[Familial Hemophagocytic Lymphohistiocytosis, That was Considered as Progressive Encephalitis before Sibling was Diagnosed].

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder that is clinically characterized by fever, hepatosplenomegaly, cytopenia and sometimes vague or dramatic central nervous system (CNS) dysfunction. FHL affecting the CNS imitates several neurologic disorders and may be misdiagnosed, in particular when family history is unknown. We report an autopsy case of FHL that was firstly considered as progressive encephalitis. FHL was suspected after sibling had been affected by hemophagocytosis and the same CNS symptoms. Histopathologically, lymphocytes and macrophages infiltrated into the meninges, perivascular space, and parenchyma of the brain. Those lymphocytes were positive for CD3, CD8, GranzymeB, and negative for CD4, perforin. FHL must be included in the differential diagnostic considerations in children with progressive encephalitis.

[A clinical study on high-dose erythropoietin therapy for acute encephalopathy or encephalitis].

OBJECTIVE: We performed high-dose erythropoietin therapy (hEPO) for acute encephalopathy or encephalitis (AE), and evaluated its safety and efficacy. METHODS: We performed hEPO in AE patients with widespread lesions demonstrated by diffusion-weighted imaging, and prospectively investigated changes in hemoglobin levels, adverse events, changes in images, and developmental quotients. RESULTS: All four patients showed neither an increase in the hemoglobin level nor adverse event possibly related to hEPO. One patient with acute encephalitis showed resolution of the lesion and normal developmental quotient. Two patients who had acute encephalopathy with febrile convulsive status epilepticus showed mild cerebral atrophy in the recovery phase;one had a normal developmental quotient. The patient with acute necrotizing encephalopathy including a brainstem lesion avoided acute-phase death. CONCLUSION: Two patients showed no sequelae despite images indicating widespread abnormality. hEPO could be performed safely in patients with AE, however further trials are necessary concerning its efficacy.

[Clinical evaluation of six patients with anti-NMDAR encephalitis].

OBJECTIVE: We examined the clinical course and the prognosis of patients with anti-NMDAR encephalitis. METHODS: We retrospectively evaluated the patients who has distinctive clinical features as anti-NMDAR encephalitis based on their medical records. RESULTS: There were two male and four female patients with anti-NMDAR encephalitis. They were aged between 13 and 16 years. One of the six, 14 years female patient was negative for anti-NMDAR antibody. All four female patients with anti-NMDAR encephalitis had an ovarian tumor. Neurocognitive dysfunction and epilepsy remained in one female patient with right temporal lobe lesion and one male patient with celebellar abnormalities had mild mental impairment. In three patients including two patients who were examined abdominal MRI for the first time after recovery from the encephalitis, overian tumors became apparent during follow-up. In one of other patients, overian tumors had a tendency to increase in size after recovery. CONCLUSION: Sequellae were seen in two cases that have abnormalities in brain MRI. As to ovarian tumor, it was considered to be necessary to checkup pelvic MRI for at least four years after the onset of encephalitis.

Higher incidence of acute symptomatic seizures in probable antibody-negative pediatric autoimmune encephalitis than in major antibody-positive autoimmune encephalitis.

Purpose: To delineate the characteristics of probable antibody-negative pediatric autoimmune encephalitis (probable Ab-negative AE), we compared the clinical features of probable Ab-negative AE to those of major antibody-positive AE. Methods: We retrospectively reviewed the clinical features of 18 patients with probable Ab-negative AE, 13 with anti-N-methyl-D-aspartate receptor encephalitis (NMDARE), and 13 with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Clinical characteristics, neuroimaging findings, treatments, and outcomes were analyzed. Results: The age of onset and length of hospital stay were significantly higher in the NMDARE group than in the other groups (p = 0.02 and p < 0.01). Regarding initial neurological symptoms, acute symptomatic seizures in the probable Ab-negative AE group (67%) were significantly more frequent than in the NMDARE (15%) and MOGAD (23%) groups (p < 0.01). Paraclinical evidence of neuroinflammation within 1 month of disease onset revealed that single-photon emission computed tomography (SPECT) detected abnormal alterations in 14/14 (100%), cerebrospinal fluid (CSF) analysis in 15/18 (83%), and magnetic resonance imaging (MRI) in 11/18 (61%) in patients with probable Ab-negative AE. In the probable Ab-negative AE group, seven patients (39%) developed autoimmune-associated epilepsy, whereas one patient (8%) had both NMDARE and MOGAD (not statistically significant, p = 0.07). Conclusion: Patients with probable Ab-negative AE exhibited acute symptomatic seizures as initial neurological symptoms significantly more frequently. They developed autoimmune-associated epilepsy more frequently than those with NMDARE and MOGAD, which was not statistically significant. SPECT within 1 month of disease onset might be a valuable surrogate marker of ongoing neuroinflammation and neuronal dysfunction, even in patients with negative MRI findings.

