Meropenem pharmacokinetics in cerebrospinal fluid: comparing intermittent and continuous infusion strategies in critically ill patients-a prospective cohort study.

Meropenem penetration into the cerebrospinal fluid (CSF) is subject to high interindividual variability resulting in uncertain target attainment in CSF. Recently, several authors recommended administering meropenem as a continuous infusion (CI) to optimize CSF exposure. This study aimed to compare the concentrations and pharmacokinetics of meropenem in CSF after intermittent infusion (II) and CI. This prospective, observational study (NCT04426383) included critically ill patients with external ventricular drains who received either II or CI of meropenem. Meropenem pharmacokinetics in plasma and CSF were characterized using population pharmacokinetic modeling (NONMEM 7.5). The developed model was used to compare the concentration-time profile and probability of target attainment (PTA) between II and CI. A total of 16 patients (8 CI, 8 II; samples: nplasma = 243, nCSF = 263) were recruited, with nine patients (5 CI, 4 II) suffering from cerebral and seven patients from extracerebral infections. A one-compartment model described the plasma concentrations adequately. Meropenem penetration into the CSF (partition coefficient (KP), cCSF/cplasma) was generally low (6.0%), exhibiting substantial between-subject variability (coefficient of variation: 84.0%). There was no correlation between the infusion mode and KP, but interleukin (IL)-6 measured in CSF showed a strong positive correlation with KP (P < 0.001). Dosing simulations revealed no relevant differences in CSF concentrations and PTA in CSF between CI and II. Our study did not demonstrate increased penetration rates or higher concentrations of meropenem in the CSF with CI compared with II. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04426383.

Plasma and Cerebrospinal Fluid Population Pharmacokinetics of Vancomycin in Patients with External Ventricular Drain.

Vancomycin is a commonly used antibacterial agent in patients with primary central nervous system (CNS) infection. This study aims to examine predictors of vancomycin penetration into cerebrospinal fluid (CSF) in patients with external ventricular drainage and the feasibility of CSF sampling from the distal drainage port for therapeutic drug monitoring. Fourteen adult patients (9 with primary CNS infection) were treated with vancomycin intravenously. The vancomycin concentrations in blood and CSF (from proximal [CSF_P] and distal [CSF_D] drainage ports) were evaluated by population pharmacokinetics. Model-based simulations were conducted to compare various infusion modes. A three-compartment model with first-order elimination best described the vancomycin data. Estimated parameters included clearance (CL, 4.53 L/h), central compartment volume (Vc, 24.0 L), apparent CSF compartment volume (VCSF, 0.445 L), and clearance between central and CSF compartments (QCSF, 0.00322 L/h and 0.00135 L/h for patients with and without primary CNS infection, respectively). Creatinine clearance was a significant covariate on vancomycin CL. CSF protein was the primary covariate to explain the variability of QCSF. There was no detectable difference between the data for sampling from the proximal and the distal port. Intermittent infusion and continuous infusion with a loading dose reached the CSF target concentration faster than continuous infusion only. All infusion schedules reached similar CSF trough concentrations. Beyond adjusting doses according to renal function, starting treatment with a loading dose in patients with primary CSF infection is recommended. Occasionally, very high and possibly toxic doses would be required to achieve adequate CSF concentrations, which calls for more investigation of direct intraventricular administration of vancomycin. (This study has been registered at ClinicalTrials.gov under registration no. NCT04426383).

Large diameter hemicraniectomy does not improve long-term outcome in malignant infarction.

