Juvenile-onset neuronal ceroid lipofuscinosis with infantile CLN1 mutation and palmitoyl-protein thioesterase deficiency.

Accurate diagnosis, especially in progressive hereditary diseases, is essential for the treatment and genetic counseling of the patient and the family. Neuronal ceroid lipofuscinoses (NCL) are amongst the most common groups of neurodegenerative diseases. Infantile, juvenile, and adult-onset types with multiple genotype-phenotype associations have been described. A fluorimetric enzyme assay for palmitoyl protein thioesterase (PPT) from leukocytes and fibroblasts has been previously developed to confirm the diagnosis of infantile NCL. We describe a patient with juvenile-onset NCL phenotype with a new CLN1 mutation and deficient PPT activity. Over 40 different mutations have been found in patients with PPT deficiency, indicating that screening for known mutations is not an efficient way to diagnose this disorder. Therefore, PPT enzyme analysis should precede mutation analysis in suspected PPT deficiency, particularly in patients with granular osmiophilic deposits (GROD) or in patients who have negative ultrastructural data. The use of enzyme assay led to the diagnosis of this patient with juvenile-onset Finnish variant NCL with PPT deficiency, and we expect that greater awareness of the utility of the enzymatic assay may lead to identification of other similar cases awaiting a definitive diagnosis.

Recurrent seizures may cause hippocampal damage in temporal lobe epilepsy.

OBJECTIVE: To investigate whether recurrent seizures cause hippocampal damage in temporal lobe epilepsy (TLE). PATIENTS: Eighteen patients with newly diagnosed cryptogenic TLE, 14 patients with chronic well-controlled cryptogenic TLE, 32 patients with chronic drug-resistant cryptogenic TLE, and 25 healthy subjects were studied. MEASUREMENTS: Hippocampal MRI volumetry and T2 relaxometry were used. RESULTS: Chronic drug-resistant patients with seizure focus in the left temporal lobe had an 18% smaller left hippocampus and chronic drug-resistant patients with seizure focus in the right temporal lobe had a 14% smaller right hippocampus than did the control group (p < 0.05). Chronic drug-resistant patients with seizure focus on the left side had longer T2 relaxation times in the body of the left hippocampus than did the control group (p < 0.001) and chronic drug-resistant patients with seizure focus on the right side had longer T2 relaxation times in the body of the right hippocampus than did the control subjects (p < 0.01). In all patients with a left seizure focus, the left hippocampal volume correlated inversely with the estimated total number of partial (r = -0.391, p < 0.01) or generalized (r = -0.312, p < 0.05) seizures the patient had experienced. The prolongation of the left T2 relaxation time in the body of the hippocampus correlated with the total number of both partial (r = 0.670, p < 0.001) and generalized (r = 0.481, p < 0.001) seizures and with the duration of TLE symptoms (r = 0.580, p < 0.001). CONCLUSIONS: In patients with cryptogenic epilepsy, recurrent seizures may cause damage to the hippocampus throughout the lifetime of the patient.

Hippocampal and amygdaloid damage in partial epilepsy: a cross-sectional MRI study of 241 patients.

Patients with drug-refractory temporal lobe epilepsy (TLE) often have hippocampal and amygdaloid damage. The present study investigated the factors associated with the occurrence and severity of damage in patients with partial epilepsy. Magnetic resonance imaging was used to measure the volumes of the hippocampus and the amygdala in 241 patients with different durations of epilepsy. We also investigated the association of damage with the location of seizure focus and clinical factors (age at onset of seizures, lifetime seizure number and medical history of complex febrile convulsions, intracranial infection or status epilepticus) with regression analysis. We found that high lifetime seizure number (P<0.05), history of complex febrile convulsions (P<0.01), and age < or = 5 years at the time of the first seizure (P<0.01) were significant risk factors for reduced hippocampal volume in TLE patients. The severity of amygdaloid damage did not differ between TLE patients with different durations of epilepsy or seizure frequency, but complex febrile convulsions (P<0.05) and intracranial infection (P<0.05) were associated with amygdaloid damage. In patients with extratemporal or unclassified partial epilepsy, the hippocampal and amygdaloid volumes did not differ when patients with different durations of epilepsy were compared with controls. The present findings indicate that a high seizure number, the occurrence of complex febrile convulsions, and an early onset of seizures contribute to hippocampal volume reduction in patients with TLE. The data provided have important implications with regard to early and effective management and seizure control in vulnerable patients.

