[18F]fluorodeoxyglucose-positron emission tomography study of genetically confirmed patients with Dravet syndrome.

OBJECTIVE: To understand cerebral brain dysfunction in patients with Dravet syndrome (DS), we conducted a [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) study in patients with DS whose SCN1A gene variant was confirmed. METHODS: FDG-PET was performed on eight patients with DS. A SCN1A mutation analysis revealed missense variants in four patients and truncation variants in four patients. The patients' ages at the time of the PET study were 2, 2, 2, 3, 6, 13, 20, and 29 years old, respectively. The patients' developmental/intelligence quotient at the time of the PET study were 62, 52, 64, 35, 30, 15, and <25, respectively. The mean standardized uptake value (SUV) was calculated in four segments (frontal, temporal, parietal, and occipital) for the semi-quantitative analysis of 18F-FDG uptake. This value represents the average of the regions of interest in each lobe and was divided by the average SUV of the cerebellar hemisphere of each patient and compared between the patients with DS and the diseased controls. RESULTS: Glucose uptake in patients with DS decreased significantly, particularly in those ≥6 years old. Importantly, a comparison between the younger and older patients with DS revealed that glucose uptake was normal in patients who were ≤3 years (2, 2, 2, and 3 years), whereas a profound reduction in glucose uptake in the fronto-temporo-parietal-occipital cortices was observed in patients ≥ 6 years (6, 13, 20, and 29 years). Magnetic resonance imaging revealed no detectable atrophic legions or other changes in the cerebral cortices of patients ≥ 6 years of age. SIGNIFICANCE: The present study showed a remarkable reduction in cerebral glucose metabolism in multiple lobes for the first time, which became obvious after the late infantile period. These findings may indicate a functional neuroimaging aspect of epileptic encephalopathy of DS or a feature of the SCN1A variant itself.

The usefulness of subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome.

The recent findings on subtraction ictal SPECT and ictal near-infrared spectroscopic topography in patients with West syndrome were summarized and its availability for presurgical evaluation was discussed. The subtraction ictal SPECT study in patients with West syndrome demonstrated the cortical epileptic region and subcortical involvement, which may consist of epilepsy networks related to the spasms. Moreover, subtraction ictal SPECT may have predictive power for short-term seizure outcome. Patients with a symmetric hyperperfusion pattern are predicted to have a better seizure outcome, whereas patients with asymmetric hyperperfusion pattern may develop poor seizure control. Importantly, asymmetric MRI findings had no predictive power for seizure outcome. Multichannel near-infrared spectroscopic topography applied to the patients with West syndrome detected an increase in regional cerebral blood volume in multiple areas which were activated either simultaneously or sequentially during spasms. Topographic changes in cerebral blood volume were closely correlated with spasm phenotype, suggesting that the cortex is involved in the generation of spasms. In conclusion, subtraction ictal SPECT may be considered as a useful tool for presurgical evaluation of patients with West syndrome and investigation of the pathophysiology of spasms. The ictal near-infrared spectroscopic topography should be more investigated to see if this is useful tool for presurgical evaluation.

Ictal vomiting as an initial symptom of severe myoclonic epilepsy in infancy: a case report.

We report on 3-year-old Japanese twin brothers suffering from ictal vomiting during infancy. Intractable seizures, including generalized tonic-clonic convulsions, and myoclonic seizures persisted in late infancy. The diagnosis of severe myoclonic epilepsy in infancy was confirmed by detecting a mutation in the voltage-gated sodium channel alpha subunit type gene. This is the first case report addressing ictal vomiting as the initial presentation of severe myoclonic epilepsy in infancy.

Utility of subtraction ictal SPECT images in detecting focal leading activity and understanding the pathophysiology of spasms in patients with West syndrome.