INTRODUCTION: In malignant cerebral infarction decompressive hemicraniectomy has demonstrated beneficial effects, but the optimum size of hemicraniectomy is still a matter of debate. Some surgeons prefer a large-sized hemicraniectomy with a diameter of more than 14 cm (HC > 14). We investigated whether this approach is associated with reduced mortality and an improved long-term functional outcome compared to a standard hemicraniectomy with a diameter of less than 14 cm (HC ≤ 14). METHODS: Patients from the DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY) registry who received hemicraniectomy were dichotomized according to the hemicraniectomy diameter (HC ≤ 14 cm vs. HC > 14 cm). The primary outcome was modified Rankin scale (mRS) score ≤ 4 after 12 months. Secondary outcomes were in-hospital mortality, mRS ≤ 3 and mortality after 12 months, and the rate of hemicraniectomy-related complications. The diameter of the hemicraniectomy was examined as an independent predictor of functional outcome in multivariable analyses. RESULTS: Among 130 patients (32.3% female, mean (SD) age 55 (11) years), the mean hemicraniectomy diameter was 13.6 cm. 42 patients (32.3%) had HC > 14. There were no significant differences in the primary outcome and mortality by size of hemicraniectomy. Rate of complications did not differ (HC ≤ 14 27.6% vs. HC > 14 36.6%, p = 0.302). Age and infarct volume but not hemicraniectomy diameter were associated with outcome in multivariable analyses. CONCLUSION: In this post-hoc analysis, large hemicraniectomy was not associated with an improved outcome or lower mortality in unselected patients with malignant middle cerebral artery infarction. Randomized trials should further examine whether individual patients could benefit from a large-sized hemicraniectomy. CLINICAL TRIAL REGISTRATION INFORMATION: German Clinical Trials Register (URL: https://www.drks.de ; Unique Identifier: DRKS00000624).

Posterior reversible encephalopathy syndrome after lung transplantation: Risk factors and management.

INTRODUCTION: Posterior reversible encephalopathy syndrome is a rare neurologic complication that can occur under immunosuppressive therapy with CNI after organ transplantation. METHODS: We retrospectively reviewed medical records of 545 patients who underwent lung transplantation between 2012 and 2019. Within this group, we identified 30 patients with neurological symptoms typical of PRES and compared the characteristics of patients who were diagnosed with PRES (n = 11) to those who were not (n = 19). RESULTS: The incidence of PRES after lung transplantation was 2%. Notably, 73% of the patients with PRES were female and the mean age was 39.2. Seizure (82% vs. 21%, p = .002) was the most common neurological presentation. The risk of developing PRES was significantly associated with age (OR = .92, p < .0001) and having cystic fibrosis (CF) (OP = 10.1, p < .0001). Creatinine level (1.9 vs. 1.1 mg/dl, p = .047) and tacrolimus trough level (19.4 vs. 16.5 ng/ml, p = .048) within 1 week prior to neurological symptoms were significantly higher in patients with PRES. CONCLUSION: Renal insufficiency and high tacrolimus levels are associated with PRES. A change of immunosuppressive drug should be done after confirmed PRES diagnosis or immediately in case of severe neurological dysfunction to improve neurological outcomes and minimize the risk of early allograft rejection.

Case Report: Minimal Neurological Deficit of Two Adult Patients With Weston-Hurst Syndrome Due to Early Craniectomy: Case Series and Review of Literature on Craniectomy.

Objectives: We describe two new cases of acute hemorrhagic leucoencephalitis (AHLE), who survived with minimal sequelae due to early measures against increased intracranial pressure, particularly craniotomy. The recently published literature review on treatment and outcome of AHLE was further examined for the effect of craniotomy. Methods: We present two cases from our institution. The outcome of 44 cases from the literature was defined either as good (no deficit, minimal deficit/no daily help) or poor outcome (severe deficit/disabled, death). Patients with purely infratentorial lesions (n = 9) were excluded. Fisher's exact test was applied. Results: Two cases are presented: A 43-year-old woman with rapidly progressive aphasia and right hemiparesis due to a huge left frontal white matter lesion with rim contrast enhancement. Pathology was consistent with AHLE. The second case was a 56-year-old woman with rapidly progressive aphasia and right hemiparesis. Cranial MRI showed a huge left temporo-occipital white matter lesion with typical morphology for AHLE. Both patients received craniotomy within the first 24 h and consequent immunosuppressive-immunomodulatory treatment and survived with minimal deficits. Out of 35 supratentorial reported AHLE cases, seven patients received decompressive craniotomy. Comparing all supratentorial cases, patients who received craniotomy were more likely to have a good outcome (71 vs. 29%). Conclusion: Due to early control of the intracranial pressure, particularly due to early craniotomy; diagnosis per biopsy; and immediate start of immunosuppressive-immunomodulatory therapies (cortisone pulse, plasma exchanges), both patients survived with minimal sequelae. Craniotomy plays an important role and should be considered early on in patients with probable AHLE.