Efficacy and safety of ketamine for pediatric and adolescent super-refractory status epilepticus and the effect of cerebral inflammatory conditions.

OBJECTIVE: To investigate the short-term benefits and adverse effects of ketamine in the treatment of pediatric and adolescent super-refractory status epilepticus (SRSE), with a focus on the inflammatory etiology. METHODS: This retrospective observational cohort study included a consecutive series of 18 pediatric to adolescent patients with SRSE admitted between 2008 and 2023 and treated with ketamine. Seizure frequency per hour before and after ketamine administration and response rate were calculated. Neurological decline, catecholamine administration, and adverse effects were also assessed. The patients were divided into inflammatory and non-inflammatory etiology groups. RESULTS: The median age at SRSE onset was 1 year 5 months (range: 11 days-24 years), and 78% of the patients were male individuals. The median duration of treatment was 7.5 days (interquartile range: 2.8-15.5 days). Fifteen (83%) patients achieved >50% seizure reduction. The median seizure frequency before and after ketamine treatment was 5.9 and 0.9, respectively, showing a significant reduction in seizure frequency (p < 0.0001). Ten patients had inflammatory etiologies including bacterial meningitis (n = 2), viral encephalitis (n = 3), and febrile infection related epilepsy syndrome (n = 5). The inflammatory etiology group required a longer treatment duration (p = 0.0453) and showed lower seizure reduction (p = 0.0264), lower response rate (p = 0.0044), and higher neurological decline (p = 0.0003) than the non-inflammatory etiology group. Three (17%) patients experienced transient adverse events requiring intervention within 24 h of initiating ketamine administration. CONCLUSIONS: Ketamine administration was associated with fewer serious adverse events and a reduced seizure frequency. Additionally, inflammatory conditions may weaken the efficacy of ketamine in patients with SRSE.

Decreased sialylation of IgA1 O-glycans associated with pneumococcal hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) in children is usually caused by Shiga-like toxin-producing Escherichia coli, but approximately 5% of cases are caused by invasive pneumococcal infection (P-HUS). Reported herein is the case of a 9-month-old HUS patient with pneumococcal meningitis who needed hemodialysis for 12 days. Decreased sialylation was characterized in both transferrin N-glycans and IgA1 O-glycans, analyzed in the acute phase on mass spectrometry, consistent with S. pneumonia-produced sialidases hydrolyzing both α2,3- and α2,6-linked sialic acids. The method will complement the T-antigen activation test and help to understand the molecular pathology related to P-HUS.

[Usefulness of 123I-iomazenil SPECT in pediatric patients with neurological disease].

This study examined the usefulness of 123I-iomazenil SPECT (IMZ-SPECT), a type of brain scintigram that focuses on the central benzodiazepine receptor in order to determine its distribution and the function of inhibitory neurons. IMZ-SPECT has been used for the detection of epileptogenic foci, especially when surgical intervention is considered. Interictal study by IMZ-SPECT is widely available at numerous institutions and its usefulness has been confirmed in patients with not only focal cortical dysplasia and hippocampal sclerosis, but also tuberous sclerosis and neuronal migration disorders, even when magnetic resonance image fails to demonstrate any abnormal findings. When interpreting scintigrams, the developmental dynamic change of the central benzodiazepine receptor in childhood and the duration of the benzodiazepine exposure period should be taken into consideration. It is expected that IMZ-SPECT will be used in various neurological disorders other than epilepsy in the future allow medical services to be provided based on findings in the inhibitory synaptic system obtained with IMZ-SPECT.

[Clinical study of patients undergoing paperless electroencephalography in emergency room].

Fifty-eight patients who visited the emergency room of our center with febrile convulsions and impaired consciousness, and underwent paperless electroencephalography soon after arrival. They consisted of 25 male and 33 female children, ranging in age from 5 months to 15 years and 4 months, with a mean age of 4 years and 10 months. The final diagnoses were poor responsiveness associated with fever and febrile delirium in 5 patients, febrile convulsions in 26, encephalitis/encephalopathy in 24, convulsions associated with mild gastroenteritis in 2, and aseptic meningitis in 1. The appearance of spindle wave within 24 hours after admission was considered to be a favorable prognostic factor, whereas generalized high-amplitude delta waves without fast-wave components and dysrhythmic flat basic waves were considered poor prognostic factors. We conclude that bed-side paperless electroencephalography is useful for the evaluation of changes in the brain function and course of treatment.

