Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease.

We sought to identify the molecular basis of the autosomal dominant form of Kufs disease, an adult onset form of neuronal ceroid lipofuscinosis. We used a combination of classic linkage analysis and Next Generation Sequencing to map and identify mutations in DNAJC5 in a total of three families. We analyzed the clinical manifestations in 20 individuals with mutation in DNAJC5. We report here the mapping and the identification of a p.L116del mutation in DNAJC5 segregating with the disease in two distinct American families, as well as a p.L115R mutation in an additional family. The age of onset and clinical manifestations were very homogeneous among mutation positive individuals, including generalized tonic-clonic seizures, myoclonus, ataxia, speech deterioration, dementia, and premature death. A few individuals also exhibited parkinsonism. DNAJC5, which encodes the cysteine string protein (CSPα), a presynaptic protein implicated in neurodegeneration, causes autosomal dominant Kufs disease. The leucine residues at positions 115 and 116 are hotspots for mutations and result in a homogeneous phenotype of progressive myoclonus epilepsy with onset around 30 years old.

SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure.

OBJECTIVE: Mutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD. METHODS: We reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1. RESULTS: Of 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found. INTERPRETATION: Mutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.

Surgical treatment of independent bitemporal lobe epilepsy defined by invasive recordings.

OBJECTIVES: Bitemporal lobe epilepsy is commonly encountered in the evaluation of pharmacoresistant epilepsy. Yet the role of surgery in the management of these patients is unclear. This study evaluates the impact of surgery on seizure tendency and quality of life, as well as prognostic indicators in individuals with proven ictal onset bitemporal lobe epilepsy. METHODS: The study population comprised all patients who underwent temporal lobe surgery over a 10 year period and had ictal onset bitemporal lobe epilepsy identified with intracranial electrode monitoring. Patients with extratemporal seizure generators were excluded. Subjects were divided into a favourable or less favourable group based on the results of surgery on seizure tendency. RESULTS: 11 subjects were studied with a mean 5.9 years of post-surgical follow-up. Six subjects constituted the favourable outcome group. Four had a less favourable outcome and continued to have frequent seizures after surgery; however, three with less favourable seizure reduction subjectively reported improvement in quality of life after surgery as a result of reduced seizure frequency and severity, and reduced medications. No single preoperative factor was significantly different between the groups, including ictal EEG laterality, epilepsy duration, age at surgery, age at seizure onset and mesial temporal atrophy. CONCLUSIONS: Surgical resection is an important treatment option for medically intractable bitemporal epilepsy. The proportion of seizures arising from one temporal lobe is not reliable as a single indicator to prognosticate the results of surgery on seizure tendency. In addition, individuals who achieved only palliation by reducing seizure frequency experienced improvement in quality of life.

Limited chronic focal encephalitis: another variant of Rasmussen syndrome?

OBJECTIVE: To describe a more limited and less malignant form of Rasmussen encephalitis (RE). METHODS: Three subjects (all women; 37, 31, and 32 years of age) developed childhood or late onset chronic focal encephalitis, with a relatively nonprogressive form of the disorder. RESULTS: In our patients, clinical features were dominated by partial seizures without marked focal motor deficit and in two with choreo-dystonic movements. The diagnosis of RE was supported by histologic examination and anatomic and functional MRI. CONCLUSIONS: These cases extend the phenotypic presentations of Rasmussen encephalitis and confirm Theodore Rasmussen's suggestion that there may be mild and nonprogressive forms of the disease.

Patterns of hippocampal abnormalities in malformations of cortical development.

OBJECTIVE: To assess whether different types of malformation of cortical development (MCD) are associated with specific patterns of hippocampal abnormalities. METHODS: A total of 122 consecutive patients with MRI diagnosis of MCD (53 males, age range 1-58 years) were included in the study. Hippocampal measurements were made on 1-3 mm coronal T1-weighted MRIs and compared with MRIs of normal controls. RESULTS: A total of 39 patients had focal cortical dysplasia, 5 had hemimegalencephaly, 5 had lissencephaly-agyria-pachygyria, 11 had SLH, 11 had PNH, 12 had bilateral contiguous PNH, 5 had schizencephaly, and 34 had polymicrogyria. The frequency of hippocampal abnormalities in these patients with MCD was 29.5%. A small hippocampus was present in all types of MCD. Only patients with lissencephaly and SLH had an enlarged hippocampus. Abnormalities in hippocampal rotation and shape were present in all types of MCD; however, these predominated in PNH. None of the patients with lissencephaly-agyria-pachygyria or SLH had hyperintense signal on T2 or FLAIR images or abnormal hippocampal internal architecture. CONCLUSION: A small hippocampus was present in all types of MCD; however, the classic MRI characteristics of hippocampal sclerosis were often lacking. Abnormal enlargement of the hippocampus was associated with only diffuse MCD due to abnormal neuronal migration (lissencephaly-agyria-pachygyria and SLH).