MRI volumetry of the hippocampus, amygdala, entorhinal cortex, and perirhinal cortex after status epilepticus.

Neuronal damage has been observed in the medial temporal lobe of both humans and animals following status epilepticus. The aim of the present study was to investigate the occurrence of medial temporal lobe damage in status epilepticus patients treated in hospital with a predetermined protocol and to assess whether the changes progress in a long-term follow-up. The volumes of the hippocampus, amygdala, entorhinal and perirhinal cortices were measured using magnetic resonance imaging (MRI) in nine adult patients with status epilepticus 3 weeks, 6 and 12 months after the insult. The control group included 20 healthy subjects. The etiology of status epilepticus was an acute process in one patient and a chronic process in eight cases. The mean duration of secondarily generalized tonic-clonic status epilepticus episodes was 1 h and 44 min. Volumetric MRI indicated that none of the patients developed marked volume reduction in the hippocampus, amygdala, or the entorhinal and perirhinal cortices during the 1-year follow-up period. Status epilepticus does not invariably lead to a progressive volume reduction in the medial temporal lobe structures of adult patients treated promptly in hospital with a predetermined protocol for rapid cessation of seizure activity.

Amygdala damage in experimental and human temporal lobe epilepsy.

The amygdala complex is one component of the temporal lobe that may be damaged unilaterally or bilaterally in children and adults with temporal lobe epilepsy (TLE) or following status epilepticus. Most MR (magnetic resonance) imaging studies of epileptic patients have shown that volume reduction of the amygdala ranges from 10-30%. In the human amygdala, neuronal loss and gliosis have been reported in the lateral and basal nuclei. Studies in rats have more specifically identified the amygdaloid regions that are sensitive to status epilepticus-induced neuronal damage. These areas include the medial division of the lateral nucleus, the parvicellular division of the basal nucleus, the accessory basal nucleus, the posterior cortical nucleus, and portions of the anterior cortical and medial nuclei. Otherwise, other amygdala nuclei, such as the magnocellular and intermediate divisions of the basal nucleus and the central nucleus, remain relatively well preserved. Amygdala kindling studies in rats have shown that the density of a subpopulation of GABAergic inhibitory neurons that also contain somatostatin may be reduced even after a low number of generalized seizures. While analyses of histological sections and MR images indicate that in approximately 10% of TLE patients, seizure-induced damage is isolated to the amygdala, more often amygdala damage is combined with damage to the hippocampus and/or other brain areas. Moreover, recent data from rodents and nonhuman primates suggest that structural and functional alterations caused by seizure activity originating in the amygdala are not limited to the amygdala itself, but may also affect other temporal lobe structures. The information gathered so far on damage to the amygdala in epilepsy or after status epilepticus suggests that local alterations in inhibitory circuitries may contribute to a lowered seizure threshold and greater excitability within the amygdala. Furthermore, damage to select nuclei in the amygdala may predict impairment of performance in behavioral tasks that depend on the integrity of the amygdaloid circuits.

MRI volumetry and T2 relaxometry of the amygdala in newly diagnosed and chronic temporal lobe epilepsy.

