Gregory J Fitt

Epileptology of the first-seizure presentation: a clinical, electroencephalographic, and magnetic resonance imaging study of 300 consecutive patients

BACKGROUND Prognosis and treatment of the first seizure depends on identification of a specific epilepsy syndrome, yet patients with first seizures are generally regarded as a homogeneous group. We studied whether it is possible to diagnose specific epilepsy syndromes promptly by use of standard clinical methods, electroencephalography (EEG) and magnetic resonance imaging (MRI). METHODS 300 consecutive adults and children presented with unexplained seizures. We systematically collected clinical data from patients and witnesses, and attempted to obtain an EEG within 24 h of the seizure. Where the EEG was negative, a sleep-deprived EEG was done. MRI was done electively. FINDINGS A generalised or partial epilepsy syndrome was clinically diagnosed in 141 (47%) patients. Subsequent analysis showed that only three of these clinical diagnoses were incorrect. Addition of the EEG data enabled us to diagnose an epilepsy syndrome in 232 (77%) patients. EEG within 24 h was more useful in diagnosis of epileptiform abnormalities than later EEG (51 vs 34%). Neuroimaging showed 38 epileptogenic lesions, including 17 tumours. There were no lesions in patients for whom generalised epilepsy was confirmed by EEG. Our final diagnoses were: generalised epilepsy (23% of patients); partial epilepsy (58%); and unclassified (19%). INTERPRETATION An epilepsy syndrome can be diagnosed in most first-seizure patients. Ideally, an EEG should be obtained within 24 h of the seizure followed by a sleep deprived EEG if necessary. MRI aids diagnosis and should be done for all patients except for those with idiopathic generalised epilepsies and for children with benign rolandic epilepsy.

Results of a Multicentre, Randomised Controlled Trial of Intra-Arterial Urokinase in the Treatment of Acute Posterior Circulation Ischaemic Stroke

Background: Patients with ischaemic stroke due to occlusion of the basilar or vertebral arteries may develop a rapid deterioration in neurological status leading to coma and often to death. While intra-arterial thrombolysis may be used in this context, no randomised controlled data exist to support its safety or efficacy. Methods: Randomised controlled trial of intra-arterial urokinase within 24 h of symptom onset in patients with stroke and angiographic evidence of posterior circulation vascular occlusion. Results: Sixteen patients were randomised, and there was some imbalance between groups, with more severe strokes occurring in the treatment arm. A good outcome was observed in 4 of 8 patients who received intra-arterial urokinase compared with 1 of 8 patients in the control group. Conclusions: These results support the need for a large-scale study to establish the efficacy of intra-arterial thrombolysis for acute basilar artery occlusion.

Infected (Mycotic) Aneurysms : Spectrum of Imaging Appearances and Management

Infected aneurysms are uncommon. The aorta, peripheral arteries, cerebral arteries, and visceral arteries are involved in descending order of frequency. Staphylococcus and Streptococcus species are the most common causative pathogens. Early clinical diagnosis of infected aneurysms is challenging owing to their protean manifestations. Clinically apparent infected aneurysms are often at an advanced stage of development or are associated with complications, such as rupture. Nontreatment or delayed treatment of infected aneurysms often has a poor outcome, with high morbidity and mortality from fulminant sepsis or hemorrhage. Current state-of-the-art imaging modalities, such as multidetector computed tomography and magnetic resonance imaging, have replaced conventional angiography as minimally invasive techniques for detection of infected aneurysms in clinically suspected cases, as well as characterization of infected aneurysms and vascular mapping for treatment planning in confirmed cases. Doppler ultrasonography allows noninvasive assessment for infected aneurysms in the peripheral arteries. Imaging features of infected aneurysms include a lobulated vascular mass, an indistinct irregular arterial wall, perianeurysmal edema, and a perianeurysmal soft-tissue mass. Perianeurysmal gas, aneurysmal thrombosis, aneurysmal wall calcification, and disrupted arterial calcification at the site of the infected aneurysm are uncommon findings. Imaging-guided endovascular stent-graft repair and embolotherapy can be performed in select cases instead of open surgery. Familiarity with the imaging appearances of infected aneurysms should alert the radiologist to the diagnosis and permit timely treatment, which may include endovascular techniques.

Ischemic Thresholds for Gray and White Matter. A Diffusion and Perfusion Magnetic Resonance Study

