Immunoglobulin A deficiency following treatment with lamotrigine.

Lamotrigine (LTG) is an anti-epileptic drug and mood-stabilizing agent, whose adverse effects include skin rash and dizziness. Interactions with the immune system are rare, and only a few cases linking hypogammaglobulinemia to LTG treatment have been previously described. In this report, we describe a case in which a patient developed hypogammaglobulinemia, and a subsequent immunoglobulin A (IgA) deficiency, following LTG treatment. As a result of her immunodeficiency, the patient presented with a severe urinary tract infection and required intravenous immunoglobulin. Serum levels of immunoglobulin G and M had recovered by seven months and one month after the discontinuation of LTG, respectively; however, IgA levels remained low (less than 4mg/dL) two years post-treatment. While previous reports have demonstrated IgA deficiencies in patients prescribed other antiepileptic drugs, this is the first case of an IgA deficiency following LTG administration.

Distinguishing Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion from Prolonged Febrile Seizures by Acute Phase EEG Spectrum Analysis.

BACKGROUND: To differentiate the features of electroencephalography (EEG) after status epileptics in febrile children with final diagnosis of either febrile seizure (FS) or acute encephalopathy for an early diagnosis. METHODS: We retrospectively collected data from 68 children who had status epilepticus and for whom EEGs were recorded within 120 h. These included subjects with a final diagnosis of FS (n = 20), epileptic status (ES; n = 11), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 18), mild encephalopathy with a reversible splenial lesion (MERS; n = 7), other febrile encephalopathies (n = 10), hypoxic-ischemic encephalopathy (n = 1), and intracranial bleeding (n = 1). Initially, all EEGs were visually assessed and graded, and correlation with outcome was explored. Representative EEG epochs were then selected for quantitative analyses. Furthermore, data from AESD (n = 7) and FS (n = 16) patients for whom EEG was recorded within 24 h were also compared. RESULTS: Although milder and most severe grades of EEG correlated with neurological outcome, the outcome of moderate EEG severity group was variable and was not predictable from usual inspection. Frequency band analysis revealed that solid delta power was not significantly different among the five groups (AESD, MERS, FS, ES and control), and that MERS group showed the highest theta band power. The ratios of delta/alpha and (delta + theta)/(alpha + beta) band powers were significantly higher in the AESD group than in other groups. The alpha and beta band powers in EEGs within 24 h from onset were significantly lower in the AESD group. The band powers and their ratios showed earlier improvement towards 24 h in FS than in AESD. CONCLUSION: Sequential EEG recording up to 24 h from onset appeared to be helpful for distinction of AESD from FS before emergence of the second phase of AESD.

Myocerebrohepatopathy spectrum disorder due to POLG mutations: A clinicopathological report.

We report on the clinical, neuropathological, and genetic findings of a Japanese case with myocerebrohepatopathy spectrum (MCHS) disorder due to polymerase gamma (POLG) mutations. A girl manifested poor sucking and failure to thrive since 4 months of age and had frequent vomiting and developmental regression at 5 months of age. She showed significant hypotonia and hepatomegaly. Laboratory tests showed hepatocellular dysfunction and elevated protein and lactate levels in the cerebrospinal fluid. Her liver function and neurologic condition exacerbated, and she died at 8 months of age. At autopsy, fatty degeneration and fibrosis were observed in the liver. Neuropathological examination revealed white matter-predominant spongy changes with Alzheimer type II glia and loss of myelin. Enzyme activities of the respiratory chain complex I, III, and IV relative to citrate synthase in the muscle were normal in the biopsied muscle tissue, but they were reduced in the liver to 0%, 10%, and 14% of normal values, respectively. In the liver, the copy number of mitochondrial DNA compared to nuclear DNA was reduced to 3.3% of normal values as evaluated by quantitative polymerase chain reaction. Genetic analysis revealed compound heterozygous mutations for POLG (I1185T/A957V). This case represents the differential involvement of multiple organs and phenotype-specific distribution of brain lesions in mitochondrial DNA depletion disorders.

Early predictors of status epilepticus-associated mortality and morbidity in children.