Etomidate speech and memory test (eSAM): a new drug and improved intracarotid procedure.

BACKGROUND: The intracarotid amobarbital procedure (IAP) is an important part of comprehensive investigation of patients who are candidates for surgical treatment of epilepsy. Owing to repeated and lengthy shortages of amobarbital, causing delays in elective surgery, attempts have been made to find a suitable alternative anesthetic. The authors report their experience using etomidate, a widely used agent for the induction of anesthesia. METHODS: Sixteen consecutive patients requiring IAP to evaluate memory or to lateralize speech underwent the procedure using etomidate. Prior to the procedure a catheter was placed in the internal carotid artery and an angiogram was performed. EEG was recorded and read online by an electroencephalographer. An anesthetist injected the drug, administered by bolus followed by an infusion, which was maintained until each speech measure had been sampled and new memory items had been introduced. The infusion was then stopped and testing continued as in a standard IAP. RESULTS: In all cases (30 hemispheres) contralateral hemiplegia followed injection. EEG slow waves were observed in every injected hemisphere, with some contralateral slowing anteriorly in 18. Global aphasia with preserved attention and cooperation followed dominant-hemisphere injections. These phenomena remained during infusion, and upon its termination returned gradually to baseline over a period of about 4 minutes. CONCLUSIONS: Etomidate is a viable alternative to amobarbital, and its administration by bolus followed by infusion offers an improvement over the traditional intracarotid amobarbital procedure. Cognitive tests can be performed during an assured hemianesthesia of the injected hemisphere.

Preictal headache in partial epilepsy.

The authors studied clinical characteristics in 11 patients with intractable focal epilepsy and preictal headache (PIHA) using a standardized interview. Headache was frontotemporal, ipsilateral to the focus, in nine patients with temporal lobe epilepsy (TLE) and contralateral in one with TLE and in one with frontal seizures. Migrainous features were found in four. After surgery, all seven seizure-free patients and two with rare seizures were free of PIHA. It may be a useful lateralizing sign in patients with TLE.

Analysis of shape and positioning of the hippocampal formation: an MRI study in patients with partial epilepsy and healthy controls.

The purpose of this study was to evaluate systematically shape and positioning of the hippocampal formation (HF) in patients with partial epilepsy related to malformations of cortical development (MCD) and those with temporal lobe epilepsy (TLE). We studied 76 patients with MCD, including focal cortical dysplasia (n = 29; lesions located outside the temporal lobe in all), heterotopia (lesions outside of the temporal lobe, n = 14; lesions extending into the temporal lobe, n = 16), polymicrogyria (bilateral perisylvian, n = 14; unilateral perisylvian, n = 3) and 30 patients with TLE (hippocampal atrophy, n = 15; normal hippocampal volumes, n = 15). Shape and positioning of the HF were evaluated using a set of eight predefined morphological characteristics. In addition, the degree of hippocampal vertical orientation and medial positioning were assessed quantitatively. Patients were compared with 50 healthy controls. At least three criteria describing abnormal HF shape and positioning were found in 5/50 (10%) healthy controls, 37/76 (49%) MCD and 13/30 (43%) TLE patients. An association with all criteria was found in MCD and TLE, but not in healthy controls. In MCD there was no association between the side of HF shape abnormalities and the side of the cortical malformation or the EEG focus. Likewise, in TLE, HF abnormalities were not related to the side of the EEG focus. In both MCD and TLE patients who had hippocampal atrophy, no association was found between the side of HF shape abnormalities and the side of atrophy. Abnormal HF shape and positioning are found in a similar proportion in MCD and TLE. In TLE, they may be a marker of a more extensive disorder of brain development and may participate in the development of this condition.

Adult-onset epilepsy in focal cortical dysplasia of Taylor type.

