Metabolic networks in epilepsy by MR spectroscopic imaging.

OBJECTIVE: The concept of an epileptic network has long been suggested from both animal and human studies of epilepsy. Based on the common observation that the MR spectroscopic imaging measure of NAA/Cr is sensitive to neuronal function and injury, we use this parameter to assess for the presence of a metabolic network in mesial temporal lobe epilepsy (MTLE) patients. MATERIALS AND METHODS: A multivariate factor analysis is performed with controls and MTLE patients, using NAA/Cr measures from 12 loci: the bilateral hippocampi, thalami, basal ganglia, and insula. The factor analysis determines which and to what extent these loci are metabolically covarying. RESULTS: We extract two independent factors that explain the data's variability in control and MTLE patients. In controls, these factors characterize a 'thalamic' and 'dominant subcortical' function. The MTLE patients also exhibit a 'thalamic' factor, in addition to a second factor involving the ipsilateral insula and bilateral basal ganglia. CONCLUSIONS: These data suggest that MTLE patients demonstrate a metabolic network that involves the thalami, also seen in controls. The MTLE patients also display a second set of metabolically covarying regions that may be a manifestation of the epileptic network that characterizes limbic seizure propagation.

Clinical use of ictal SPECT in secondarily generalized tonic-clonic seizures.

Partial seizures produce increased cerebral blood flow in the region of seizure onset. These regional cerebral blood flow increases can be detected by single photon emission computed tomography (ictal SPECT), providing a useful clinical tool for seizure localization. However, when partial seizures secondarily generalize, there are often questions of interpretation since propagation of seizures could produce ambiguous results. Ictal SPECT from secondarily generalized seizures has not been thoroughly investigated. We analysed ictal SPECT from 59 secondarily generalized tonic-clonic seizures obtained during epilepsy surgery evaluation in 53 patients. Ictal versus baseline interictal SPECT difference analysis was performed using ISAS (http://spect.yale.edu). SPECT injection times were classified based on video/EEG review as either pre-generalization, during generalization or in the immediate post-ictal period. We found that in the pre-generalization and generalization phases, ictal SPECT showed significantly more regions of cerebral blood flow increases than in partial seizures without secondary generalization. This made identification of a single unambiguous region of seizure onset impossible 50% of the time with ictal SPECT in secondarily generalized seizures. However, cerebral blood flow increases on ictal SPECT correctly identified the hemisphere (left versus right) of seizure onset in 84% of cases. In addition, when a single unambiguous region of cerebral blood flow increase was seen on ictal SPECT, this was the correct localization 80% of the time. In agreement with findings from partial seizures without secondary generalization, cerebral blood flow increases in the post-ictal period and cerebral blood flow decreases during or following seizures were not useful for localizing seizure onset. Interestingly, however, cerebral blood flow hypoperfusion during the generalization phase (but not pre-generalization) was greater on the side opposite to seizure onset in 90% of patients. These findings suggest that, with appropriate cautious interpretation, ictal SPECT in secondarily generalized seizures can help localize the region of seizure onset.

Cortical and subcortical networks in human secondarily generalized tonic-clonic seizures.

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

Expectations prior to epilepsy surgery: an exploratory comparison of men and women.

Although the clinical goal of resective epilepsy surgery is seizure freedom, patients have a wide set of expectations for this invasive procedure. The goal of this study was to evaluate potential gender differences in expectations among patients undergoing resective epilepsy surgery. Ratings of the importance of 12 potential impacts ("expectations") of resective surgery were analyzed in a seven-center cohort study including 389 adults aged 16 and older who underwent resective epilepsy surgery. Men and women both ranked anticipated changes in driving and memory as the most important presurgical expectations. Women rated driving, physical activity limitations, and economic worries as less important, and fatigue and pregnancy concerns as more important than did men (p's< or =0.05). Exploratory factor analysis indicated a different pattern of associations among the 12 importance items for men and women. Whether gender differences in presurgical values are associated with outcomes needs exploration.

Differential regulation of the cell wall integrity mitogen-activated protein kinase pathway in budding yeast by the protein tyrosine phosphatases Ptp2 and Ptp3.

