hippocampal atrophy was found after both WBRT and HA-WBRT (p < 10-6). However, hippocampal decline across time following HA-WBRT was approximately three times lower than following conventional WBRT (p < 10-6), with an average atrophy of 3.1% versus 8.5% in the first 2 years after radiation therapy, respectively. CONCLUSION: HA-WBRT is a therapeutic option for patients with multiple brain metastases, which can effectively and durably minimize hippocampal atrophy compared to conventional WBRT.

Spinal Cord Motion in Degenerative Cervical Myelopathy: The Level of the Stenotic Segment and Gender Cause Altered Pathodynamics.

In degenerative cervical myelopathy (DCM), focally increased spinal cord motion has been observed for C5/C6, but whether stenoses at other cervical segments lead to similar pathodynamics and how severity of stenosis, age, and gender affect them is still unclear. We report a prospective matched-pair controlled trial on 65 DCM patients. A high-resolution 3D T2 sampling perfection with application-optimized contrasts using different flip angle evolution (SPACE) and a phase-contrast magnetic resonance imaging (MRI) sequence were performed and automatically segmented. Anatomical and spinal cord motion data were assessed per segment from C2/C3 to C7/T1. Spinal cord motion was focally increased at a level of stenosis among patients with stenosis at C4/C5 (n = 14), C5/C6 (n = 33), and C6/C7 (n = 10) (p < 0.033). Patients with stenosis at C2/C3 (n = 2) and C3/C4 (n = 6) presented a similar pattern, not reaching significance. Gender was a significant predictor of higher spinal cord dynamics among men with stenosis at C5/C6 (p = 0.048) and C6/C7 (p = 0.033). Age and severity of stenosis did not relate to spinal cord motion. Thus, the data demonstrates focally increased spinal cord motion depending on the specific level of stenosis. Gender-related effects lead to dynamic alterations among men with stenosis at C5/C6 and C6/C7. The missing relation of motion to severity of stenosis underlines a possible additive diagnostic value of spinal cord motion analysis in DCM.

[Interdisciplinary networking for optimal treatment decision-making : Fast decision-making in acute ischemic stroke management]. / Mittels interdisziplinärer Vernetzung zur optimalen Therapieentscheidung : Der schnelle Weg zur Therapieentscheidung beim akuten Schlaganfall.

Every year, about 270,000 strokes occur in Germany. In the entire DACH region (Germany, Austria, Switzerland), more than 310,000 cases are reported each year. Two thirds of the surviving patients are dependent on external assistance after the stroke. Increasingly, imaging data are becoming the focus of treatment decisions. These data provide critical information about the location and extent of vessel occlusion, infarct size, volume of salvageable brain tissue, and degree of collateralization. Certified stroke units and stroke networks already specialize in state-of-the-art therapeutic options, but they need additional information technology tools to deliver the right therapy to the right patient population as quickly as possible. For multidisciplinary, seamless support in stroke care, both prehospital and in-hospital processes need to be optimized. This article presents a concept for supraregional stroke care by means of networking all involved actors in the prehospital as well as in the in-hospital area. Further needs analyses should ensure the implementation as well as the generalizability to different regions.

The extreme capsule and aphasia: proof-of-concept of a new way relating structure to neurological symptoms.

We present anatomy-based symptom-lesion mapping to assess the association between lesions of tracts in the extreme capsule and aphasia. The study cohort consisted of 123 patients with acute left-hemispheric stroke without a lesion of language-related cortical areas of the Stanford atlas of functional regions of interest. On templates generated through global fibre tractography, lesions of the extreme capsule and of the arcuate fascicle were quantified and correlated with the occurrence of aphasia (n = 18) as defined by the Token Test. More than 15% damage of the slice plane through the extreme capsule was a strong independent predictor of aphasia in stroke patients, odds ratio 16.37, 95% confidence interval: 3.11-86.16, P < 0.01. In contrast, stroke lesions of >15% in the arcuate fascicle were not associated with aphasia. Our results support the relevance of a ventral pathway in the language network running through the extreme capsule.

The ventral pathway of the human brain: A continuous association tract system.