Effect of higher body temperature and acute brain edema on mortality in hemorrhagic shock and encephalopathy syndrome.

OBJECTIVE: Hemorrhagic shock and encephalopathy syndrome (HSES) is a severe subtype of acute encephalopathy with a poor prognosis. The factors associated with acute neurological outcomes in patients with HSES remain unclear. This study aimed to determine the clinical features, laboratory and radiological findings, and treatments that determine the acute outcomes of HSES. METHODS: Forty children with HSES registered in a database of Osaka City General Hospital between 1995 and 2020 were included in this observational study. We retrospectively collected data on clinical features, laboratory and radiological items, and treatments. We divided acute neurological outcomes into two groups: the non-death and death groups in 1 week. Correlations were assessed between these items and acute neurological outcomes. RESULTS: Twenty-seven and 13 patients comprised the non-death and death groups, respectively. Univariate logistic regression analysis showed that higher body temperature, presence of hemorrhagic episode, elevated lactate level, high glucose level in the cerebrospinal fluid, and brain edema at initial computed tomography (CT) were correlated with the death group. Regarding treatments, barbiturate therapy, intravenous immunoglobulin, and intravenous methylprednisolone were significantly initiated in the non-death group. The multivariate logistic regression model showed higher body temperature (odds ratio [OR], 4.210 [1.409-12.584]; p = 0.010) and brain edema on initial head CT (OR, 46.917 [3.995-550.976]; p = 0.002) were independent factors. CONCLUSIONS: Higher body temperature and brain edema at the onset of HSES were associated with acute outcomes. The results of this study may be useful for treatment planning and acute outcomes in patients with HSES.

A case of bilateral limbic and recurrent unilateral cortical encephalitis with anti-myelin oligodendrocyte glycoprotein antibody positivity.

BACKGROUND: Anti-myelin oligodendrocyte glycoprotein (MOG) antibody can be detected not only in acute disseminated encephalomyelitis or optic neuritis but also in limbic or cortical encephalitis. However, no previous reports have demonstrated a relapsing case of these two types of encephalitis. CASE REPORT: An 11-year-old girl presented with fever, headache, abnormal behavior, focal impaired awareness seizures (FIAS) on the left side, and MRI hyperintensities in the bilateral amygdala, hippocampus, and right posterior temporal cortex. The symptoms were alleviated with two courses of intravenous methylprednisolone (IVMP) and one course of immunoglobulin. At 16 years of age, the patient returned with left-sided headache and MRI hyperintensities in the left temporal, parietal, and insular cortices, which improved after 3 courses of IVMP. Oral prednisolone (PSL) was tapered over 6 months, when FIAS reappeared on the right side of the body. MRI showed recurrence in the same regions as in the second episode. She received 3 courses of IVMP, followed by gradually tapered PSL without relapse for 1.5 year. Anti-MOG antibodies were positive in both serum and the cerebrospinal fluid prior to treatment in all three episodes. CONCLUSION: Our results revealed that anti-MOG antibody-related bilateral limbic and unilateral cortical encephalitis can manifest with a variety of phenotypes over time in the same patient.

Longitudinal electroencephalogram findings predict acute neurological and epilepsy outcomes in patients with hemorrhagic shock and encephalopathy syndrome.

OBJECTIVE: Hemorrhagic shock and encephalopathy syndrome (HSES) is a severe subtype of acute encephalopathy with a poor prognosis. The association between electroencephalogram (EEG) findings and neurological outcomes in patients with HSES, including the onset of epilepsy, remains unclear. METHODS: Thirty-two children with HSES registered in a database of Osaka City General Hospital between 2003 and 2018 were included in this study. The EEG findings which consisted of continuity, reactivity, state change, voltage, rhythmic and periodic patterns, and electrographic or electroclinical seizures, in the onset phase were evaluated for patient outcome. Patients who avoided acute death were investigated for epilepsy by a longitudinal EEG. Seizure types were determined by ictal video recordings. RESULTS: We analyzed EEG findings in the onset phase of 30 patients. Severely to extremely abnormal EEG pattern (deteriorated continuity more than discontinuous pattern, presence of generalized abnormal low voltage slow wave, and presence of generalized rhythmic and periodic patterns) in the onset phase correlated with poor outcome (p = 0.0024). Subsequently, 9/23 patients (39%) developed epilepsy, of which a total of eight had epileptic spasms. A significant correlation between interictal epileptic discharges and the development of epilepsy was observed as early as within three months (p = 0.0003). CONCLUSIONS: EEG pattern in the onset phase may be useful to predict the neurological prognosis in the acute stage. Moreover, this study demonstrated that longitudinal EEG findings after the acute phase of HSES were significantly related to the development of epilepsy. EEG findings are useful for predicting acute prognosis and epilepsy in patients with HSES.

