Long-term outcome in new onset refractory status epilepticus: a retrospective study.

BACKGROUND: New onset refractory status epilepticus (NORSE) is a neurologic emergency without an immediately identifiable cause. The complicated and long ICU stay of the patients can lead to perceiving a prolongation of therapies as futile. However, a recovery is possible even in severe cases. This retrospective study investigates ICU treatments, short- and long-term outcome and ethical decisions of a case series of patients with NORSE. METHODS: Overall, 283 adults were admitted with status epilepticus (SE) to the Neurocritical Care Unit of the University Hospital Zurich, Switzerland, between 01.2010 and 12.2022. Of them, 25 had a NORSE. We collected demographic, clinical, therapeutic and outcome data. Descriptive statistics was performed. RESULTS: Most patients were female (68%), previously healthy (Charlson comorbidity index 1 [0-4]) and relatively young (54 ± 17 years). 96% presented with super-refractory SE. Despite extensive workup, the majority (68%) of cases remained cryptogenic. Most patients had a long and complicated ICU stay. The in-hospital mortality was 36% (n = 9). The mortality at last available follow-up was 56% (n = 14) on average 30 months after ICU admission. The cause of in-hospital death for 89% (n = 8) of the patients was the withholding/withdrawing of therapies. Medical staff except for one patient triggered the decision. The end of life (EOL) decision was taken 29 [12-51] days after the ICU admission. Death occurred on day 6 [1-8.5] after the decision was taken. The functional outcome improved over time for 13/16 (81%) hospital survivors (median mRS at hospital discharge 4 [3.75-5] vs. median mRS at last available follow-up 2 [1.75-3], p < 0.001). CONCLUSIONS: Our data suggest that the long-term outcome can still be favorable in NORSE survivors, despite a prolonged and complicated ICU stay. Clinicians should be careful in taking EOL decisions to avoid the risk of a self-fulfilling prophecy. Our results encourage clinicians to continue treatment even in initially refractory cases.

Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis.

Background: Myelin oligodendrocyte glycoprotein antibody-associated autoimmune disease (MOGAD) is a rare monophasic or relapsing inflammatory demyelinating disease of the central nervous system (CNS) and can mimic multiple sclerosis (MS). The variable availability of live cell-based MOG-antibody assays and difficulties in interpreting low-positive antibody titers can complicate diagnosis. Literature on cerebrospinal fluid (CSF) profiles in MOGAD versus MS, one of the most common differential diagnoses, is scarce. We here analyzed the value of basic CSF parameters to i) distinguish different clinical MOGAD manifestations and ii) differentiate MOGAD from MS. Methods: This is retrospective, single-center analysis of clinical and laboratory data of 30 adult MOGAD patients and 189 adult patients with relapsing-remitting multiple sclerosis. Basic CSF parameters included CSF white cell count (WCC) and differentiation, CSF/serum albumin ratio (QAlb), intrathecal production of immunoglobulins, CSF-restricted oligoclonal bands (OCB) and MRZ reaction, defined as intrathecal production of IgG reactive against at least 2 of the 3 viruses measles (M), rubella (R) and varicella zoster virus (Z). Results: MOGAD patients with myelitis were more likely to have a pleocytosis, a QAlb elevation and a higher WCC than those with optic neuritis, and, after review and combined analysis of our and published cases, they also showed a higher frequency of intrathecal IgM synthesis. Compared to MS, MOGAD patients had significantly more frequently neutrophils in CSF and WCC>30/µl, QAlb>10×10-3, as well as higher mean QAlb values, but significantly less frequently CSF plasma cells and CSF-restricted OCB. A positive MRZ reaction was present in 35.4% of MS patients but absent in all MOGAD patients. Despite these associations, the only CSF parameters with relevant positive likelihood ratios (PLR) indicating MOGAD were QAlb>10×10-3 (PLR 12.60) and absence of CSF-restricted OCB (PLR 14.32), whereas the only relevant negative likelihood ratio (NLR) was absence of positive MRZ reaction (NLR 0.00). Conclusion: Basic CSF parameters vary considerably in different clinical phenotypes of MOGAD, but QAlb>10×10-3 and absence of CSF-restricted OCB are highly useful to differentiate MOGAD from MS. A positive MRZ reaction is confirmed as the strongest CSF rule-out parameter in MOGAD and could be useful to complement the recently proposed diagnostic criteria.

