Exacerbation of restless legs syndrome following amygdalohippocampectomy: A case report.

Background: Restless legs syndrome (RLS) is a neurological sensorimotor disorder characterized by an uncontrollable urge to move the legs. In the perioperative period, patients with RLS may experience an acute exacerbation of symptoms. Although studies on the exacerbation of RLS after brain surgery are limited, we present a case wherein symptoms worsened following left amygdalohippocampectomy. Case Presentation: A 58-year-old woman diagnosed with mesiotemporal lobe epilepsy accompanied by left hippocampal sclerosis underwent a left amygdalohippocampectomy. The patient reported uncomfortable sensations in the lower limbs preoperatively. However, the urge to move her legs was manageable and not distinctly diagnosed with RLS. The symptoms began to deteriorate on the fifth postoperative day primarily affecting the legs and back, with a notable emphasis on the right side. Pramipexole treatment effectively ameliorated these symptoms. Conclusion: No reports are available highlighting the exacerbation of RLS after amygdalohippocampectomy. Perioperative factors, such as anesthesia and iron deficiency due to hemorrhage, have been proposed as aggravating factors for RLS; however, the asymmetry of RLS, particularly the atypical right-sided exacerbation in this case, makes it unlikely that this was the primary cause. A negative correlation between opioid receptor availability in the amygdala and RLS severity has been reported, suggesting that amygdalohippocampectomy contributes to the exacerbation of RLS symptoms. This case provides valuable insights into the possible involvement of the amygdala in the pathophysiology of RLS and practical considerations for the clinical management of the condition.

Frontal Encephalocele Plus Epilepsy: A Case Report and Review of the Literature.

An encephalocele is a pathological brain herniation caused by osseous dural defects. Encephaloceles are known to be regions of epileptogenic foci. We describe the case of a 44-year-old woman with refractory epilepsy associated with a frontal skull base encephalocele. Epilepsy surgery for encephalocele resection was performed; however, the epilepsy was refractory. A second epilepsy surgery for frontal lobectomy using intraoperative electroencephalography was required to achieve adequate seizure control. Previous reports have shown that only encephalocele resection can result in good seizure control, and refractory epilepsy due to frontal lobe encephalocele has rarely been reported. To the best of our knowledge, this is the first report of frontal encephalocele plus epilepsy in which good seizure control using only encephalocele resection was difficult to achieve. Herein, we describe the possible mechanisms of encephalocele plus epilepsy and the surgical strategy for refractory epilepsy with encephalocele, including a literature review.

RNA-seq analysis, targeted long-read sequencing and in silico prediction to unravel pathogenic intronic events and complicated splicing abnormalities in dystrophinopathy.

Dystrophinopathy is caused by alterations in DMD. Approximately 1% of patients remain genetically undiagnosed, because intronic variations are not detected by standard methods. Here, we combined laboratory and in silico analyses to identify disease-causing genomic variants in genetically undiagnosed patients and determine the regulatory mechanisms underlying abnormal DMD transcript generation. DMD transcripts from 20 genetically undiagnosed dystrophinopathy patients in whom no exon variants were identified, despite dystrophin deficiency on muscle biopsy, were analyzed by transcriptome sequencing. Genome sequencing captured intronic variants and their effects were interpreted using in silico tools. Targeted long-read sequencing was applied in cases with suspected structural genomic abnormalities. Abnormal DMD transcripts were detected in 19 of 20 cases; Exonization of intronic sequences in 15 cases, exon skipping in one case, aberrantly spliced and polyadenylated transcripts in two cases and transcription termination in one case. Intronic single nucleotide variants, chromosomal rearrangements and nucleotide repeat expansion were identified in DMD gene as pathogenic causes of transcript alteration. Our combined analysis approach successfully identified pathogenic events. Detection of diseasing-causing mechanisms in DMD transcripts could inform the therapeutic options for patients with dystrophinopathy.

Diagnostic challenges of primary diffuse leptomeningeal melanomatosis in early adolescence: A case report.

INTRODUCTION: Primary diffuse leptomeningeal melanomatosis is an extremely rare variant of primary melanoma of the central nervous system. It is characterized by a variety of nonspecific clinical, radiological, and histopathological features requiring differential diagnosis from a variety of diseases. Here, we aimed to use our own clinical case as an example of the difficulties in the diagnosis of this disease. CASE PRESENTATION: A 14-year-old boy presented with focal to bilateral tonic-clonic seizures. Brain MRI showed diffuse cortical surface and subcortical lesions, isointense on T1-weighted images and hypointense on T2-weighted images, respectively, with diffuse leptomeningeal gadolinium enhancement. Cytology of the cerebrospinal fluid revealed atypical mononuclear cells, but characteristic melanoma cells were not found. Although we suspected meningeal carcinomatosis, we did not perform abrainbiopsy under the tentative diagnosis of Sturge-Weber syndrome. A definitive diagnosis of primary diffuse leptomeningeal melanomatosis was made with abrainbiopsy after hedevelopednon-convulsive status epilepticus. Despite treatment, he died of hydrocephalus 1 year and 8 months after onset. CONCLUSION: Primary diffuse leptomeningeal melanomatosis poses a clinical diagnostic and therapeutic challenge. Leptomeningeal enhancement extending into the cerebral sulci and signal changes in T1/T2 weighted images of cortical and subcortical lesions on MRI are key to an early decision regarding whether to perform a biopsy, even in the pediatric population.