The brain hemispheres can be divided into an upper dorsal and a lower ventral system. Each system consists of distinct cortical regions connected via long association tracts. The tracts cross the central sulcus or the limen insulae to connect the frontal lobe with the posterior brain. The dorsal stream is associated with sensorimotor mapping. The ventral stream serves structural analysis and semantics in different domains, as visual, acoustic or space processing. How does the prefrontal cortex, regarded as the platform for the highest level of integration, incorporate information from these different domains? In the current view, the ventral pathway consists of several separate tracts, related to different modalities. Originally the assumption was that the ventral path is a continuum, covering all modalities. The latter would imply a very different anatomical basis for cognitive and clinical models of processing. To further define the ventral connections, we used cutting-edge in vivo global tractography on high-resolution diffusion tensor imaging (DTI) data from 100 normal subjects from the human connectome project and ex vivo preparation of fiber bundles in the extreme capsule of 8 humans using the Klingler technique. Our data showed that ventral stream tracts, traversing through the extreme capsule, form a continuous band of fibers that fan out anteriorly to the prefrontal cortex, and posteriorly to temporal, occipital and parietal cortical regions. Introduction of additional volumes of interest in temporal and occipital lobes differentiated between the inferior fronto-occipital fascicle (IFOF) and uncinate fascicle (UF). Unequivocally, in both experiments, in all subjects a connection between the inferior frontal and middle-to-posterior temporal cortical region, otherwise known as the temporo-frontal extreme capsule fascicle (ECF) from nonhuman primate brain-tracing experiments was identified. In the human brain, this tract connects the language domains of "Broca's area" and "Wernicke's area". The differentiation in the three tracts, IFOF, UF and ECF seems arbitrary, all three pass through the extreme capsule. Our data show that the ventral pathway represents a continuum. The three tracts merge seamlessly and streamlines showed considerable overlap in their anterior and posterior course. Terminal maps identified prefrontal cortex in the frontal lobe and association cortex in temporal, occipital and parietal lobes as streamline endings. This anatomical substrate potentially facilitates the prefrontal cortex to integrate information across different domains and modalities.

The final diagnoses of patients with clinically suspected atypical parkinsonian syndromes.

We report on 189 patients who were evaluated for APS. Final diagnoses included 77 cases of PSP, 32 patients with MSA and 11 patients with CBS. 35 patients were diagnosed or confirmed with iPD, while in 26 cases a differentiation between iPD and APS could not be definitely made.

Interaction between cognitive reserve and age moderates effect of lesion load on stroke outcome.

The concepts of brain reserve and cognitive reserve were recently suggested as valuable predictors of stroke outcome. To test this hypothesis, we used age, years of education and lesion size as clinically feasible coarse proxies of brain reserve, cognitive reserve, and the extent of stroke pathology correspondingly. Linear and logistic regression models were used to predict cognitive outcome (Montreal Cognitive Assessment) and stroke-induced impairment and disability (NIH Stroke Scale; modified Rankin Score) in a sample of 104 chronic stroke patients carefully controlled for potential confounds. Results revealed 46% of explained variance for cognitive outcome (p < 0.001) and yielded a significant three-way interaction: Larger lesions did not lead to cognitive impairment in younger patients with higher education, but did so in younger patients with lower education. Conversely, even small lesions led to poor cognitive outcome in older patients with lower education, but didn't in older patients with higher education. We observed comparable three-way interactions for clinical scores of stroke-induced impairment and disability both in the acute and chronic stroke phase. In line with the hypothesis, years of education conjointly with age moderated effects of lesion on stroke outcome. This non-additive effect of cognitive reserve suggests its post-stroke protective impact on stroke outcome.

Focal cervical spinal stenosis causes mechanical strain on the entire cervical spinal cord tissue - A prospective controlled, matched-pair analysis based on phase-contrast MRI.