The role of neuronal antibodies in cryptogenic new onset refractory status epilepticus.

Most cases with new onset refractory status epilepticus (NORSE) remain cryptogenic despite extensive diagnostic workup. The aim of this study was to analyze the etiology and clinical features of NORSE and investigate known or potentially novel autoantibodies in cryptogenic NORSE (cNORSE). We retrospectively assessed the medical records of adults with status epilepticus at a Swiss tertiary referral center between 2010 and 2021. Demographic, diagnostic, therapeutic, and outcome parameters were characterized. We performed post hoc screening for known or potentially novel autoantibodies including immunohistochemistry (IHC) on rat brain with cerebrospinal fluid (CSF) and serum samples of cNORSE. Twenty patients with NORSE were identified. Etiologies included infections (n = 4), Creutzfeldt-Jakob disease (n = 1), CASPR2 autoimmune encephalitis (n = 1), and carotid artery stenosis with recurrent perfusion deficit (n = 1). Thirteen cases (65%) were cryptogenic despite detailed evaluation. A posteriori IHC for neuronal autoantibodies yielded negative results in all available serum (n = 11) and CSF (n = 9) samples of cNORSE. Our results suggest that neuronal antibodies are unlikely to play a major role in the pathogenesis of cNORSE. Future studies should rather focus on other-especially T-cell- and cytokine-mediated-mechanisms of autoinflammation in this devastating disease, which is far too poorly understood so far.

Functional NIRS to detect covert consciousness in neurocritical patients.

OBJECTIVE: This pilot study assesses the feasibility to detect covert consciousness in clinically unresponsive patients by means of functional near infrared spectroscopy (fNIRS) in a real intensive care unit setting. We aimed to verify if the hemodynamic response to familiar music measured with fNIRS varies according to the level consciousness of the patients. METHODS: 22 neurocritical patients and 6 healthy controls were included. The experiment consisted in 3 subsequent blocks including a first resting state recording, a period of music playback and a second resting state recording. fNIRS measurement were performed on each subject with two optodes on the forehead. Main oscillatory frequencies of oxyhemoglobin signal were analyzed. Spectral changes of low frequency oscillations (LFO) between subsequent experimental blocks were used as a marker of cortical response. Cortical response was compared to the level of consciousness of the patients and their functional outcome, through validated clinical scores. RESULTS: Cortical hemodynamic response to music on the left prefrontal brain was associated with the level of consciousness of the patients and with their clinical outcome after three months. CONCLUSIONS: Variations in LFO spectral power measured with fNIRS may be a new marker of cortical responsiveness to detect covert consciousness in neurocritical patients. Left prefrontal cortex may play an important role in the perception of familiar music. SIGNIFICANCE: We showed the feasibility of a simple fNIRS approach to detect cortical response in the real setting of an intensive care unit.

Plasma Inflammatory Markers and Ventriculostomy-Related Infection in Patients With Hemorrhagic Stroke: A Retrospective and Descriptive Study.

