A Case of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis Responsive to Intravenous Immunoglobulin (IVIG) Therapy in a Pediatric Patient.

We present a case of an eight-year-old boy who presented with complaints of headache, blurry vision, and eye pain. Ophthalmological exams and magnetic resonance imaging confirmed the presence of optic neuritis. Initial cerebrospinal fluid analysis was negative for all antibodies (Abs) associated with optic neuritis and other acute demyelinating syndromes, including anti-myelin oligodendrocyte glycoprotein Ab (anti-MOG-Ab). The child was treated with a course of pulse methylprednisolone therapy for five days, with significant improvement in his symptoms. However, the child went on to have a recurrent episode of optic neuritis one month after his initial presentation. Hence, investigations targeting immunological biomarkers were repeated and turned out to be positive for anti-MOG-Abs with elevated titers. The child was diagnosed with MOG-Ab-associated optic neuritis presenting as chronic relapsing inflammatory optic neuropathy (CRION). He was then started on maintenance intravenous immunoglobulin (IVIG) therapy as a disease-modifying therapy, following which he has not had any further relapses over two years.

Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease - United States.

The term "chronic Lyme disease" is used by some health care providers as a diagnosis for various constitutional, musculoskeletal, and neuropsychiatric symptoms (1,2). Patients with a diagnosis of chronic Lyme disease have been provided a wide range of medications as treatment, including long courses of intravenous (IV) antibiotics (3,4). Studies have not shown that such treatments lead to substantial long-term improvement for patients, and they can be harmful (1,5). This report describes cases of septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess resulting from treatments for chronic Lyme disease. Patients, clinicians, and public health practitioners should be aware that treatments for chronic Lyme disease can carry serious risks.

Ring chromosome 20.

Ring Chromosome 20 syndrome is a rare chromosomal disorder characterized by refractory epilepsy, with seizures in wakefulness and sleep, behavioral problems and mild to severe cognitive impairment. Facial dysmorphism or other congenital malformations are rarely reported making it difficult to diagnose the syndrome based on clinical findings alone. Therefore, diagnosis requires cytogenetic testing. More than 100 cases have been published since the initial report in 1972. In some patients, the ring (20) is found in all cells analyzed and in these cases, the ring is almost always accompanied by deletions of 20pter and/or 20qter. However, in the majority of cases the ring is present in only a proportion of cells, with two normal 20's in the remaining cells (mosaicism), and in these cases, no deletions of chromosome 20 have been observed. Patients with supernumerary r(20) chromosomes have also been identified, but these individuals do not generally have seizures and are not discussed in this review. Characterization by fluorescence in situ hybridization and array-based analysis has shed insight into the molecular composition and possible mechanisms of ring formation, in both the mosaic and non-mosaic patients. The age of onset of seizures correlates with the percentage of cells with the ring in mosaic patients. While the underlying etiology of the phenotype is still not understood, evidence is accumulating which suggests the deletion of candidate genes on chromosome 20 is not responsible. Cytogenetic analysis, rather than chromosomal microarray analysis is recommended for diagnosis of this syndrome, as the mosaic cases do not have copy number alterations and are therefore not identified by array-based analysis.

Molecular analysis of ring chromosome 20 syndrome reveals two distinct groups of patients.

BACKGROUND: The ring chromosome 20 syndrome (R20) is a rare genetic disorder associated with a refractory electroclinical epilepsy syndrome and variably expressed comorbidities of intellectual disability and dysmorphism. METHODS: To understand the structure and composition of the ring chromosome 20 (r(20)) in this patient cohort, blood specimens from 28 affected individuals were analysed by cytogenetic, fluorescence in situ hybridisation, and/or high resolution whole genome single nucleotide polymorphism array analysis. RESULTS: These studies revealed two distinct groups of patients. Group 1 (N=21) was mosaic for the r(20) and a normal cell line with no detectable deletions or duplications of chromosome 20 in either cell line. The mosaic nature of these rings suggests a postzygotic origin with formation of the ring by fusion of the telomeric regions with no apparent loss of subtelomeric or telomeric DNA. Group 2 (N=7) had non-mosaic ring chromosomes with a deletion at one or both ends of the chromosome, near the ring fusion point. The non-mosaic nature of these rings is consistent with a meiotic origin. The age of onset of seizures was significantly lower in the non-mosaic patients (group 2, median age of onset 2.1 years) than in the mosaic patients (group 1, median age of onset 6.0 years). Patients from group 2 had more extensive comorbidities. CONCLUSIONS: These studies demonstrate that r(20) is molecularly heterogeneous and formed by two distinct mechanisms, which, in turn, produce different phenotypic spectrums.