PURPOSES: The aims of the study were to evaluate the detectability of focal leading activity in three cases of West syndrome having focal abnormal activity on EEG by comparing subtraction ictal images and raw ictal images, and to interpret the results in 16 cases. METHODS: Subtraction images were constructed using iNeurostat (revision 2). RESULTS: In three cases with focal abnormal activity on EEG, subtraction ictal images reflected the EEG findings; in contrast, raw ictal images did not. Diverse degrees of cortical hyperperfusion, ranging from zero to 10 sites, seen in the other 13 cases seemed to reflect spasm pathophysiology and rapid spasm propagation. Subtraction ictal images also allowed the ready detection of hyperperfusion of subcortical structures and of a tight cortico-subcortical relationship in a subset of cases. CONCLUSIONS: We showed the superiority of subtraction ictal images in detecting the focal epileptic region and in showing propagation pathways from the cortex to subcortical structures. A subset of spasms in WS may be focal cortical-onset secondarily generalized seizures. We believe that subtraction analysis is valuable in patients with complex WS who have partial seizures and spasms simultaneously along with focal epileptic EEG activity, as they will likely be candidates for epilepsy surgery.

Mapping the signal-to-noise-ratios of cortical sources in magnetoencephalography and electroencephalography.

Although magnetoencephalography (MEG) and electroencephalography (EEG) have been available for decades, their relative merits are still debated. We examined regional differences in signal-to-noise-ratios (SNRs) of cortical sources in MEG and EEG. Data from four subjects were used to simulate focal and extended sources located on the cortical surface reconstructed from high-resolution magnetic resonance images. The SNR maps for MEG and EEG were found to be complementary. The SNR of deep sources was larger in EEG than in MEG, whereas the opposite was typically the case for superficial sources. Overall, the SNR maps were more uniform for EEG than for MEG. When using a noise model based on uniformly distributed random sources on the cortex, the SNR in MEG was found to be underestimated, compared with the maps obtained with noise estimated from actual recorded MEG and EEG data. With extended sources, the total area of cortex in which the SNR was higher in EEG than in MEG was larger than with focal sources. Clinically, SNR maps in a patient explained differential sensitivity of MEG and EEG in detecting epileptic activity. Our results emphasize the benefits of recording MEG and EEG simultaneously.

Spike orientation may predict epileptogenic side across cerebral sulci containing the estimated equivalent dipole.

OBJECTIVE: To evaluate whether the orientation of interictal spikes, localized in major sulci by magnetoencephalography (MEG), predicts the epileptogenic side of the sulcal wall. METHODS: Sixteen epilepsy patients were analyzed in whom equivalent current dipoles (ECDs) of MEG spikes were localized on the central (four patients), interhemispheric (4), or sylvian fissure (8); and the epileptogenic side across the sulci had been confirmed by seizure semiology, structural lesions, or intracranial electroencephalography (EEG). ECD was classified as epileptogenic side or normal side oriented and correlated to the scalp EEG map. RESULTS: All central (n=50) and interhemispheric (n=83) spike ECDs were oriented toward the epileptogenic side at peak latency. In scalp EEG, 91% of the spikes showed radial pattern of broad negativity above the sulcus whereas 9% showed tangential pattern with positive maximum above the epileptogenic side. Sylvian spikes were only found in patients with temporal lobe epilepsy (TLE). In sylvian spikes (n=220), 73% of ECDs were oriented toward the epileptogenic side, whereas 27% were oriented toward the normal side. CONCLUSIONS: In central and interhemispheric spikes, epileptogenic side cortex may be gross surface negative through the sulcal wall to the adjacent gyrus. Inconsistent orientation of the sylvian spikes suggests a complex pattern of spike propagation in TLE. SIGNIFICANCE: ECD orientation of central and interhemispheric spikes in MEG may predict the epileptogenic side.

Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum.

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a rare leukoencephalopathy presenting in the infantile period and characterized by diffuse cerebral hypomyelination, and atrophy of the basal ganglia and cerebellum. As patients with H-ABC lack remarkable laboratory findings, the diagnosis is based on brain magnetic resonance imaging findings alone. Only eight cases have been reported in the literature, and thus the natural course and treatment of this disease are not fully understood. We report a 35-month-old boy with H-ABC who had hemidystonia, hypomyelination, and cerebellar ataxia. We diagnosed H-ABC after considering a thorough differential diagnosis, excluding other diseases involving hemidystonia, hypomyelination, and cerebellar ataxia. Furthermore, technetium-99m ethyl cysteinate dimmer-single-photon emission computerized tomography (Tc-ECD-SPECT) and positron emission tomography with fluorodeoxyglucose (18)F (FDG-PET) revealed decreased blood flow and glucose metabolism in the bilateral lenticular nucleus, thalamus, and cerebellum. A peroral levodopa preparation containing carbidopa (levodopa-carbidopa) was effective at ameliorating and stopping the progression of the patient's dystonia (final effective doses: levodopa, 200 mg/day and carbidopa, 20 mg/day). This is the first case report of a Japanese patient with H-ABC and treatment for this disease. Levodopa-carbidopa may be an effective treatment for H-ABC.