Patient-reported outcomes in Friedreich's ataxia after withdrawal from idebenone.

OBJECTIVES: Friedreich's ataxia is the most common inherited ataxia, and pathogenesis is known to involve mitochondrial oxidative stress. Idebenone is a potent antioxidant which has already been evaluated in several clinical trials in FRDA, with reports of symptomatic benefit but inconclusive objective results. Following patient consultation on design, we have completed a treatment-withdrawal study to establish whether patients could correctly determine their treatment allocation to placebo or idebenone. Our aim was to capture subjective experiences of symptoms such as fatigue, which can be difficult to measure with questionnaires or semi-quantitative scales, particularly in chronic, slowly progressive conditions. MATERIALS AND METHODS: Patients taking idebenone for at least 12 months as part of the open-label MICONOS Extension Study were randomized to receive either placebo or idebenone continuation for 2-month treatment cycles. The primary endpoint was patient assessment of treatment assignment. RESULTS: A total of 29 patients were randomized, forming the idebenone group (n = 16) and the placebo group (n = 13). No significant differences were detected between the idebenone and placebo groups on assessment of treatment assignment or early study withdrawal. A small but significant difference in ataxia rating scale scores was detected between treatment groups when considering ambulatory patients only. CONCLUSIONS: This study provides no data to suggest that FRDA patients could correctly determine their treatment assignment over a 2-month period. We hope that this study design will help inform future trials so that patients' experiences of symptoms are more reliably measured.

Consciousness Indexing and Outcome Prediction with Resting-State EEG in Severe Disorders of Consciousness.

We applied the following methods to resting-state EEG data from patients with disorders of consciousness (DOC) for consciousness indexing and outcome prediction: microstates, entropy (i.e. approximate, permutation), power in alpha and delta frequency bands, and connectivity (i.e. weighted symbolic mutual information, symbolic transfer entropy, complex network analysis). Patients with unresponsive wakefulness syndrome (UWS) and patients in a minimally conscious state (MCS) were classified into these two categories by fitting and testing a generalised linear model. We aimed subsequently to develop an automated system for outcome prediction in severe DOC by selecting an optimal subset of features using sequential floating forward selection (SFFS). The two outcome categories were defined as UWS or dead, and MCS or emerged from MCS. Percentage of time spent in microstate D in the alpha frequency band performed best at distinguishing MCS from UWS patients. The average clustering coefficient obtained from thresholding beta coherence performed best at predicting outcome. The optimal subset of features selected with SFFS consisted of the frequency of microstate A in the 2-20 Hz frequency band, path length obtained from thresholding alpha coherence, and average path length obtained from thresholding alpha coherence. Combining these features seemed to afford high prediction power. Python and MATLAB toolboxes for the above calculations are freely available under the GNU public license for non-commercial use ( https://qeeg.wordpress.com ).

Acute basilar thrombosis: Recanalization following intravenous thrombolysis is dependent on thrombus length.