Mitogen-activated protein kinases (MAPKs) are inactivated by dual-specificity and protein tyrosine phosphatases (PTPs) in yeasts. In Saccharomyces cerevisiae, two PTPs, Ptp2 and Ptp3, inactivate the MAPKs, Hog1 and Fus3, with different specificities. To further examine the functions and substrate specificities of Ptp2 and Ptp3, we tested whether they could inactivate a third MAPK, Mpk1, in the cell wall integrity pathway. In vivo and in vitro evidence indicates that both PTPs inactivate Mpk1, but Ptp2 is the more effective negative regulator. Multicopy expression of PTP2, but not PTP3, suppressed growth defects due to the MEK kinase mutation, BCK1-20, and the MEK mutation, MKK1-386, that hyperactivate this pathway. In addition, deletion of PTP2, but not PTP3, exacerbated growth defects due to MKK1-386. Other evidence supported a role for Ptp3 in this pathway. Expression of MKK1-386 was lethal in the ptp2Delta ptp3Delta strain but not in either single PTP deletion strain. In addition, the ptp2Delta ptp3Delta strain showed higher levels of heat stress-induced Mpk1-phosphotyrosine than the wild-type strain or strains lacking either PTP. The PTPs also showed differences in vitro. Ptp2 was more efficient than Ptp3 at binding and dephosphorylating Mpk1. Another factor that may contribute to the greater effectiveness of Ptp2 is its subcellular localization. Ptp2 is predominantly nuclear whereas Ptp3 is cytoplasmic, suggesting that active Mpk1 is present in the nucleus. Last, PTP2 but not PTP3 transcript increased in response to heat shock in a Mpk1-dependent manner, suggesting that Ptp2 acts in a negative feedback loop to inactivate Mpk1.

A cerebral effect of carotid sinus stimulation. Observation during intraoperative electroencephalographic monitoring.

Surgical manipulation in the region of the carotid sinus resulted in diffuse electroencephalographic slowing in two patients, despite the absence of bradycardia or hypotension. Direct observation confirmed the absence of carotid compression. The effect was abolished by infiltration of lidocaine hydrochloride into the carotid sinus area. Carotid clamping in one patient failed to produce similar electroencephalographic changes. We believe that this is the first observation of an influence of carotid sinus stimulation on human cerebral activity not attributable to reflex cardiovascular changes or complicated by the possibility of carotid compression.

Progressive and treatable cerebellar ataxia in macroglobulinemia.

Ataxia in macroglobulinemia has been attributed to cerebral infarction and blood hyperviscosity, but no previous case reports documented gradually progressive cerebellar signs without these concomitants and with regression on therapy. Hematologically "benign" macroglobulinemia should be part of the differential diagnosis in patients with unexplained progressive ataxia, and may respond to treatment that would otherwise not be prescribed. There is a possible relationship between the pathogenesis of this disorder and other hereditary ataxia or dysgammaglobulinemia syndromes; methods of treatment should be investigated for possible overlap.

Diagnosis of medial temporal lobe seizure onset: relative specificity and sensitivity of quantitative MRI.

Measurement of hippocampal volume by MRI is a new technique with potential value in the localization of epileptic regions, but whether reduced hippocampal volume predicts the location of electrical seizure onset in mixed patient groups is not known. We examined the sensitivity and specificity of this technique among 56 refractory epileptic patients for the diagnosis of medial temporal lobe epilepsy as judged by intracranial EEG recording of spontaneous seizure onset. Since these patients had intracranial EEG because of inconsistent or insufficient localization by noninvasive electrophysiologic, functional, and structural assessment, this patient population can be considered the most difficult to localize. Hippocampal atrophy by MRI volumetry was 75% sensitive to, and 64% specific for, ipsilateral medial temporal lobe seizure onset in this group. Hippocampal atrophy was significantly correlated with longer duration of epilepsy. MRI compared favorably with all other noninvasive means of localization, which had 41 to 73% sensitivity and 45 to 65% specificity to medial temporal ictal onset; of these, none had as acceptable a combination of both adequate sensitivity and specificity. We conclude that MRI volumetry of the hippocampus is a valuable, noninvasive localization method in chronic epilepsy, with a yield and accuracy surpassing all other noninvasive studies used to predict the presence of medial temporal seizure onset.

