Does diabetes mellitus affect the safety profile of valproic acid for the treatment of status epilepticus? A retrospective cohort study.

BACKGROUND: In the treatment of status epilepticus less is known about the influence of comorbidities on the safety profile of anticonvulsive drugs. Especially patients with diabetes mellitus may be predisposed to certain adverse events that have been related to therapy with valproic acid. In this single-center retrospective cohort study we examined if the complications of the intravenous treatment with valproic acid is different in patients with or without diabetes. METHODS: Patients who were treated for status epilepticus with intravenous valproic acid between 2008 and 2020 were identified. Primary endpoint was the discontinuation of therapy with valproic acid due to adverse events. Relevant secondary endpoints were the functional status at the time of discharge from hospital in comparison to the premorbid state and the in-hospital mortality. Both groups (patients with or without diabetes) were compared by Mann-Whitney U-Test or Pearson´s Chi2 test. To identify therapy with valproic acid as a risk factor of in-hospital mortality, a binary regression model was used. RESULTS: During the study period 408 patients and 482 episodes of status epilepticus were treated with intravenous valproic acid. Group comparisons did not reveal a significant difference in the rates of discontinuation of therapy. A difference was found in the rate of thrombocytopenia (p = 0.015), which occurred more often in patients with diabetes. In total, 36 hypoglycemic episodes could be identified, two occurred spontaneously under intravenous valproic acid. After correction for potential confounders, continuous therapy with valproic acid could not be confirmed as an independent risk factor for in-hospital mortality (p = 0.079). In patients with diabetes, the proportion of patients with a good functional state, indicated by the modified Rankin Scale, was significantly lower in both times (premorbid: 55% vs. 69%, p = 0.008; at discharge: 22% vs. 36%, p = 0.004). CONCLUSIONS: Tolerability of the treatment with valproic acid was similar in patients with or without diabetes. Diabetes as a relevant comorbidity can signal a potentially increased risk of a poor outcome after status epilepticus. TRIAL REGISTRATION: The study was registered at the German Clinical Trials Register on 8 April 2022 (DRKS 00,027,836).

Treatment of established status epilepticus in the elderly - a study protocol for a prospective multicenter double-blind comparative effectiveness trial (ToSEE).

BACKGROUND: Status epilepticus (SE) is a common neurological emergency condition that especially affects the elderly and old population. Older people with SE frequently have non-convulsive SE (NCSE) and are also at special risk of suffering a poor outcome. The application of benzodiazepines fails to control SE in about one third of the cases. For benzodiazepine refractory SE (BRSE) in elderly, there is little evidence that would justify the choice of one of the commonly used antiepileptic drugs. The present study aims to generate evidence for the treatment of BRSE in this age group. METHODS: We will conduct a prospective, randomized, double-blind comparative effectiveness study in more than twenty hospitals in Germany over a four-year period. Four hundred and seventy-seven elderly patients (≥ 65 years old) diagnosed with BRSE will be allocated by 1:1 randomization to receive either levetiracetam or valproate. All types of SE will be considered. For the diagnosis NCSE a verification by EEG is required. Levetiracetam or valproate will be administered in one single infusion. The primary endpoint is the stable cessation of ictal activity 15 min after the start of infusion persisting for the following 45 min of observation. EEG recording is maintained over the whole observation period, clinical examinations are conducted in predefined intervals. In case of treatment success patients and study staff remain blinded until 60 min after the start of the infusion. Adverse events will be recorded until the end of the study. EEG data will be reviewed by two external independent experts. To obtain data about the further treatment of SE, intrahospital complications and the functional outcome in the short term the study participants will be observed until the day of discharge or day 30 whichever is earliest. DISCUSSION: ToSEE is the first study which shall deliver evidence for the SE-therapy in the elderly and old population in a controlled prospective comparator study. By design it also shall collect information about therapy regimes and outcome aspects of this disease. TRIAL REGISTRATION: The trial has been registered at the German Clinical Trials Register on 3 July, 2020 ( DRKS00022308 ,  https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00022308 ).

Delirium Screening in Neurocritical Care and Stroke Unit Patients: A Pilot Study on the Influence of Neurological Deficits on CAM-ICU and ICDSC Outcome.

BACKGROUND/OBJECTIVE: Delirium is a common complication in critically ill patients with a negative impact on hospital length of stay, morbidity, and mortality. Little is known on how neurological deficits affect the outcome of commonly used delirium screening tools such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) in neurocritical care patients. METHODS: Over a period of 1 month, all patients admitted to a neurocritical care and stroke unit at a single academic center were prospectively screened for delirium using both CAM-ICU and ICDSC. Tool-based delirium screening was compared with delirium evaluation by the treating clinical team. Additionally, ICD-10 delirium criteria were assessed. RESULTS: One hundred twenty-three patients with a total of 644 daily screenings were included. Twenty-three patients (18.7%) were diagnosed with delirium according to the clinical evaluation. Delirium incidence amounted to 23.6% (CAM-ICU) and 26.8% (ICDSC). Sensitivity and specificity of both screening tools were 66.9% and 93.3% for CAM-ICU and 69.9% and 93.9% for ICDSC, respectively. Patients identified with delirium by either CAM-ICU or ICDSC presented a higher proportion of neurological deficits such as impaired consciousness, expressive aphasia, impaired language comprehension, and hemineglect. Subsequently, generalized estimating equations identified a significant association between impaired consciousness (as indexed by Richmond Agitation and Sedation Scale) and a positive delirium assessment with both CAM-ICU and ICDSC, while impaired language comprehension and hemineglect were only associated with a positive CAM-ICU result. CONCLUSIONS: A positive delirium screening with both CAM-ICU and ICDSC in neurocritical care and stroke unit patients was found to be significantly associated with the presence of neurological deficits. These findings underline the need for a more specific delirium screening tool in neurocritical care patients.

Critical Comparison of Different Biomarkers for Alzheimer's Disease in a Clinical Setting.

BACKGROUND: Biomarkers of neuronal injury and amyloid pathology play a pivotal role in the diagnosis of Alzheimer's disease (AD). The degree of AD biomarker congruence is still unclear in clinical practice. OBJECTIVE: Diagnosis of AD with regard to the congruence of the clinical diagnosis and different biomarkers. METHODS: In this prospective cross-sectional observational study, 54 patients with mild cognitive impairment or dementia due to AD or not due to AD were investigated. Biomarkers of neuronal injury were medial temporal lobe atrophy (MTA) on magnetic resonance imaging (MRI) and tau concentration in the cerebrospinal fluid (CSF). CSF Aß(1-42) and amyloid-targeting positron emission tomography (PET) were considered as biomarkers of amyloid pathology. RESULTS: Forty cases were diagnosed as AD and 14 cases were diagnosed as non-AD based on clinical and routine MRI assessment. AD cases had higher MTA scores, higher levels of CSF tau and lower levels of CSF Aß(1- 42), and higher amyloid load on PET compared to the non-AD group. In the AD group, completely consistently pathological biomarkers were found in 32.5% , non-pathological in 5% . In 62.5% the findings were inconsistent. Congruence of biomarkers was 67.5% for neuronal injury and for amyloid dysfunction, respectively. In two patients, clinical diagnosis switched to non-AD due to completely consistent non-pathological biomarker findings. The criteria of the international working group were met in 75.0% . CONCLUSION: Surprisingly, the number of completely congruent biomarkers was relatively low. Interpretation of AD biomarkers is complicated by multiple biomarker constellations. However, the level of biomarker consistency required to reliably diagnose AD remains uncertain.