Little is known about the appearance and severity of amygdaloid damage in temporal lobe epilepsy, particularly in its early stages. In the present magnetic resonance imaging study, we measured amygdaloid volumes and T2 relaxation times in 29 patients with newly diagnosed and in 54 patients with chronic temporal lobe epilepsy. The control population included 25 normal subjects. In the newly diagnosed patients, the mean amygdaloid volume did not differ from that in controls. Also, in the chronic patients the mean amygdaloid volume did not differ from that in controls or in newly diagnosed patients. However, in 19% of the chronic patients the amygdaloid volume was reduced by at least 20%. Moreover, in all of the epilepsy patients, both chronic and newly diagnosed, we found an inverse correlation between the number of epileptic seizures the patient had experienced and the amygdaloid volume on the focal side (focus on the left, r = -0.371, P < 0.01; focus on the right, r = -0.348, P < 0.05). The mean T2 relaxation time in newly diagnosed or chronic patients did not differ from each other or from control values. However, the T2 relaxation time of the left amygdala was > or = 111 msec (i.e., > or = 2 S.D. over the mean T2 time of the left amygdala in control subjects) in seven (10%) patients, one of which was newly diagnosed and six were chronic. The T2 time of the right amygdala was prolonged in eight (12%) patients, three of which were newly diagnosed and five were chronic. We did not find any clear asymmetries in amygdaloid volumes or T2 relaxation times between the ipsilateral and contralateral sides relative to seizure focus. According to the present findings, signs of amygdaloid damage were observed in approximately 20% of patients with temporal lobe epilepsy, most of which had chronic epilepsy.

Quantitative MRI volumetry of the entorhinal cortex in temporal lobe epilepsy.

The entorhinal cortex (Brodmann's area 28) is located at the anterior aspect of the parahippocampal gyrus ventral to the amygdala and the hippocampus. It is reciprocally interconnected with the hippocampus via glutamatergic pathways. We investigated whether the entorhinal cortex is damaged in human temporal lobe epilepsy (TLE). The volume of the entorhinal cortex was measured using magnetic resonance imaging (MRI) in 36 patients with cryptogenic TLE and in 21 controls. The mean volumes of the entorhinal cortex on the focal side did not differ from controls. In 11 of 36 patients, however, the entorhinal cortex volume was reduced by 25%. Entorhinal volume correlated with hippocampal volume in TLE (ipsilaterally, r= 0.454, P<0.01; contralaterally, r = 0.340, P<0.05). Further, 64% of patients with 25% entorhinal cortex damage had ipsilateral hippocampal atrophy. On the other hand, right focal TLE patients with hippocampal atrophy had a 19% volume reduction of the ipsilateral entorhinal cortex (P<0.05). The volume of the entorhinal cortex correlated with the duration of TLE (r= -0.335, P< 0.05). The present study indicates that the entorhinal cortex might be damaged in a subpopulation of patients with cryptogenic TLE. In most cases, volume reduction was associated with hippocampal damage. These data suggest that entorhinal damage contributes to the symptomatology in TLE.

Long-term treatment with vigabatrin - 10 years of clinical experience.

This report describes the long-term follow-up of 56 patients with refractory partial epilepsy who, within 3 months of vigabatrin add-on therapy (3 g/day), showed a reduction in monthly seizure frequency of more than 50%. The short-term (6 months) and long-term (5 years) effects of vigabatrin on seizure frequency in this patient cohort have been published separately. The reduction in seizure frequency appeared to be long-lasting in the patients followed-up (n = 36) and, importantly, a significant number of the patients (n = 7) became seizure-free, especially during long-term treatment. Thus, the efficacy of vigabatrin appears to be progressive, at least in patients who show an early response to treatment. These results are consistent with experimental findings that suggest that vigabatrin may have anti-epileptogenic and neuroprotective effects.

A suicide epidemic in a psychiatric hospital.

The authors report in detail on an epidemic of six inpatient suicides in a psychiatric hospital in Finland. Suggestion and identification had an effect on the timing as well as on the method of four of the suicides. The epidemic is viewed from individual, network, and organizational perspectives. The authors speculate on how such epidemics could be avoided. An increase in inpatient suicide rates has been reported from many countries, and the Werther effect may thus become a topic of considerable importance in psychiatric hospitals in the future.

Correlation of quantitative MRI and neuropathology in epilepsy surgical resection specimens--T2 correlates with neuronal tissue in gray matter.