Clinical and electrographic effects of acute anticonvulsant withdrawal in epileptic patients.

We retrospectively investigated the effects of acute antiepileptic drug (AED) withdrawal on seizure symptomatology--including frequency, clinical features, and electrical onset--by studying 35 patients during evaluation for epilepsy surgery. The highest risk for both partial and secondary generalized seizures occurred during absent or subtherapeutic, and not during rapidly falling, AED levels. AED withdrawal had minimal effect on clinical symptomatology or electrographic onset.

Seizure localization and pathology following head injury in patients with uncontrolled epilepsy.

We studied seizure localization and surgical pathology in 25 patients who developed intractable complex partial seizures following head trauma. All patients underwent an extensive presurgical evaluation that included MRI, neuropsychological evaluation, and surface EEG monitoring, and 21 had intracranial EEG monitoring. Seizures were successfully localized in nine patients; all nine underwent a surgical procedure and are seizure-free. Six of these patients had a mesial temporal lobe seizure focus, of whom five had a pathologic diagnosis of mesial temporal sclerosis. All five patients who developed mesial temporal sclerosis sustained their head injury at or before age 5 years. The three remaining patients whose seizures were successfully localized had neocortical foci and circumscribed radiographic abnormalities, which were presumed to be secondary to head trauma, and all had successful surgical resections of the epileptogenic focus. The remaining 16 patients sustained later trauma, and all had successful surgical resections of the epileptogenic focus. The remaining 16 patients sustained later trauma and did not have a focal MRI lesion, and their seizures were not adequately localized. We conclude that as a group, seizure foci secondary to head trauma are difficult to localize accurately, and this should deter surgical intervention. There was an association between early head injury (ie, at or before age 5 years) and mesial temporal sclerosis, and this association aided seizure localization and successful surgical intervention. Therefore, under the right circumstances, trauma can be a suitable historical element in the profile of patients in whom epilepsy surgery is successful.

Frontal lobe partial seizures and psychogenic seizures: comparison of clinical and ictal characteristics.

Of all partial seizures, those of frontal lobe origin (FLPS) are most bizarre and are often mistaken for psychogenic seizures (PS). The reverse can also be true. To clarify the confusing clinical presentation of these different seizure types, we compared the clinical ictal characteristics of 63 FLPS in 11 patients with 29 PS in 12 patients. Patients with PS had significantly later age at onset and longer ictal duration. There was no statistically significant difference between the two groups with respect to history of psychiatric disorder, ictal pelvic thrusting, rocking of body, side-to-side head movements, or rapid postictal recovery, all of which previously have been reported as characteristic features of PS. Turning to a prone position during the seizure occurred only in FLPS. Nocturnal occurrence, short ictal duration, younger age at onset, stereotyped patterns of movements, and MRI and EEG abnormality suggested FLPS.

Characteristics of intractable seizures following meningitis and encephalitis.

We studied clinical seizure characteristics, seizure localization, and pathology in 38 patients who developed medically intractable partial seizures following meningitis (n = 16) or encephalitis (n = 22) and were evaluated for epilepsy surgery. Whereas meningitis in this group was commonly associated with mesial temporal sclerosis (MTS), most encephalitis patients had neocortical foci. The age of onset of the encephalitic illness was important in predicting mesial temporal or neocortical foci in that group: encephalitis before, but not after, age 4 years was associated with MTS. Since almost all meningitis occurred before age 4 years, these data support the hypothesis that the medial temporal lobe is particularly susceptible to early insults, establishing the initial pathologic entity of MTS and the subsequent cascade of partial seizures. Later-onset encephalitis produced extrahippocampal neocortical seizure foci, was rarely associated with MRI abnormality, and was difficult to localize precisely. In contrast, meningitis was commonly associated with MTS, aiding seizure localization and successful surgical intervention when seizures were medically uncontrolled.

EEG findings in frontal lobe epilepsies.