Current medico-psycho-social conditions of patients with West syndrome in Japan.

OBJECTIVE: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. METHODS: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. RESULTS: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. SIGNIFICANCE: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

Acute encephalopathy in children with tuberous sclerosis complex.

OBJECTIVE: We examined the clinical manifestations of acute encephalopathy (AE) and identify risk factors for AE in children with tuberous sclerosis complex (TSC). METHODS: The clinical data of 11 children with clinically diagnosed TSC associated with AE and 109 children with clinically diagnosed TSC alone aged 4 years or older were collected from 13 hospitals. RESULTS: Of the 11 children with AE, 5 had histories of febrile seizures (FS), and all had histories of febrile status epilepticus (FSE). AE developed within 24 h after fever onset in all children with seizures lasting 30 min or longer. All children developed coma after seizure cessation. Head magnetic resonance imaging (MRI) revealed widespread abnormalities in the cerebral cortex, subcortical white matter, corpus callosum, basal ganglia, and thalamus. One child died; seven had severe neurological sequelae; and the other three, mild sequelae. Logistic regression analysis revealed that a history of FSE was correlated with the development of AE. SIGNIFICANCE: AE in children with TSC was characterized by sudden onset after fever, followed by coma, widespread brain edema evident on MRI, and poor outcomes. A history of FSE was a risk factor for the development of AE.

Prenatal clinical manifestations in individuals with COL4A1/2 variants.

BACKGROUND: Variants in the type IV collagen gene (COL4A1/2) cause early-onset cerebrovascular diseases. Most individuals are diagnosed postnatally, and the prenatal features of individuals with COL4A1/2 variants remain unclear. METHODS: We examined COL4A1/2 in 218 individuals with suspected COL4A1/2-related brain defects. Among those arising from COL4A1/2 variants, we focused on individuals showing prenatal abnormal ultrasound findings and validated their prenatal and postnatal clinical features in detail. RESULTS: Pathogenic COL4A1/2 variants were detected in 56 individuals (n=56/218, 25.7%) showing porencephaly (n=29), schizencephaly (n=12) and others (n=15). Thirty-four variants occurred de novo (n=34/56, 60.7%). Foetal information was available in 47 of 56 individuals, 32 of whom (n=32/47, 68.1%) had one or more foetal abnormalities. The median gestational age at the detection of initial prenatal abnormal features was 31 weeks of gestation. Only 14 individuals had specific prenatal findings that were strongly suggestive of features associated with COL4A1/2 variants. Foetal ventriculomegaly was the most common initial feature (n=20/32, 62.5%). Posterior fossa abnormalities, including Dandy-Walker malformation, were observed prenatally in four individuals. Regarding extrabrain features, foetal growth restriction was present in 16 individuals, including eight individuals with comorbid ventriculomegaly. CONCLUSIONS: Prenatal observation of ventriculomegaly with comorbid foetal growth restriction should prompt a thorough ultrasound examination and COL4A1/2 gene testing should be considered when pathogenic variants are strongly suspected.

Functional neuroimaging in Rasmussen syndrome.

PURPOSE: For a diagnosis of Rasmussen syndrome (RS), clinical course together with electroencephalography (EEG) and magnetic resonance imaging (MRI) findings are considered important, but there are few reports on functional neuroimaging. This study investigated cerebral blood flow (CBF)-single photon emission computed tomography (SPECT), central benzodiazepine receptor (BZR)-SPECT, and fluorine-18 fluorodeoxy glucose-positron emission tomography (FDG-PET) in RS patients, and correlated neuroimaging results with MRI and pathological findings. METHODS: Twenty-three patients diagnosed with RS according to Bien's (2005) diagnostic criteria (including 12 patients with a histological diagnosis) were studied. CBF-SPECT, BZR-SPECT and FDG-PET images were visually evaluated, and the findings correlated with MRI and histological findings. RESULTS: Hypoperfusion areas were observed in 16 of 22 patients by interictal CBF-SPECT. Hyperperfusion areas were observed in 10 of 12 patients by ictal CBF-SPECT, which correlated with ictal onset area by ictal EEG (IOAE). In the limited data of BZR-SPECT in nine patients, lowered uptake was detected in all nine patients, including two with no MRI abnormalities. Lowered glucose metabolism was observed in affected areas in all five patients by FDG-PET. Histological examination revealed findings of chronic encephalitis in all 12 patients examined, concomitant with focal cortical dysplasia in five patients. CONCLUSION: In RS patients, functional neuroimaging reveals clear abnormal findings, even before the appearance of MRI abnormalities. BZR-SPECT and FDG-PET could detect the IOAE efficiently even in the absence of MRI abnormalities, while interictal CBF-SPECT occasionally failed to detect IOAE if MRI was normal. Based on BZR-SPECT, refractory epileptic seizures in RS may suggest possible impairment of inhibitory neurons.

