Rasmussen encephalitis: Incidence and course under randomized therapy with tacrolimus or intravenous immunoglobulins

Purpose: Rasmussen encephalitis (RE) leads to progressive tissue and function loss of one brain hemisphere and often intractable epilepsy. This is the first randomized prospective treatment trial in RE. Methods: Germany‐wide, patients with suspected recent‐onset RE were recruited and if eligible randomized to tacrolimus or intravenous immunoglobulins (IVIGs). A loss of motor function or hemispheric volume by ≥15% (in patients >12 years at disease onset: ≥8%) led to study exit. Untreated patients served as a historical control group. Key Findings: Over 6.3 years, 21 patients with recent‐onset RE were identified. Sixteen were randomized to tacrolimus (n = 9) or IVIG (n = 7). Immunotreated patients had a longer “survival” than the historical controls. Neither treatment was more efficacious than the other. Two tacrolimus patients experienced serious adverse events. No immunotreated but several untreated patients developed intractable epilepsy. No patient with refractory epilepsy became treatment‐responsive under immunotherapy. Significance: The countrywide incidence rate of diagnosed RE is estimated as 2.4 cases/10⁷ people ≤ age 18/year. Treatment with tacrolimus or IVIG may slow down tissue and function loss and prevent development of intractable epilepsy. However, immunotherapy may “arrest” patients in a dilemma state of pharmacoresistant epilepsy but too good function to be offered functional hemispherectomy. These compounds may therefore contribute to the therapeutic armamentarium for RE patients without difficult‐to‐treat epilepsies.     

Awake craniotomies without any sedation: the awake-awake-awake technique

Background

Temporary anaesthesia or analgosedation used for awake craniotomies carry substantial risks like hemodynamic instabilities, airway obstruction, hypoventilation, nausea and vomiting, agitation, and interference with test performances. We tested the actual need for sedatives and opioids in 50 patients undergoing awake craniotomy for brain tumour resection in eloquent or motoric brain areas when cranial nerve blocks, permanent presence of a contact person, and therapeutic communication are provided.

Methods

Therapeutic communication was based on the assumption that patients in such an extreme medical situation enter a natural trance-like state with elevated suggestibility. The anaesthesiologist acted as a continuous guide, using a strong rapport, nonverbal communication, hypnotic suggestions, such as dissociation to a “safe place”, and the reframing of disturbing noises, while simultaneously avoiding negative suggestions. Analgesics or sedatives were at hand according to the principle “as much as necessary, but not more than needed”.

Results

No sedation was necessary for any of the patients besides for the treatment of seizures. Only two-thirds of the patients requested remifentanil, with a mean dosage of 96 μg before the end of tumour resection and a total of 156 μg. Hemodynamic reactions indicative of stress were mainly seen during nerve blockades and neurological testing. Postoperative vigilance tests showed equal or higher scores than preoperative tests.

Conclusions

The main challenges for patients undergoing awake craniotomies include anxiety and fears, terrifying noises and surroundings, immobility, loss of control, and the feeling of helplessness and being left alone. In such situations, psychological support might be more helpful than the pharmacological approach. With adequate therapeutic communication, patients do not require any sedation and no or only low-dose opioid treatment during awake craniotomies, leaving patients fully awake and competent during the entire surgical procedure without stress. This approach can be termed “awake-awake-awake-technique”.     

Stimulation sites in the subthalamic nucleus projected onto a mean 3-D atlas of the thalamus and basal ganglia

Background

In patients with severe forms of Parkinson’s disease (PD), deep brain stimulation (DBS) commonly targets the subthalamic nucleus (STN). Recently, the mean 3-D Morel-Atlas of the basal ganglia and the thalamus was introduced. It combines information contained in histological data from ten post-mortem brains. We were interested whether the Morel-Atlas is applicable for the visualization of stimulation sites.

Methods

In a consecutive PD patient series, we documented preoperative MRI planning, intraoperative target adjustment based on electrophysiological and neurological testing, and perioperative CT target reconstruction. The localization of the DBS electrodes and the optimal stimulation sites were projected onto the Morel-Atlas.

Results

We included 20 patients (median age 62 years). The active contact had mean coordinates X_lat?=?±12.1 mm, Y_ap?=??1.8 mm, Z_vert?=??3.2 mm. There was a significant difference between the initially planned site and the coordinates of the postoperative active contact site (median 2.2 mm). The stimulation site was, on average, more anterior and more dorsal. The electrode contact used for optimal stimulation was found within the STN of the atlas in 38/40 (95 %) of implantations.

Conclusions

The cluster of stimulation sites in individual patients—as deduced from preoperative MR, intraoperative electrophysiology and neurological testing—showed a high degree of congruence with the atlas. The mean 3D Morel Atlas is thus a useful tool for postoperative target visualization. This represents the first clinical evaluation of the recently created atlas.     

Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted Metabolomics Approach

Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39–1.95], P = 8.46 × 10⁻⁹) and was moderately heritable (h² = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34–2.11], P = 6.52 × 10⁻⁶) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27–2.75], P = 1 × 10⁻³). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.Currently, stratification of individuals at risk for type 2 diabetes (T2D) within the general population is based on well-established factors such as age, BMI, and fasting glucose (1). Although these factors contribute considerably to disease risk, they may not identify at-risk individuals before the disease process is well under way.Recently, a number of studies have found several metabolites to be correlated with insulin resistance and T2D (2–6), and T2D-associated metabolic profiles have been identified 10–15 years before the diagnosis/onset of the disease (7–9). To help preventive strategies, and maximize the potential for existing effective interventions, it is important to characterize the molecular changes that take place in the development of T2D.We aim to understand other biochemical changes, in addition to hyperglycemia, that take place at the onset of T2D using the largest metabolomic screening approach to date. We assessed >400 metabolites to determine which metabolomic profiles are correlated with T2D and impaired fasting glucose (IFG) in a large cohort of females from TwinsUK with independent replication.