Hippocampal deformation mapping in MRI negative PET positive temporal lobe epilepsy.

OBJECTIVES: To compare hippocampal surface structure, using large deformation high dimensional mapping (HDM-LD), in subjects with temporal lobe epilepsy (TLE) with (HS+ve) and without (HS-ve) hippocampal sclerosis. METHODS: The study included 30 HS-ve subjects matched with 30 HS+ve subjects from the previously reported epilepsy patient cohort. To control for normal right-left asymmetries of hippocampal surface structure, subjects were regrouped based on laterality of onset of epileptic seizures and presence of HS. Gender ratio, age, duration of epilepsy and seizure frequency were calculated for each of the four groups. Final HDM-LD surface maps of the right and left TLE groups were compared to define differences in subregional hippocampal involvement within the groups. RESULTS: There were no significant differences in comparisons of the left TLE (left HS-ve compared with HS+ve) or right TLE (right HS-ve compared with HS+ve) groups with respect to age, duration of epilepsy or seizure severity scores. HDM-LD maps showed accentuated surface changes over the lateral hippocampal surface, in the region of the Sommer sector, in the hippocampi affected by HS. However, HS-ve hippocampi showed maximal surface changes in a different pattern, and did not involve the region of Sommer sector. CONCLUSION: We conclude that differences in segmental volume loss between the HS-ve and HS+ve groups are suggestive that the underlying pathophysiology of hippocampal changes in the two groups is different, and not related to chronic seizure duration or severity.

"Magnetic resonance imaging negative positron emission tomography positive" temporal lobe epilepsy: FDG-PET pattern differs from mesial temporal lobe epilepsy.

PURPOSE: Some patients with temporal lobe epilepsy (TLE) lack evidence of hippocampal sclerosis (HS) on MRI (HS-ve). We hypothesized that this group would have a different pattern of 2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) hypometabolism than typical mesial TLE/HS patients with evidence of hippocampal atrophy on magnetic resonance imaging (MRI) (HS+ve), with a lateral temporal neocortical rather than mesial focus. PROCEDURES: Thirty consecutive HS-ve patients and 30 age- and sex-matched HS+ve patients with well-lateralized EEG were identified. FDG-PET was performed on 28 HS-ve patients and 24 HS+ve patients. Both groups were compared using statistical parametric mapping (SPM), directly and with FDG-PET from 20 healthy controls. RESULTS: Both groups showed lateralized temporal hypometabolism compared to controls. In HS+ve, this was antero-infero-mesial (T = 17.13); in HS-ve the main clustering was inferolateral (T = 17.63). When directly compared, HS+ve had greater hypometabolism inmesial temporal/hippocampal regions (T = 4.86); HS-ve had greater inferolateral temporal hypometabolism (T = 4.18). CONCLUSIONS: These data support the hypothesis that focal hypometabolism involves primarily lateal neocortical rather than mesial temporal structures in 'MRI-negative PET-positive TLE.'

Contrast-enhanced perfusion and diffusion MRI accurately lateralize temporal lobe epilepsy: a pilot study.

AIMS: To undertake a pilot study to assess whether magnetic resonance (MR) contrast-enhanced perfusion imaging (CEPI) and diffusion-weighted imaging (DWI) provide lateralizing information in medically refractory temporal lobe epilepsy (TLE),and to compare this to standard quantitative hippocampal assessments (volumetric measurements and T2 relaxometry). METHODS: Ten patients with 'non-lesional' TLE and 10 control subjects were studied. Quantification of the relative cerebral blood flow (rCBF) and apparent diffusion coefficient (ADC) was performed for the hippocampal regions. The ratios of the ipsilateral-to-contralateral side (to the EEG lateralization) were compared with the side-to-side ratios in the controls. RESULTS: Six patients (60%) had an ADC ratio outside the control range (the larger ADC ipsilateral to the EEG lateralization in all cases). The CBF ratios were outside the control range in all eight patients (100%) in whom CEPI was performed (the lower value ipsilateral to the EEG lateralization in all cases). The magnitude of the hippocampal volume (HV) ratios showed no significant correlation with the magnitude of the ADC ratios (R=-0.03, p=0.93) or CBF ratios (R=0.36, p=0.39). There was a closer relationship with the T2 relaxometry ratios, but this was also not significant (R=-0.40, p=0.32; R=0.58, p=0.08). CONCLUSIONS: DWI and CEPI show potential as reliable tools for the lateralization of non-lesional TLE. Further studies with larger numbers are necessary to determine whether these techniques provide independent data to established MR quantitative measures.