Background: Diagnosis of ventriculostomy-related infection (VRI) remains difficult due to the various existing definitions. In patients with hemorrhagic stroke, its diagnosis might be further complicated by the presence of intraventricular blood. Furthermore, hemorrhagic stroke per se may cause symptoms compatible with VRI. This study aimed to evaluate the benefit of plasma inflammatory markers for the diagnosis of VRI and its differentiation from patients with non-cerebral infection and patients without infection in a cohort of patients with hemorrhagic stroke. Methods: A total of 329 patients with hemorrhagic stroke and an external ventricular drain (EVD) in situ were admitted to the Neurocritical Care Unit, University Hospital Zurich over a period of 6 years. Of those patients, 187 with subarachnoid hemorrhage and 76 with spontaneous intracerebral hemorrhage were included. Patients with VRI were compared to patients without any infection and to patients with non-cerebral infection, with regards to their clinical characteristics, as well as their inflammatory plasma and cerebrospinal fluid (CSF) markers. For the analysis, peak values were considered. Results: The VRI was diagnosed in 36% of patients with subarachnoid and in 17% of patients with intracerebral hemorrhage. The VRI was diagnosed on an average day 9±6.2 after EVD insertion, one day after the white blood cell count (WBC) peaked in CSF (8 ± 6.3). Plasma inflammatory markers (WBC, C-reactive protein "CRP" and procalcitonin "PCT") did not differ among patients with VRI compared to patients without infection. The CRP and PCT, however, were higher in patients with non-cerebral infection than in patients with VRI. The WBC in CSF was generally higher in patients with VRI compared to both patients without any infection and patients with non-cerebral infection. Conclusions: No differences in plasma inflammatory markers could be found between patients with VRI and patients without any infection. Conversely, CRP/PCT were higher in patients with non-cerebral infection than in patients with VRI. Altogether, CRP, PCT, and WBC are not suitable parameters for VRI diagnosis in neurocritical care unit patients.

Venous thromboembolic events in glioblastoma patients: An epidemiological study.

BACKGROUND AND PURPOSE: Venous thromboembolic events (VTEs) are a major complication in cancer patients, and therefore, also in brain cancer patients, anticoagulants are considered appropriate in the treatment of VTEs. METHODS: Frequency, risk factors, and treatment of VTEs, as well as associated complications, were assessed in a population-based cohort of glioblastoma patients in the Canton of Zurich, Switzerland. Correlations between clinical data and survival were retrospectively analyzed using the log-rank test and Cox regression models. RESULTS: Four hundred fourteen glioblastoma patients with isocitrate dehydrogenase wild-type status were identified. VTEs were documented in 65 patients (15.7%). Median time from tumor diagnosis to the occurrence of a VTE was 1.8 months, and 27 patients were diagnosed with VTEs postoperatively (within 35 days; 42.2%). History of a prior VTE was more common in patients who developed VTEs than in those who did not (p = 0.004). Bevacizumab treatment at any time during the disease course was not associated with occurrence of VTEs (p = 0.593). Most patients with VTEs (n = 61, 93.8%) were treated with therapeutic anticoagulation. Complications occurred in 14 patients (23.0%), mainly intracranial hemorrhages (n = 7, 11.5%). Overall survival did not differ between patients diagnosed with VTEs and those who had no VTE (p = 0.139). Tumor progression was the major cause of death (n = 283, 90.7%), and only three patients (1.0%) died in association with acute VTEs. CONCLUSIONS: Venous thromboembolic events occurred early in the disease course, suggesting that the implementation of primary venous thromboembolism prophylaxis during first-line chemoradiotherapy could be explored in a randomized setting.

Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.

BACKGROUND: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far. OBJECTIVE: To analyze systematically the CSF profile in COVID-19. METHODS: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease. CONCLUSIONS: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19.

Magnetic Resonance Spectroscopy following Mild Traumatic Brain Injury: A Systematic Review and Meta-Analysis on the Potential to Detect Posttraumatic Neurodegeneration.

