Long-term sequelae after viral meningitis and meningoencephalitis are frequent, even in mildly affected patients, a prospective observational study.

Introduction: An increasing number of studies demonstrate that viral meningitis and meningoencephalitis, even those with a mild course of meningitis, can result in residual sequelae. Methods: We aimed to investigate the long-term outcome in both viral meningitis and meningoencephalitis/encephalitis patients and impact of long-term sequelae on patients' social and professional daily lives in a prospective observational study with a follow-up period of 20 months. Results: A total of 50 patients (12% encephalitis, 58% meningoencephalitis and 30% meningitis) and 21 control persons participated in the study. The most common cause was the tick-borne encephalitis (TBE) virus. The most important persistent signs and symptoms after 2 years were subjective cognitive impairment (36%), fatigue and/or excessive daytime sleepiness (31%), disturbed nighttime sleep (31%) and headaches (13%), as well as feeling more rapidly exhausted after cognitive effort (53%). Independent of disease severity in the acute phase, almost one third of patients still reported mildly impaired social and/or professional life due to the long-term sequelae, with scores in the health status assessment still significantly lower compared to healthy controls. Discussion: Regardless of the severity of the acute illness and despite constant improvement within 2 years, 67% of patients still had persistent signs and symptoms, but these were only relevant to everyday social or professional life in about 30% of these patients.

Magnetic resonance imaging in acute meningoencephalitis of viral and unknown origin: frequent findings and prognostic potential.

Background: Magnetic resonance imaging (MRI) findings in meningoencephalitis have mainly been described in terms of their diagnostic value rather than their prognostic potential, except for herpes simplex virus (HSV) encephalitis. The aims of our study were to describe frequency and anatomic locations of MRI abnormalities specific to limbic, circadian and motor systems in a cohort of meningoencephalitis patients, as well as to investigate the prognostic value of these MRI findings. Methods: A secondary, selective analysis of a retrospective database including all meningitis, meningoencephalitis and encephalitis cases treated between 2016 and 2018 in the University hospital of Bern, Switzerland was performed. Patients with meningitis of any cause, bacterial or autoimmune causes of encephalitis were excluded. Results: MRI scans and clinical data from 129 meningoencephalitis cases found that the most frequent causes were tick-borne encephalitis (TBE, 42%), unknown pathogens (40%), VZV (7%), and HSV1 (5%). At discharge, median modified Rankin Score (mRS) was 3 (interquartile range, IQR, 1), 88% of patients had persisting signs and symptoms. After a median of 17 months, median Glasgow Outcome Score (GOS) was 5 (IQR 1), 39% of patients still had residual signs or symptoms. All patients with HSV, 27% with TBE and 31% of those with meningoencephalitis of unknown etiology had fluid-attenuated inversion recovery (FLAIR) and to a lesser extent diffusion-weighted imaging (DWI) lesions in their initial MRI, with highly overlapping anatomical distribution. In one fifth of TBE patients the limbic system was affected. Worse outcome was associated with presence of DWI and/or FLAIR lesions and lower normalized apparent diffusion coefficient (ADC) signal intensities. Conclusion: Presence of FLAIR lesions, restricted diffusion as well as the extent of ADC hypointensity in initial MRI are parameters which might be of prognostic value regarding the longterm clinical outcome for patients with meningoencephalitis of viral and of unknown origin. Although not described before, affection of limbic structures by TBE is possible as shown by our results: A substantial proportion of our TBE patients had FLAIR signal abnormalities in these regions.

Disentangling the complex landscape of sleep-wake disorders with data-driven phenotyping: A study of the Bernese center.

