Christoph J. Ploner

Cognitive deficits following anti-NMDA receptor encephalitis

Background Anti-NMDA receptor (NMDAR) encephalitis is a recently characterised autoimmune disorder mainly affecting young women. Although the clinical features of the acute disease are well characterised, cognitive long-term outcome has not been examined in detail. Methods The authors investigated cognitive performance in nine patients with proven anti-NMDAR encephalitis after recovery from the acute disease period (median 43 months after disease onset, range 23 to 69). Patients underwent a comprehensive neuropsychological assessment, including memory tasks that have previously been shown to be sensitive for hippocampal dysfunction. Results Substantial persistent cognitive impairments were observed in eight out of nine patients that mainly consisted of deficits in executive functions and memory. The severity of these deficits varied inter-individually. Patients with early immunotherapy performed significantly better. The most severe deficits were observed with inefficient or delayed initial treatment. Conclusion Our results suggest that cognitive deficits constitute a major long-term morbidity of anti-NMDAR encephalitis. These deficits relate to the distribution of NMDARs in the human brain and their functional role in normal cognition. Good cognitive long-term outcome may depend on early and aggressive treatment.

Does hypothermia influence the predictive value of bilateral absent N20 after cardiac arrest

Background: Bilateral absent N20 responses of median nerve somatosensory evoked potentials (SEPs) reliably predict poor prognosis after cardiac arrest. However, the studies supporting this fact were carried out before hypothermia was established as standard treatment. Recent evidence suggests that hypothermia treatment affects the predictive value of clinical findings in cardiac arrest patients, raising the question whether the predictive value of N20 responses has changed as well. Methods: We retrospectively studied 185 consecutive patients treated with hypothermia after cardiac arrest. SEP recordings were available for 112 patients. SEPs were classified as bilateral absent N20, pathologic N20, or normal. Baseline and follow-up information were obtained from our database. Results: We identified 36 patients with bilateral absent N20, 35 (97%) of whom had poor outcome. One patient had prolonged high amplitude peripheral SEP, but bilaterally absent N20 3 days after cardiac arrest and regained consciousness with normal cognitive functions and reproducible N20 responses. One further patient had minimally detectable N20 at day 3 and recovered consciousness and normal N20 responses on follow-up. Conclusions: Our data indicate that recovery of consciousness and cognitive functions is possible in spite of absent or minimally present N20 responses more than 24 hours after cardiac arrest in a very small proportion of patients. N20 responses may recover beyond this time window. The predictive value of bilateral absent N20 responses needs to be reevaluated in larger prospective studies. Until these studies are available, decisions to stop therapy in cardiac arrest survivors should not be based on N20 responses alone.

Mild therapeutic hypothermia alters neuron specific enolase as an outcome predictor after resuscitation: 97 prospective hypothermia patients compared to 133 historical non-hypothermia patients

IntroductionNeuron specific enolase (NSE) has been proven effective in predicting neurological outcome after cardiac arrest with a current cut off recommendation of 33 μg/l. However, most of the corresponding studies were conducted before the introduction of mild therapeutic hypothermia (MTH). Therefore we conducted a study investigating the association between NSE and neurological outcome in patients treated with MTHMethodsIn this prospective observational cohort study the data of patients after cardiac arrest receiving MTH (n = 97) were consecutively collected and compared with a retrospective non-hypothermia (NH) group (n = 133). Serum NSE was measured 72 hours after admission to ICU. Neurological outcome was classified according to the Pittsburgh cerebral performance category (CPC 1 to 5) at ICU discharge.ResultsNSE serum levels were significantly lower under MTH compared to NH in univariate analysis. However, in a linear regression model NSE was affected significantly by time to return of spontaneous circulation (ROSC) and ventricular fibrillation rhythm but not by MTH. The model for neurological outcome identified NSE, NSE*MTH (interaction) as well as time to ROSC as significant predictors. Receiver Operating Characteristic (ROC) analysis revealed a higher cutoff value for unfavourable outcome (CPC 3 to 5) with a specificity of 100% in the hypothermia group (78.9 μg/l) compared to the NH group (26.9 μg/l).ConclusionsRecommended cutoff levels for NSE 72 hours after ROSC do not reliably predict poor neurological outcome in cardiac arrest patients treated with MTH. Prospective multicentre trials are required to re-evaluate NSE cutoff values for the prediction of neurological outcome in patients treated with MTH.