INTRODUCTION: We investigated whether thrombus length measured in Computed Tomography Angiography (CTA) is predictive of the success rate of intravenous thrombolysis (IVT) in acute basilar occlusion and whether recanalization can be achieved by additional mechanical endovascular thrombectomy. METHODS: In 51 patients with acute basilar thrombosis thrombus length was measured on CTA images before intravenous thrombolysis (IVT) with rt-PA was started. After 114 minutes on average success of IVT was evaluated either by CTA or DSA. Patients with persistent basilar occlusion and no major brainstem infarction on CT underwent endovascular recanalization. RESULTS: 87% of patients had no recanalization of basilar artery after IVT alone. The average thrombus length was 15 mm in patients with persistent basilar occlusion after IVT and 7 mm in patients with recanalization after IVT. Thrombi longer than 13 mm did not resolve after IVT alone and 80% of thrombi shorter than 13 mm did not resolve either. 41 patients were transferred to endovascular recanalization; endovascular therapy was performed successfully in 90% (37 / 41). CONCLUSIONS: Recanalization rates in acute basilar occlusion after IVT alone are low and dependent on thrombus length. Additional mechanical endovascular thrombectomy showed to be a very successful recanalization therapy.

Long-term Neurological Outcome and Quality of Life after World Federation of Neurosurgical Societies Grades IV and V Aneurysmal Subarachnoid Hemorrhage in an Interdisciplinary Treatment Concept.

BACKGROUND: Detailed data on long-term functional outcome of patients with World Federation of Neurosurgical Societies (WFNS) grades IV and V aneurysmal subarachnoid hemorrhages (aSAH) are still scarce. OBJECTIVE: Assessment of long-term outcome of WFNS IV and V aSAH patients. METHODS: Functional outcome and quality of life were assessed by the modified Rankin scale (mRS) and the 36-item short-form health survey in consecutively treated aSAH WFNS IV and V patients between 2005 and 2010. Scores from the 36-item short-form health survey were compared to a healthy German population. Prognostic factors were analyzed by uni- and multivariate models. RESULTS: One hundred and seven eligible patients (median age: 53.0 years) were identified. After interdisciplinary consensus on optimal treatment, aneurysms were obliterated either by clipping (n = 35) or by coiling (n = 72). Ten patients were lost to long-term follow-up; the median clinical follow-up period was 3.2 years for the remaining 97 cases. Twenty-five of 97 died during the acute hospital phase and another 10 patients over the follow-up period leaving 62 long-term survivors. At the end of clinical follow-up, 40/97 patients, including 40/62 of long-term survivors, reached functional independence (mRS ≤ 2). Twelve of 97 patients were moderately (mRS = 3), 10/97 patients were severely disabled (mRS ≥ 4). Younger age (≤ 53 years; P = .001) and radiological absence of cerebral infarction ( P = .03) were the strongest predictors for favorable outcome. Quality of life was perceived to be only moderately reduced compared to the healthy control group. CONCLUSION: Poor-grade aSAH is not necessarily associated with poor long-term functional outcome; after aneurysm repair ∼60% of patients survived and among long-term survivors ∼ 60% regained functional independence.

Severe disorders of consciousness after acquired brain injury: A single-centre long-term follow-up study.

OBJECTIVES: To assess long-term clinical outcome, functional independence and health-related quality of life (HRQOL) in acquired brain injury (ABI) patients with a disorder of consciousness at admission to inpatient rehabilitation. METHODS: We selected patients from a cohort of ABI patients from a single centre. In addition to mortality, we measured level of consciousness with the Coma Remission Scale, functional independence with the Barthel Index, as well as generic and condition-specific HRQOL with the EQ5D and the "Quality of Life after Brain Injury" (QOLIBRI) respectively. RESULTS: Half of the obtained sample had died by follow-up. Survivors were younger at onset, in a minimally conscious state (MCS) at admission and had spent longer time in rehabilitation. Patients in a MCS were more likely to survive, and be in a state better than MCS over the follow-up time than patients with an unresponsive wakefulness syndrome (UWS). A small proportion of patients with UWS at admission emerged from MCS at follow-up. Emergence from MCS was associated with traumatic brain injury (TBI) and higher functional independence. CONCLUSION: Clinical outcome is mostly concordant with previous findings. Survivors' rehabilitation duration suggest revision of current standards. HRQOL results indicate a correlation with functional independence and that condition-specific HRQOL should not be neglected.