BACKGROUND AND PURPOSE: The diagnosis of sleep-wake disorders (SWDs) is challenging because of the existence of only few accurate biomarkers and the frequent coexistence of multiple SWDs and/or other comorbidities. The aim of this study was to assess in a large cohort of well-characterized SWD patients the potential of a data-driven approach for the identification of SWDs. METHODS: We included 6958 patients from the Bernese Sleep Registry and 300 variables/biomarkers including questionnaires, results of polysomnography/vigilance tests, and final clinical diagnoses. A pipeline, based on machine learning, was created to extract and cluster the clinical data. Our analysis was performed on three cohorts: patients with central disorders of hypersomnolence (CDHs), a full cohort of patients with SWDs, and a clean cohort without coexisting SWDs. RESULTS: A first analysis focused on the cohort of patients with CDHs and revealed four patient clusters: two clusters for narcolepsy type 1 (NT1) but not for narcolepsy type 2 or idiopathic hypersomnia. In the full cohort of SWDs, nine clusters were found: four contained patients with obstructive and central sleep apnea syndrome, one with NT1, and four with intermixed SWDs. In the cohort of patients without coexisting SWDs, an additional cluster of patients with chronic insomnia disorder was identified. CONCLUSIONS: This study confirms the existence of clear clusters of NT1 in CDHs, but mainly intermixed groups in the full spectrum of SWDs, with the exception of sleep apnea syndromes and NT1. New biomarkers are needed for better phenotyping and diagnosis of SWDs.

Neuropathies related to hepatitis E virus infection: A prospective, matched case-control study.

BACKGROUND: Acute hepatitis E virus (HEV) infection has recently emerged as a potential trigger for acute dysimmune neuropathies, but prospective controlled studies are lacking. AIMS: To compare the frequency of concomitant acute HEV infection in patients with neuralgic amyotrophy (NA), Guillain-Barré syndrome (GBS), and Bell's palsy with a matched control population. METHODS: Swiss multicenter, prospective, observational, matched case-control study over 3 years (September 2019-October 2022). Neurological cases with NA, GBS, or Bell's palsy were recruited within 1 month of disease onset. Healthy controls were matched for age, sex, geographical location, and timing of blood collection. Diagnostic criteria for acute hepatitis E were reactive serum anti-HEV IgM and IgG assays (ELISA test) and/or HEV RNA detection in serum by real-time polymerase chain reaction (RT-PCR). RT-PCR was performed on sera to confirm IgM positivity. RESULTS: We included 180 patients (59 GBS, 51 NA, 70 Bell's palsy cases) and corresponding matched controls (blood donors) with median age 51 years for both groups and equal gender distribution. Six IgM+ cases were detected in the NA, two in the GBS, and none in the Bell's palsy group. Two controls were anti-HEV IgM-positive. At disease onset, most cases with acute HEV infection had increased liver enzymes. A moderate association (p = 0.027, Fisher's exact test; Cramér's V = -0.25) was observed only between acute HEV infection and NA. CONCLUSION: This prospective observational study suggests an association between concomitant acute HEV infection and NA, but not with GBS or Bell's palsy.

Can we forecast poor outcome in herpes simplex and varicella zoster encephalitis? A narrative review.

Herpes simplex virus (HSV) and varicella zoster virus (VZV) are among the most commonly diagnosed infectious causes of sporadic encephalitis worldwide. Despite treatment, mortality and morbidity rates remain high, especially for HSV encephalitis. This review is intended to provide an overview of the existing scientific literature on this topic from the perspective of a clinician who is confronted with serious decisions about continuation or withdrawal of therapeutic interventions. We performed a literature review searching two databases and included 55 studies in the review. These studies documented or investigated specifically outcome and predictive parameters of outcome of HSV and/or VZV encephalitis. Two reviewers independently screened and reviewed full-text articles meeting the inclusion criteria. Key data were extracted and presented as a narrative summary. Both, HSV and VZV encephalitis have mortality rates between 5 and 20% and complete recovery rates range from 14 to 43% for HSV and 33 to 49% for VZV encephalitis. Prognostic factors for both VZV and HSV encephalitis are older age and comorbidity, as well as severity of disease and extent of magnetic resonance imaging (MRI) lesions on admission, and delay in treatment initiation for HSV encephalitis. Although numerous studies are available, the main limiting factors are the inconsistent patient selection and case definitions as well as the non-standardised outcome measures, which hampers the comparability of the studies. Therefore, larger and standardised observational studies applying validated case definitions and outcome measures including quality of life assessment are required to provide solid evidence to answer the research question.