Successful treatment of arrhythmia-induced cardiomyopathy in an infant with tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal-dominant tumor suppressor gene syndrome that is characterized by the development of distinctive benign tumors and malformations in multiple organ systems (N Eng J Med 355:1345-1356, 2006). Cardiac rhabdomyomas are intracavitary or intramural tumors observed in 50-70 % of infants with TSC but only cause serious clinical problems in a very small fraction of these patients (N Eng J Med 355:1345-1356, 2006; Pediatrics 118:1146-1151, 2006; Eur J Pediatr 153:155-7, 1994); most individuals have no clinical symptoms and their tumors spontaneously regress. However, despite being clinically silent, these lesions can provoke arrhythmias and heart failure (Pediatrics 118:1146-1151, 2006; Eur J Pediatr 153:155-7, 1994). CASE PRESENTATION: We here report the clinical findings of an infant suffering from TSC complicated with dilated cardiomyopathy (DCM) after the regression of cardiac rhabdomyomas. Although his tumors improved spontaneously, tachycardia and irregular heart rate due to frequent premature ventricular and supraventricular contractions persisted from the newborn period and were refractory to several medications. His cardiomyopathy was suspected to have been induced by the tachycardia or arrhythmia. We found carvedilol therapy to be safe and highly effective in treating the cardiomyopathy. To our knowledge, this is the first case report of TSC with DCM after regression of cardiac tumors and its successful treatment. CONCLUSION: The patient's clinical course suggests that careful life-long disease management is important, even in TSC patients without apparent symptoms.

An Adolescent Case of Citrin Deficiency With Severe Anorexia Mimicking Anorexia Nervosa.

We report a 12-year-old female citrin-deficient patient presenting with severe anorexia and body weight loss, mimicking the restricting type of anorexia nervosa (AN). She showed normal development until age 10 years when she started to play volleyball at school. She then became gradually anorexic, and her growth was stunted. At age 12, she was admitted to hospital because of severe anorexia and thinness. She was first thought to have AN, and drip infusion of glucose solution and high-calorie drinks were given, but her condition deteriorated further. She had a history of neonatal hepatitis and was therefore suspected to have citrin deficiency (CD). Genetic analysis of SLC25A13 revealed that she was compound heterozygous for 851del4 and IVS16ins3kb, and a diagnosis of CD was made. A low-carbohydrate diet with oral intake of arginine and ursodeoxycholic acid was started, and her condition gradually improved. The clinical features in our patient were similar to those of AN, and therefore AN may also be an important clinical sign in adolescent patients with CD.

Successful treatment for West syndrome with severe combined immunodeficiency.

Several immune mechanisms are suspected in the unknown etiology of West syndrome (WS). We report a male infant who suffered from WS and X-linked T-B+NK- severe combined immunodeficiency (X-SCID) with a missense mutation of the IL2RG gene (c.202G>A, p.Glu68Lys). He promptly began vitamin B6 and valproic acid treatment, but infantile spasms (IS) and hypsarrhythmia persisted. Administration of intravenous immunoglobulin and the change to topiramate (TPM) at 7 months of age resulted in the rapid resolution of IS. The CD4/8 ratio in his peripheral blood increased from 0.04-0.09 to 0.20-1.95 following unrelated cord blood transplantation (UCBT). In vitro lymphocyte proliferation in response to phytohemagglutinin or concanavalin A and the ability of B lymphocytes to produce antibodies improved as well. Electroencephalogram findings became normal 1 month after UCBT. Thus, we consider that T-cell dysfunction and/or impairments in T-B cell interactions due to X-SCID may have played important roles in the onset of WS. Immune-modulating therapies along with the administration of TPM effectively treated this severe epileptic syndrome in our patient.

Critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis in acute lymphoblastic leukemia.