Reversible cerebral vasoconstriction syndrome and posterior reversible encephalopathy syndrome associated with intracranial hypotension.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) and posterior reversible encephalopathy syndrome (PRES) are both rare disorders. The pathophysiology of both diseases is not yet fully understood. METHODS: We report the unique case of a 19-year-old comatose woman who was brought to the ER after a series of generalized tonic-clonic seizures 6 days post peridural anesthesia for cesarean section. Vital signs and initial laboratory testing including urine analysis and drug screening were unremarkable. Initial cranial CT scan showed an acute small subdural hematoma (17 mm length × 6 mm width × 30 mm height), cerebral edema with slit ventricles, and slight cerebellar tonsillar herniation as signs of intracranial hypotension. CT angiography depicted narrowing of the proximal intracranial vessels consistent with RCVS. MR imaging was also suggestive of both intracranial hypotension and RCVS and showed, in addition, vasogenic edema consistent with PRES. An extensive CSF leakage involving T1 to L2/L3 was confirmed by spinal MRI. RESULTS: The patient underwent conservative therapy for intracranial hypotension (e.g., head-down position) as well as epidural blood patch, which led to regression of the clinical symptoms within a few days. Follow-up MRI showed complete resolution of all radiological changes. CONCLUSIONS: In summary, our patient developed clinical and neuroradiological signs of intracranial hypotension and a combination of PRES and RCVS associated with a CSF leakage caused by peridural anesthesia; by treating the intracranial hypotension, the other syndromes resolved. From a clinical point of view, it is important to look for CSF leakage as a treatable possible cause of PRES and/or RCVS triggered by intracranial hypotension as in our patient postpartum. Moreover, it is vital to obtain a good history as, in cases of suspected CSF leakage with classic postural headache, a recent spinal/cranial procedure is typically present.

Miliary pattern of brain metastases - a case report of a hyperacute onset in a patient with malignant melanoma documented by magnetic resonance imaging.

BACKGROUND: Miliary brain metastases are a rare condition but associated with an exceedingly poor prognosis. We present the case of a patient suffering from malignant melanoma with an acute progressively worsening of neurological symptoms up to the loss of consciousness. The magnetic resonance imaging (MRI) demonstrated a new onset of disseminated, miliary spread of central nervous system metastases from a malignant melanoma within 4 days. CASE PRESENTATION: We report on a 57-year-old woman suffering from metastatic malignant melanoma positive for BRAF-V600E mutation who developed an acute onset of neurological symptoms. The patient received vemurafenib and dacarbacin as chemotherapeutic regime for treatment of malignant melanoma. After admission to our hospital due to progressive disturbance of memory and speech difficulty a magnetic resonance tomography (MRI) was performed. This showed no evidence of cerebral tumour manifestation. The symptoms progressed until a loss of consciousness occurred on day five after admission and the patient was admitted to our intensive care unit for orotracheal intubation. No evidence for infectious, metabolic or autoimmune cerebral disorders was found. Due to the inexplicable acute worsening of the neurological symptoms a second MRI was performed on day five. This revealed a new onset of innumerable contrast-enhancing miliary lesions, especially in the grey matter which was proven as metastases from malignant melanoma on histopathology. CONCLUSION: This case describes an unique hyperacute onset of tumour progression correlating with an acute deterioration of neurological symptoms in a patient suffering from miliary brain metastasis from BRAF positive malignant melanoma.

Effects of idebenone on color vision in patients with leber hereditary optic neuropathy.