Focal cortical dysplasia of Taylor type (FCDT) usually presents with seizures at an early age, whereas adult onset of epilepsy is uncommon. We reviewed the medical records of 213 patients with FCDT. In 21 patients (10%), age at seizure onset ranged from 18 to 55 years (mean 25.3). The outcome of seizures in patients with FCDT and adult-onset epilepsy seems favorable vs childhood-onset seizures.

[Familial cavernous malformations of the central nervous system. A clinical and genetic study of 15 German families]. / Familiäre Kavernome des Zentralnervensystems. Eine klinische und genetische Studie an 15 deutsche Familien.

In 1928, Hugo Friedrich Kufs reported on a family with cerebral, retinal, and cutaneous cavernous malformations. Since then, more than 300 families with inherited cavernous malformations have been reported. Genetic studies showed three loci, on chromosomes 7q21-q22 (with the gene CCM1), 7p15-p13 (CCM2), and 3q25.2-q27 (CCM3). The gene product of CCM1 is Krit 1 (Krev interaction trapped 1), a protein interacting with angiogenesis by various mechanisms. Recently, CCM2 has also been identified; its product is a protein which might have a function similar to that of Krit 1. However, the CCM3 gene has still not been found. In this study, we present clinical and genetic findings on 15 German families.

Posterior quadrantic dysplasia or hemi-hemimegalencephaly: a characteristic brain malformation.

INTRODUCTION: Posterior quadrantic dysplasia (PQD), a developmental malformation involving the temporal, parietal, and occipital lobes of one cerebral hemisphere, leads to intractable epilepsy. OBJECTIVE: To characterize the clinical features of 19 patients with PQD and analyze the postsurgical outcome of those who underwent resection of dysplastic tissue. METHODS: The extent and nature of the malformation were primarily assessed with high-resolution brain imaging. Fourteen patients underwent complete or partial temporoparieto-occipital resection or temporal resection associated with parieto-occipital disconnection. Postoperative follow-up period ranged from 8 months to 7 years. The authors used the Engel classification for postoperative outcome. RESULTS: All patients were sporadic. Clinical features included infantile spasms, partial seizures, mental retardation, mild hemiparesis, and visual field defects. Neuroimaging localized the malformation within the posterior cerebral quadrant contralateral to the neurologic deficit and demonstrated hemi-hemimegalencephaly in 14 of 19 patients and multilobar cortical dysplasia in 5 of 19 patients. The authors observed class I outcome in six patients. Two patients had class II and four patients had class III outcome. Class IV outcome was seen in two patients. After surgery, two patients developed mild hemiparesis, and two developed a visual field defect. CONCLUSIONS: Widespread cortical dysplasia is more frequent in the posterior quadrant. In our series, posterior quadrantic dysplasia represents either hemi-hemimegalencephaly or multilobar cortical dysplasia. Individuals with posterior quadrantic dysplasia share a spectrum of clinical features. The intractable epilepsy in these patients may be alleviated by a large quadrantic temporoparieto-occipital resection.

Neuroimaging findings in scleroderma en coup de sabre.

OBJECTIVES: To describe the neuroimaging and clinical findings in patients with localized scleroderma en coup de sabre (LScs). METHODS: Patients with LScs were evaluated by high-resolution MRI and CT. The authors performed three-dimensional reconstructions of MRI and CT scans to evaluate brain and bone structures. RESULTS: Nine patients with LScs were evaluated (five women), with ages ranging from 6 to 53 years (mean, 30.7 years). Brain CT showed bone deformities with thinning of the skull under the skin lesions in six patients. MRI scans showed focal atrophy and blurring of the gray-white matter interface localized under the skin lesion in all patients. In three patients it was associated with hyperintense signal on fluid-attenuated inversion recovery (FLAIR) and T2-weighted images. Follow-up MRI showed extension of the brain lesion in one patient; in the remaining patients, the lesion did not progress. Four of the nine patients had partial epilepsy. One had surgery for management of refractory seizures, and pathologic findings indicated a focal inflammatory process. CONCLUSION: Localized scleroderma en coup de sabre is associated with focal, and in some progressive, brain lesions underlying the skin atrophy. Epilepsy, when present, is related to these brain lesions. Imaging findings and histopathology indicated that the process, most likely focal inflammatory, may be progressive.

CCM1 mutation screen of sporadic cases with cerebral cavernous malformations.