BACKGROUND: Focally increased spinal cord motion at the level of cervical spinal stenosis has been revealed by phase-contrast MRI (PC-MRI). OBJECTIVE: To investigate spinal cord motion among patients suffering of degenerative cervical myelopathy (DCM) across the entire cervical spine applying automated segmentation and standardized PC-MRI post-processing protocols. METHODS: Prospective, matched-pair controlled trial on 29 patients with stenosis at C5/C6. MRI-protocol covering all cervical segments: 3D T2-SPACE, prospectively ECG-triggered sagittal PC-MRI. Segmentation by trained 3D hierarchical deep convolutional neural network and data processing were conducted via in-house software pipeline. Parameters per segment: maximum velocity, peak-to-peak (PTP)-amplitude, total displacement, PTP-amplitudeHB (PTP-amplitude per duration of heartbeat), and, for characterization of intraindividual alterations, the PTP-amplitude index between the cervical segments C3/C4-C7/T1 and C2/C3. RESULTS: Spinal cord motion was increased at C4/C5, C5/C6 and C6/C7 among patients (all parameters, p < 0.001-0.025). The PTP-amplitude index revealed an increase from C3/C4 to C4/C5 (p = 0.002), C4/C5 to C5/C6 (p = 0.037) and a decrease from C5/C6 to C6/C7 and C6/C7 to C7/T1 (p < 0.001, each). This implied an up-building stretch on spinal cord tissue cranial and a mechanical compression caudal of the stenotic level. Furthermore, significant far range effects across the entire cervical spinal cord were observed (e.g. PTP-amplitude C2/C3 vs. C6/C7, p = 0.026) in contrast to controls (p = 1.00). CONCLUSION: This study revealed the nature and extends of mechanical stress on the entire cervical spinal cord tissue due to focal stenosis. These pathophysiological alterations of spinal cord motion can be expected to be clinically relevant.

SVM-Based Normal Pressure Hydrocephalus Detection.

BACKGROUND AND PURPOSE: As magnetic resonance imaging (MRI) signs of normal pressure hydrocephalus (NPH) may precede clinical symptoms we sought to evaluate an algorithm that automatically detects this pattern. METHODS: A support vector machine (SVM) was trained in 30 NPH patients treated with ventriculoperitoneal shunts and 30 healthy controls. For comparison, four neuroradiologists visually assessed sagittal MPRAGE images and graded them as no NPH pattern, possible NPH pattern, or definite NPH pattern. RESULTS: Human accuracy to visually detect a NPH was between 0.85 and 0.97. Interobserver agreement was substantial (κ = 0.656). Accuracy of the SVM algorithm was 0.93 and AUROC 0.99. Among 272 prespecified regions, gray matter and CSF volumes of both caudate, the right parietal operculum, the left basal forebrain, and the 4th ventricle showed the highest discriminative power to separate a NPH and a no NPH pattern. CONCLUSION: A NPH pattern can be reliably detected using a support vector machine (SVM). Its role in the work-up of asymptomatic patients or neurodegenerative disease has to be evaluated.

The rostro-caudal gradient in the prefrontal cortex and its modulation by subthalamic deep brain stimulation in Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) alleviates motor symptoms in Parkinson's disease (PD) but also affects the prefrontal cortex (PFC), potentially leading to cognitive side effects. The present study tested alterations within the rostro-caudal hierarchy of neural processing in the PFC induced by STN-DBS in PD. Granger-causality analyses of fast functional near-infrared spectroscopy (fNIRS) measurements were used to infer directed functional connectivity from intrinsic PFC activity in 24 PD patients treated with STN-DBS. Functional connectivity was assessed ON stimulation, in steady-state OFF stimulation and immediately after the stimulator was switched ON again. Results revealed that STN-DBS significantly enhanced the rostro-caudal hierarchical organization of the PFC in patients who had undergone implantation early in the course of the disease, whereas it attenuated the rostro-caudal hierarchy in late-implanted patients. Most crucially, this systematic network effect of STN-DBS was reproducible in the second ON stimulation measurement. Supplemental analyses demonstrated the significance of prefrontal networks for cognitive functions in patients and matched healthy controls. These findings show that the modulation of prefrontal functional networks by STN-DBS is dependent on the disease duration before DBS implantation and suggest a neurophysiological mechanism underlying the side effects on prefrontally-guided cognitive functions observed under STN-DBS.

