[Effective therapy in highly active pediatric multiple sclerosis]. / Magas aktivitású sclerosis multiplex hatásos kezelése gyermekkorban.

Multiple sclerosis (MS) is typically a disease of young adults. Childhood MS can be defined in patients under 18 years of age, although some authors set the limit un-der the age of 16 formerly known as "early-onset multiple sclerosis" or "juvenile multiple sclerosis", seen in 3-5% of all MS patients. Nowadays, owing to ever-evolving, better diagnostic tools and well-traced, strictly defined diagnostic criteria, childhood MS is showing an increasing incidence worldwide (0.05-2.85/100 000). MS is characterized by recurrent episodes of the central nervous system with demyelination separated in space and time. In childhood almost exclusively the relapsing-remitting (RR) type of MS occurs. Based on experience in adults, the goal in the pediatric population is also the early diagnosis, to initiate adequate DMT as soon as possible and to achieve symptom relief and good quality of life. Based on efficacy and safety studies in the adult population, inter-feron ß-1a and glatiramer acetate were first approved by the FDA and EMA for the treatment of childhood MS also. The increased relapse rate and rapid progression of childhood MS and unfavorable therapeutic response to nearly 45% of the first DMT necessitated the testing of more effective and second-line drugs in the population under 18 years of age (PARADIGMS, CONNECT). Although natalizumab was reported to be effective and well-tolerated in highly active RRMS in childhood, evidence based studies were not yet available when our patients' treatment started. In this article, we report on the successful treatment of three active RRMS patients with individually authorized off-label use of natalizumab.

Rituximab, IVIg, and Tetracosactide (ACTH1-24) Combination Immunotherapy ("RITE-CI") for Pediatric Opsoclonus-Myoclonus Syndrome: Immunomarkers and Clinical Observations.

Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder with pervasive morbidity that warrants better treatments. Twelve children with moderate/severe OMS (total score 23 ± 6) who did not remit to multiple immunotherapies were evaluated for neuroinflammation in a case-control study using cerebrospinal fluid (CSF) lymphocyte subset analysis by flow cytometry, chemokine/cytokine analysis by enzyme-linked immunoadsorption assay (ELISA), and oligoclonal bands by immunofixation with isoelectric focusing. Observations made on empirical treatment with rituximab, IVIg, and tetracosactide combination immunotherapy (coined "RITE-CI") were analyzed. All of the patients tested for multiple inflammatory markers were positive; 75% had ≥3 CSF markers. Fifty percent had CSF oligoclonal bands; 58%, B cell expansion; and 50 to 100%, elevated concentrations of multiple chemokines and neuronal/axonal marker neurofilament light chain. After RITE-CI, total score dropped significantly in the group (-85%, p < 0.0001) from moderate to trace, and by 2 to 4 severity categories in each patient. The 24-week schedule was well tolerated and clinically effective for moderate or severe OMS, as were other schedules. RITE-CI is feasible and effective as rescue therapy and presents an initial option for children with moderate/severe OMS. Though preliminary, the schedule can be adjusted to patient severity, propensity for relapse, and other factors.

[The role of zonisamide in the management of pediatric partial epilepsy]. / A zonisamid szerepe a gyermekkori fokális epilepszia gyógyszeres kezelésében.

In our review we discuss the group of approved antiepileptic drugs for children in Hungary. We cite the results of the review conducted by the International League Against Epilepsy on antiepileptic drug efficacy and effectiveness as initial monotherapy for newly diagnosed epileptic seizures and syndromes in pediatric age group. 25% of pediatric epilepsy is therapy resistant, so we further need new drugs, which must be investigated according to the rules of the European Medicine Agency. The ethical dilemmas of childhood drug studies lead to the situation that the new antiepileptic drugs, approved as monotherapy in adult epilepsies, are in the majority just in add-on regimen tested in pediatric patients. As clinicians we appreciate open label extension safety studies. An old-new antiepileptic drug in Europe is zonisamide. Though it was approved for first line monotherapy in pediatric and adult patients with partial and generalised epilepsy in 1989 in Japan, the European Medicine Agency licensed its use as adjunctive therapy in children aged 6 years or older with partial seizures (with or without secondary generalisation) just in 2013. The results of the openlabel extension study appeared in 2014. The mean dose received was 7.5 mg/kg/day. During the open label phase 11% of the patients achieved seizure freedom and it was maintained throughout the study. The drug was generally well tolerated. The most frequently reported treatment-related adverse events were decreased weight (6%), decreased appetite (4%), and headache (2%). No new or unexpected side effects emerged. In conclusion oral zonisamide as adjunctive therapy in pediatric patients aged 6-17 years with partial seizures demonstrated an acceptable safety and tolerability profile and efficacy over a period at least 1 year. So it is a good treatment option in this population.