Evaluation of interhemispheric time difference by magnetoencephalography before and after total callosotomy. Two case reports.

Interhemispheric time difference (ITD) measured by electroencephalography (EEG) and magnetoencephalography (MEG) was compared to seizure outcome after callosotomy. Two patients with frequent drop attacks underwent simultaneous EEG and MEG before and after total callosotomy. ITDs in 30 bilateral synchronized (BS) discharges were calculated independently by EEG and MEG. As minimum transcallosal conduction time was suggested to be approximately 20 msec, BS discharges were classified into five categories according to ITD and side: left- or right-leading long (300 to 80 msec), left- or right-leading moderate (80 to 20 msec), and negligible (<20 msec). In Case 1 before callosotomy, EEG detected 77% negligible and 23% right-leading moderate BS discharges, whereas MEG detected 30% and 63%, respectively. After callosotomy, drop attacks reduced remarkably and EEG and MEG detected no BS discharges. In Case 2 before callosotomy, EEG detected 77% negligible and 23% moderate BS discharges, whereas MEG detected 80% and 20%, respectively. After callosotomy, drop attacks recurred 2 months later and EEG and MEG detected left- and right-leading long BS discharges (63% by EEG and 56% by MEG). MEG detected a large number of BS discharges with moderate ITD before surgery in Case 1, suggesting that the transcallosal pathway was the main pathway for the synchronization, whereas the negligible ITD in Case 2 excludes transcallosal propagation. BS discharges with longer ITD after surgery in Case 2 suggest a persistent poly-synaptic non-transcallosal pathway. MEG with higher spatial resolution than EEG may provide surgical indications for callosotomy.

Successful treatment of a 2-year-old girl with intractable myasthenia gravis using tacrolimus.

We used tacrolimus to successfully treat a patient with childhood-onset oropharyngeal myasthenia gravis (MG). A girl (2 years, 5 months old) with oropharyngeal MG responded partially to treatment including pyridostigmine bromide, intravenous immunoglobulin, and prednisolone (2 mg/kg/day) for 7 weeks, but this resulted in worsening of her eye symptoms. By contrast, tacrolimus at 2 mg/day resulted in complete remission of the MG, which made it possible to reduce the dose of prednisolone. This is a rare report of the use of tacrolimus as an effective treatment for patients with intractable childhood-onset MG.

The effects of copper-histidine therapy on brain metabolism in a patient with Menkes disease: a proton magnetic resonance spectroscopic study.

We report on metabolic changes in the brain of a boy with Menkes disease. He was treated with parenteral copper (Cu)-histidine supplementation, from 5 months of age, and assessed with proton magnetic resonance spectroscopy ((1)H-MRS). The single-voxel (1)H-MRS before treatment revealed an accumulation of lactate and a reduced N-acetyl aspartate (NAA)/total creatine (tCr) ratio with a z-score of -3.0. During treatment, the lactate signal faded away, whereas the NAA signal gradually increased to a z-score of -1.5 at 120 days of treatment. The choline/tCr ratio did not deviate much initially (z-score +0.5), but the ratio increased markedly during treatment (z-score +4.8). Consequently, the Cu-histidine therapy initiated after the critical period still improved the neuronal metabolism, suggesting that some Cu was delivered to neurons. Nevertheless, the brain atrophy, impaired myelination, and severe neurological symptoms were not ameliorated.

Opercular to interhemispheric source distribution of benign rolandic spikes of childhood.