Enterovirus 68 in children with acute respiratory tract infections, Osaka, Japan.

Enterovirus 68 strains were detected in 14 specimens from children with respiratory tract infections and 1 specimen from a child with febrile convulsions during 2010 in Osaka, Japan. These strains had deletions in the 5' untranslated region and were genetically different from reported strains. This virus is associated with respiratory tract infections in Japan.

MRI findings at neurological onset predict neurological prognosis in hemorrhagic shock and encephalopathy syndrome.

BACKGROUND: Hemorrhagic shock and encephalopathy syndrome (HSES) is a devastating disease and has an uncertain pathogenesis. The aim of this study was to predict neurological outcomes for HSES using magnetic resonance imaging (MRI) findings at neurological onset and elucidate the pathophysiology of HSES in the acute phase from serial MRI changes. MATERIALS AND METHODS: We analyzed the MRI findings of 13 patients who underwent an initial MRI within 24 h of neurological onset. According to neurological prognosis, seven patients were included in the severe group and six in the non-severe group. All patients in the non-severe group had a follow-up MRI. We divided the whole brain into 14 regions and each region was scored according to diffusion-weighted imaging findings. We compared the total scores of each region between the two groups and between onset and follow-up MRI. RESULTS: At neurological onset, symmetrical lesions were found predominantly in the frontal, parietal, and occipital lobes in 12 of 13 patients (92%). In the severe group, the total score for onset MRI was significantly higher than those in the non-severe group (p = 0.003). The total score was significantly higher for follow-up than those of onset MRI (p = 0.036). White matter lesions that showed a bright tree appearance were observed in the follow-up MRIs of all patients. CONCLUSION: Total scores for onset MRIs are useful for predicting neurological prognosis in patients with HSES. In addition to widespread cortical involvement of predominantly watershed areas, white matter lesions may play a role in the progression of brain edema.

Intrathecal dexamethasone therapy for febrile infection-related epilepsy syndrome.

OBJECTIVE: Increasing reports suggest a role for immunological mechanisms in febrile infection-related epilepsy syndrome (FIRES). The objective of this study was to elucidate the efficacy and safety of intrathecal dexamethasone therapy (IT-DEX). METHODS: We assessed six pediatric patients with FIRES who were administered add-on IT-DEX in the acute (n = 5) and chronic (n = 1) phases. We evaluated clinical courses and prognosis. We measured cytokines/chemokines in cerebrospinal fluid (CSF) from FIRES patients at several points, including pre- and post-IT-DEX, and compared them with control patients with chronic epilepsy (n = 12, for cytokines/chemokines) or with noninflammatory neurological disease (NIND, n = 13, for neopterin). RESULTS: Anesthesia was weaned after a median of 5.5 days from IT-DEX initiation (n = 6). There was a positive correlation between the duration from the disease onset to the introduction of IT-DEX and the length of ICU stay and the duration of mechanical ventilation. No patient experienced severe adverse events. Seizure spreading and background activities on electroencephalography were improved after IT-DEX in all patients. The levels of CXCL10, CXCL9, IFN-γ, and neopterin at pre-IT-DEX were significantly elevated compared to levels in epilepsy controls, and CXCL10 and neopterin were significantly decreased post-IT-DEX, but were still higher compared to patients with chronic epilepsy. IL-6, IL-8, and IL-1ß were significantly elevated before IT-DEX compared to epilepsy controls, though there was no significant decrease post-treatment. INTERPRETATION: IT-DEX represents a therapeutic option for patients with FIRES that could shorten the duration of the critical stage of the disease. The effect of IT-DEX on FIRES might include cytokine-independent mechanisms.

[Attempt of differentiation acute encephalopathy with febrile convulsive status epilepticus from febrile convulsive status epilepticus induced by human herpesvirus 6 at early stage].