MRI-negative PET-positive temporal lobe epilepsy: a distinct surgically remediable syndrome.

Most patients with non-lesional temporal lobe epilepsy (NLTLE) will have the findings of hippocampal sclerosis (HS) on a high resolution MRI. However, a significant minority of patients with NLTLE and electroclinically well-lateralized temporal lobe seizures have no evidence of HS on MRI. Many of these patients have concordant hypometabolism on fluorodeoxyglucose-PET ([18F]FDG-PET). The pathophysiological basis of this latter group remains uncertain. We aimed to determine whether NLTLE without HS on MRI represents a variant of or a different clinicopathological syndrome from that of NLTLE with HS on MRI. The clinical, EEG, [18F]FDG-PET, histopathological and surgical outcomes of 30 consecutive NLTLE patients with well-lateralized EEG but without HS on MRI (HS-ve TLE) were compared with 30 consecutive age- and sex-matched NLTLE patients with well-lateralized EEG with HS on MRI (HS+ve TLE). Both the HS+ve TLE group and the HS-ve TLE patients had a high degree of [18F]FDG-PET concordant lateralization (26 out of 30 HS-ve TLE versus 27 out of 27 HS+ve TLE). HS-ve TLE patients had more widespread hypometabolism on [18F]FDG-PET by blinded visual analysis [odds ratio (OR = + infinity (2.51, -), P = 0.001]. The HS-ve TLE group less frequently had a history of febrile convulsions [OR = 0.077 (0.002-0.512), P = 0.002], more commonly had a delta rhythm at ictal onset [OR = 3.67 (0.97-20.47), P = 0.057], and less frequently had histopathological evidence of HS [OR = 0 (0-0.85), P = 0.031]. There was no significant difference in surgical outcome despite half of those without HS having a hippocampal-sparing procedure. Based on the findings outlined, HS-ve PET-positive TLE may be a surgically remediable syndrome distinct from HS+ve TLE, with a pathophysiological basis that primarily involves lateral temporal neocortical rather than mesial temporal structures.

Early seizures after acute stroke. Risk of late seizures.

The prognosis of early seizures after stroke is controversial. We assessed the incidence of late seizures in 31 patients with early seizures complicating acute stroke and compared this with the incidence of late seizures in 31 matched patients with stroke without early seizures. Ten (32%) of 31 patients with early seizures had late seizures during a mean follow-up period of 26 months. Only three (10%) of 31 patients without early seizures had late seizures during the follow-up period of 28 months, a significantly lower incidence than in patients with early seizures. The risk of seizure recurrence in patients with early seizures did not correlate with stroke type or lesion size as imaged on the computed tomographic scan. We conclude that early seizures are not benign and are associated with a significant risk of seizure recurrence.

Epileptic seizures in acute stroke.

We evaluated prospectively the incidence of early seizures in 1000 consecutive patients with stroke and transient ischemic attacks to determine whether seizure occurrence correlates with stroke type, pathogenesis, or outcome. Seizures occurred in 44 patients (4.4%; SE, 0.7%), including 10 (15.4%) of 65 (SE, 4.5%) with lobar or extensive hemorrhage, 6 (8.5%) of 71 (SE, 3.3%) with subarachnoid hemorrhage, 24 (6.5%) of 370 (SE, 1.3%) with cortical infarction, and 4 (3.7%) of 109 (SE, 1.8%) with hemispheric transient ischemic attacks. Lacunar infarcts and deep hemorrhages were not associated with seizures. Arteriovenous malformation was a common cause of lobar hemorrhage with early seizures, but in cortical infarcts there was no association between seizure occurrence and pathogenesis. Seizures generally occurred within 48 hours of stroke onset, were usually single, partial, and readily controlled. Seizures were not associated with a higher mortality or worse functional outcome.

Onset seizures independently predict poor outcome after subarachnoid hemorrhage.