BACKGROUND: Early predictors of status epilepticus (SE)-associated mortality and morbidity have not been systematically studied in children, considerably impeding the identification of patients at risk. OBJECTIVES: To determine reliable early predictors of SE-associated mortality and morbidity and identify the etiology of SE-associated sequelae in Japanese children. METHODS: We conducted a prospective multicenter study of clinical findings and initial laboratory data acquired at SE onset, and assessed outcomes at the last follow-up examination. In-hospital death during the acute period and neurological sequelae were classified as poor outcomes. RESULTS: Of the 201 children who experienced their first SE episode, 16 exhibited poor outcome that was most commonly associated with acute encephalopathy. Univariate analysis revealed that the following were associated with poor outcomes: young age (⩽24 months); seizure duration >90 min; seizure intractability (failure of the second anticonvulsive drug); biphasic seizures; abnormal blood glucose levels (<61 or >250 mg/dL); serum aspartate aminotransferase (AST) ⩾56 U/L; and C-reactive protein (CRP) levels >2.00 mg/dL. Multivariate analysis revealed that young age, seizure intractability, abnormal blood glucose levels, and elevated AST and CRP levels were statistically significant. CONCLUSIONS: Young age and seizure intractability were highly predictive of poor outcomes in pediatric SE. Moreover, abnormal blood glucose levels and elevated AST and CRP levels were predictors that might be closely associated with the etiology, especially acute encephalopathy and severe bacterial infection (sepsis and meningitis) in Japanese children.

ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus.

OBJECTIVE: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures, leaving neurologic sequelae in many patients. However, its pathogenesis remains unclear. In this study, we clarified that genetic variation in the adenosine A2A receptor (ADORA2A), whose activation is involved in excitotoxicity, may be a predisposing factor of AESD. METHODS: We analyzed 4 ADORA2A single nucleotide polymorphisms in 85 patients with AESD. The mRNA expression in brain samples, mRNA and protein expression in lymphoblasts, as well as the production of cyclic adenosine monophosphate (cAMP) by lymphoblasts in response to adenosine were compared among ADORA2A diplotypes. RESULTS: Four single nucleotide polymorphisms were completely linked, which resulted in 2 haplotypes, A and B. Haplotype A (C at rs2298383, T at rs5751876, deletion at rs35320474, and C at rs4822492) frequency in patients was significantly higher than in controls (p = 0.005). Homozygous haplotype A (AA diplotype) had a higher risk of developing AESD (odds ratio 2.32, 95% confidence interval 1.32-4.08; p = 0.003) via a recessive model. mRNA expression was significantly higher in AA than AB and BB diplotypes, both in the brain (p = 0.003 and 0.002, respectively) and lymphoblasts (p = 0.035 and 0.003, respectively). In lymphoblasts, ADORA2A protein expression (p = 0.024), as well as cellular cAMP production (p = 0.0006), was significantly higher in AA than BB diplotype. CONCLUSIONS: AA diplotype of ADORA2A is associated with AESD and may alter the intracellular adenosine/cAMP cascade, thereby promoting seizures and excitotoxic brain damage in patients.

Association of acute cerebellar ataxia and human papilloma virus vaccination: a case report.

INTRODUCTION: We report the case of a patient who developed symptoms of acute cerebellar ataxia (ACA) after administration of the human papilloma virus (HPV)-16/18 vaccine. PATIENT AND METHOD: This patient developed symptoms of ACA, including nausea, vertigo, severe limb and truncal ataxia, and bilateral spontaneous continuous horizontal nystagmus with irregular rhythm, 12 days after administration of the HPV-16/18 AS04-adjuvanted cervical cancer vaccine. After this, the patient received methylprednisolone pulse and intravenous immunoglobulin (IVIG) therapies as well as immunoadsorption plasmapheresis. RESULTS: Severe ACA symptoms did not improve after methylprednisolone pulse and IVIG therapies, but the patient recovered completely after immunoadsorption plasmapheresis. CONCLUSION: This temporal association strongly suggests that ACA was induced by the vaccination.

Quantitative computed tomography for enzyme replacement therapy in Pompe disease.

OBJECTIVE: Pompe disease is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme, acid alpha-glucosidase (GAA). To the best of our knowledge, no studies have reported the results of systematic and sequential CT analyses before and during ERT. In this study we have treated three patients with late onset Pompe disease by ERT, and investigated the efficacy of treatment by computed tomography number. METHODS: We measured the serial changes in the computed tomography (CT) number of multiple organs in three patients with late onset of Pompe disease during 24 months of enzyme replacement therapy (ERT). RESULTS: Before treatment, the liver and muscle CT numbers were higher in these patients than in the controls. The liver CT number decreased after performing ERT. Furthermore, the urinary glucose tetrasaccharide levels, a biomarker of glycogen accumulation, were elevated before ERT and reduced thereafter. CONCLUSIONS: The findings in these cases suggest that the elevation of the liver CT number represents glycogen accumulation in the liver and that the analysis of the liver CT number is therefore a useful tool for assessing the efficacy of ERT.

Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1 : Subtle Abnormality in Urinary Organic Acid Analysis and Blood Acylcarnitine Analysis Using Tandem Mass Spectrometry.

Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects both isoleucine catabolism and ketone body metabolism. The disorder is characterized by intermittent ketoacidotic episodes. We report three Japanese patients. One patient (GK69) experienced two ketoacidotic episodes at the age of 9 months and 3 years, and no further episodes until the age of 25 years. She had two uncomplicated pregnancies. GK69 was a compound heterozygote of the c.431A>C (H144P) and c.1168T>C (S390P) mutations in T2 (ACAT1) gene. She was not suspected of having T2 deficiency during her childhood, but she was diagnosed as T2 deficient at the age of 25 years by enzyme assay using fibroblasts. The other two patients were identical twin siblings who presented their first ketoacidotic crisis simultaneously at the age of 3 years 4 months. One of them (GK77b) died during the first crisis and the other (GK77) survived. Even during severe crises, C5-OH and C5:1 were within normal ranges in their blood acylcarnitine profiles and trace amounts of tiglylglycine and small amounts of 2-methyl-3-hydroxybutyrate were detected in their urinary organic acid profiles. They were H144P homozygotes. This H144P mutation has retained the highest residual T2 activity in the transient expression analysis of mutant cDNA thus far, while the S390P mutation did not retain any residual T2 activity. The "mild" H144P mutation may result in subtle profiles in blood acylcarnitine and urinary organic acid analyses. T2-deficient patients with "mild" mutations have severe ketoacidotic crises but their chemical phenotypes may be subtle even during acute crises.

Clinical and MRI characteristics of acute encephalopathy in congenital adrenal hyperplasia.

Acute encephalopathy in childhood is frequently associated with common infections, especially in East Asia. Various types have been identified although many cases remain unclassified. Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease presenting impairment of cortisol biosynthesis. We report three CAH children with acute infection-related encephalopathy. They exhibited disturbed consciousness or seizures, which did not improve after glucocorticoid administration, accompanied by clinical and laboratory findings of adrenal insufficiency. Brain MRI disclosed various patterns of white matter lesions, suggesting different types of acute encephalopathy such as clinically mild encephalitis/encephalopathy with a reversible splenial lesion or hemiconvulsion-hemiplegia syndrome. Acute encephalopathy should be considered and brain MRI immediately performed when impairment of consciousness does not improve after intravenous glucocorticoid administration in CAH patients. Further research is required to elucidate the epidemiology and pathogenic mechanisms of acute encephalopathy in CAH.

Transethmoidal meningoencephalocele involving the olfactory bulb with enlarged foramina of the lamina cribrosa--case report.

A 3-year-old girl presented with a transethmoidal meningoencephalocele manifesting as recurrent rhinorrhea. Initially, she developed meningitis, but after treatment she experienced rhinorrhea. Two months later, she again presented with rhinorrhea. Neuroimaging studies revealed a small protrusion (15 mm x 10 mm) at the roof of the ethmoidal sinus. Nasal endoscopy confirmed the diagnosis of meningoencephalocele. The operative findings revealed a small hole in the left olfactory bulb, which had descended into an enlarged foramen along with the arachnoid membrane. The left olfactory bulb was removed, and the enlarged foramina of the lamina cribrosa were covered with a frontal pericranial flap. The defect in the bone was very small, but contributed to the development of meningitis and leakage of the cerebrospinal fluid. Basal cephalocele should be considered in a patient with recurrent rhinorrhea and intracranial infections, even in the absence of any apparent anomaly.

Vertebral fusion in a patient with supernumerary-der(22)t(11;22) syndrome.