It is difficult for clinicians to predict the subsequent development of acute encephalopathy with febrile convulsive status epilepticus (AEFCSE), when febrile convulsive status epilepticus (FCSE) develops. Comparing clinical and laboratory characteristics between patients with AEFCSE and those with FCSE, we investigated the factors which predict the later development of febrile convulsive status caused by HHV6. The subjects of this study were patients treated for FCSE or AEFCSE due to HHV6 in our hospital between April 2004 and January 2008. The AEFCSE group included 5 patients, and the FCSE group included 6 patients. There were few differences in clinical characteristics or brain images on admission between the 2 groups. Disturbance of consciousness persisted for 24 hours or more in all patients in the AEFCSE group and in 2 patients in the FCSE group. The serum creatinine concentration was significantly higher in the AEFCSE group. Serum creatinine concentration could be a good indicator for the prediction of AEFCSE in patients with FCSE.

[Study of an efficacy and a pharmacokinetics of intranasal midazolam for status epilepticus on childhood epilepsy].

We reviewed the efficacy and a pharmacokinetics of intranasal midazolam (MDL) for status epilepticus in childhood epilepsies. This trial was planned for the patients who developed status epilepticus at least once in the past and had no responses with diazepam. Intranasal midazolam was proved to be effective (complete remission;65%), rapidly (an average time to stop seizures; 5.7 min) and safe with no adverse effects including respiratory depression with this dosage (an average of 0.26 mg/kg). In patients whose longitudinal concentrations of MDL in the blood were measured, MDL level was increased rapidly within five minutes after nasal application. Intranasal MDL is useful as a simple and safe method in the child emergency situation.

[Guidelines for treating and managing pediatric HIV/AIDS in Japan].

Infant to post-pubertal adolescent pediatric HIV/AIDS cases in Japan nowadays are almost exclusively originated via mother-to-child transmission of HIV-1(MTCT). According to the National Cooperative Study Group on HIV Infected Pregnant Women and MTCT in Japan, most recent MTCT rate in Japan is 0.45 %, so the cumulative number of MTCT cases is only 46. In this paper the guidelines to control pediatric HIV/AIDS are introduced to Japanese doctors who are unfamiliar to this disease and just considering or starting initial antiretrovirals (ARV). ARV for children should be palatable, unrelated to foods, CNS-penetrating and should have least short and long acting side effects. Optimal adherence to treatment is best kept through the awareness of its importance by the patients and their guardians.

[HIV infected pregnant women in Japan and prevention of mother-to-child transmission].

By the investigation of our study group 595 HIV infected pregnant women have been confirmed in Japan since 1984. In recent years, around 40 pregnant women a year were diagnosed as HIV positive. These HIV infected pregnant women were not concerned with a value of CD4 and received antiretroviral therapy such as zidovudine (AZT) monotherapy or highly active antiretroviral therapy (HAART) starting from the second trimester of pregnancy. According to recommendations and current data, cesarean delivery before the onset of labor is performed around 37 weeks of pregnancy and prophylactic AZT syrups are given to infants starting 8-12 hrs after birth for 6 weeks. These preventive managements such as antiretroviral therapy, elective cesarean delivery and formula feeding significantly reduced mother-to-child transmission (MTCT) of HIV. The transmission rate of HIV fell to 0.5% in Japan, but the problem of the teratogenicity of antiretroviral drugs remain unclear. Further studies are needed.

DWI scoring system for prognosis of acute encephalopathy with biphasic seizures and late reduced diffusion.

PURPOSE: The aim of this study was to predict neurological outcomes for acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) using diffusion-weighted imaging (DWI), and assess relationships between anatomical sites of lesions and their outcomes. MATERIALS AND METHODS: We assessed DWI abnormalities and neurological outcomes in 30 patients with AESD, and classified patients into severe and non-severe groups according to their neurological outcomes. We also established a DWI scoring system as follows: zero for normal, and one for lesion at each location. Differences between the severe and non-severe groups were examined, and receiver operating characteristic (ROC) curve analysis was performed. RESULTS: Nine (30%) patients were classified into the severe group. On DWI, patients in the severe group were more likely to have temporal lobe (P = 0.014), perirolandic (P = 0.008), and corpus callosum (P = 0.0008) lesions than those in the non-severe group. The total DWI scores were significantly higher in the severe group than those in the non-severe group (P = 0.0002). ROC curve showed an area under the curve of 0.929, with a cutoff value of five, sensitivity of 88.9%, and specificity of 81.0%. CONCLUSION: Patients with severe AESD had more extensive DWI abnormalities than those with non-severe AESD. Our DWI scoring system may be useful for the prediction of outcomes of AESD. Widespread lesions seemed to have stronger influence on outcomes than each lesion location.