OBJECTIVE: To determine whether onset seizures after subarachnoid hemorrhage (SAH) carry independent prognostic information and to investigate the risk factors for late seizures after SAH. BACKGROUND: Modern management of SAH, including early operation, has substantially reduced mortality. No study has adequately assessed the importance of onset seizures in a contemporary SAH cohort. METHODS: The authors analyzed the records and initial CT scans of 412 consecutive patients with aneurysmal or nonaneurysmal SAH admitted to the Royal Melbourne Hospital from 1990 to 1996. Each patient with an onset seizure (n = 32, 7.8% of cohort) was age and sex matched to two nonseizure patients of the same cohort. Each patient with a late seizure (n = 17, 5.1% of cohort) was matched to five control subjects of the same cohort. RESULTS: With use of logistic regression analysis, onset seizures correlated with the sum score of blood on initial CT scan (OR = 1.1, p = 0.05), but there was no significant correlation with duration of loss of consciousness at onset, Glasgow Coma Score (GCS), presence of aneurysm, or past history of hypertension or epilepsy. Disability 6 weeks after SAH according to the Glasgow Outcome Scale was independently predicted by initial GCS of <6 (OR = 13.7, p < 0.01) and onset seizure (OR = 7.8, p = 0.04). Late seizures within the first 6 weeks were independently related to rebleeding (OR = 94, p < 0.01) and onset seizures (OR = 27, p < 0.01) but not to other onset variables, development of hydrocephalus, or vasospasm. CONCLUSION: In this single-institution cohort of patients with SAH, onset seizures were an independent risk factor for late seizures and a predictor of poor outcome.

Accuracy of coregistration of single-photon emission CT with MR via a brain surface matching technique.

We describe a technique of brain surface matching of single-photon emission CT and MR images in human subjects and document the accuracy of this technique with the use of fiduciary markers. This mismatch averaged 4.3 mm as measured by the fiduciary markers and 2.1 mm as measured by the root mean square distance.

Recanalisation and outcome cerebral venous thrombosis.

Little is known of the natural history and rate of sinus recanalisation after cerebral venous thrombosis (CVT). Although acute anticoagulation is effective, the duration of therapy remains speculative. We aimed to determine the relationship between sinus recanalisation and clinical outcome. We studied 12 consecutive patients with aseptic CVT with evidence of sinus thrombosis on initial magnetic resonance imaging, followed up 5-68 months after onset, using 15 repeat magnetic resonance scans in 9 of the patients to assess recanalisation. All patients initially had one or more thrombosed sinuses and were treated with anticoagulants for at least 6 months, including 3 with haemorrhagic infarction. Residual neurological deficits were present in only one patient. No patient had a recurrent thrombosis. Recanalisations was incomplete in 6 of the 9 cases. Sinus recanalisation after cerebral venous thrombosis does not correlate with clinical outcome. Although empirical, the general recommendation of 6 months anticoagulant therapy is appropriate.

The effect of pregnancy on the epilepsies: a study of 37 pregnancies.

BACKGROUND: Although studies have assessed the effect of pregnancy on epilepsy, usually the types of epilepsy are not differentiated and most have not included a control group, despite the natural history of epilepsy including fluctuations in seizure frequency. AIMS: To assess the effect of pregnancy on seizure frequency and compare this with changes in seizure frequency in non-pregnant patients. In addition, the relationship between seizure frequency during pregnancy and epilepsy type, seizure frequency prior to pregnancy and duration of epilepsy will be assessed. METHODS: Seizure frequency was assessed retrospectively in 37 pregnancies from 24 women by comparing the seizure number for the nine-month period prior to pregnancy with the number during the pregnancy. An increase in frequency was defined as a 50% or greater increase in the number of seizures. Twenty-four non-pregnant women, matched for age and epilepsy type, were included to assess fluctuations in control. RESULTS: In 41% of pregnant women, there was an increase in seizure frequency, in 51% no change and in 8% improvement. In the control group, 24% had an increase, 65% no change and 11% improvement. There was no correlation between seizure frequency during pregnancy and epilepsy type and seizure frequency prior to pregnancy, but those with longer duration of epilepsy were more likely to deteriorate (p < 0.05). Alterations in anticonvulsants to reduce the risk of teratogenicity was a common identifiable cause of deterioration in control. CONCLUSIONS: Significant random fluctuations in epileptic control occur, but pregnancy may have a deleterious effect on epilepsy, particularly when appropriate therapy is withdrawn to reduce teratogenicity.