Effects of high resistance muscle training on corticospinal output during motor fatigue assessed by transcranial magnetic stimulation.

Introduction: Central fatigue refers to a reduced drive of motor cortical output during exercise, and performance can be enhanced after training. However, the effects of training on central fatigue remain unclear. Changes in cortical output can be addressed non-invasively using transcranial magnetic stimulation (TMS). The aim of the study was to compare responses to TMS during a fatiguing exercise before and after a 3 weeks lasting resistance training, in healthy subjects. Methods: The triple stimulation technique (TST) was used to quantify a central conduction index (CCI = amplitude ratio of central conduction response and peripheral nerve response) to the abductor digiti minimi muscle (ADM) in 15 subjects. The training consisted of repetitive isometric maximal voluntary contractions (MVC) of ADM for 2 min twice a day. Before and after this training, TST recordings were obtained every 15 s during an 2 min exercise of MVC of the ADM, where subjects performed repetitive contractions of the ADM, and repeatedly during a recovery period of 7 min. Results: There was a consistent decrease of force to approximately 40% of MVC in all experiments and in all subjects, both before and after training. In all subjects, CCI decreased during exercise. While before training, theCCI decreased to 49% (SD 23.7%) after 2 min of exercise, it decreased after training onlyto 79% (SD 26.4%) after exercise (p < 0.01). Discussion: The training regimen increased the proportion of target motor units that could be activated by TMS during a fatiguing exercise. The results point to a reduced intracortical inhibition, which may be a transient physiological response to facilitate the motor task. Possible underlying mechanisms at spinal and supraspinal sites are discussed.

Spontaneous ischemic neuropathy of the sciatic nerve due to arterial occlusion - a rare cause of acute neuropathy not to be missed, a report of two cases.

BACKGROUND: Ischemic neuropathy of the sciatic nerve without preceding vascular surgical procedures is a rare condition and may be due to arterial occlusion in one limb. CASE PRESENTATIONS: We present two cases with acute onset of pain and sensory symptoms such as pins and needles and numbness in the foot with no or mild motor symptoms. In the neurological work-up, electrophysiological signs of axonal neuropathy of both peroneal and tibial nerves were demonstrated and T2 hyperintensity was seen in the distal sciatic nerves on MR neurography as well as signs indicating arterial thrombosis in the corresponding vessels. Recanalization was obtained in both patients angiographically with significant improvement in one patient. CONCLUSIONS: Spontaneous arterial occlusion of major or peripheral arteries is a rare but important cause of acute onset of single or multiple axonal mononeuropathies of one extremity. Recognition of this infrequent cause is essential since it requires immediate and specific therapeutic options.

Pearls & Oy-sters: Bilateral Mononeuropathic Neuralgic Amyotrophy Triggered by Bartonella henselae Infection Responsive to Immunoglobulin.

We present a case of a cat owner with a scar on his right thenar eminence, followed by lymphadenopathy in the right axilla, general malaise and fever, and subsequent onset of bilateral neuralgic amyotrophy within one week. After a comprehensive workup, cat scratch disease caused by Bartonella henselae was confirmed serologically and adequately treated. Despite antibiotic treatment, the patient presented clinically with persistent bilateral, asymmetric neuropathy of the median nerve, predominantly the interosseous anterior nerve, which was confirmed by multifocal swelling and hyperintense signal of the nerves on T2-weighted MR neurography. Electrophysiological examination confirmed axonal median neuropathies bilaterally. After an unsuccessful steroid treatment trial, the patient showed an excellent and sustained response to intravenous immunoglobulin despite a delay from symptom onset to treatment of 10 months.

Sleep-Wake and Circadian Disorders after Tick-Borne Encephalitis.