The prefrontal substrate of reflexive saccade inhibition in humans.

BACKGROUND Prefrontal dysfunction in neuropsychiatric disorders such as schizophrenia has been shown to impair inhibition of reflexive saccadic eye movements; however, it is unclear whether reflexive saccade inhibition can be attributed to a distinct subregion of the human prefrontal cortex. METHODS We tested 15 patients with acute unilateral ischemic lesions of the prefrontal cortex and 20 control subjects with an antisaccade task. Lesions were reconstructed using Talairach coordinates, and possible candidate regions for reflexive saccade inhibition were identified. RESULTS Significantly increased antisaccade error rates were observed in patients with lesions affecting a region in mid-dorsolateral prefrontal cortex or the white matter between this region and the anterior portions of the internal capsule. Antisaccade error rates of patients with lesions outside this region were normal. These findings were largely independent of lesion volume, postlesion delay, and subject age. CONCLUSIONS Our findings suggest that inhibition of reflexive saccades depends on a circumscribed subregion of the human dorsolateral prefrontal cortex. This region closely corresponds to Brodmann area 46 as defined by recent cytoarchitectonic studies. Increased antisaccade error rates in patients with prefrontal pathology may be explained by dysfunction of this region.

Cortical control of ocular saccades in humans: a model for motricity.

Our knowledge of the cortical control of saccadic eye movements (saccades) in humans has recently progressed mainly thanks to lesion and transcranial magnetic stimulation (TMS) studies, but also to functional imaging. It is now well-known that the frontal eye field is involved in the triggering of intentional saccades, the parietal eye field in that of reflexive saccades, the supplementary eye field (SEF) in the initiation of motor programs comprising saccades, the pre-SEF in learning of these programs, and the dorsolateral prefrontal cortex (DLPFC) in saccade inhibition, prediction and spatial working memory. Saccades may also be used as a convenient model of motricity to study general cognitive processes preparing movements, such as attention, spatial memory and motivation. Visuo-spatial attention appears to be controlled by a bilateral parieto-frontal network comprising different parts of the posterior parietal cortex and the frontal areas involved in saccade control, suggesting that visual attentional shifts and saccades are closely linked. Recently, our understanding of the cortical control of spatial memory has noticeably progressed by using the simple visuo-oculomotor model represented by the memory-guided saccade paradigm, in which a single saccade is made to the remembered position of a unique visual item presented a while before. TMS studies have determined that, after a brief stage of spatial integration in the posterior parietal cortex (inferior to 300 ms), short-term spatial memory (i.e. up to 15-20 s) is controlled by the DLPFC. Behavioral and lesion studies have shown that medium-term spatial memory (between 15-20 s and a few minutes) is specifically controlled by the parahippocampal cortex, before long-term memorization (i.e. after a few minutes) in the hippocampal formation. Lastly, it has been shown that the posterior part of the anterior cingulate cortex, called the cingulate eye field, is involved in motivation and the preparation of all intentional saccades, but not in reflexive saccades. These different but complementary study methods used in humans have thus contributed to a better understanding of both eye movement physiology and general cognitive processes preparing motricity as whole.

Functional and structural brain changes in anti-N-methyl-D-aspartate receptor encephalitis.

Anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis with a characteristic neuropsychiatric syndrome and severe and prolonged clinical courses. In contrast, standard clinical magnetic resonance imaging (MRI) remains normal in the majority of patients. Here, we investigated structural and functional brain changes in a cohort of patients with anti‐NMDAR encephalitis.