Anticonvulsants in pregnancy.

OBJECTIVE: To review the potential problems and their management associated with the use of anticonvulsant drugs during pregnancy. DATA SOURCES: Studies published between 1968 and 1990 assessing the effect of pregnancy on the pharmacokinetics of anticonvulsant drugs, the teratogenicity of anticonvulsants, breast feeding and anticonvulsants and use of the oral contraceptive pill in patients taking anticonvulsant medication, were reviewed. RESULTS OF DATA SYNTHESIS: In general, plasma levels fall during pregnancy and rise during the puerperium. A number of factors including possible reduced absorption, increased volume of distribution, reduced protein binding, increased clearance and noncompliance, contribute to this fall in plasma concentration. All anticonvulsants are potentially teratogenic. The incidence of fetal malformations is higher in patients treated with multiple anticonvulsant drugs and on higher dosages with higher plasma levels. Anticonvulsants are excreted in low concentrations in breast milk. All anticonvulsants except valproic acid have been associated with failure of the oral contraceptive pill. This is due to liver enzyme induction of these drugs. CONCLUSION: As plasma levels of anticonvulsants fall during pregnancy, concentrations should be monitored regularly. Due to the fall in protein binding, marginally low total plasma levels of highly protein bound drugs may not reflect reduced unbound levels, and hence an increase in dosage may not be required. In order to reduce teratogenicity, one should aim to use a single anticonvulsant drug and the lowest dosage able to achieve seizure control. In general, breast feeding is not contraindicated.

PIP: The objective of this study was to review the potential problems and their management associated with the use of anticonvulsants in pregnancy. Studies published between 1968-90 assessing the effect of pregnancy on the pharmacokinetics of anticonvulsant drugs, the teratogenicity of anticonvulsants, breastfeeding, and anticonvulsants and the use of oral contraceptives (OCs) in patients taking anticonvulsant medication were reviewed. In general, plasma levels fall during pregnancy and rise during the puerperium. A number of factors including possible reduced absorption, increased volume of distribution, reduced protein binding, increased clearance, and noncompliance all contribute to this fall in plasma concentration. All such drugs are potentially teratogenic. The incidence of fetal malformations is higher in those patients treated with multiple anticonvulsant drugs and on higher dosages with higher plasma levels. Anticonvulsants are excreted i low concentrations in breastmilk. All except valproic acid have been associated with the failure of OCs, this due to liver enzyme induction of these drugs. As plasma levels of anticonvulsants fall during pregnancy, concentrations should be monitored regularly. Due to the fall in protein binding, marginally low total plasma levels of highly protein bound drugs may not reflect reduced unbound levels, and thus an increase in dosage may not be required. In order to reduce teratogenicity, one should aim to use a single anticonvulsant drug and the lowest dosage able to receive seizure control. In general, breastfeeding is not contraindicated.

Intra-dose variation in plasma protein binding of sodium valproate in epileptic patients.

1 The fluctuations in protein binding of sodium valproate during one dosing interval were studied in five patients stabilized on valproate and taking concurrent anticonvulsant therapy. 2 The patients took their usual morning dose of valproate (400-800 mg) and serial blood samples were collected by venepuncture at 0, 1, 2, 3, 4, and 6 h post-dose. 3 Free valproate was separated from protein bound drug by plasma ultrafiltration and the ultrafiltrate and total plasma valproate concentrations were measured by a gas chromatographic method. 4 The maximum and minimum concentrations in the ultrafiltrates occurred at the same times as in the plasma. However, the percentage fluctuation was always greater in the ultrafiltrates (range 192-412%) compared with the plasma (range 153-374%) due to the concentration-dependent nature of valproate protein binding. 5 If free valproate levels are to be monitored, knowledge of sampling time and dosage history is important for interpretation of the results.

Plasma concentrations of unbound phenytoin in the management of epilepsy.

