A case of early-infantile onset, rapidly progressive leukoencephalopathy with calcifications and cysts caused by biallelic SNORD118 variants.

Leukoencephalopathy with calcifications and cysts is a rare autosomal recessive genetic disorder neuroradiologically characterized by intracranial calcification, cerebral white matter disease, and multiple cysts. Although SNORD118 genes have recently been identified as a cause of this disorder, its clinical course varies for each patient. We report an early infantile case of this disease that progressed rapidly with confirmed SNORD118 variants. A 3-month-old female infant presented with epileptic seizures. Computed tomography revealed intracranial calcifications in the basal ganglia and thalamus. Magnetic resonance imaging demonstrated hyperintense lesions in the diffuse white matter on T2-weighted images starting at 7 months of age. Calcifications developed in the cerebral white matter, pons, and cerebellum. Small cysts appeared in the cerebral white matter at 1 year and 6 months. These cysts then began to increase bilaterally and expand rapidly. Although her epilepsy was controlled, she exhibited severe developmental delays and was unable to speak or walk at the age of 4 years. Whole-exome sequencing did not reveal any causal variants in the coding sequences. Further, Sanger sequencing revealed biallelic SNORD118 variants. Clinical features of this disease have not been established. To date, no cases with rapid changes in imaging results have been reported in detail prior to the appearance of cysts. Thus, we report a novel case that had an early infantile-onset and progressed rapidly with sequential appearance of calcification, white matter lesions and cysts. As SNORD118 variants might be missed by regular whole-exome sequencing, careful neuroimaging follow-up may be necessary to diagnose this disease.

Clinical effectiveness of efinaconazole 10% solution for treatment of onychomycosis with longitudinal spikes.

Onychomycosis with longitudinal spikes in the nail plate has been reported to be refractory to oral drugs as with dermatophytoma. We evaluated the efficacy of 10% efinaconazole solution in the treatment of onychomycosis with longitudinal spikes. Of the 223 subjects who were enrolled in a previous study, a post-hoc analysis of 82 subjects with longitudinal spikes was performed in this study. The opacity ratio of longitudinal spikes was decreased over time from 8.1 to 0.9 at the final assessment. In addition, the longitudinal spike disappearance rate increased early after the application to 81.7% at the final assessment. Therefore, 10% efinaconazole solution can be a first-line drug for longitudinal spikes, which have been regarded as refractory to oral drugs.

Efficacy of long-term treatment with efinaconazole 10% solution in patients with onychomycosis, including severe cases: A multicenter, single-arm study.

We evaluated the efficacy of efinaconazole 10% topical solution in long-term use, for up to 72 weeks, for onychomycosis, including severe cases. Among 605 participants, 219 patients diagnosed as having onychomycosis were evaluated for the efficacy of efinaconazole. The treatment success rate (<10% clinical involvement of the target toenail) at the final assessment time point was 56.6%, the complete cure rate was 31.1% and the mycological cure rate was 61.6%, all of which increased over time, demonstrating that continuous application contributed to the improvement of cure rate. Even in severe cases, reduction of the affected nail area was observed, showing the potential efficacy of the treatment. Responses to a quality of life questionnaire among patients with onychomycosis, OnyCOE-t, suggested that efinaconazole treatment improved the patients' quality of life. The incidence of adverse drug reaction in the patients eligible for the assessment was 6.3%, and this developed only in the administration site in all cases. No systemic adverse event was observed. In addition, no increase in the incidence of adverse drug reaction due to long-term use was found. Efinaconazole therapy was proved to exhibit excellent balance between efficacy and safety, and thus may serve as a useful treatment option for onychomycosis.

Potassium Bromide in the Treatment of Pediatric Refractory Epilepsy.