A direct prefrontotectal tract against distractibility in the human brain

Distractibility, which can be defined as an attention deficit in which orientation toward irrelevant targets can be hardly inhibited, is commonly related to a dysfunction of the dorsolateral prefrontal cortex. Here, we show that increased distractibility, observed in a patient with an exceptionally small lesion located in the upper brainstem, may result from the interruption of a direct tract that connects the prefrontal cortex to the superior colliculus, a structure involved in both eye movement control and attentional shifts. Ann Neurol 2003;53:542–545

Improvement of memory guided saccades in parkinsonian patients by high frequency subthalamic nucleus stimulation

Recent studies in the monkey suggest that the subthalamic nucleus (STN) is involved in control of eye movement, yet its functional significance in humans is unknown. Saccadic eye movements were studied in eight parkinsonian patients treated by bilateral electrical stimulation of the STN. STN stimulation improved the accuracy of memory guided saccades but not of reflexive visually guided saccades and had no effect on the antisaccade task. This study shows that, by contrast with levodopa, STN stimulation improves memory guided saccade deficits, and illustrates for the first time in humans the role of the STN in the control of purposive saccades.

The Glasgow coma score is a predictor of good outcome in cardiac arrest patients treated with therapeutic hypothermia

BACKGROUND With the recent introduction of therapeutic hypothermia the application of sedation becomes necessary in cardiac arrest patients. We therefore analysed the usefulness of the Glasgow coma score (GCS) for outcome prediction in survivors of cardiac arrest treated with therapeutic hypothermia. PATIENTS AND METHODS In a prospective observational study we identified 72 comatose patients admitted to our intensive care unit after cardiac arrest. All patients were treated with therapeutic hypothermia. After sedation stop the Glasgow coma scale (GCS) was recorded until day 4. Neurological outcome was assessed using the Pittsburgh cerebral performance category (CPC) score. RESULTS Forty-four of 72 patients (61%) were discharged with a favourable neurological outcome (CPC 1+2). GCS was significantly higher in patients with good outcome compared to patients with unfavourable outcome at every point in time after sedation stop (p<0.001). The value for prediction of good outcome with the highest accuracy was a GCS>4 at the first day after sedation stop (sensitivity 61%, PPV 90% and AUC 0.808) and GCS>6 in the following days (sensitivity 84%, PPV 92.5% and AUC 0.921 at day 4). In particular a score of >3 on the motor component of the GCS predicted good outcome with a specificity of 100% (sensitivity 43%) at the first day. CONCLUSIONS Our results indicate that monitoring of the GCS is a simple and reliable method for clinical outcome assessment in patients treated with therapeutic hypothermia. Thus, GCS monitoring remains a powerful tool to predict outcome of patients treated with therapeutic hypothermia.

Cortical control of spatial memory in humans: the visuooculomotor model.

We review current knowledge of the cortical control of spatial memory, studied using visuooculomotor paradigms. Spatial memory is an essential cognitive process that can be involved in preparing motor responses. Our knowledge of spatial memory in humans recently has progressed thanks to the use of ocular saccades as a convenient model of motor behavior. Accuracy of memory‐guided saccades, made to the remembered locations of visual targets, is a reflection of spatial memory. For the performance of memory‐guided saccades with brief delays (up to 15–20 seconds), that is, involving short‐term spatial memory, lesion studies have shown that the posterior parietal cortex, the dorsolateral prefrontal cortex, and the frontal eye field play significant roles. Studies of memory‐guided saccades using transcranial magnetic stimulation have suggested that the right posterior parietal cortex is involved at the initial stage (<300 milliseconds) of visuospatial integration, whereas the dorsolateral prefrontal cortex in both hemispheres controls the following phase of short‐term memorization, the frontal eye field mainly serving to trigger saccades. The new concept of a medium‐term spatial memory has emerged from a behavioral study of memory‐guided saccades in normal subjects, showing a paradoxical spontaneous improvement of spatial memory after delays of approximately 20 seconds. Lesion studies have shown that the parahippocampal cortex could specifically control this medium‐term spatial memory. Last, different experimental and clinical arguments suggest that, after a few minutes, the hippocampal formation finally takes over the control of spatial memory for long‐term spatial memorization. Therefore, spatial memory involved in the memorization of visual items could be successively controlled by the dorsolateral prefrontal cortex (short‐term spatial memory), the parahippocampal cortex (medium‐term spatial memory), and the hippocampal formation (long‐term spatial memory), depending on specific periods of times. The applicability of this simple visuooculomotor model of spatial memory to other types of stimuli and general motoricity has yet to be confirmed.