Background and Purpose— Although gray matter (GM) and white matter (WM) have differing neurochemical responses to ischemia in animal models, it is unclear whether this translates into differing thresholds for infarction. We studied this issue in ischemic stroke patients using magnetic resonance (MR) techniques. Methods— MR studies were performed in patients with acute hemispheric ischemic stroke occurring within 24 hours and at 3 months. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and apparent diffusion coefficient (ADC) were calculated. After segmentation based on a probabilistic map of GM and WM, tissue-specific diffusion and perfusion thresholds for infarction were established. Results— Twenty-one patients were studied. Infarction thresholds for CBF were significantly higher in GM (median 34.6 mL/100 g per minute, interquartile range 26.0 to 38.8) than in WM (20.8 mL/100 g per minute; interquartile range 18.0 to 25.9; P<0.0001). Thresholds were also significantly higher in GM than WM for CBV (GM: 1.67 mL/100 g; interquartile range 1.39 to 2.17; WM: 1.19 mL/100 g; interquartile range 0.94 to 1.53; P<0.0001), ADC (GM: 918×10−6 mm2/s; 868 to 975×10−6; WM: 805×10−6; 747 to 870×10−6; P<0.001), and there was a trend toward a shorter MTT in GM (GM 4.94 s, 4.44 to 5.38; WM 5.15, 4.11 to 5.68; P=0.11). Conclusions— GM has a higher infarction threshold for CBF, CBV, and ADC than WM in patients within 24 hours of ischemic stroke onset. Hence, when assessing patients for potential therapies, tissue-specific rather than whole-brain thresholds may be a more precise measure of predicting the likelihood of infarction.

Baseline Blood Pressure but Not Early Computed Tomography Changes Predicts Major Hemorrhage After Streptokinase in Acute Ischemic Stroke

Background and Purpose— Intracerebral hemorrhage is the most serious complication of thrombolytic therapy for stroke. We explored factors associated with this complication in the Australian Streptokinase Trial. Methods— The initial CT scans (≤4 hours after stroke) of 270 patients were reviewed retrospectively by an expert panel for early signs of ischemia and classified into the following 3 categories: no signs or ≤1/3 or >1/3 of the vascular territory. Hemorrhage on late CT scans was categorized as major or minor on the basis of location and mass effect. Stepwise, backward elimination, multivariate logistic regression analysis was used to identify risk factors for each hemorrhage category. Results— Major hemorrhage occurred in 21% of streptokinase (SK) and 4% of placebo patients. Predictors of major hemorrhage were SK treatment (odds ratio [OR], 6.40; 95% CI, 2.50 to 16.36) and elevated systolic blood pressure before therapy (OR, 1.03; 95% CI, 1.01 to 1.05). Baseline systolic blood pressure >165 mm Hg in SK-treated patients resulted in a >25% risk of major secondary hemorrhage. Early ischemic CT changes, either ≤1/3 or >1/3, were not associated with major hemorrhage (OR, 1.58; 95% CI, 0.65 to 3.83; and OR, 1.11; 95% CI, 0.45 to 2.76, respectively). Minor hemorrhage occurred in 30% of the SK and 26% of the placebo group. Predictors of minor hemorrhage were male sex, severe stroke, early CT changes, and SK treatment. Ninety-one percent of patients with major hemorrhage deteriorated clinically compared with 23% with minor hemorrhage. Conclusions— SK increased the risk of both minor and major hemorrhage. Major hemorrhage was also more likely in patients with elevated baseline systolic blood pressure. However, early CT changes did not predict major hemorrhage. Results from this study highlight the importance of baseline systolic blood pressure as a potential cause of hemorrhage in patients undergoing thrombolysis.

Reperfusion after thrombolytic therapy in ischemic stroke measured by single-photon emission computed tomography.

Background and Purpose We used 99mTc-hexamethylpropyleneamine oxime single-photon emission computed tomography (SPECT) to study cerebral perfusion in patients treated with streptokinase for acute ischemic stroke in an open and prospective study. Our primary aims were (1) to compare the extent of reperfusion between patients who had received thrombolytic therapy and a control group studied during the same period who were ineligible to receive such therapy and (2) to determine if, among all patients, reperfusion led to improved outcome. Methods Fifty-seven patients (22 treated with streptokinase) had two SPECT studies performed, the first before streptokinase administration and the second 24 hours later. Results On the first SPECT study hypoperfusion was present in the middle cerebral artery or anterior cerebral artery territories in 40 patients (17 treated with streptokinase). Patients in the treatment and control groups with initial hypoperfusion on SPECT were well matched for the volume of the perfusion defect and the severity of neurological deficit. A greater number of patients who received streptokinase developed at least partial reperfusion (streptokinase, 65%; control, 52%) on the second study but not significantly so (P=.43). Similarly, the proportion of each hypoperfused region that reperfused (P=.74) and the reduction in the size of the perfusion defect (P =.06) were higher in the streptokinase group but did not reach statistical significance. When all patients were considered, those who did not reperfuse had higher mortality rates (P=.008), less neurological improvement (P=.016), and more functional disability (P < .001) than patients who had reperfusion or normal perfusion initially. Conclusions These findings suggest that at least some reperfusion during the first 48 hours of ischemic stroke is a common natural occurrence and is of prognostic significance. The observed trend toward better reperfusion indexes among patients treated with streptokinase is encouraging, but larger controlled trials are required to answer this definitively.