Bilateral intracranial electrodes for lateralizing intractable epilepsy: efficacy, risk, and outcome.

OBJECTIVE: Medically refractory epilepsy is amenable to neurosurgical intervention if the epileptogenic focus is accurately localized. If the scalp video-electroencephalography (EEG) and magnetic resonance imaging are nonlateralizing, yet a single focus is suspected, video-EEG monitoring with bilateral intracranial electrode placement is helpful to lateralize the ictal onset zone. We describe the indications, risks, and utility of such bilateral surveys at our institution. METHODS: We retrospectively reviewed 26 patients with medically refractory seizures who were treated over a 5-year period and underwent bilateral placement of intracranial electrodes. Subdural strips were used in all cases, and additional stereotactic implantation of depth electrodes into mesial temporal lobes occurred in 50%. The mean patient age was 37.7 years, and 65.4% of patients were male. RESULTS: The most common indication for bilateral invasive monitoring was bilateral ictal onsets on surface video-EEG (76.9%), followed by frequent interictal spikes contralateral to a single ictal focus (7.7%). Intracranial monitoring lasted an average of 8.2 days, with ictal events recorded in all cases. Ten patients (38.5%) subsequently underwent more extensive unilateral monitoring via implantation of subdural and depth electrodes through a craniotomy. A therapeutic procedure was performed in 17 patients (65.4%), whereas 1 patient underwent a palliative corpus callosotomy (3.8%). Nine patients underwent a resection without unilateral invasive mapping. Reasons for no therapeutic surgery (n = 8) included multifocal onsets, failing the Wada test, refusal of further treatment, and negative intraoperative electrocorticogram. There was 1 surgical complication, involving a retained electrode fragment that was removed in a separate minor procedure. Of the 26 patients, 15 (57.7%) are now seizure-free or have seizure disorders that have substantially improved (modified Engel classes I and II). Of the 17 patients who underwent a potentially curative surgery, 13 (76.5%) were Engel classes I and II. CONCLUSION: Bilateral placement of subdural strip and depth electrodes for epilepsy monitoring in patients with nonlateralizing scalp EEG and/or discordant imaging studies but clinical suspicion for focal seizure origin is both safe and effective. Given the safety and efficacy of this procedure, epileptologists should have a low threshold to consider bilateral implants for suitable patients.

Topiramate for the treatment of infantile spasms.

Topiramate is a new antiepileptic drug with a broad spectrum of efficacy. Reports on the use of topiramate for treatment of infantile spasms are limited. We prospectively followed 15 children with recently diagnosed infantile spasms treated with topiramate for efficacy and tolerability. Twelve patients had symptomatic infantile spasms, and two patients had cryptogenic infantile spasms. Topiramate was started at a dose of 3 mg/kg/day and titrated up to a dose of 27 mg/kg/day in 2 to 3 weeks. The primary efficacy measure was comparison of the seizure rate during the 2-week baseline with the median seizure rate during the first 2 months of treatment with topiramate. We also compared baseline electroencephalograms (EEGs) with post-treatment EEGs. The median seizure rate reduction during the first 2 months of treatment was 41% (P = .002). Three patients became spasm free (20%), five had > 50% reduction, and three had at least 25% reduction. Four patients did not respond. Three of 15 patients had clearing of hypsarrhythmia. Topiramate was generally well tolerated, with irritability being the most common side effect. Topiramate was efficacious and well tolerated; one patient discontinued the medication because of adverse effects. (J Child Neurol 2006;21:17-19).