OBJECTIVE: We evaluated potassium bromide's (KBr's) efficacy and tolerability for pediatric refractory epilepsy. METHODS: We retrospectively reviewed the records of 42 patients treated with KBr in our hospital between 2008 and 2016 (age: 4 months to 19 years; mean: 6.2 years). Thirteen of them had 2 seizure types. The treatment durations ranged from 1 month to 6 years (mean: 15.0 months). RESULTS: KBr had an excellent effect (seizure-free status) in 3 patients (7.1%), a moderate effect (>50% reduction in seizure frequency from the pretreatment baseline) in 21 patients (50.0%), and no effect (<50% reduction in seizure frequency from the pretreatment baseline) in 18 patients (42.9%). The effective daily doses ranged from 20 to 80 mg/kg (mean: 50.0 mg/kg). KBr was effective in 59.1% patients with generalized epilepsy (n = 22), 55.6% patients with focal epilepsy (n = 18), and both patients with Dravet syndrome. An excellent or moderate effect was found in 72.2% patients with tonic seizures (n = 18), 66.6% patients with generalized tonic-clonic seizures (n = 6), 75.0% patients with secondary generalized seizures (n = 4), 46.2% patients with focal seizures (n = 13), and 20% patients with infantile spasms (n = 10) but no patients with myoclonic seizures (n = 2). Adverse effects including drowsiness, excitement, and rashes were reported in 13 patients (31.0%). CONCLUSIONS: These findings suggest that KBr is particularly effective for tonic seizures, generalized tonic-clonic seizures, and secondary generalized seizures. Although the adverse effects need further attention, KBr should be considered for pediatric refractory epilepsy.

Ovarian teratoma development after anti-NMDA receptor encephalitis treatment.

BACKGROUND: Anti-NMDA-R receptor encephalitis occurs predominantly in younger women and is often comorbid with ovarian teratoma, a feature that is often absent in children. Here, we report our experience with two pediatric patients, in whom no tumors were present during treatment for encephalitis, but in whom ovarian teratomas developed without encephalitis relapse after treatment was completed. CASES: Patient 1 was a 14-year-old girl who was diagnosed due to characteristic symptoms and anti-NMDA-R antibody. MRI scanning during treatment revealed no ovarian tumors, but a tumor developed in the right ovary 10months after onset. Another tumor developed in the left ovary 3years after onset, and a mature ovarian teratoma was confirmed after bilateral partial ovariectomy. Patient 2 was an 11-year old girl who was also diagnosed due to characteristic symptoms and anti-NMDA-R antibody. Imaging during treatment revealed no ovarian tumors, but a 2.5-cm tumor mass was found in the left ovary 10months after onset, and a mature ovarian teratoma was confirmed after partial ovariectomy. DISCUSSION: This case report suggests the need for regular tumor screening after treatment for anti-NMDA receptor encephalitis because of potential subsequent tumor development, even in pediatric patients who initially present with no comorbid tumors. No analysis of relapse risk has yet been reported in cases of tumor development after treatment, and at this point, whether or not resection is needed to prevent relapse remains unclear. However, because teratomas usually grow, have an associated risk of torsion, and can be malignant, tumor removal should be considered.

[Study of the efficacy of low-dose synthetic ACTH therapy without tapering to treat West syndrome].

OBJECTIVE: We evaluated the effectiveness of synthetic adrenocorticotropic hormone (ACTH) therapy without tapering in treating patients with West syndrome. METHODS: Forty-four patients with cryptogenic (n = 7) or symptomatic (n = 37) West syndrome were treated with synthetic ACTH therapy between 2003 and 2012. The synthetic ACTH dosage was 0.0125 mg/kg/day administered daily for 2 weeks and then stopped without a tapering period. The initial effectiveness, long-term seizure outcome, and adverse effects were examined. RESULTS: During synthetic ACTH therapy, epileptic spasms disappeared in 37 of 44 patients (84.1%) and hypsarrhythmia on electroencephalography disappeared in 42 of 44 patients (95.5%). The average number of synthetic ACTH injections needed to achieve spasm control in these 37 patients was 5.8. Long-term seizure outcomes were assessed in 31 patients followed up for longer than half a year after synthetic ACTH therapy. Nine (29.0%) of these patients experienced recurrence of epileptic spasms, with a mean interval to recurrence of 2.4 months. Overall, 12 patients (38.7%) experienced various types of seizures other than spasms with a mean interval to recurrence of 8.0 months. Although adverse effects such as hypertension, infection, and mild brain shrinkage were noted in 13 patients (29.5%), no severe adverse effects were observed. CONCLUSIONS: These results are comparable to those of other reports on the initial effectiveness and long-term seizure control following synthetic ACTH therapy, and suggest that administration without tapering is reasonable to treat patients with West syndrome.