INTRODUCTION: Traumatic brain injury (TBI) is the most relevant external risk factor for dementia and a major global health burden. Mild TBI (mTBI) contributes to up to 90% of all TBIs, and the classification "mild" often misrepresents the patient's burden who suffer from neuropsychiatric long-term sequelae. Magnetic resonance spectroscopy (MRS) allows in vivo detection of compromised brain metabolism although it is not routinely used after TBI. OBJECTIVE: Thus, we performed a systematic review and meta-analysis to elucidate if MRS has the potential to identify changes in brain metabolism in adult patients after a single mTBI with a negative routine brain scan (CCT and/or MRI scan) compared to aged- and sex-matched healthy controls (HC) during the acute or subacute postinjury phase (≤90 days after mTBI). METHODS: A comprehensive literature search was conducted from the first edition of electronic databases until January 31, 2020. Group analyses were performed per metabolite using a random-effects model. RESULTS: Four and 2 out of 5,417 articles met the inclusion criteria for the meta-analysis and systematic review, respectively. For the meta-analysis, 50 mTBI patients and 51 HC with a mean age of 31 and 30 years, respectively, were scanned using N-acetyl-aspartate (NAA), a marker for neuronal integrity. Glutamate (Glu), a marker for disturbed brain metabolism, choline (Cho), a marker for increased cell membrane turnover, and creatine (Cr) were used in 2 out of the 4 included articles. Regions of interests were the frontal lobe, the white matter around 1 cm above the lateral ventricles, or the whole brain. NAA was decreased in patients compared to HC with an effect size (ES) of -0.49 (95% CI -1.08 to 0.09), primarily measured in the frontal lobe. Glu was increased in the white matter in 22 mTBI patients compared to 22 HC (ES 0.79; 95% CI 0.17-1.41). Cho was decreased in 31 mTBI patients compared to 31 HC (ES -0.31; 95% CI -0.81 to 0.19). Cr was contradictory and, therefore, potentially not suitable as a reference marker after mTBI. CONCLUSIONS: MRS pinpoints changes in posttraumatic brain metabolism that correlate with cognitive dysfunction and, thus, might possibly help to detect mTBI patients at risk for unfavorable outcome or posttraumatic neurodegeneration early.

Internet Cognitive Behavioral Therapy With or Without Face-to-Face Psychotherapy: A 12-Weeks Clinical Trial of Patients With Depression.

Depressive disorders are a curable, global health problem. However, most patients remain untreated, and more and more patients use internet-based interventions, but it is unclear whether it is beneficial for ongoing face-to-face psychotherapy. Thus, we compared the outcome of internet cognitive behavioral therapy (ICBT) with (ICBT+) or without (ICBT) additional face-to-face outpatient psychotherapy in adult patients with moderate to severe depressive disorder. For this longitudinal interventional clinical trial (NCT02112266), 168 of 252 online recruited adults with depressive symptoms received ICBT+ (n = 96) or ICBT (n = 72). Demographics (sex, age, age at first depressive episode, years of education, duration of depressive symptoms) were assessed and compared between groups. All patients underwent ICBT for 12 weeks. Quality of life (QoL) and severity of depressive symptoms were assessed within each group at three time points [baseline (T0), postinterventional after ICBT at 12 weeks (T1), and for follow-up at 6 months (T2)] using the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) global score to assess QoL as primary and the Beck Depression Inventory (BDI-II) to assess self-rated depressive symptoms as secondary outcome variables, respectively. Differences were assessed between groups using t test and over time using repeated-measures analysis of variance. Data of intention-to-treat analysis are given as mean ± SD. Group differences were assumed at p < 0.05. Partial η2 is given as effect size. Demographic data, QoL, and depressive symptoms did not differ between groups (ICBT+/ICBT) at baseline (T0). Patients of both groups suffered from moderate to severe depressive disorders and gained improved QoL scores (WHOQOL-BREF-global: p < 0.001, η2 = 0.16), as well as experienced decreased depressive symptoms (BDI-II: p < 0.001, η2 = 0.2) after 12 weeks of ICBT compared to baseline. Patients without additional face-to-face outpatient psychotherapy lost QoL-albeit not significant-and had increased depressive symptoms (BDI: p = 0.02, η2 = 0.04) at 6 months' follow-up. Thus, ICBT is suitable for psychiatric treatment, although additional face-to-face outpatient psychotherapy helps stabilizing long-term outcome.