We report a pediatric case of critical illness polyneuropathy and myopathy caused by Bacillus cereus sepsis during acute lymphoblastic leukemia therapy. A 15-year-old boy developed B. cereus sepsis and multiple organ failure on the 19th day after initiation of chemotherapy, and multidisciplinary treatment was started. Treatment was effective and septic shock with multiple organ failure remitted. He was weaned from a respirator on day 23 after the onset of sepsis, but complete flaccid paralysis of the 4 extremities occurred. His compound muscle action potential and F-wave occurrence were reduced on a nerve conduction test. The number of motor units was markedly decreased, and the amplitude and duration of individual motor units were low and short, respectively, on electromyography. Cerebrospinal fluid was normal. On the basis of these findings, he was diagnosed with critical illness polyneuropathy/myopathy. He underwent intensive rehabilitation and recovered the ability to walk 3 months after onset. He was discharged 1 year after the initiation of chemotherapy, and remission has been maintained without inconvenience to daily living activities for 3 years since disease onset.

Prophylactic treatment for hypertension and seizure in a case of allogeneic hematopoietic stem cell transplantation after posterior reversible encephalopathy syndrome.

A six-yr-old boy developed PRES after induction chemotherapy for the relapse of acute lymphoblastic leukemia. Two months after PRES, he underwent BMT from an unrelated HLA-mismatched donor. There were many risk factors for PRES in the BMT including the long-term use of FK506 and methylprednisolone, grade III graft-versus-host disease, thrombotic microangiopathy, and sepsis. Prophylactic treatment for hypertension with nicardipine in conjunction with close monitoring of the magnesium level and the use of valproic acid might be an effective management approach to prevent post-transplant PRES.

Polymyxin-direct hemoperfusion for sepsis-induced multiple organ failure.

We report a case of multiple organ failure caused by the Bacillus cereus infection during acute lymphoblastic leukemia therapy, who was treated successfully. A 15-year-old male developed (B. cereus) sepsis on the 19th day after chemotherapy initiation. Polymyxin-direct hemoperfusion for septic shock was started, followed by continuous hemodiafiltration. His condition improved after starting the hemoperfusion. At the onset of sepsis, elevated levels of serum inflammatory cytokines, anti-inflammatory cytokines, and plasminogen-activator inhibitor complex-1 were observed. Serum levels of these cytokines and bioactive substances decreased after blood purification therapy, which correlated with the improvement of clinical symptoms.

Urinary excretion of ganciclovir contributes to improvement of adenovirus-associated hemorrhagic cystitis after allogeneic bone marrow transplantation.

A nine-yr-old girl developed AdV-associated HC after bone marrow transplantation. Intravenous GCV markedly reduced urinary AdV DNA loads and improved clinical findings. This appeared to result partly from a high concentration of GCV in urine. GCV may be effective for AdV-induced HC without definitive disseminated infection.

Treatment of neurodegenerative CNS disease in Langerhans cell histiocytosis with a combination of intravenous immunoglobulin and chemotherapy.

BACKGROUND: In rare cases, patients with Langerhans cell histiocytosis (LCH) develop neurodegenerative CNS disease (ND-CNS-LCH). Management of ND-CNS-LCH has not been established. METHODS: We treated five pediatric patients with a combination of intravenous immunoglobulin (IVIG) and chemotherapy (steroid +/- vinblastine +/- 6-mercaptopurine +/- methotrexate). Prior to the therapy, three of the five patients had cerebellar ataxia while the remaining two had abnormal MRI findings without apparent neurological deficits. IVIG was given monthly or twice monthly at the dosage of 250-400 mg/kg/dose. RESULTS: The four patients administered more than 23 doses of IVIG and chemotherapy remained in a stable condition and did not show significant progression signs in neurological deficits or brain MRI findings during the 30-month follow-up period (median; range: 19+ to 38+) following the initiation of therapy for ND-CNS-LCH. CONCLUSION: The IVIG-containing treatment may be promising for ND-CNS-LCH; however, its effectiveness remains to be further tested in more patients as well as in a randomized trial.

Transplanted human amniotic epithelial cells express connexin 26 and Na-K-adenosine triphosphatase in the inner ear.

Cochlear fibrocytes are the crucial component of the inner ear homeostasis and its defect by various causes; GJB2 (connexin [Cx] 26) mutation, for example, leads to hearing loss. In the present study, we investigated the potential use of human amniotic epithelial cells, proposed to possess pluripotential properties, as a source of transplantation therapy in inner ear disease. The mRNA of the gap junction protein Cx26 and Na-K-adenosine triphosphatase, the immunohistologic expression of these proteins, and the cells' intercellular communication capacity were detected in vitro. Their transplantation into the guinea pig cochlea revealed the survival and expression of the proteins even 3 weeks after transplantation. Transplanted human amniotic epithelial cells were localized at the site where the proteins function, strongly indicating their cooperation in the regional potassium ion recycling. This technology suggests the therapeutic potential for the treatment of hearing loss.