Ictal and interictal electric source imaging in pre-surgical evaluation: a prospective study.

BACKGROUND AND PURPOSE: Accurate localization of the epileptic focus is essential for surgical treatment of patients with drug-resistant epilepsy. Electric source imaging (ESI) is increasingly used in pre-surgical evaluation. However, most previous studies have analysed interictal (II) discharges. Prospective studies comparing the feasibility and accuracy of II and ictal (IC) ESI are lacking. METHODS: We prospectively analysed long-term video-electroencephalography recordings (LTM) of patients admitted for pre-surgical evaluation. We performed ESI of II and IC signals using two methods, i.e. equivalent current dipole (ECD) and a distributed source model (DSM). LTM recordings employed the standard 25-electrode array (including inferior temporal electrodes). An age-matched template head model was used for source analysis. Results were compared with intracranial recordings, conventional neuroimaging methods [magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT)] and outcome at 1 year after surgery. RESULTS: A total of 87 consecutive patients were analysed. ECD gave a significantly higher proportion of patients with localized focal abnormalities (94%) compared with MRI (70%), PET (66%) and SPECT (64%). Agreement between the ESI methods and intracranial recording was moderate to substantial (k = 0.56-0.79). A total of 54 patients were operated (47 patients more than 1 year ago) and 62% of them became seizure-free. The localization accuracy of II-ESI was 51% for DSM and 57% for ECD, and that for IC-ESI was 51% for DSM and 62% for ECD. The differences between the ESI methods were not significant. Differences in localization accuracy between ESI and MRI (55%), PET (33%) and SPECT (40%) were not significant. CONCLUSIONS: The II-ESI and IC-ESI of LTM data have high feasibility and their localization accuracy is similar to that of conventional neuroimaging methods.

Efficacy of the Danish epilepsy surgery programme.

OBJECTIVE: Despite optimal medical treatment, approximately one-third of patients with epilepsy continue to have seizures. Epilepsy surgery is widely accepted as a therapeutic option in the selected subset of patients with drug-resistant focal epilepsy. Here, we report the results of the Danish epilepsy surgery programme from 2009 to 2014. MATERIAL AND METHODS: A total of 169 consecutive patients, operated at Rigshospitalet, were included. Information was gathered from digital patient records. Before 1-year follow-up, two patients were lost to follow-up and three were referred to new surgery. RESULTS: The median years of drug resistance before operation were 11 years. At 1-year follow-up (n = 164), seizure outcomes were as follows: 65% Engel I (free from disabling seizures), 51% Engel IA (completely seizure free) and 9% Engel IV (no worthwhile improvement), and for patients operated in the medial temporal lobe (n = 114): 70% Engel I, 56% Engel IA, 5% Engel IV. The outcomes of the 53 patients needing intracranial EEG recording (ICR) were not significantly different from the patients only evaluated with surface EEG. None of the eight MRI-negative patients operated outside the medial temporal lobe after ICR were free of disabling seizures. 12% of MTLE patients developed de novo depression after epilepsy surgery despite good surgical outcome. Three patients required rehabilitation due to post-operative hemiplegia. CONCLUSION: The outcomes of the Danish epilepsy surgery programme align with international results found in recent meta-analyses. Serious complications to epilepsy surgery are seldom. In accordance with international recommendations, Danish drug-resistant patients should be referred to epilepsy surgery evaluation at an earlier stage of the disease.

Posttraumatic hypopituitarism is associated with an unfavorable body composition and lipid profile, and decreased quality of life 12 months after injury.