As a group, epilepsies of frontal lobe origin are thought to be poorly localized using surface EEG recordings. This finding may depend on the specific areas of frontal lobe from which the seizures originate or the pathologic substrate. We reviewed the presurgical surface EEGs of patients with frontal lobe epilepsy who underwent epilepsy surgery. The specific area of the frontal lobe where seizures originated was determined by 1) intracranial ictal EEG recordings, or 2) the presence of a structural lesion, identified by imaging studies in patients who achieved complete seizure control following surgery. We differentiated patients whose seizures began in the dorsolateral frontal convexity from those whose seizures began in the medial frontal region, and we correlated EEG findings in the interictal, postictal, and ictal states with seizure semiology, pathologic substrate, and surgical outcome. Four of nine patients had seizures originating in the dorsolateral frontal convexity and five had medial frontal onset seizures. Patients whose seizures originated from the dorsolateral convexity had focal interictal epileptiform abnormalities that localized to the region of seizure onset. Patients whose seizures began in the medial frontal region had either no interictal epileptiform abnormality or had multifocal epileptiform discharges. Patients whose seizures began in the dorsolateral convexity showed focal electrographic seizure activity that was localizing. This rhythmic fast activity did not appear to be substrate-specific. Patients whose seizure onset localized to the medial frontal region did not show focal electrographic seizure at clinical onset. We conclude that the scalp EEG recordings of frontal lobe epilepsies contain features that enable differentiation of seizures originating from two different regions of the frontal lobe.

Combined depth and subdural electrode investigation in uncontrolled epilepsy.

We used both depth and subdural electrodes to obtain localization of the seizure focus in 47 medically refractory epileptic patients. Seizures were localized in 33 patients. Onset was consistently localized by the depth electrodes in 23 patients, was variable or simultaneous in depth and subdural electrodes in 6 (in the same lobe), and was consistently localized to subdural electrodes in 4. All patients localized with subdural electrodes were extratemporal and 3 of the 4 had lesions on imaging studies which helped guide location of electrode placement. Eighty-seven percent of temporal lobe seizures began in hippocampus (recorded by the depth electrode), and 80% were eventually propagated to the ipsilateral temporal neocortex (recorded by the subdural electrode). In 8 patients with bilateral temporal depth and subdural recording, seizures never spread to the contralateral neocortex before the ipsilateral neocortex. Subdural electrodes were 20% less sensitive than depth electrodes in detection of seizures beginning in hippocampus but were accurate when lateralized. Variable or simultaneous unilateral neocortical versus hippocampal temporal lobe seizure onset, determined by the combined study, was significantly correlated with less favorable seizure control after anteromedial temporal lobectomy and hippocampectomy.

SPECT in patients with epilepsia partialis continua.

We report 2 patients with epilepsia partialis continua (EPC) in whom ictal single photon emission computed tomography (SPECT) showed focal increased signal while EEG failed to show epileptic changes. SPECT may clarify confusing situations when EPC is suspected.

Surface and depth EEG findings in patients with hippocampal atrophy.

OBJECTIVE: To establish if MRI evidence of hippocampal atrophy (HcA) is an independent surrogate of EEG criteria for the diagnosis of medial temporal lobe (MTL) epilepsy (MTLE). BACKGROUND: MRI evidence of HcA has been shown to correlate with mesial temporal sclerosis (MTS), intracranial evidence of MTL seizure onset, and outcome after temporal lobectomy. The reported rate of discordance between scalp ictal EEG recordings and MRI evidence of unilateral HcA ranges from rare to moderate. We examined the surface and depth ictal EEG findings of patients with HcA, as detected by volumetric MRI, to clarify their significance in detecting areas of epileptogenicity in this group of patients. METHODS: From a group of patients with refractory epilepsy, we identified 119 patients with HcA (97 with unilateral and 13 with bilateral HcA, 9 with HcA and mass lesion). MRI volumetric studies were used to obtain Hc ratios. Absolute volumes were used to detect bilateral atrophy. Surface and depth EEG recordings were analyzed for localization of ictal abnormalities, and their distribution was compared for concordance with the location of HcA. Surgical outcome was reviewed. RESULTS: Of the 110 patients with isolated HcA, 63 had surgery; 82% of ictal depth EEG onsets were concordant with the atrophic Hc, and 72% ictal surface EEG onsets were concordant. Four patients with concordant EEG and HcA failed to achieve seizure control with resection of the atrophic Hc. Furthermore, 3 patients with discordant EEG and HcA had resection of the non-atrophic Hc with excellent results. Among the 47 non-operated patients, 54% had discordant or unlocalized ictal depth EEG results and 52% had discordant ictal surface EEG. Four of the 9 lesional patients with HcA had excellent outcome after lesionectomy without hippocampectomy. CONCLUSION: The presence of HcA is not an independent predictor of the site of epileptogenesis.