In 46 epileptic patients the range of the unbound fraction of phenytoin in plasma measured by ultrafiltration (at 37 degrees C) and tracer-labelling with [14C]-phenytoin was 6.7%-33.3% with a median of 11.9%. The total and unbound phenytoin plasma concentrations were significantly correlated (r = 0.93, P less than 0.001), but in six patients the unbound concentration fell on or outside the 90% predictability limits for a single value. In all patients the unbound concentration reflected the clinical status of the patient equally or better than the total concentration. An inverse relationship was found between the plasma albumin concentration (within the normal reference range) and the phenytoin unbound fraction (r = -0.83, P less than 0.001) indicating that plasma albumin concentration is one of the important overall determinants of phenytoin protein binding. Saliva and plasma unbound phenytoin concentrations were significantly correlated (r = 0.98, P less than 0.001) but both collection of plasma samples and preparation of plasma ultrafiltrate using the Amicon micropartition system are simpler than collection and processing saliva, and interpretation of plasma unbound concentration does not require allowance for potential contamination. The additional value of the unbound phenytoin concentration in a clinically significant number of individuals would justify routine measurement of unbound phenytoin concentration in monitoring therapy, once available simplified methodology has been adequately characterised.

Plasma concentrations of unbound valproate and the management of epilepsy.

The range of protein binding of valproate and the use of unbound and total plasma concentrations of the drug were studied in an outpatient population of 70 epileptics. The unbound fraction of plasma valproate ranged from 4.2% to 11.7% with a median of 7.1%. A non-linear relationship was found between unbound and total plasma valproate concentrations and was best described by a cubic regression (r2 = 0.88). This concentration dependent protein binding was also demonstrated by a linear relationship between total plasma valproate concentration and unbound fraction (r = 0.46). As expected, there was no correlation across the patient population between plasma concentrations of valproate and seizure frequency. In an individual patient, however, plasma valproate levels usually correlated with change in clinical status, although this correlation was no better for unbound levels than total levels. There were only three patients in whom unbound valproate levels correlated better with clinical effect than total levels, whereas there were six patients in whom total levels correlated better than unbound levels. It is therefore concluded that monitoring sodium valproate therapy with unbound concentrations is rarely helpful and the routine use of unbound valproate levels cannot be advocated.

Changes in clearance of sodium valproate with changes in dose.

The relationship between total sodium valproate concentrations and drug clearance was studied in four patients, by the evaluation of clearance at two different doses. In each patient, the average unbound fraction for a dosing interval increased with increase in sodium valproate dose. Despite this increase in unbound fraction, there was no increase in total drug clearance, and in each patient there was a decrease in clearance of the unbound drug. These findings suggest either that the drug is restrictively cleared and there is a dose-related decline in intrinsic clearance, or, contrary to previous reports, that sodium valproate is cleared nonrestrictively.

Degree of hippocampal atrophy is not related to a history of febrile seizures in patients with proved hippocampal sclerosis.

OBJECTIVES: To examine the degree of hippocampal atrophy in patients with temporal lobe epilepsy and proved hippocampal sclerosis to determine whether or not patients with febrile seizures have more severe hippocampal atrophy. To determine whether or not there is a relation between age of seizure onset, duration of temporal lobe epilepsy, or seizure frequency, and severity of hippocampal atrophy. METHODS: Hippocampal volumes were measured from volumetrically acquired MR images in 77 consecutive surgical patients with temporal lobe epilepsy (37 febrile seizures (FS)+, 40 FS-) with proved hippocampal sclerosis, and compared with 98 controls. RESULTS: Ipsilateral and contralateral hippocampal volumes were not significantly different between the FS+ and FS- groups. There was no difference in the age of onset of habitual seizures, duration of epilepsy, or age at the time of surgery, between these groups. No clinically significant correlations were found between hippocampal volumes and age of onset of first non-febrile seizure, duration of temporal lobe epilepsy, or complex partial and secondarily generalised seizure frequency, in patients with and without febrile seizures. CONCLUSIONS: Although febrile seizures was associated with hippocampal sclerosis in 48% of patients in this surgical series, the degree of MRI determined hippocampal atrophy was not related to a history of such seizures. The results do not support the view that febrile seizures cause more severe hippocampal sclerosis and are consistent with the hypothesis that hippocampal sclerosis is a pre-existing abnormality.

