Richard Wennberg

A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease.

Alzheimer disease (AD) is characterized by functional impairment in the neural elements and circuits underlying cognitive and memory functions. We hypothesized that fornix/hypothalamus deep brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits.

Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns

PURPOSE. We sought to evaluate the sensitivity and specificity of total serum bilirubin concentration (TSB) and free (unbound) bilirubin concentration (Bf) as predictors of risk for bilirubin toxicity and kernicterus and to examine consistency between these findings and proposed mechanisms of bilirubin transport and brain uptake. METHODS. A review of literature was undertaken to define basic principles of bilirubin transport and brain uptake leading to neurotoxicity. We then reviewed experimental and clinical evidence that relate TSB or Bf to risk for bilirubin toxicity and kernicterus. RESULTS. There are insufficient published data to precisely define sensitivity and specificity of either TSB or Bf in determining risk for acute bilirubin neurotoxicity or chronic sequelae (kernicterus). However, available laboratory and clinical evidence indicate that Bf is better than TSB in discriminating risk for bilirubin toxicity in patients with severe hyperbilirubinemia. These findings are consistent with basic pharmacokinetic principles involved in bilirubin transport and tissue uptake. CONCLUSIONS. Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.

Phase synchronization measurements using electroencephalographic recordings: what can we really say about neuronal synchrony?

Phase synchrony analysis is a relatively new concept that is being increasingly used on neurophysiological data obtained through different methodologies. It is currently believed that phase synchrony is an important signature of information binding between distant sites of the brain, especially during cognitive tasks. Electroencephalographic (EEG) recordings are the most widely used recording technique for recording brain signals and assessing phase synchrony patterns. In this study, we address the suitability of phase synchrony analysis in EEG recordings. Using geometrical arguments and numerical examples, employing EEG and magnetoencephalographic data, we show that the presence of a common reference signal in the case of EEG recordings results in a distortion of the synchrony values observed, in that the amplitudes of the signals influence the synchrony measured, and in general destroys the intended physical interpretation of phase synchrony.

The contribution of 18F-FDG PET in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy: A meta-analysis

OBJECTIVE To assess the predictive diagnostic added value of positron emission tomography (PET) in preoperative epilepsy surgery evaluation for patients with temporal lobe epilepsy (TLE). METHODS A meta-analysis of publications from 1992 to 2006 was performed. Forty-six studies were identified that met inclusion criteria presenting detailed diagnostic test results and a classified postoperative outcome. Studies exclusively reporting on patients with brain tumors or on children were excluded. RESULTS The analyses were complicated by significant differences in study design and often by lack of precise patient data. Ipsilateral PET hypometabolism showed a predictive value of 86% for good outcome. The predictive value was 80% in patients with normal MRI and 72% in patients with non-localized ictal scalp EEG. In a selected population of 153 TLE patients with a follow-up of >12 months PET correlated well with other non-invasive diagnostic tests, but none of the odds ratios of any test combination was significant. CONCLUSION Our data confirm that ipsilateral PET hypometabolism may be an indicator for good postoperative outcome in presurgical evaluation of drug-resistant TLE, although the actual diagnostic added value remained questionable and unclear. PET does not appear to add value in patients localized by ictal scalp EEG and MRI. Prospective studies limited to non-localized ictal scalp EEG or MRI-negative patients are required for validation.

Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology

Background: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimers disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established. Also, the prevalence of CTE among athletes with multiple concussions is unknown. Methods: We performed a consecutive case series brain autopsy study on six retired professional football players from the Canadian Football League (CFL) with histories of multiple concussions and significant neurological decline. Results: All participants had progressive neurocognitive decline prior to death; however, only 3 cases had post-mortem neuropathological findings consistent with CTE. The other 3 participants had pathological diagnoses of AD, amyotrophic lateral sclerosis (ALS), and Parkinsons disease (PD). Moreover, the CTE cases showed co-morbid pathology of cancer, vascular disease, and AD. Discussion: Our case studies highlight that not all athletes with history of repeated concussions and neurological symptomology present neuropathological changes of CTE. These preliminary findings support the need for further research into the link between concussion and CTE as well as the need to expand the research to other possible causes of taupathy in athletes. They point to a critical need for prospective studies with good sampling methods to allow us to understand the relationship between multiple concussions and the development of CTE.