Cerebral cavernous malformations (CCM) are CNS vascular anomalies associated with seizures, headaches, and hemorrhagic strokes. The CCM1 gene was screened in 35 sporadic cases with either single or multiple CCM. It was found that 29% of the individuals with multiple CCM have a CCM1 mutation, whereas cases with only one malformation have none. Sporadic cases with multiple malformations warrant the same approach as individuals who have a familial history of CCM.

Herpesviral DNA in brain tissue from patients with temporal lobe epilepsy.

OBJECTIVES: Presence of DNA from six herpesviruses were examined in brain tissue from patients operated for temporal lobe epilepsy. MATERIAL AND METHODS: A total of 19 Canadian patients (I) with a median age of 22 years, 17 Swedish patients (II) with a median age of 14 years and a reference group comprising 12 individuals were studied. Presence of herpesviral DNA was detected by nested polymerase chain reaction. RESULTS: Of three children with Rasmussen's encephalitis, Cytomegalovirus (CMV) DNA was found in two, and human herpesvirus type 6 DNA in two. In six children with ganglioglioma, Epstein-Barr virus (EBV) was detected in four. CMV DNA was found significantly more in group I compared with II, while the reverse occurred with EBV DNA. Malformations of cortical development were found significantly more in group II compared with I. CONCLUSION: Detection of DNA from some herpesviruses in epileptic brain tissue may possibly be associated with distinct clinical conditions, but factors such as age and malformations of cortical development should also be considered.

Intractable temporal lobe epilepsy with rare spikes is less severe than with frequent spikes.

OBJECTIVE: To analyze clinical, electrophysiologic, and neuroradiologic characteristics of a group of patients with nonlesional intractable temporal lobe epilepsy (TLE) and rare or absent interictal epileptiform abnormalities (IEA). METHODS: Between 1990 and 2000, 31 patients (11 men; mean +/- SD age 34.3 +/- 11.7 years) with nonlesional intractable TLE were consecutively selected on the basis of the absence or paucity of IEA (<1/h) on serial scalp EEG recording; these were defined as "oligospikers." The clinical and laboratory characteristics of oligospikers were compared with those of a group of 27 age-matched control subjects (10 men; mean +/- SD age 38.5 +/- 11 years), randomly selected from a pool of patients with nonlesional TLE with frequent IEA. RESULTS: Oligospikers showed a later age at seizure onset (mean +/- SD 19.1 +/- 14.4 versus 10.2 +/- 7.4 years; p = 0.004), lower monthly frequency of complex partial seizures (median 6 versus 12; p = 0.035), lower incidence of secondarily generalized tonic-clonic seizures (10 versus 81%; p < 0.001), and no status epilepticus (0 versus 22%) than control subjects. Also, hippocampal atrophy (HA) was less commonly found in oligospikers (55 versus 96%; p = 0.001). However, there were no differences between the two groups in the frequency of family history of epilepsy, risk factors, febrile convulsions, and type of medication. Twenty-three (74%) oligospikers and 25 (93%) control patients underwent either a selective amygdalohippocampectomy or corticoamygdalohippocampectomy. Excellent surgical outcome (Engel's Class Ia) was found in 14 of 23 (61%) oligospikers and 17 of 25 (67%) control patients. CONCLUSIONS: This study identified a subgroup of patients with nonlesional intractable TLE with no or few IEA. Oligospikers have a later age at seizure onset, less frequent and less severe seizures, besides a lower incidence of HA. The similarity of etiologic factors compared with patients with frequent IEA suggests that the rarity of spikes could reflect a disease not really distinct but less severe, even though still intractable and incapacitating enough to consider surgery. In spite of the absence or paucity of IEA, oligospikers have excellent surgical outcome.

Resection of the lesion in patients with hypothalamic hamartomas and catastrophic epilepsy.