Rhinocerebral mucormycosis.

Two cases of rhinocerebral mucormycosis are reported to draw attention to this fulminating fungal disease. Both patients had diabetes, and presented with a rapidly progressive orbital apex syndrome.

Optic nerve decompression in benign intracranial hypertension.

Fourteen patients with benign intracranial hypertension who failed to respond to medical treatment, were treated with optic nerve decompression to prevent the sequelae of chronic unrelieved papilloedema. The mechanism by which optic nerve decompression protects the optic nerve is uncertain. These patients were reviewed to evaluate the efficacy of the procedure in the treatment of benign intracranial hypertension and to assess its mechanism of action. Preoperatively all patients had papilloedema, 11 patients had visual obscurations and 6 patients had evidence of visual failure. Postoperatively, visual obscurations and papilloedema resolved in all patients, and 5 of 6 patients had no further deterioration of visual function. Six patients had symptoms of raised intracranial pressure preoperatively and in 3 the symptoms resolved after surgery. Three patients had unilateral optic nerve decompression and papilloedema resolved in both eyes. In 1 patient intracranial pressure monitoring revealed raised pressure preoperatively with no significant change in the first 24 hours after surgery. We conclude that optic nerve decompression is effective in the treatment of benign intracranial hypertension, has its effect locally, and in some patients may lower the intracranial pressure.

Unbound phenytoin plasma concentrations in patients comedicated with sodium valproate--the predictive value of plasma albumin concentration.

1. Phenytoin protein binding in epileptic patients on phenytoin as monotherapy has been compared with protein binding in patients treated with both phenytoin and sodium valproate. In addition the relative value of assayed total phenytoin plasma concentrations and assayed unbound phenytoin plasma concentrations and the value of predicted unbound phenytoin plasma concentrations in predicting phenytoin toxicity has been assessed. 2. The mean phenytoin unbound fraction for patients taking sodium valproate (0.122) was significantly greater than for those on monotherapy (0.082). 3. There were six episodes of clinical toxicity. In five toxic episodes the assayed unbound phenytoin plasma concentration was a better reflection of toxicity than the assayed total phenytoin plasma concentration, and four of these occurred in patients on sodium valproate. 4. Unbound phenytoin plasma concentrations were predicted from a single regression equation correlating all assayed total phenytoin plasma concentrations with assayed unbound phenytoin plasma concentrations, from two separate regression equations for each group of patients, and from the correlation between phenytoin protein binding and plasma albumin concentration. 5. The unbound phenytoin plasma concentrations predicted from the two regression equations were statistically no less effective than the assayed unbound phenytoin plasma concentrations in assessing toxicity. 6. Despite a correlation between plasma albumin concentrations and phenytoin protein binding, the use of albumin concentrations in predicting unbound phenytoin plasma concentrations appeared to be of little additional benefit.

Magnetic resonance imaging and late-onset epilepsy.

The value of magnetic resonance imaging (MRI) in investigation of patients with late-onset epilepsy has not been studied systematically. We evaluated prospectively the usefulness of MRI in 50 patients with late-onset epilepsy in whom a computed tomography (CT) scan was normal (32), did not allow a definitive diagnosis to be made (12), or showed irrelevant lesions (6). Patients were assessed clinically and had an EEG, and CT and MRI scans were reported by one neuroradiologist blinded to clinical and laboratory data. Of the 32 patients with a normal CT scan, MRI was normal in 20, showed irrelevant ischemic lesions in 8, and showed the cause of seizures in 4 patients. Of the 12 patients with nondiagnostic CT, MRI clarified the diagnosis in 5 and was normal in 2 patients. In 6 patients, both scans showed irrelevant ischemic lesions, and in 1 patient MRI showed a relevant additional lesion. The incidence of MRI-detected white matter ischemic lesions was no greater than in an age- and sex-matched group of subjects without seizures. MRI was diagnostic in 32% of the patients with partial seizures and/or focal EEG findings, as compared with 0% of patients without focal features (p less than 0.01). We conclude that MRI is useful in investigation of patients with late-onset epilepsy with focal features.