Tonic seizures: A diagnostic clue of anti-LGI1 encephalitis?

Seizures and memory loss are common features of anti-LGI1 limbic encephalitis,1 a recently described autoimmune encephalitis, previously attributed to voltage-gated potassium channel antibodies (VGKC-ab).2,3 Abnormal involuntary movements are frequently seen in patients diagnosed with anti-LGI1 limbic encephalitis. However, to date it is not clear if these abnormal movements represent seizures or an extrapyramidal movement disorder. Here we describe 3 patients with anti-LGI1 limbic encephalitis, who presented with severe movement abnormalities that were associated with ictal EEG changes. ### Methods. We present 3 female patients (ages 80, 46, and 72) with similar features. #### Clinical features. All patients developed abnormal movements of face, shoulders, arms, or legs (videos 1–3 on the Neurology ® Web site at www.neurology.org). These strong, massive movements were slightly slower than typical myoclonus, occurring 5 to 100 times per day. Their consciousness was preserved during the movements. #### EEG. Continuous video-EEG recordings showed that the longer movements were clearly associated with generalized EEG electrodecremental events (EDEs), usually preceding the onset of movement by approximately 500 msec (figure), a pattern typical of epileptic tonic …

Unbound (Free) Bilirubin: Improving the Paradigm for Evaluating Neonatal Jaundice

BACKGROUND The serum or plasma total bilirubin concentration (B(T)) has long been the standard clinical laboratory test for evaluating neonatal jaundice, despite studies showing that B(T) correlates poorly with acute bilirubin encephalopathy (ABE) and its sequelae including death, classical kernicterus, or bilirubin-induced neurological dysfunction (BIND). The poor correlation between B(T) and ABE is commonly attributed to the confounding effects of comorbidities such as hemolytic diseases, prematurity, asphyxia, or infection. Mounting evidence suggests, however, that B(T) inherently performs poorly because it is the plasma non-protein-bound (unbound or free) bilirubin concentration (B(f)), rather than B(T), that is more closely associated with central nervous system bilirubin concentrations and therefore ABE and its sequelae. CONTENT This article reviews (a) the complex relationship between serum or plasma bilirubin measurements and ABE, (b) the history underlying the limited use of B(f) in the clinical setting, (c) the peroxidase method for measuring B(f) and technical and other issues involved in adapting the measurement to routine clinical use, (d) clinical experience using B(f) in the management of newborn jaundice, and (e) the value of B(f) measurements in research investigating bilirubin pathochemistry. SUMMARY Increasing evidence from clinical studies, clinical experience, and basic research investigating bilirubin neurotoxicity supports efforts to incorporate B(f) expeditiously into the routine evaluation of newborn jaundice.

Intraoperative localization of an epileptogenic focus with alfentanil and fentanyl

We evaluated the effectiveness of alfentanil and fentanyl in stimulating epileptogenic activity during surgery for intractable temporal lobe epilepsy under general anesthesia. Ten patients received a standardized anesthetic induction with IV fentanyl 5 mg/kg, propofol 3‐5 mg/kg, and atracurium 0.5 mg/kg. Maintenance was with isoflurane, 70% N2O/30% O2, and an atracurium infusion. After dural opening, droperidol 0.02 mg/kg was administered IV. Both inhaled anesthetics were discontinued and verified to be at 0 endtidal concentration before the study. Baseline electrocorticography over the surface of the temporal lobe and depth electrode recordings in the amygdala and hippocampus were obtained, followed by 10 min of recording before and after the IV administration of both alfentanil 50 mg/kg and fentanyl 10 mg/kg. Any changes in cardiovascular variables were documented. The number of interictal epileptiform spikes at the most active site for each patient was tabulated before and after the administration of each drug. Both alfentanil and fentanyl induced an increase in spike activity in all patients. Alfentanil was more potent, increasing the median number of spikes per epoch from 18 to 58, compared with fentanyl (20 to 42 spikes) (P , 0.05). Alfentanil had a shorter duration of action (4.9 6 1.3 min) compared with fentanyl (8.5 6 2 min) (P , 0.009). In nine patients, the most active site was the hippocampus or amygdala. There was a decrease in mean blood pressure, but only after the administration of alfentanil (P , 0.05). Two patients had electrographic evidence of seizure activity. These opioids can be used to assist in the localization of the epileptogenic focus during surgery. Implications: Both alfentanil and fentanyl activate epileptiform activity in patients with temporal lobe epilepsy. These opioids can be used to assist in the localization of the epileptogenic focus during surgery.