Sexual automatisms in complex partial seizures.

Ictal sexual automatisms such as masturbatory activity, pelvic thrusting, or similar automatisms for which the patient is amnesic have been attributed to temporal lobe disease. Of 61 patients with medically refractory complex partial seizures, 14 had frontal lobe seizure foci. Four of these patients manifested sexual automatisms in some or all of their seizures. Frontal lobe seizure origin was documented by depth EEG in three patients. In the fourth, a calcified lesion was demonstrated radiologically. In three patients, frontal lobectomy revealed abnormal frontal lobe pathology and was followed by 75 to 100% reduction in seizure frequency. Sexual automatisms did not occur in patients with seizures originating in any area other than the frontal lobe.

Intracerebral masses in patients with intractable partial epilepsy.

One hundred ninety patients were considered for surgical treatment of uncontrolled partial seizures. Twenty-seven (15%) had intracranial mass lesions detected during preoperative evaluation. Seizures were present for a mean of 10 years. Sixty percent of the patients had prior negative radiologic studies. The lesions included 19 neoplasms and 8 non-neoplastic structural (non-atrophic) lesions. Refractory simple partial seizures and a changing neurologic examination were more commonly associated with neoplasms. Treatment included biopsy and radiation, mass resection, or subtotal lobectomy. Although any form of treatment gave better seizure control, patients undergoing subtotal lobectomy had more than 95% reduction in seizures.

Training clinical researchers in neurology: we must do better.

The pace of scientific discoveries, the increasing complexity of managing patients, and the runaway cost of neurological services have created an urgent need for a wide range of clinical research in neurology. Despite increasing recognition of this need and recent increases in funding for training clinical investigators, neurologists conducting cellular and molecular investigations are more likely to join faculties, maintain research careers, and attain academic advancement. Because academic departments of neurology are successful in producing and nurturing basic science researchers, why aren't they just as triumphant in spawning clinical investigators? This crisis in the preparation of clinical investigators has been brought about by many factors: competing time demands for clinical service, lack of methodologically rigorous training in the disciplines necessary to conduct clinical research, and lack of mentorship. Neurology residents contemplating a clinical research career may observe junior faculty who lack career guidance, are ill-prepared as independent investigators, and must juggle patient demands while trying to write a research grant or conduct a study. Already burdened by medical school debts, is it any wonder that our neurology graduates don't leap to a career with a future that seems so insecure? Academic departments of neurology must develop full-scale clinical research training programs if they are to meet the pressing need for clinical research. As a starting point, they must free themselves from their dependence on providing clinical services to generate income. Following the model which has produced successful basic researchers, much greater effort must be given to establishing rigorous methodological training in collaboration with other departments, creating senior role models, and protecting time for clinical investigators to conduct research. Unless we create incentives to careers in clinical research, we will never answer the growing number of clinical research questions we face today.

Episodic aphemia and epileptic focus in nondominant hemisphere: relieved by section of corpus callosum.

A patient had right hemiparesis since infancy. At age 31, she had recurrent right focal motor and sensory seizures. In prolonged focal seizures, she could not speak but retained most other language-related functions. Intracarotid cerebral amytal testing demonstrated right hemisphere speech. Left intracarotid amytal injection stopped a typical attack. Complete section of the corpus callosum abolished the aphemic episodes and reduced the frequency and intensity of the focal seizures. Focal seizure activity in the left nondominant hemisphere appears to have caused restricted functional disturbance in the right dominant hemisphere.