Drugs indicated for mitochondrial dysfunction as treatments for acute encephalopathy with onset of febrile convulsive status epileptics.

We studied the efficacy of drugs indicated for mitochondrial dysfunction in the treatment of 21 patients with acute encephalopathy with onset of febrile convulsive status epilepticus at our hospital from January 2006 to December 2014. Among them, 11 patients had been treated with a mitochondrial drug cocktail consisting of vitamin B1, vitamin C, biotin, vitamin E, coenzyme Q10, and l-carnitine (prescription group) and 10 patients were not treated with the cocktail (non-prescription group). We retrospectively reviewed age, trigger, clinical form, treatment start time, and sequelae. Clinical form was classified into a biphasic group presenting acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) and a monophasic group. Sequelae were classified as (A) no sequelae group or (B) sequelae group, and differences in the interval between diagnosis and treatment were also evaluated. The sequelae were not different between the mitochondrial drug cocktail prescription and non-prescription groups, but significantly better in the group administered the mitochondrial drug cocktail within 24h (P=0.035). We expect that early treatment with a mitochondrial drug cocktail could prevent sequelae in acute encephalopathy with onset of febrile convulsive status epilepticus.

Focal Coxsackie virus B5 encephalitis with synchronous seizure cluster and eruption: Infantile case.

Enterovirus focal encephalitis is a rare clinical entity that is characterized by focal neurological signs including seizure, hemiparesis, hemichorea, and headache, which are mainly followed by rapid spontaneous improvement. We herein describe the case of a 9-month-old boy who developed Coxsackie virus B5 (CVB5) focal encephalitis with seizure clusters in the eruption stage of roseola infantum-like illness, which were followed by rapid improvement and benign outcome. Lumbar puncture indicated pleocytosis, and CVB5 infection in the cerebrospinal fluid was subsequently identified on genome sequencing and virus isolation. Magnetic resonance imaging and electroencephalography showed no abnormal findings at the acute stage or on 2 month follow up. Although the pathogenesis of enterovirus focal encephalitis currently remains unclear, the pure synchronism of seizure cluster and eruption in this case suggests the involvement of local vascular impairment as the underlying pathogenesis.

Validity and reliability of the Japanese version of the family needs survey.

Early intervention and disability services in Japan historically have focused on supporting the individual with a disability, with only secondary attention to family needs and priorities. Since the Basic Law for Persons with Disabilities was codified in 2011, the Japanese government has been responsible for supporting families with members who have disabilities. To assess the needs of these families, we evaluated the reliability and validity of the Family Needs Survey (FNS), initially developed in 1988 (Bailey & Simeonsson), to determine its usefulness for programs providing services for Japanese families who have a child with a disability. The FNS is a practical tool to assess family needs and is already used across many different cultures and populations. To evaluate the reliability and validity of the FNS, we conducted an anonymous survey with a self-administered questionnaire at 6 treatment and education institutions, 3 medical institutions mainly for children with disabilities, and 39 special needs schools in the Osaka area. We analyzed 1171 parents' survey responses: 452 fathers and 719 mothers of children with disabilities aged 0-15 years old who answered all items on the Japanese version of the FNS. Another survey was administered to 130 specialists who work with children with disabilities to assess the content validity of the Japanese version of the FNS. We verified the factor structure, content validity, and reliability of the Japanese version of the FNS as an assessment tool with 34 items among four factors that were based on the same items in the original FNS. The assessment could be used for families with school-age children as well as younger children, in contrast to the original version, which is not appropriate for school-age children. We also confirmed that it could be used without regard to type or degree of disability.