EEG and MEG in mesial temporal lobe epilepsy: Where do the spikes really come from?

OBJECTIVE There is persistent debate as to whether or not EEG and MEG recordings in patients with mesial temporal lobe epilepsy (MTLE) can detect mesial temporal interictal epileptiform discharges (spikes), and this issue is particularly relevant for source localization studies. With the aim of providing direct evidence pertinent to this debate we present detailed examples of the intracranial sources of spikes recorded with EEG and MEG in MTLE. METHODS Spikes recorded in five different patients with MTLE during intracranial EEG (n=2), intraoperative electrocorticography (ECOG; n=1), combined scalp-intracranial EEG (n=2) and combined EEG-MEG (n=1) were analyzed and the intracranial sources of the spike foci were matched with their corresponding extracranial EEG and/or MEG fields. EEG and MEG dipole source localization was performed on six independent spike foci identified in one representative patient with bilateral MTLE. RESULTS Spikes with an electrical field maximal at F7/8, F9/10≥T3/4 were generated in the anterolateral temporal neocortex. The absence of coincident spiking at mesial locations indicated that these were not propagated from or to the hippocampus. Spikes with an electrical field maximal at T3/4≥T9/10 were generated in the lateral temporal neocortex and likewise did not involve the hippocampus. Individual spikes generated in the mesiobasal temporal neocortex, including the fusiform gyrus, were difficult to detect with EEG (low amplitude diphasic waves most apparent after spike averaging at T3/4, T9/10≥T5/6, P9/10) and only slightly more identifiable with MEG. Spikes generated within and confined to the mesial temporal structures, as confirmed by intracranial recordings, could not be detected with EEG or MEG. Notably, such spikes could not be detected even at intracranial recording sites on the lateral surface of the temporal lobe. CONCLUSIONS We present detailed evidence in a small case series showing that typical anterior temporal spikes recorded with EEG and MEG in MTLE arose from the anterolateral temporal neocortex and were neither propagated from nor to the hippocampus. Mid temporal EEG spikes were localized to the lateral temporal neocortex. Intracranially detected mesial temporal spikes were not detected with EEG or MEG. SIGNIFICANCE The spikes recorded with EEG and MEG in MTLE are localized to neocortical foci, and not to the mesial temporal structures. Current noninvasive EEG and MEG source localization studies cannot accurately identify true mesial temporal spikes.

Risk Factors for Neurotoxicity in Newborns With Severe Neonatal Hyperbilirubinemia

OBJECTIVE: To evaluate the importance of total serum bilirubin (TSB) and neurotoxicity risk factors in predicting acute bilirubin encephalopathy (ABE) at admission or posttreatment bilirubin encephalopathy (BE) in infants with severe hyperbilirubinemia. METHODS: We analyzed the interaction of TSB and risk factors as determinants of ABE and BE in 249 newborns admitted with a TSB level of ≥25 mg/dL (427 μmol/L) to Cairo University Childrens Hospital during a 12-month period. RESULTS: Admission TSB values ranged from 25 to 76.4 mg/dL. Forty-four newborns had moderate or severe ABE at admission; 35 of 249 infants (14%) had evidence of BE at the time of discharge or death. Rh incompatibility (odds ratio [OR]: 48.6) and sepsis (OR: 20.6) greatly increased the risk for ABE/BE, but TSB levels correlated poorly with the presence or absence of ABE or BE in these patients. The OR for ABO incompatibility with anemia (1.8) was not statistically significant. Low admission weight (OR: 0.83 per 100 g) increased the risk for BE, especially when other risk factors were present. The threshold TSB level that identified 90% of infants with ABE/BE was 25.4 mg/dL when neurotoxicity risk factors were present. In contrast, neurotoxicity was first observed at a TSB level of >31.5 mg/dL in 111 infants without risk factors. CONCLUSIONS: Newborns without risk factors for neurotoxicity have a higher tolerance for hyperbilirubinemia than recognized in management guidelines. The risk for BE in hemolytic disease varies with etiology. The great variation in response to TSB indicates that biological factors other than TSB values are important in the pathogenesis of BE.