OBJECTIVE: Our objective was to describe body composition, lipid profile, and health-related quality of life (HRQL) in patients with traumatic brain injury (TBI) in relation to the development of posttraumatic hypopituitarism. DESIGN: This is a cross-sectional evaluation with a nested prospective substudy. PATIENTS: The cross-sectional cohort included 104 hospitalized patients with TBI [26 females/78 males; median age 41 yr (range 18-64); body mass index (BMI) 25 kg/m(2) (range 17-39); and severity, mild (Glasgow Coma Scale score (GCS) 13-15) n = 44, moderate (GCS 9-12) n = 20, and severe (GCS <9) n = 40)]. A nested cohort of 46 patients was followed prospectively. MEASUREMENTS: BMI, waist circumference, lipid profile, total- and regional-fat mass were assessed 3 and 12 months (prospective) or only 12 months (cross-sectional) posttraumatically. HRQL questionnaires (Nottingham Health Profile, EuroQoL-5D, and the GH deficiency (GHD) specific instrument, Quality of Life Assessment of GHD in Adults) were completed "pre-traumatically," 3 and 12 months (prospective), or only 12 months (cross-sectional) posttraumatically. RESULTS: Patients with posttraumatic hypopituitarism had higher age-, gender-, and BMI-adjusted 12-month low-density lipoprotein-cholesterol, waist circumference, and total fat mass (P < 0.05 in all cases), and a higher increase in total cholesterol (P = 0.01) during follow-up compared with sufficient patients. These findings were unrelated to 12-month IGF-I and IGF-I sd scores. Hypopituitary patients also had worse age, BMI, and TBI severity adjusted overall EuroQoL-5D visual analog scale (P = 0.03) and Quality of Life Assessment of GHD in Adults (P = 0.01) scores, and worse Nottingham Health Profile dimension scores of sleep (P = 0.03), energy (P = 0.02), and social isolation (P = 0.04), compared with patients with an intact pituitary function. CONCLUSION: Posttraumatic hypopituitarism was an independent predictor of the classical phenotypical features of hypopituitarism, including an unfavorable lipid and body composition profile, as well as worsened HRQL.

Prevalence and predictive factors of post-traumatic hypopituitarism.

OBJECTIVE: To estimate the prevalence and predictive factors of hypopituitarism following traumatic brain injury (TBI). DESIGN: A cross-sectional cohort study. PATIENTS: One hundred and four hospitalized TBI patients (26F/78M), median age 41 (range 18-64) years, body mass index (BMI) 25 (17-39) kg/m(2); severity: mild [Glasgow Coma Scale (GCS) score 13-15) n = 44, moderate (GCS 9-12) n = 20, severe (GCS < 9) n = 40]. MEASUREMENTS: Patients were evaluated 13 (10-27) months post-injury, with measurement of baseline (0800-1000 h) and post-stimulatory hormonal levels during an insulin tolerance test (ITT) (86%) or, if contraindicated, an arginine(arg)-GHRH test + Synacthen test (14%). Insufficiencies were confirmed by retesting. RESULTS: Hypopituitarism was found in 16 (15%) patients, affecting one axis in 10, two axes in four and more than two axes in two patients. The GH axis was most frequently affected (15%), followed by secondary hypoadrenalism (5%), hypogonadism (2%), hypothyroidism (2%) and diabetes insipidus (2%). The risk of pituitary insufficiency was increased in patients with severe TBI as opposed to mild TBI [odds ratio (OR) 10.1, 95% confidence interval (CI) 2.1-48.4, P = 0.004], and in those patients with increased intracerebral pressure [OR 6.5, 95% CI 1.0-42.2, P = 0.03]. Patients with only one affected axis were all GH deficient; 60% (n = 6) of these were overweight or obese. CONCLUSION: The prevalence of hypopituitarism was estimated at 16%. Although high, this value was lower than previously reported, and may still be overestimated because of well-known confounding factors, such as obesity. Indicators of increased TBI severity were predictive of hypopituitarism, with a high negative predictive value. Neuroendocrine evaluation should therefore be considered in patients with severe TBI, and in particular in those with increased intracerebral pressure (ICP).

What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment.

Idiopathic intracranial hypertension (IIH) is the syndrome of raised intracranial pressure without clinical, laboratory or radiological evidence of intracranial pathology. IIH is a relatively rare disease but rapidly increasing incidence is reported due to a global increasing incidence of obesity. Disease course is generally said to be self-limiting within a few months. However, some patients experience a disabling condition of chronic severe headache and visual disturbances for years that limit their capacity to work. Permanent visual defects are serious and not infrequent complications. The pathophysiology of IIH is still not fully understood. Advances in neuroimaging techniques have facilitated the exclusion of associated conditions that may mimic IIH. No causal treatment is yet known for IIH and existing treatment is symptomatic and rarely sufficient. The aim of this review is to provide an updated overview of this potentially disabling disease which may show a future escalating incidence due to obesity. Theories of pathogenesis, diagnostic criteria and treatment strategies are discussed.

Effect of naloxone on primary and secondary hyperalgesia induced by the human burn injury model.