BACKGROUND: Patients with hypothalamic hamartomas (HH) often have severe refractory epilepsy, incapacitating behavioral abnormalities, and cognitive decline. Attempts to control the seizure disorder by resection of apparently epileptogenic mesial temporal or other cortical structures have failed consistently. OBJECTIVE: To report a series of 13 patients in whom the hamartoma itself was resected. METHODS: All patients underwent preoperative evaluation between ages 2 and 33 years and had subtotal or complete resection of the hamartoma. Follow-up ranged from 1 to 5.5 years (mean: 2.8 y). RESULTS: Preoperatively, all patients had variable combinations of gelastic, complex partial, and generalized seizures. Eight had drop attacks. In addition, all had marked behavior abnormalities and cognitive impairment. Postoperatively, two patients are completely seizure-free and 11 are either seizure-free or have achieved a greater than 90% reduction of drop attacks and generalized tonic-clonic seizures. However, minor gelastic, complex partial, and atypical absence seizures have persisted in 11 patients, although at significantly reduced rates. In addition, there has been a dramatic improvement in behavior and cognition. Three patients had an anterior thalamic and one a capsular infarct, which left only minimal long-term deficits. Exact location of the lesion in relation to the interpeduncular fossa and the walls of the third ventricle correlated with extent of excision, seizure control, and complication rate. CONCLUSION: Resection can alleviate both the seizures and the behavioral and cognitive abnormalities of hypothalamic hamartomas, but complications are frequent.

Localizing value of alpha-methyl-L-tryptophan PET in intractable epilepsy of neocortical origin.

BACKGROUND: [(11)C] alpha-methyl-L-tryptophan (alpha-MTrp) has been developed as a tracer for the study of the synthesis of serotonin in the brain with PET. However, it has been shown that in pathologic conditions the tracer may reflect the activation of kynurenine metabolism. Increased levels of serotonin and quinolinic acid have been described in resected epileptogenic cortex, raising the possibility that alpha-MTrp can localize seizure foci in patients with intractable partial epilepsy. The authors assessed the uptake of alpha-MTrp in 18 patients (11 men, mean +/- SD age 27.1 +/- 10.1 years, range 13 to 54) with intractable partial epilepsy to correlate the PET findings with the epileptogenic area defined by electroclinical and neuroimaging data. METHOD: Seven patients with cortical dysplasia (CD) and 11 with partial epilepsy in which conventional MRI and fluorine-18-deoxyglucose ((18)FDG)-PET studies failed to detect any abnormality were studied. All underwent scalp EEG monitoring during the PET scan to exclude ictal events and estimate the interictal epileptic activity. RESULTS: In seven patients (39%; CD four and cryptogenic partial epilepsy three), PET showed focal increased uptake of alpha-MTrp corresponding to the epileptogenic area. alpha-MTrp uptake in the epileptic focus correlated with the frequency of interictal spikes (r = 0.7, p < 0.05). CONCLUSIONS: alpha-MTrp-PET may be of value in the localization of the epileptogenic area not only in patients with visible dysplastic lesions, but also in those with cryptogenic partial epilepsy.

Benign nocturnal alternating hemiplegia of childhood: six patients and long-term follow-up.

Benign familial nocturnal alternating hemiplegia of childhood refers to recurrent attacks of hemiplegia arising from sleep, described in young children without neurologic or mental impairment. It is probably migraine related. The authors report two unrelated patients with nocturnal attacks starting at 22 and 31 months, followed by daytime episodes in one. The authors confirm the benign course of this disorder. It is distinct from the classic malignant form of alternating hemiplegia of childhood.

Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extra-temporal partial epilepsy.

In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. To increase the sensitivity of magnetic resonance imaging (MRI) for the detection of subtle lesions of FCD, we developed voxel-based image postprocessing methods, including first-order texture analysis and morphological processing modeled on known MRI features of FCD. We selected 16 patients with histologically proven FCD. Image processing features were calculated over a neighborhood for each voxel in the three-dimensional T1-weighted MRI. Three feature maps were generated: (1) gray matter thickness map to model cortical thickening, (2) gradient map to model blurring of the gray matter-white matter junction, and (3) relative intensity map to model the hyperintense signal within the lesion. Two observers detected lesions on conventional MRI in 8/16 and on ratio maps in 14/16 patients. Sensitivity was 87.5% (14/16) for the ratio maps compared to 50% (8/16) for MRI (p < 0.003). Specificity was 95% (19/20) for ratio maps and 100% (20/20) for MRIs. Cohen's kappa was 0.53 for MRIs, indicating moderate agreement, and 0.83 for ratio maps, indicating strong agreement beyond chance between the 2 observers. The image-processing methods developed in this study improve visual detection of FCD, even in cases where no lesion is obvious on MRI. These techniques could increase the number of patients with partial epilepsy who could benefit from surgery.