A patient with a 47,XX,+der(22)t(11;22)(q23.3;q11.2) karyotype exhibited brisk tendon reflex and Babinski sign with suggested pyramidal sign. A three-dimensional computed tomographic reconstruction revealed a T1-T2 vertebral fusion without hemivertebrae. Sagittal magnetic resonance imaging revealed degenerative disk changes, mild disk herniation, and mild spinal cord compression. Congenital vertebral fusion may be one of the anomalies in supernumerary-der(22)t(11;22) syndrome. Once clinical diagnosis of this chromosome aberration is established, radiologic evaluation of vertebrae and spinal neuroimaging should be performed.

Live birth prevalence of Down syndrome in Tottori, Japan, 1980-1999.

One hundred sixty-four patients with Down syndrome (DS) were confirmed in Tottori Prefecture, Japan, from 1980 to 1999. The sex ratio of 1.52 (99 males and 65 females) was comparable to that reported in previous studies. The live birth prevalence per 1,000 was 1.52 (95% CI: 1.29-1.75) from 1980 to 1999, with a prevalence of 1.34 (95% CI: 1.05-1.63) recorded between 1980 and 1989, and 1.74 (95% CI: 1.37-2.11) between 1990 and 1999. There was no statistically significant change between these two decades (chi(2)-test). Live birth prevalence in these two decades showed a significant increase (chi(2)-test, P < 0.005) compared with that recorded in 1969-1978 in Tottori Prefecture (0.803, 95% CI: 0.677-0.929). Mean ages of mothers at the birth of a DS patient were 31.0 years in 1980-1989 and 32.4 years in 1990-1999 (t-test, no significant difference). Dispersion analysis on the mean age of mothers at birth for patients born between 1969-1978, 1980-1989, and 1990-1999 showed a significant difference (t-test, P < 0.005), while comparing the mean age of mothers in 1969-1978 to those in 1990-1999 also revealed a significant difference (t-test, P < 0.001). Live birth prevalence has increased due to the rise in fertility rates among older women, although maternal age-specific risk rates remain unchanged. The widespread introduction of induced abortion following prenatal diagnosis decreased live birth prevalence of DS largely in European (and a few Asian) countries after 1990, or kept prevalence steady, despite increasing fertility rates among women aged 30 and over. In contrast, all published studies have reported an increase in live birth prevalence of this syndrome in Japan, probably resulting from the fact that prenatal diagnoses are used only exceptionally in this country (due to the negative attitude toward selection of life in Japanese culture).

Proinflammatory cytokines in cerebrospinal fluid from patients with nontyphoidal Salmonella encephalopathy.

Nontyphoidal Salmonella (NTS) encephalopathy is characterized by rapidly progressive brain dysfunction that develops after NTS enteritis. The mechanism of central nervous system involvement remains unclear. We examined cerebrospinal fluids from 7 patients for cytokines and found elevated interleukin-6, interleukin-8, and monocyte chemotactic protein-1 concentrations in all the patients, suggesting that the proinflammatory cytokines are involved in the pathogenesis of NTS encephalopathy.

Mental retardation, spasticity, basal ganglia calcification, cerebral white matter lesions, multiple endocrine defects, telangiectasia and atrophic skin: a new syndrome?

We report on an 8-year-old boy with mental retardation and spastic tetraparesis associated with atrophic skin on the face and extremities, telangiectasia, and severe dental caries. Basal ganglia calcification and multiple lesions in the subcortical white matter have been present since infancy. The patient has complications of liver dysfunction, multiple endocrine defects, and elevation of blood/cerebrospinal fluid lactate. Extensive laboratory examinations, including skin and muscle biopsies, and UV- and mitomycin C-sensitivity tests on fibroblasts, provided no evidence of a specific disease entity. No deterioration was noted, and supplementation of riboflavin and other vitamins had no apparent effect on the neurodevelopmental status of this patient. This patient may represent a novel disease entity, with unclear pathogenesis.

Antiphospholipid syndrome associated with human herpesvirus-6 infection.

The case of a patient with basal ganglia infarction associated with primary human herpesvirus-6 infection is reported. Anticardiolipin antibody immunoglobulin G was elevated after human herpesvirus-6 infection and then decreased gradually. The transient elevation in the antiphospholipid antibody level suggests that the human herpesvirus-6 infection can induce antiphospholipid syndrome, thus resulting in a cerebral infarction.

Serial diffusion-weighted MRI in hemorrhagic shock and encephalopathy syndrome.