Tick-borne encephalitis (TBE) is an infectious disease affecting the central nervous system. Recently, the occurrence of TBEV infections has steadily increased, reaching all-time high incidence rates in European countries. Up to 50% of patients with TBE present neurological sequelae, among them sleep-wake and circadian disorders (SWCD), which are poorly characterized. The aim of this review is to investigate the prevalence, clinical characteristics, and prognosis of SWCD after TBE. The literature review was performed in accordance with PRISMA guidelines. The quality of the paper was assessed using a standardized quality assessment. The analysis of SWCD was categorized into four different time intervals and two age groups. The literature search identified 15 studies, five including children and 10 including adults. In children, fatigue was most frequently observed with a prevalence of 73.9%, followed by somnolence/sleepiness, restlessness, and sleep-wake inversion. In adults, tiredness/fatigue was the most reported sequela with a prevalence of 27.4%, followed by extensive daytime sleepiness/somnolence, and insomnia (3.3%). Two studies showed impaired social outcomes in patients after TBE infections. SWCD after TBE in children and adults is a newly recognized sequela. Additional clinical and experimental research is needed to gain more precise insight into the clinical burden of SWCD after TBE and the underlying mechanisms.

Meningitis, meningoencephalitis and encephalitis in Bern: an observational study of 258 patients.

BACKGROUND: Depending on geographic location, causes of encephalitis, meningoencephalitis and meningitis vary substantially. We aimed to identify the most frequent causes, clinical presentation and long-term outcome of encephalitis, meningoencephalitis and meningitis cases treated in the Inselspital University Hospital Bern, Switzerland. METHODS: In this monocentric, observational study, we performed a retrospective review of clinical patient records for all patients treated within a 3-year period. Patients were contacted for a telephone follow-up interview and to fill out questionnaires, especially related to disturbances of sleep and wakefulness. RESULTS: We included 258 patients with the following conditions: encephalitis (18%), nonbacterial meningoencephalitis (42%), nonbacterial meningitis (27%) and bacterial meningoencephalitis/meningitis (13%). Herpes simplex virus (HSV) was the most common cause of encephalitis (18%); tick-borne encephalitis virus (TBEV) was the most common cause of nonbacterial meningoencephalitis (46%), enterovirus was the most common cause of nonbacterial meningitis (21%) and Streptococcus pneumoniae was the most common cause of bacterial meningoencephalitis/meningitis (49%). Overall, 35% patients remained without a known cause. After a median time of 16 months, 162 patients participated in the follow-up interview; 56% reported suffering from neurological long-term sequelae such as fatigue and/or excessive daytime sleepiness (34%), cognitive impairment and memory deficits (22%), headache (14%) and epileptic seizures (11%). CONCLUSIONS: In the Bern region, Switzerland, TBEV was the overall most frequently detected infectious cause, with a clinical manifestation of meningoencephalitis in the majority of cases. Long-term neurological sequelae, most importantly cognitive impairment, fatigue and headache, were frequently self-reported not only in encephalitis and meningoencephalitis survivors but also in viral meningitis survivors up to 40 months after acute infection.

The Swiss Primary Hypersomnolence and Narcolepsy Cohort study (SPHYNCS): Study protocol for a prospective, multicentre cohort observational study.

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL. The primary aim is to validate new and reappraise well-known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3-year recruitment phase. Healthy controls and patients with EDS due to severe sleep-disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long-term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagnosis, better prognosis and personalized management of CDH.

Multiple sleep latency test and polysomnography in patients with central disorders of hypersomnolence.

A multiple sleep latency test (MSLT) with occurrence of sleep onset REM periods (SOREMP) is considered one of the central diagnostic criteria for narcolepsy according to the International Classification of Sleep Disorders, but its sensitivity and specificity have been questioned. This study aims to describe MSLT and polysomnography (PSG) findings, including frequency and distribution of SOREMP during the day, in a large cohort of patients with central disorders of hypersomnolence (CDH). We retrospectively analyzed electrophysiological data from MSLT and PSG in 370 consecutive patients with narcolepsy type 1 (NT1, n = 97), type 2 (NT2, n = 31), idiopathic hypersomnia (IH, n = 48), nonorganic hypersomnia (NOH, n = 116) and insufficient sleep syndrome (ISS, n = 78). NT1 and NT2 patients had a significantly shorter mean Sleep Latency (mSL) and REM-Latency (REML) in MSLT and PSG. SOREMP occurred more frequently in narcoleptic vs. non-narcoleptic patients in MSLT and PSG. Occurrence of 3 or more SOREMP in MSLT and a SOREMP in PSG had a very high specificity and positive predictive value (98%/96% and 100% respectively), however relatively low sensitivity (65% and 45% respectively). NT1 more than NT2 patients have shorter mSL and more frequent SOREMP in MSLT and shorter SL as well as REML during nocturnal PSG. Increasing numbers of SOREMP in MSLT and especially SOREMP during PSG increase specificity on the expense of sensitivity in diagnosing narcolepsy. Therefore, frequency of SOREMP in MSLT naps and PSG can help to discriminate but not clearly separate narcoleptic from non-narcoleptic patients.