We evaluated the source distribution of benign rolandic spikes of childhood along and across the central sulcus in 15 patients, aged between 7 and 15 years, who suffered from seizure disorders. Previous routine EEG showed centrotemporal spikes, but none of them had major abnormalities on brain magnetic resonance imaging or neurological deficits. The equivalent current dipoles (ECDs) of the spikes measured by whole-head magnetoencephalography (MEG) were compared to the spike distributions detected by simultaneous scalp EEG according to the international 10-20 system. Locations and orientations of the MEG spikes corresponded to the EEG spike distribution as follows: superiorly oriented spike MEG dipoles in the opercular area corresponded to T3/4 negative peaks (8 spike groups in 6 patients); anteriorly oriented spike dipoles in the rolandic area corresponded to C3/4 or P3/4 negative peaks (17 spike groups in 13 patients); laterally oriented spike dipoles in the interhemispheric area corresponded to Cz/Pz negative peaks (4 spike groups in 3 patients); and others (4 spike groups in 4 patients). Rolandic spikes include three main types according to the ECD location from the opercular to the interhemispheric areas. The functional anatomy of benign rolandic spikes was correlated with partial seizure semiology. All three rolandic spike types can be explained by a precentral origin, assuming that the surface negative potential is continuous from the gyral to fissural cortices.

Abnormal primary somatosensory function in unilateral polymicrogyria: an MEG study.

The purpose of this study is to investigate the primary somatosensory function in patients with unilateral polymicrogyria. Somatosensory evoked fields (SEFs) due to median and posterior tibial nerve stimulation were compared in the normal and dysplastic cortices of five patients with unilateral polymicrogyria. SEFs were observed in all five normal hemispheres and three dysplastic hemispheres. Latencies of N20m and P38m, the first cortical components of and SEFs for median nerve and tibial nerve stimulation, were all within the normal range in both normal and dysplastic hemispheres. The amplitudes of the N20m and P38m in the dysplastic hemispheres were smaller in one patient and larger in two patients compared to the normal hemispheres. Equivalent current dipoles of N20m and P38m were localized on the anatomical central sulcus of the normal hemispheres and over the central area of the dysplastic hemispheres. P38m dipoles were localized medial and upward to the N20m dipole in both normal and dysplastic hemispheres. N20m dipole orientation was normal in all normal hemispheres and in one dysplastic hemisphere, but abnormally inferior in two dysplastic hemispheres. P38m dipole had normal medial orientation in all hemispheres except one dysplastic hemisphere. Abnormality of the primary somatosensory function in the dysplastic cortex of patients with unilateral polymicrogyria was clearly demonstrated by magnetoencephalography with high resolution in time and space. The normal somatotopic arrangement was preserved.

Acute dysautonomia: complete recovery after two courses of IVIg.

An 11-year-old boy presented with acute dysautonomia manifesting as severe orthostatic hypotension following fever. Serial orthostatic tests with measurement of the coefficient of variation in the R-R intervals showed improvement after one course and complete recovery after two courses of intravenous high-dose immunoglobulin therapy (IVIg). Repeated courses of IVIg should be considered to treat this disorder if spontaneous remission does not occur.

Dynamic cortical activity during spasms in three patients with West syndrome: a multichannel near-infrared spectroscopic topography study.

PURPOSE: To investigate spatial and temporal cortical activity during clusters of naturally occurring epileptic spasms in patients with West syndrome (WS) by using multichannel near-infrared spectroscopy (mNIRS). METHODS: Conventional magnetic resonance imaging (MRI) and interictal and ictal single-photon emission computed tomography (SPECT) were carried out in three patients with WS. Thereafter, cortical hemodynamics during naturally occurring epileptic spasms were measured by mNIRS with simultaneous video/electroencephalographic (EEG) monitoring. RESULTS: Ictal SPECT revealed multiple hyperperfused areas within the cortex. With the use of mNIRS, an increase in regional cerebral blood volume (CBV) was observed in these areas, which is representative of cortical activation. The increase in CBV was accompanied by an increase in the concentrations of both oxy- and deoxyhemoglobin. The following heterogeneous regional changes in CBV during ictus were observed: (a) transient increases that were synchronized with spasms; (b) a gradual increase during an ictal event that fluctuated in synchrony with spasms; and (c) a combination of transient and gradual increases. An increase in regional CBV occurred in multiple areas that were activated either simultaneously or sequentially during an ictal event. Topographic changes in CBV were closely correlated with the phenotype of the spasm. CONCLUSIONS: During ictal events, multiple cortical areas were activated simultaneously or sequentially. The pattern of cortical activation closely affected the phenotype of the spasm, which suggested that the cortex was involved in the generation of spasms.