This report presents a case of hemorrhagic shock and encephalopathy syndrome. In the acute stage, brain magnetic resonance imaging demonstrated symmetrical hyperintensity on diffusion-weighted images and hypointensity on the apparent diffusion coefficient maps in the subcortical white matter. Whereas the abnormal diffusion-weighted imaging signals of the white matter resolved in the subacute stage, the adjacent gray matter became hyperintense on diffusion-weighted images and hypointense on apparent diffusion coefficient maps. The evolution of diffusion-weighted imaging signals is thus considered to be one of the early findings in hemorrhagic shock and encephalopathy syndrome.

[Pulmonary atelectasis in patients with neurological or muscular disease; gravity-related lung compression by the heart and intra-abdominal organs on persistent supine position].

We report 10 cases of pulmonary atelectasis diagnosed by chest computed tomography in patients with neurological or muscular disease. Atelectasis was frequently seen in hypotonic patients who could not roll over on their own. The atelectases located mostly in the dorsal bronchopulmonary segments, adjacent to the heart or diaphragm. Atelectasis diminished in two patients after they became able to roll themselves over. Gravity-related lung compression by the heart and intra-abdominal organs on persistent supine position can cause pulmonary atelectasis in patients with neurological or muscular disease who can not roll over by their own power. To confirm that the prone position reduces compression of the lungs, chest computed tomography was performed in both the supine and the prone position in three patients. Sagittal images with three-dimensional computed tomographic reconstruction revealed significant sternad displacements of the heart and caudal displacements of the dorsal portion of the diaphragm on prone position compared with supine position. The prone position, motor exercises for rolling over, and biphasic cuirass ventilation are effective in reducing gravity-related lung compression. Some patients with intellectual disabilities were also able to cooperate in chest physiotherapy. Chest physiotherapy is useful in preventing atelectasis in patients with neurological or muscular disease.

[Polycystic ovary syndrome and hepatocellular adenoma related to long-term use of sodium valproate in a young woman].

Previous studies have reported a high prevalence of polycystic ovary syndrome (PCOS) among women taking sodium valproate (VPA). We report the case of a 28 year-old epileptic female taking VPA, who developed PCOS and later hepatocellular adenoma. She had been taking VPA for intractable epilepsy since the age of 15 months. At the age of 22 years, she suffered spontaneous rupture of a liver tumor that was diagnosed as hepatocellular adenoma. At the age of 24 years, bilateral polycystic ovaries were found by transabdominal ultrasonography, and PCOS was diagnosed. VPA may directly influence steroidogenesis in the ovary and cause hyperandrogenemia with ensuing PCOS. It is known that abnormality in the sex hormones contributes to the onset of hepatocellular adenoma. Therefore, we speculate that hyperandrogenemia due to VPA contributed to the development of hepatocellular adenoma in this case.

Monozygotic twins discordant for Klippel-Feil syndrome.

In a pair of Japanese monozygotic twins, one manifested Klippel-Feil syndrome, a short neck with C(1-4) vertebra fusion, whereas the other was normal. The discordance between the twins suggests that Klippel-Feil syndrome results in part from a postzygotic somatic mutation or intrauterine environmental factors.

Thiamine-responsive congenital lactic acidosis: clinical and biochemical studies.

We studied six infants with thiamine-responsive congenital lactic acidosis and normal pyruvate dehydrogenase complex activity in vitro, through clinical and biochemical analysis. In addition to elevated lactate and pyruvate levels, the data revealed increased urinary excretion of alpha-ketoglutarate, alpha-ketoadipate, and branched chain ketoacids, indicating functional impairment of thiamine-requiring enzymes, such as pyruvate dehydrogenase complex, alpha-ketoglutarate dehydrogenase complex, alpha-ketoadipate dehydrogenase, and branched chain amino acid dehydrogenase. The metabolism of thiamine has not been investigated in patients with thiamine-responsive congenital lactic acidosis. We evaluated two specific transport systems, THTR-1 (SLC19A2) and THTR-2 (SLC19A3), and a pyrophosphorylating enzyme of thiamine, thiamine pyrophosphokinase (hTPK 1), in addition to pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex activity; no abnormality was found. Although the clinical features of thiamine-responsive congenital lactic acidosis are heterogeneous and clinical responses to thiamine administration vary, we emphasize the importance of early diagnosis and initiation of thiamine therapy before the occurrence of permanent brain damage. Careful monitoring of lactate and pyruvate would be useful in determining thiamine dosage.