Conventional autoantibodies against brain antigens are not routinely detectable in serum and CSF of narcolepsy type 1 and 2 patients.

Narcolepsy with cataplexy (NT1) is a chronic hypothalamic disorder with a presumed immune-mediated etiology leading to a loss of hypocretin neurons. Previous studies reported conflicting results in terms of presence of auto-antibodies involved in narcolepsy pathophysiology. A total of 86 patients with primary/idiopathic narcolepsy (74 NT1, 12 NT2) and 23 control patients with excessive daytime sleepiness due to other causes were tested for the presence of a wide range of anti-neuronal antibodies in both serum and cerebrospinal fluid (CSF). Anti-neuronal antibodies were rarely found in patients with narcolepsy (n = 2) and in controls (n = 1). Our results are in line with previous reports. We can therefore support the current evidence, that conventional anti-neuronal antibodies are not routinely detected during the workup of NT1 and other CDH patients.

The Swiss Narcolepsy Scale (SNS) and its short form (sSNS) for the discrimination of narcolepsy in patients with hypersomnolence: a cohort study based on the Bern Sleep-Wake Database.

Previous studies reported high sensitivity and specificity of the Swiss Narcolepsy Scale (SNS) for the diagnosis of narcolepsy type 1. We used data from the Bern Sleep-Wake Database to investigate the discriminating capacity of both the SNS and the Epworth Sleepiness Scale (ESS) to identify narcolepsy type 1 and type 2 in patients with central disorders of hypersomnolence (CDH) or sleepy patients with obstructive sleep apnea (OSA). In addition, we aimed to develop a simplified version of the SNS. We created the two-item short-form SNS (sSNS), based on the discriminative capability of the models including all possible combinations of the five questions of the SNS. Using the previously published co-efficiencies, we confirmed the high capacity of the SNS in identifying narcolepsy type 1. The updated SNS (based on new co-efficiencies and cutoff) and the sSNS showed high capacity and were both superior to ESS in identifying narcolepsy type 1. The sSNS correlated significantly with the SNS (r = - 0.897, p < 0.001). No scale showed sufficient discrimination for narcolepsy type 2. This is the largest cohort study that confirms the discriminating power of SNS for narcolepsy type 1 in patients with hypersomnolence and the first study to assess its discriminative power for narcolepsy type 2. The easy-to-use and easy-to-calculate short-form scale has a high discriminating power for narcolepsy type 1 and may be used as screening tool, especially among general practitioners, to identify patients and accelerate their referral to a center of expertise.

Successful Mechanical Thrombectomy of a Middle Cerebral Artery Occlusion 14 Hours after Stroke Onset.

A 54-year-old patient presented with mild right-sided weakness of hand and face with a National Institutes of Health Stroke Scale (NIHSS) of 2 and occlusion of the left middle cerebral artery (MCA) in the M1 segment with a large perfusion deficit on computed tomography (CT). Due to mild neurological deficits no IVT was performed. Nine hours after symptom onset the patient gradually deteriorated with a NIHSS fluctuating between 9 and 15. MRI showed a persistent occlusion of the MCA with a large diffusion-perfusion mismatch. Immediate endovascular thrombectomy was performed 14 hours after symptom onset with complete recanalization and complete clinical recovery. Although mechanical thrombectomy is generally considered an effective alternative strategy up to 8 hours after stroke onset, selected patients with a large diffusion/perfusion mismatch and small infarct cores may benefit from an expanded therapeutic window.