BACKGROUND: The authors investigated the correlation of protan and tritan color vision with disease characteristics in Leber hereditary optic neuropathy (LHON). The authors also characterized the therapeutic potential of idebenone in protecting patients from developing dyschromatopsia in LHON. METHODS: Color contrast data of 39 LHON patients participating in a randomized, double-blind placebo-controlled intervention study were evaluated. Patients reported disease onset <5 years before enrolment and were genetically confirmed. Protan and tritan color contrast sensitivity was measured using a computer graphics method in patients receiving idebenone (Catena; 900 mg/d; N = 28) or placebo (N = 11) for 6 months. RESULTS: Mean age of patients was 28.1 years, 87.2% were men, 76.9% carried the m11778G>A mutation, and mean duration since onset was 2 years. Assessing protan and tritan color vision at baseline revealed a high degree of color confusion even in young patients (<25 years) and with a short history of disease (<1 year). Treatment with idebenone improved tritan color vision compared with placebo (P = 0.008 at week 24); a similar trend was seen for protan. The effect of idebenone was most prominent in patients with discordant visual acuity (interocular difference of logMAR >0.2). In this subgroup, the treatment effect at week 24 was 20.4% (P = 0.005) in favor of idebenone for the tritan color domain and 13.5% (P = 0.067) for the protan domain. CONCLUSION: This study confirms that protan and tritan color confusion is an early symptom in LHON. Treatment with idebenone can protect from loss of color vision, particularly in patients who are at imminent risk of further vision loss.

A randomized placebo-controlled trial of idebenone in Leber's hereditary optic neuropathy.

Major advances in understanding the pathogenesis of inherited metabolic disease caused by mitochondrial DNA mutations have yet to translate into treatments of proven efficacy. Leber's hereditary optic neuropathy is the most common mitochondrial DNA disorder causing irreversible blindness in young adult life. Anecdotal reports support the use of idebenone in Leber's hereditary optic neuropathy, but this has not been evaluated in a randomized controlled trial. We conducted a 24-week multi-centre double-blind, randomized, placebo-controlled trial in 85 patients with Leber's hereditary optic neuropathy due to m.3460G>A, m.11778G>A, and m.14484T>C or mitochondrial DNA mutations. The active drug was idebenone 900 mg/day. The primary end-point was the best recovery in visual acuity. The main secondary end-point was the change in best visual acuity. Other secondary end-points were changes in visual acuity of the best eye at baseline and changes in visual acuity for both eyes in each patient. Colour-contrast sensitivity and retinal nerve fibre layer thickness were measured in subgroups. Idebenone was safe and well tolerated. The primary end-point did not reach statistical significance in the intention to treat population. However, post hoc interaction analysis showed a different response to idebenone in patients with discordant visual acuities at baseline; in these patients, all secondary end-points were significantly different between the idebenone and placebo groups. This first randomized controlled trial in the mitochondrial disorder, Leber's hereditary optic neuropathy, provides evidence that patients with discordant visual acuities are the most likely to benefit from idebenone treatment, which is safe and well tolerated.

Comparison of three clinical rating scales in Friedreich ataxia (FRDA).

To test the validity and reliability of the scale for the assessment and rating of ataxia (SARA) in Friedreich ataxia (FRDA). SARA is limited to eight items and can be performed rapidly. Ninety-six patients with a molecular genetic diagnosis of FRDA were rated using three different clinical scales, the FRDA Rating Scale (FARS), the International Cooperative Ataxia Rating Scale (ICARS), and SARA. Despite considerable discrepancies in scale size and subscale structure, SARA total scores were significantly correlated with ICARS (r = 0.953, P < 0.0001) and FARS (r = 0.938, P < 0.0001) total scores. SARA total scores also correlated with the activities of daily living (ADL, r = 0.929, P < 0.0001). Although originally developed for the use in dominantly inherited ataxias, which are primarily ataxias of the cerebellar type, SARA can also be used successfully to assess afferent ataxia, which is the predominant form in FRDA. Because SARA is characterized by high interrater reliability and practicability, SARA is applicable and well suited forclinical trials of FRDA.