Newer MRI methods can detect cerebral abnormalities not identified on routine imaging in patients with focal epilepsy. Correlation of MRI with histopathology is necessary to understand the basis of MRI abnormalities and subsequently predict histopathology from in vivo MRI. The aim of this study was to determine if particular quantitative MR parameters were associated with particular histological features. Nine patients with temporal lobe epilepsy were imaged at 1.5 T using standard presurgical volumetric and quantifiable sequences: magnetization transfer and FFT2. The resected temporal lobe was registered with the volumetric MRI data according to our previously described method to permit correlation of the modalities. Stereologically measured neuronal densities and field fraction of GFAP, MAP2, synaptophysin and NeuN immunohistochemistry were obtained. Analyses were performed in the middle temporal gyrus and compared with quantitative MRI data from the equivalent regions. There was a significant Spearman Rho negative correlation between NeuN field fraction and the T2 value in gray matter (correlation coefficient -0.72, p=0.028). There were no significant correlations between any neuropathological and MR measures in white matter. These preliminary findings suggest that T2 in gray matter is sensitive to the proportion of neuronal tissue. Novel quantitative MRI measures acquired with higher field strength magnets, and so with superior signal to noise ratios, may generate data that correlate with histopathological measures. This will enable better identification and delineation of the structural causes of refractory focal epilepsy, and will be of particular benefit in patients in whom current optimal MRI does not identify a relevant abnormality.

Hippocampal damage in newly diagnosed focal epilepsy: a prospective MRI study.

OBJECTIVE: To examine the longitudinal appearance of hippocampal (HC) damage in a prospective follow-up study of patients with newly diagnosed epilepsy. METHODS: A total of 103 patients with newly diagnosed focal epilepsy were scanned with MRI before antiepileptic medication was started. Serial MRI studies were scheduled after 1, 2 to 3, and 5 years of treatment in the ongoing follow-up study. Volumes of the HC were measured from MRI scans according to the Cavalieri method of modern design stereology and compared at different time points together with clinical variables. RESULTS: No difference was observed in the mean HC volumes between controls and patients at baseline, after 1, 2 to 3, and 5 years of follow-up. Individual analysis showed that 8% of patients had HC damage at the time of the diagnosis and 13% of patients developed HC volume decrease during 2 to 3 years of follow-up. These patients had longer duration of seizure disorder and larger seizure number before the epilepsy was diagnosed and treatment started compared with patients who did not show HC damage. CONCLUSIONS: Hippocampal volume decreases occur in individual patients with newly diagnosed focal epilepsy during the first years of treatment. The data obtained suggest that hippocampal volumetry provides a surrogate marker of the epileptic process.

Association between the density of mossy fiber sprouting and seizure frequency in experimental and human temporal lobe epilepsy.

PURPOSE: If the sprouting of granule cell axons or mossy fibers in the dentate gyrus is critical for the generation of spontaneous seizures in temporal lobe epilepsy (TLE), one could hypothesize that epileptic animals or humans with increased sprouting would have more frequent seizures. This hypothesis was tested by analyzing the data gathered from experimental and human epilepsy. METHODS: In experiment I (rats with "newly diagnosed" TLE), self-sustained status epilepticus was induced in rats by electrically stimulating the amygdala. Thereafter, the appearance of spontaneous seizures was monitored by continuous video-electroencephalography (EEG) until the animal developed two spontaneous seizures and for 11 d thereafter. Rats were perfused for histology, and mossy fibers were stained using the Timm method. In experiment II (rats with "recently diagnosed" TLE), status epilepticus was induced in rats and the development of seizures was monitored by video-EEG for 24 h/d every other day for 60 days. All animals were then perfused for histology. In experiment III (rats with "chronic" TLE), animals were monitored by video-EEG for 24 h/d every other day for 6 months before histologic analysis. To assess mossy fiber sprouting in human TLE, hippocampal sections from 31 patients who had undergone surgery for drug-refractory TLE were stained with an antibody raised against dynorphin. RESULTS AND CONCLUSIONS: Our data indicate that the density of mossy fiber sprouting is not associated with the total number of lifetime seizures or the seizure frequency in experimental or human TLE.