Neuroinflammation is Associated with Brain Extracellular TAU-Protein Release After Spontaneous Subarachnoid Hemorrhage.

INTRODUCTION: Animal data suggest an association between neuroinflammation and secondary brain injury including axonal injury after aneurysmal subarachnoid hemorrhage (aSAH). We sought to study the association between brain extracellular interleukin (IL)-6 and TAU-protein levels as a surrogate marker for neuroinflammation and axonal injury in patients with poor grade aSAH. METHODS: Prospectively collected data from 26 consecutive poor-grade aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD) were retrospectively analyzed. IL-6 and TAU-protein levels were analyzed using ELISA from a single CMD-sample every 24 hours and correlated with brain metabolic and hemodynamic parameters. Patients were dichotomized to highgrade (N=10) or low-grade (N=16) neuroinflammation according to their median CMD-IL-6 levels. Data were analyzed using generalized estimating equations to account for multiple within-subject measurements. RESULTS: Perilesional probe location (P=0.02) and aSAH related intracerebral hemorrhage (aICH) volume (P=0.003) at admission were associated with high-grade neuroinflammation. Brain extracellular TAU-protein levels (P=0.001), metabolic distress and delayed cerebral infarction (DCI; P=0.001) were linked to high-grade neuroinflammation. Relative or absolute phosphor-TAU levels were not correlated with CMD-IL-6 levels. High-grade neuroinflammation was a predictor for worse outcome three months after ictus, independently from probe location, initial Hunt&Hess grade and age (P=0.01). CONCLUSION: Neuroinflammation after aSAH is associated with intraparenchymal bleeding, deranged cerebral metabolism and TAU-protein release. The impact of potential anti-inflammatory treatment strategies on secondary brain injury after aSAH has to be investigated in future studies.

Cerebral glucose hypometabolism in Tick-Borne Encephalitis, a pilot study in 10 Patients.

BACKGROUND: Tick borne encephalitis (TBE) is an acute meningoencephalitis with or without myelitis caused by an RNA virus from the flavivirus family transmitted by Ixodes spp ticks. The neurotropic TBE virus infects preferentially large neurons in basal ganglia, anterior horns, medulla oblongata, Purkinje cells and thalamus. Brain metabolic changes related to radiologic and clinical findings have not been described so far. METHODS: Here we describe the clinical course of 10 consecutive TBE patients with outcome assessment at discharge and after 12 month using a modified Rankin Scale. Patients underwent cerebral MRI after confirmation of diagnosis and before discharge. 18F-FDG PET/CT scans were performed within day 5 to day 14 after TBE diagnosis. Extended analysis of coagulation parameters by thrombelastometry (ROTEM® InTEM, ExTEM, FibTEM) was performed every other day after confirmation of TBE diagnosis up to day 10 after hospital admission or discharge. RESULTS: All patients presented with a meningoencephalitic course of disease. Cerebral MRI scans showed unspecific findings at predilection areas in 3 patients. 18F-FDG PET/CT showed increased glucose utilization in one patient and decreased 18F-FDG uptake in seven patients. Changes in coagulation measured by standard parameters and thrombelastometry were not found in any of the patients. DISCUSSION: Glucose hypometabolism was present in 7 out of 10 TBE patients reflecting neuronal dysfunction in predilection areas of TBE virus infiltration responsible for development of clinical signs and symptoms.

Cryptococcal transmigration across a model brain blood-barrier: evidence of the Trojan horse mechanism and differences between Cryptococcus neoformans var. grubii strain H99 and Cryptococcus gattii strain R265.

Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg) cause neurological disease and cross the BBB as free cells or in mononuclear phagocytes via the Trojan horse mechanism, although evidence for the latter is indirect. There is emerging evidence that Cn and the North American outbreak Cg strain (R265) more commonly cause neurological and lung disease, respectively. We have employed a widely validated in vitro model of the BBB, which utilizes the hCMEC/D3 cell line derived from human brain endothelial cells (HBEC) and the human macrophage-like cell line, THP-1, to investigate whether transport of dual fluorescence-labelled Cn and Cg across the BBB occurs within macrophages. We showed that phagocytosis of Cn by non-interferon (IFN)-γ stimulated THP-1 cells was higher than that of Cg. Although Cn and Cg-loaded THP-1 bound similarly to TNF-activated HBECs under shear stress, more Cn-loaded macrophages were transported across an intact HBEC monolayer, consistent with the predilection of Cn for CNS infection. Furthermore, Cn exhibited a higher rate of expulsion from transmigrated THP-1 compared with Cg. Our results therefore provide further evidence for transmigration of both Cn and Cg via the Trojan horse mechanism and a potential explanation for the predilection of Cn to cause CNS infection.

Early brain injury after aneurysmal subarachnoid hemorrhage: a multimodal neuromonitoring study.

INTRODUCTION: There is a substantial amount of evidence from animal models that early brain injury (EBI) may play an important role for secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Cerebral microdialysis (CMD) allows online measurement of brain metabolites, including the pro-inflammatory cytokine interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9), which is indicative for disruption of the blood-brain barrier. METHODS: Twenty-six consecutive poor-grade aSAH patients with multimodal neuromonitoring were analyzed for brain hemodynamic and metabolic changes, including CMD-IL-6 and CMD-MMP-9 levels. Statistical analysis was performed by using a generalized estimating equation with an autoregressive function. RESULTS: The baseline cerebral metabolic profile revealed brain metabolic distress and an excitatory response which improved over the following 5 days (P <0.001). Brain tissue hypoxia (brain tissue oxygen tension of less than 20 mm Hg) was common (more than 60% of patients) in the first 24 hours of neuromonitoring and improved thereafter (P <0.05). Baseline CMD-IL-6 and CMD-MMP-9 levels were elevated in all patients (median = 4,059 pg/mL, interquartile range (IQR) = 1,316 to 12,456 pg/mL and median = 851 pg/mL, IQR = 98 to 25,860 pg/mL) and significantly decreased over days (P <0.05). A higher pro-inflammatory response was associated with the development of delayed cerebral ischemia (P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P <0.03). Brain metabolic distress and increased IL-6 levels were associated with poor functional outcome (modified Rankin Scale of more than 3, P ≤0.01). All models were adjusted for probe location, aneurysm securing procedure, and disease severity as appropriate. CONCLUSIONS: Multimodal neuromonitoring techniques allow insight into pathophysiologic changes in the early phase after aSAH. The results may be used as endpoints for future interventions targeting EBI in poor-grade aSAH patients.

Nodding syndrome in Tanzania may not be associated with circulating anti-NMDA-and anti-VGKC receptor antibodies or decreased pyridoxal phosphate serum levels-a pilot study.

BACKGROUND: Nodding syndrome (NS) is a seemingly progressive epilepsy disorder of unknown underlying cause. We investigated association of pyridoxal-phosphate serum levels and occurrence of anti-neuronal antibodies against N-methyl-D-aspartate (NMDA) receptor and voltage gated potassium channel (VGKC) complex in NS patients. METHODS: Sera of a Tanzanian cohort of epilepsy and NS patients and community controls were tested for the presence of anti-NMDA-receptor and anti-VGKC complex antibodies by indirect immunofluorescence assay. Furthermore pyridoxal-phosphate levels were measured. RESULTS: Auto-antibodies against NMDA receptor or VGKC (LG1 or Caspr2) complex were not detected in sera of patients suffering from NS (n=6), NS plus other seizure types (n=16), primary generalized epilepsy (n=1) and community controls without epilepsy (n=7). Median Pyridoxal-phosphate levels in patients with NS compared to patients with primary generalized seizures and community controls were not significantly different. However, these median pyridoxal-phosphate levels are significantly lower compared to the range considered normal in Europeans. CONCLUSIONS: In this pilot study NS was not associated with serum anti-NMDA receptor or anti-VGKC complex antibodies and no association to pyridoxal-phosphate serum levels was found.