Confronting the issues of therapeutic misconception, enrollment decisions, and personal motives in genetic medicine-based clinical research studies for fatal disorders.

Genetic medicine-based therapies have unlocked the potential for ameliorating diseases previously considered inevitably fatal. Inherent in the clinical trials of genetic medicines are ethical issues of therapeutic misconception, enrollment decisions as they relate to the risks and benefits of research, and the complex relationships among funding sources, investigators, and the families of affected individuals. The purpose of this paper is to help define these complex issues relevant to the use of genetic medicines and to describe the strategy we have used to confront these issues in a phase I trial of adeno-associated virus-mediated gene transfer to the central nervous system of children with late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal lysosomal storage disease associated with progressive neurodegeneration and death by mid-childhood. Our approach to these challenges should provide a useful paradigm for investigators initiating other genetic medicine- based studies to treat inevitably fatal diseases.

Frameless stereotactic placement of depth electrodes in epilepsy surgery.

OBJECT: Depth electrodes are useful in the identification of deep epileptogenic foci. Computerized tomography-magnetic resonance (CT/MR)- and angiography-guided frame-based techniques are safe and accurate but require four-point skull fixation that limits cranial access for the placement of additional grids and strips. The authors investigated the viability and accuracy of placing depth electrodes by using a commercially available frameless system. METHODS: A slotted, custom-designed adapter was built to interface with the StealthStation Guide Frame-DT and 960-525 StealthFighter. The Cranial Navigation software was used to plan the trajectory and entry site based on preoperative spoiled gradient MR imaging studies. Forty-one depth electrodes were placed in 51 targets in 20 patients. Thirty-one of these electrodes were inserted through the temporal neocortex following craniotomy and placement of subdural grids, whereas 10 were placed through burr holes. All electrodes had contact either within (71%) or touching (29%) the target, 50 of which (98%) provided adequate recordings. Although the mean distance of the distal electrode contact from the intended target was 3.1 +/- 0.5 mm, the mean distance to the edge of the anatomical structure was 0.4 +/- 0.9 mm. Placement via the laterotemporal approach was significantly (p < 0.001) more accurate than that via the occipitotemporal approach. No complication occurred. CONCLUSIONS: Depth electrodes can be placed safely and accurately by using a commercially available frameless stereotactic navigation system and a custom-made adapter. Depth electrode placement to record ictal onsets during epilepsy surgery only requires the contacts to touch rather than to reside within the intended structure. The laterotemporal approach is a more accurate method of placing electrodes than is the occipitotemporal one, likely due to the increased distance from the entry point to the target.

Electroencephalographic patterns in unresponsive pediatric patients.

To study the occurrence and incidence of various electroencephalographic patterns, the electroencephalograms of unresponsive pediatric patients admitted to the intensive care unit were analyzed. The interpreters were unaware of the patients' clinical diagnoses. A total of 178 electroencephalographic studies performed on unresponsive patients were analyzed over a period of 3 years. The mean age of the study patients was 7.9 years. Sixty-six patients were less than 1 year old. The following electroencephalographic patterns were observed: 58 patients (33%) manifested electroencephalographic patterns consistent with nonconvulsive status epilepticus. Of the patients with nonconvulsive status epilepticus, 32 patients (18%) had generalized nonconvulsive status epilepticus and 26 patients (14%) manifested partial nonconvulsive status epilepticus. The remaining 120 patients (67%) manifested diffuse cerebral dysfunction, with the majority having severe diffuse cerebral dysfunction. Only 4 patients (2%) had triphasic waves, suggesting a metabolic encephalopathy. Thirty-six percent of the patients under the age of 1 year had electroencephalographic patterns consistent with nonconvulsive status epilepticus. Nonconvulsive status epilepticus is a relatively common electroencephalographic pattern in unresponsive pediatric patients. Metabolic encephalopathy is uncommon in this patient group.

Ketogenic diet in pediatric epilepsy patients with gastrostomy feeding.