Nimodipine and Perfusion Changes After Stroke

BACKGROUND AND PURPOSE Meta-analysis of previous trials of oral nimodipine in acute stroke has suggested a benefit when commenced within 12 hours of onset. We sought to study the effect of oral nimodipine on reperfusion after acute stroke and the relation between reperfusion and outcome. METHODS Fifty patients with acute middle cerebral artery territory cortical infarction were blindly randomized within 12 hours of onset to either oral nimodipine (30 mg every 6 hours) or placebo. Treatment was continued for 2 weeks. Cerebral blood flow was assessed with the use of 99mTc-hexamethylpropyleneamine oxime single-photon emission CT before therapy, 24 hours later, and at 3 months. Hypoperfusion was measured by a validated volumetric technique. Neurological impairment and functional outcome were assessed with the Canadian Neurological Scale and Barthel Index, respectively. Tissue loss was measured with CT at 3 months. Four patients were excluded from analysis for technical reasons. RESULTS Twenty-three patients received nimodipine, and 23 received placebo. In the nimodipine group, there was early reperfusion that was not maintained at outcome (P=0.01). In the placebo group, mean infarct hypoperfusion volumes showed no overall change. Nonnutritional reperfusion in nimodipine-treated patients was associated with adverse neurological (P=0.05) and functional outcome (P=0.06). There was, however, no difference in clinical outcome between the 2 groups. CONCLUSIONS Oral nimodipine administered within 12 hours enhanced acute reperfusion, but this was largely nonnutritional. Larger studies using a shorter treatment delay are required to evaluate the clinical efficacy of nimodipine in acute ischemic stroke.

The learning curve of pedicle screw placement: how many screws are enough?

Study Design. A retrospective study. Objective. Assess the learning curve of pedicle screw (PS) placement of a Spinal Surgery Fellow (SSF) with no previous experience with the technique. Summary of Background Data. Recent studies have attempted to identify the learning curve for different surgical procedures to define training requirements. Several authors have described a learning curve for PS placement. However, no one has defined the number of PS necessary to be competent in this skill. Methods. All patients who had PS inserted by the SSF under the supervision of an Attending Spinal Consultant (ASC) and had adequate postoperative radiographs and computed tomography scans available, were included in this study. PS position was assessed by 2 blinded independent observers using a grading scale. PS placement by the SSF was evaluated by examining the assessed position in chronological groups of 40 screws. Results. Ninety-four patients underwent internal fixation of the spine with 582 PS. Eight cases (40 screws) were excluded because of lack of imaging studies. Of the 542 screws under evaluation, 320 (59%) were performed by the SSF, 187 (34.5%) by the ASC, and 35 (6.5%) by advanced orthopedic or neurosurgical trainees. The rate of misplaced PS performed by the SSF for the first 80 PS was 12.5% and dropped to 3.4% for the remaining 240 screws, which is a statistically significant difference (P < 0.01). Evaluation of computed tomography of vertebrae with PS placed by the SSF on one side and by the ASC on the other showed that the ASC achieved better placement during the first 80 PS (P < 0.01). However, this difference disappeared in the last 240 (P = 1.00). Conclusion. The findings demonstrate a learning curve for PS placement. In this series, the asymptote for this technique for an inexperienced SSF, started after about 80 screws (approximately 25 cases).

The surgically remediable syndrome of epilepsy associated with bottom-of-sulcus dysplasia

Objective: To determine clinical and EEG features that might help identify patients with epilepsy harboring small, intrinsically epileptogenic, surgically treatable, bottom-of-sulcus dysplasias (BOSDs). Methods: Retrospective review of clinical records, EEG, MRI, and histopathology in 32 patients with drug-resistant epilepsy and MRI-positive (72% 3.0 tesla), pathologically proven (type 2B cortical dysplasia) BOSDs operated at our centers during 2005–2013. Results: Localization of BOSDs was frontal in 19, insula in 5, parietal in 5, and temporal in 3, on the convexity or interhemispheric surfaces. BOSDs were missed on initial MRI at our centers in 22% of patients. Patients presented with focal seizures during infancy in 9, preschool years in 15, and school years in 8 (median age 5 years). Seizures were stereotyped, predominantly nocturnal, and typically nonconvulsive, with semiology referable to the fronto-central or perisylvian regions. Seizures occurred at high frequency during active periods, but often went into prolonged remission with carbamazepine or phenytoin. Intellect was normal or borderline, except in patients with seizure onset during infancy. Scalp EEG frequently revealed localized interictal epileptiform discharges and ictal rhythms. Patients underwent lesionectomy (median age 14 years) guided by electrocorticography and MRI, with prior intracranial EEG monitoring in only one patient. Twenty-eight patients (88%) became seizure-free, and 20 discontinued antiepileptic medication (median follow-up 4.1 years). Conclusions: In patients with cryptogenic focal epilepsy, this clinical presentation and course should prompt review of or repeat MRI, looking for a BOSD in the frontal, parietal, or insula cortex. If a BOSD is identified, the patient might be considered for single-stage lesionectomy.

Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma

BACKGROUND The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy. METHODS This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0-2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS). RESULTS One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64-1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82-1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately. CONCLUSIONS Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies. CLINICAL TRIALS REGISTRATION NR ACTRN12610000915055.