Hearing profile and MRI myelination of auditory pathway in Pelizaeus-Merzbacher disease.

CONCLUSIONS: This study showed that delayed auditory pathway myelination is common in Pelizaeus-Merzbacher disease (PMD), but this delay does not necessarily indicate poor hearing function. OBJECTIVE: PMD is a rare recessively inherited X-linked leukodystrophy characterized by defective central nervous system myelination owing to a mutation in the proteolipid protein gene (PLP). The aims of this study were to evaluate the hearing function and auditory brain response (ABR) findings of patients with PMD and relate these findings to MRI-assessed myelination in the central auditory pathway. PATIENTS AND METHODS: We retrospectively studied eight male pediatric patients with PMD. Serial auditory examinations included audiometry, behavior audiometry, distortion product otoacoustic emission (DPOAE), and ABR. MRI-assessed myelination in the auditory pathway was evaluated in the PMD patients and in 23 normal young children as a control group. RESULTS: Audiometry showed normal to moderate hearing impairment and the hearing threshold improved with age and became almost normal over time. DPOAEs positivity and only ABR wave I or waves I and II were found in all the patients. MRI showed delayed myelination in all the patients and the auditory pathway was myelinated up to the inferior colliculus in four cases and up to the medial geniculate body in four cases. Serial MRIs showed no progression in myelination. No clear relation was found between hearing threshold and MRI-assessed myelination in the auditory pathway.

Nature of inflammatory infiltrate in superficial cutaneous malignancies during topical imiquimod treatment.

Topical imiquimod (IQ) is an effective treatment for genital warts and various malignant tumors of the skin. IQ acts through the Toll-like receptor 7 leading to the production of cytokines and chemokines such as interferons, interleukins, and growth factors. We investigated the composition of the inflammatory cell infiltrate before, during, and after the treatment of 10 superficial cutaneous malignancies (melanoma in situ (n = 4), melanoma metastasis (n = 1), squamous cell carcinoma in situ (n = 4), and basal cell carcinoma (n = 1) with 5% IQ cream. Immunophenotyping revealed in all cases during treatment an increased population of T-lymphocytes positive for CD3, CD4 and CD8, as well as a considerable number of cytotoxic cells (TIA-1+, granzyme B+) and plasmacytoid dendritic cells (CD 123+). These findings further support previous investigations that the antitumor effects of IQ result from an enhanced cytotoxic T-cell mediated immune response and from the recruitment of plasmacytoid dendritic cells to the skin. The population of infiltrative inflammatory cells was similar in all patients irrespective of the type of tumor.

Feasibility and diagnostic agreement in teledermatopathology using a virtual slide system.

We investigated the feasibility and diagnostic agreement of a virtual slide system (VSS) in teledermatopathology. Forty-six biopsy specimens from inflammatory skin diseases were selected and scanned with a VSS at the Research Unit of Teledermatology, Medical University of Graz, Graz, Austria. Images were stored on a virtual slide server on which a specific Web application suited for telepathology (http://telederm.org/research/dermatopath/) runs. Twelve teleconsultants from 6 different countries reviewed the 46 cases, working directly on the Web application. Telediagnoses agreed with gold standard and conventional diagnosis with an average of 73% and 74%, respectively. Complete concordance among all teleconsultants with gold standard and conventional diagnosis was found in 20% of the cases. In 10 cases in which complete clinical data were missing, the average agreement of telediagnosis with gold standard diagnosis and conventional diagnosis decreased to 65% and 66%, respectively. Only 3 of 4 cases of inflammatory skin diseases were correctly diagnosed remotely with VSS. The system that we have used, despite its usability, is not completely feasible for teledermatopathology of inflammatory skin disease. Moreover, the performance seems to have been influenced by the availability of complete clinical data and by the intrinsic difficulty of the pathology of inflammatory skin diseases.