Ketogenic diet is effective in the control of intractable seizures. Poor compliance is a major limiting factor. In one study, only 50% of children receiving the oral ketogenic diet remained on the diet after 1 year. Twelve children with static encephalopathy and intractable symptomatic epilepsy were given the ketogenic diet via gastrostomy tube. Mean age was 3 years (range, 7 months to 6.5 years). Mean seizure frequency at baseline was 199/month. Seizure frequency after 12 and 18 months of diet was compared with baseline. After 12 months on the diet, the number of antiepileptic drugs was compared with baseline. Median seizure reduction at 1 year and 18 months was 61% and 66%, respectively (P = 0.02). Individually, six patients had 90% seizure reduction, one had 75% reduction, three had 50% reduction, and two patients did not improve. Mean antiepileptic drugs at baseline was 2.8; at 12 months 1.6 (49% reduction). Three patients had weight loss. Two patients discontinued the diet at 13 months and 21 months, respectively, because of diarrhea and weight loss. Compliance with diet was 100% during treatment. This study suggests that the ketogenic diet via gastrostomy feeding tube is safe and effective in children with intractable seizures and ensures compliance.

Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neuronal ceroid lipofuscinosis.

Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal childhood neurodegenerative lysosomal storage disease with no known therapy. There are estimated to be 200 to 300 children in the United States at any one time with the disease. LINCL is a genetic disease resulting from a deficiency of tripeptidyl peptidase I (TPP-I), a proteolytic enzyme encoded by CLN2, the gene that is mutated in individuals with LINCL. The subjects are chronically ill, with a progressive CNS disorder that invariably results in death, typically by age 8 to 12 years. The strategy of this clinical study is based on the concept that persistent expression in the CNS of the normal CLN2 cDNA with production of sufficient amounts of TPP-I should prevent further loss of neurons, and hence limit disease progression. To assess this concept, an adeno-associated virus vector (AAV2CUh-CLN2) will be used to transfer to and express the human CLN2 cDNA in the brain of children with LINCL. The vector consists of the AAV2 capsid enclosing the 4278-base single-stranded genome consisting of the two inverted terminal repeats of AAV serotype 2 and an expression cassette composed of the human cytomegalovirus (CMV) enhancer, the chicken beta-actin promoter/splice donor and 5' end of the intron, the 3' end of the rabbit P-globin intron and splice acceptor, the human CLN2 cDNA with an optimized Kozak translation initiation signal, and the polyadenylation/transcription stop codon from rabbit 3-globin. The proposed study will include 10 individuals and will be divided into two parts. Group A, to be studied first, will include four individuals with the severe form of the disease. Group B of the trial will include six individuals with a moderate form of the disease. After direct intracranial administration of the vector, there will be neurological assessment based on the LINCL clinical rating scale and magnetic resonance imaging/magnetic resonance spectroscopy assessment of the brain in regions of vector administration. The data generated will help evaluate two hypotheses: (1) that it is safe to carry out direct intracranial administration of the AAV2cuhCLN2 vector to the CNS of individuals with LINCL, and (2) that administration of the AAV2cuhCLN2 vector will slow down or halt the progression of the disease in the central nervous system.

Nitrazepam for the treatment of Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome is a severe childhood epileptic syndrome with encephalopathy and multiple seizure types, which are often intractable to treatment. Most of these children will ultimately become mentally retarded and dependent on others for their daily care. Antiepileptic drugs are the mainstay of treatment, however, no particular drug is entirely effective. Apart from the use of antiepileptic drugs, nonpharmacologic treatments are also considered (i.e., callosotomy, ketogenic diet, and vagus nerve stimulation), which have proven to be partially effective. We prospectively studied 14 children (11 months-8 years of age) with medication-resistant Lennox-Gastaut syndrome, being treated with nitrazepam (open-label compassionate protocol). We compared the 1-month baseline seizure frequency with the median seizure rate reduction during the first 12 months of treatment with nitrazepam. The median seizure rate reduction during the first 12 months of treatment with nitrazepam was 41% (P = 0.001), with more than 50% seizure reduction in 60% of patients. Two patients became seizure free, five patients demonstrated at least 50% reduction in seizure rates, six patients had at least 25% seizure rate reduction, and one patient did not respond. No patient had any serious adverse effects. Side effects included sedation in six children (40%) and drooling in nine patients (60%).