Probable Autoimmune Depression in a Patient With Multiple Sclerosis and Antineuronal Antibodies.

BACKGROUND: In a subgroup of patients with mood disorders, clear-cut organic disorders are responsible for depressive symptoms (e.g., autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus). In these cases, an organic affective disorder can be diagnosed. CASE PRESENTATION: The authors present the case of a 59-year-old male patient who developed a severe depressive episode over approximately 6 months and was, therefore, admitted to the hospital. In retrospect, he reported that, at age 39, he suffered from self-limiting sensory disturbances and muscle weakness in both legs. The current magnetic resonance imaging of his brain showed several conspicuous FLAIR-hyperintense supratentorial white matter lesions compatible with chronic inflammatory brain disease. Imaging of the spinal axis revealed no clear spinal lesions. Cerebrospinal fluid (CSF) analyses showed CSF-specific oligoclonal bands. Therefore, multiple sclerosis was diagnosed. Further CSF analyses, using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue, revealed a (peri-)nuclear signal and a strong neuritic signal of many neurons, especially on granule cells in the cerebellum, hippocampus, and olfactory bulb, as well as in the corpus callosum. Additionally, antinuclear antibody (ANA) titers of 1:12,800 and a lymphopenia were detected in blood tests. Further system clarification showed no suspicion of rheumatic or oncological disease. Anti-inflammatory treatment led to rapid and sustained improvement. CONCLUSION: The present patient suffered from a probable "autoimmune depression" in the context of newly diagnosed multiple sclerosis with typical MRI and CSF pathologies, alongside mild concomitant latent systemic autoimmune process (with high-titer ANAs and lymphopenia) and unknown antineuronal antibodies. The case report illustrates that a depressive syndrome suggestive of primary idiopathic depressive disorder may be associated with an autoimmune brain involvement. The detection of such organic affective disorders is of high clinical relevance for affected patients, as it enables alternative and more causal treatment approaches.

Novel Antineuronal Autoantibodies With Somatodendritic Staining Pattern in a Patient With Autoimmune Psychosis.

BACKGROUND: Autoimmune encephalitis, such as anti-NMDA-receptor encephalitis, typically presenting with subacute onset of neuropsychiatric symptoms, can be detected by antineuronal autoantibodies or inflammatory changes in the cerebrospinal fluid (CSF), as well as pathological alterations in electroencephalography (EEG), magnetic resonance imaging (MRI), or [18F]fluorodeoxyglucose positron emission tomography (FDG PET). For patients with predominant psychotic symptoms, the term autoimmune psychosis was proposed. Here, the authors present the case of a patient with probable autoimmune psychosis associated with unknown antineuronal antibodies. CASE PRESENTATION: A 18-year-old male patient with preexisting autism spectrum disorder developed a severe catatonic syndrome over 2.5 years. The MRI showed normal findings, the EEG depicted intermittent slowing, and the independent component analyses showed additional sharp spikes. However, FDG PET, the basic laboratory analysis and testing of the serum/CSF for well-characterized antineuronal autoantibodies were unsuspicious. The serum and CSF "tissue-based assay" using indirect immunofluorescence on unfixed murine brain tissue revealed antineuronal autoantibodies against an unknown epitope in granule cells in the cerebellum and to neurites of hippocampal interneurons with a somatodendritic staining pattern. The immunosuppressive treatment with high-dose glucocorticoids, plasma exchange, and rituximab led to partial improvement. CONCLUSION: The patient probably suffered from autoantibody-associated autoimmune psychosis. The special features of the case were that the patient (1) presented with mostly inconspicuous basic diagnostics, except for the altered EEG in combination with the detection of CSF autoantibodies directed against a currently unknown epitope, (2) experienced an isolated and long-lasting psychotic course, and (3) had pre-existing autism spectrum disorder. The detection of a probable autoimmune pathophysiology in such cases seems important, as it offers new and more causal immunosuppressive treatment alternatives.

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) - a phase II prospective randomized multicenter trial (NOA-14, ARO 2015-3, DKTK-ROG).

BACKGROUND: Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB). METHODS: This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter. DISCUSSION: This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases. TRIAL REGISTRATION: The HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).