BACKGROUND: Opioid antagonists may change the responses in models of experimental hyperalgesia. This indicates a possible involvement of the endogenous opioid system in these models. The aim of the present study was to evaluate whether activation of the endogenous opioid system could be demonstrated in the human burn injury model of cutaneous hyperalgesia, using an intravenous challenge with the non-selective opioid antagonist naloxone. METHODS: We studied 25 healthy male volunteers aged 20-31 yrs in a randomised, double-blind, triple crossover design. A 25x50 mm rectangular burn injury was produced on the calf on 3 separate days, at least 1 week apart. Subjects received an intravenous bolus dose of naloxone 0.4 mg, 10 mg or placebo 3 h after induction of the burn injury. RESULTS: Primary and secondary hyperalgesia was induced by the burn injury. Naloxone did not affect any of the measured variables: heat pain detection threshold in non-injured or injured tissue, pain produced by short or prolonged noxious heat in non-injured or injured tissue, secondary hyperalgesia elicited by pin prick or stroke, or pain produced by short or prolonged noxious mechanical stimulation in non-injured tissue. No significant adverse effects of naloxone were encountered. CONCLUSIONS: Activation of an endogenous opioid response following induction of hyperalgesia in human volunteers by a burn injury could not be demonstrated with an intravenous naloxone challenge. These findings suggest that the endogenous opioid response is not a confounding factor in this model.

European neurosurgical education--the next generation.

Questionnaires regarding neurosurgical training were sent to all participants of the EANS-training course in Barcelona 1999 and to all national neurosurgical societies of EANS. The completed questionnaires show a significant variation in 1) the demands for education prior to obtaining a neurosurgical training position, 2) in the theoretical training programme and 3) in the surgical experience obtained within the training period. The trainees express a need for improvement of the neurosurgical training programmes. The need for common guidelines for European neurosurgical training as well as regular evaluation of the training programmes are discussed.

Effect of oral ketamine on secondary hyperalgesia, thermal and mechanical pain thresholds, and sedation in humans.

BACKGROUND AND OBJECTIVES: Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and has been proven effective in alleviating secondary hyperalgesia in human subjects when injected intravenously. After oral ingestion, ketamine is metabolized into norketamine, which in vitro possesses NMDA receptor antagonistic effect. The aim of this study was to investigate the effects of oral administration of ketamine on secondary hyperalgesia evoked by standardized tissue injury. METHODS: Twenty-four male volunteers were included in the study. Each volunteer received the following treatment regimen, in randomized, double-blind, 3-way cross-over fashion: (A) placebo; (B) ketamine, 0.5 mg/kg; and (C) ketamine, 1.0 mg/kg. Standardized tissue injury was induced after study medication by heating the right calf with a rectangular thermode. The temperature was 47 degrees C, and heating time was 7 minutes. The following parameters were investigated: Pain during induction of the burn injury; heat-pain detection thresholds in the injured area and a corresponding noninjured area; secondary hyperalgesia surrounding the injured area on the calf; secondary hyperalgesia induced by heating an area on the thigh with 45 degrees C in 3 minutes; pressure-pain detection thresholds measured on the middle phalanx of the 4th left finger; pain during a 60-second thermal stimulation of 46 degrees C on undamaged skin on the left thigh; and side effects. RESULTS: Some degree of sedation was observed after oral administration of ketamine. No effects on any of the other investigated parameters were observed. CONCLUSION: Oral ketamine 0.5 or 1.0 mg/kg has no effect on secondary hyperalgesia or thermal or mechanical pain thresholds in human volunteers.

The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans.

BACKGROUND: The (NMDA) receptor plays a significant role in wind-up and spinal hypersensitivity and is involved in the occurrence of secondary hyperalgesia. Ketamine is an NMDA-receptor antagonist and has proven effective in alleviating secondary hyperalgesia in humans. Although it is disputed, the actions of ketamine have been ascribed not only to NMDA receptor antagonism, but also to opioid receptor agonism. A study therefore was designed in which the abolishment of a previously demonstrated effect of ketamine on secondary hyperalgesia was sought by pretreatment with naloxone. METHODS: Twenty-five volunteers were subjected to three treatment regimens. A standardized first-degree burn injury was induced. On appearance of primary and secondary hyperalgesia, one of the following infusion schemes was applied in a randomized, double-blind, cross-over fashion: (1) infusion of naloxone (0.8 mg/15 min followed by 0.4 mg/h), succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); (2) infusion of placebo, succeeded by infusion of ketamine (0.3 mg x kg(-1) x 15 min(-1) followed by 0.3 mg x kg(-1) x h(-1)); and (3) infusion of placebo, succeeded by infusion of placebo. Heat-pain detection thresholds, magnitude of secondary hyperalgesia around the burn injury, and side effects were determined. RESULTS: Ketamine reduced secondary hyperalgesia. Naloxone did not affect the action of ketamine. The magnitudes of side effects were equal if the subjects received ketamine, regardless of preceding infusion of naloxone. CONCLUSIONS: In this experimental setting, opioid receptor blockade does not inhibit ketamine-induced reductions of secondary hyperalgesia.

Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery.

We studied 60 patients undergoing operation on the kidney with combined general and epidural anaesthesia, in a double-blind, randomized, controlled study. Patients were allocated to receive a preoperative bolus dose of ketamine 10 mg i.v., followed by an i.v. infusion of ketamine 10 mg h-1 for 48 h after operation, or placebo. During the first 24 h after surgery, all patients received 4 ml h-1 of epidural bupivacaine 2.5 mg ml-1. From 24 to 48 h after operation, patients received epidural morphine 0.2 mg h-1 preceded by a bolus dose of 2 mg. In addition, patient-controlled analgesia (PCA) with i.v. morphine (2.5 mg, lockout time 15 min) was offered from 0 to 48 h after operation. Patients who received ketamine felt significantly more sedated at 0-24 h, but not at 24-48 h after operation, compared with patients who received placebo (P = 0.002 and P = 0.127, respectively). There were no significant differences in pain (VAS) at rest, during mobilization or cough, PCA morphine consumption, sensory block to pinprick, pressure pain detection threshold assessed with an algometer, touch and pain detection thresholds assessed with von Frey hairs, peak flow or side effects other than sedation. The power of detecting a reduction in VAS scores of 20 mm in our study was 80% at the 5% significance level. We conclude that we were unable to demonstrate an (additive) analgesic or opioid sparing effect of ketamine 10 mg h-1 i.v. combined with epidural bupivacaine at 0-24 h, or epidural morphine at 24-48 h after renal surgery.

[Effects of nitrogen oxide donor glyceryl trinitrate on pressure pain threshold in humans]. / Effekten af nitrogenoxiddonoren glyceryltrinitrat på humane smertetaerskler for tryk.

The purpose of the present study was to examine the effect of the nitric oxide (NO) donor glyceryl trinitrate (GTN) on nociceptive thresholds in man. On two different study days twelve healthy subjects received a stair case infusion of GTN (0.015, 0.25, 1.0, 2.0 micrograms/kg/min 20 min each dose) or placebo in a randomized double-blind cross-over design. Before the infusion and after 15 min of infusion on each dose, pressure pain detection- and tolerance thresholds were determined by pressure algometry in three different anatomic regions (finger, a temporal region with interposed myofascial tissue and a temporal region without interposed myofascial tissue). Relative to placebo the three higher GTN doses induced a decrease in both detection- and tolerance-thresholds in the temporal region with interposed myofascial tissue. No such changes were observed in the two other stimulated regions. These results could reflect central facilitation of nociception by NO. However, convergence of nociceptive input from pericranial myofascial tissue and from cephalic blood vessels dilated by NO may provide a more likely explanation.

Experimental evaluation of the analgesic effect of ibuprofen on primary and secondary hyperalgesia.

The analgesic effect of systemic ibuprofen was investigated with two human experimental pain models: (i) static mechanical stimulation of the inter digital web between the 2nd and 3rd finger and (ii) primary and secondary hyperalgesia induced by a 7-min burn injury on the calf. In each double-blind, randomized, two-way cross-over study 20 healthy male volunteers received either ibuprofen 600 mg or placebo tablets. Ibuprofen reduced pain evoked by static mechanical pressure in normal skin and by motor brush stimulation in the area of secondary hyperalgesia following burn injury. In contrast, ibuprofen did not reduce the area of secondary hyperalgesia to either pinprick or stroke following burn injury. Previous human experimental studies concerning the analgesic effect of NSAIDs are reviewed. Based on the previous literature and the present results we suggest that NSAIDs inhibit progressive tactile hypersensitivity but not the central sensitization itself.

Effect of systemic N-methyl-D-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans.

Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist known to inhibit wind-up and central hyperexcitability of dorsal horn neurones. We studied 24 healthy, unmedicated male volunteers, aged 21-28 yr, in a randomized, double-blind, placebo-controlled, crossover study. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On three separate days, at least 1 week apart, subjects were given oral dextromethorphan 60 mg, 120 mg or placebo. Dextromethorphan reduced the magnitude of secondary hyperalgesia to pinprick but not to stroke. Dextromethorphan had no influence on primary hyperalgesia, pain during prolonged noxious heat stimulation or heat pain detection thresholds in undamaged skin. Side effects were frequent but clinically acceptable. The effects of dextromethorphan were in agreement with experimental studies indicating that dextromethorphan is a NMDA receptor antagonist. The effects of dextromethorphan in the burn injury model were similar to those of ketamine and distinct from those of local anaesthetics and opioids.

Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans.

Ketamine reduces nociception by binding noncompetitively to the N-methyl-D-aspartate (NMDA) receptor, activation of which increases spinal hypersensitivity. We studied 19 healthy, unmedicated male volunteers, aged 20-31 yr. Burn injuries were produced on the medial surface of the dominant calf with a 25 x 50 mm rectangular thermode. On 3 separate days, at least 1 week apart, subjects received a bolus of either ketamine 0.15 mg kg-1, ketamine 0.30 mg kg-1 or placebo, delivered by a mechanical infusion pump over 15 min. The bolus was followed by continuous infusion of ketamine 0.15 mg kg-1 h-1, ketamine 0.30 mg kg-1 h-1 or placebo, respectively, for 135 min. Ketamine reduced the magnitude of both primary and secondary hyperalgesia, and also pain evoked by prolonged noxious heat stimulation, in a dose-dependent manner. In contrast, ketamine did not alter phasic heat pain perception (perception of transient, painful, thermal stimuli) in undamaged skin. The analgesic effects of ketamine in the burn injury model are in agreement with results from experimental studies, and can be distinguished from those of local anaesthetics and opioids. Side effects caused by continuous infusion of ketamine 0.15 and 0.30 mg kg-1 h-1 were frequent but clinically acceptable.

Exteroceptive suppression of temporal muscle activity is normal in chronic tension-type headache and not related to actual headache state.

The aim of the present study was to compare the late exteroceptive suppression period (ES2) of temporalis muscle activity between patients with chronic tension-type headache and healthy controls, and to investigate the influence, if any, of actual headache on ES2. ES2 was recorded in 55 patients and in 55 controls with a previously evaluated methodology and analysed by a blinded observer. The first 20 patients were randomly studied on 2 additional days, 1 day with and 1 day without headache. The duration of ES2 did not differ between patients and controls and did not differ on days with headache compared with days without headache. ES2 duration was not related to the frequency of headache, headache intensity, age, pericranial muscle tenderness or electrical pain threshold. Our results strongly indicate that ES2 is normal in chronic tension-type headache and therefore may not be related to the pathophysiology of this disorder.

Effect of preemptive nerve block on inflammation and hyperalgesia after human thermal injury.

BACKGROUND: Postoperative pain relief may be improved by reducing sensitization of nociceptive pathways caused by surgical trauma. Such a reduction may depend on the timing and efficacy of analgesia and the duration of the nociceptive block versus the duration of the nociceptive input. We examined whether a prolonged nerve block administered before a superficial burn injury could reduce local inflammation and late hyperalgesia after recovery from the block. METHODS: The effects of a preemptive saphenous nerve block on primary and secondary hyperalgesia, skin erythema, and blister formation, were compared to the opposite unblocked leg for 12 h after bilateral thermal injuries (15 x 25 mm, 49 degrees C for 5 min) in 20 healthy volunteers. Recovery from the block was identified by return of sensation to cold. RESULTS: Six subjects were excluded because of insufficient initial block (2 subjects) or because the block lasted beyond the study period (4 subjects). The remaining 14 subjects experienced significantly reduced primary (P = 0.005) and secondary hyperplasia (P = 0.01) in the blocked leg after return of cold sensation compared to the unblocked leg. Erythema intensity and blister formation were not significantly affected by the blockade (P = 0.94 and P = 0.07, respectively). CONCLUSIONS: These data suggest that a prolonged, preemptive nerve block reduced late hyperalgesia after thermal injury, whereas the erythema and blister formation were not significantly affected.