Visual and neurologic deterioration in otogenic lateral sinus thrombosis: 15 year experience.

OBJECTIVES: Otogenic lateral sinus thrombosis is a rare complication of acute otitis media whose clinical presentation has changed with the early use of antibiotics. The aim of this study was to analyze the changing clinical signs, vaccination status, therapeutic management and outcome of these patients. METHODS: Retrospective chart review of 10 children treated with otogenic lateral sinus thrombosis in a tertiary level teaching hospital in Budapest, Hungary, from January 1998 till August 2013. RESULTS: Patients were divided into Early and Late presenting groups. In the Early presenting group, sepsis developed within one week after the onset of acute otitis media. At admission otological symptoms were predominant. The Late presenting group experienced acute otitis media several weeks prior to presentation and in this group neurologic symptoms dominated the clinical picture at admission. All patients received antibiotics. Eight of them were also treated with low molecular weight heparin. All children underwent cortical mastoidectomy. After surgery, the clinical signs of elevated intracranial pressure transiently worsened. This manifested as progression of papilledema in seven children, causing severe visual disturbance in two cases. After medical treatment and serial lumbar punctures all patients except one recovered. This child has permanent visual acuity failure of 0.5D unilaterally. At one year follow up complete and partial recanalization were noted in five and two patients, respectively. CONCLUSIONS: After mastoidectomy the signs of elevated intracranial pressure can transiently worsen, papilledema can progress. Daily bedside monitoring of visual acuity and regular ophthalmoscopy with neurologic examination is recommended during hospitalization. Close follow up is advised up to one year. When the dominant sinus is occluded, the clinical scenario is more protracted and severe.

Timely recanalization of lateral sinus thrombosis in children: should we consider hypoplasia of contralateral sinuses in treatment planning?

The objective of this study was to evaluate long-term clinical and radiological outcomes in children treated with lateral sinus thrombosis secondary to acute mastoiditis considering also contralateral sinus hypoplasia. This study was a retrospective chart review, conducted in tertiary pediatric hospital. Medical reports of eight children with acute mastoiditis and lateral sinus thrombosis from 1998 to 2011 were examined in terms of therapy, clinical recovery and radiological proof of lateral sinus recanalization. Three children presented hypoplasia of contralateral venous drainage system. Condition of sinuses was regularly monitored with MRI. Otologically and neurologically, all children recovered fully. All received antibiotics; six received additional low molecular weight heparin therapy. Mastoidectomy was performed on six cases. Incision and thrombectomy were applied in the other two, one involving internal jugular vein ligation. This latter case presented also contralateral venous hypoplasia; visual impairment proved permanent. The other two children with contralateral sinus hypoplasia recovered fully after steroid, dehydration and low molecular weight heparin therapy. Recanalization occurred in all children except the one with internal jugular vein ligation, in whom good collateral circulation was observed. There were no bleeding complications. Anatomical variations of cerebral venous drainage system can frequently be observed and should be considered in treatment planning. Mastoidectomy with antibiotics and additional low molecular weight heparin treatment is a safe, promising alternative to thrombectomy and internal jugular vein ligation in children with lateral sinus thrombosis following acute mastoiditis, also having contralateral sinus hypoplasia. Recanalization can be expected within two to five months.

[Guillain-Barré syndrome in childhood]. / Guillain-Barré-szindróma gyermekkorban.

BACKGROUND: Guillain-Barré syndrome (GBS) is clinically well known since 1916. It can occur at any age. Its main characteristic is acute rapidly ascending flaccid paresis. It is a neuro-immunologic disorder with heterogeneous background. In Hungary we could not find reports about big paediatric population with GBS. PATIENT AND METHOD: We analysed retrospectively the data of 38 children diagnosed and treated with GBS at the Neurological Department of Paul Heim Children's Hospital or at the Paediatric Department of St. László Hospital from January 2000 till April 2008. We analysed the clinical characteristics, seriousness of clinical signs, laboratory results, and electrophysiological features of them as well documented the preceding illness. We observed the effectiveness of our treatment; we measured the speed and time of the healing process and documented the residual clinical signs. RESULTS: 35 children could be classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 2 as having acute motor axonal neuropathy (AMAN) and 1 as Miller-Fisher syndrome. By those patients who at the very beginning did not show the characteristic clinical signs, electrophysiology helped in establishing the diagnosis. By one child spinal MRI with gadolinium supported our diagnosis. Those children, who lost their ambulation, got immunotherapy: intravenous immunoglobulin (IVIG) or plasmapheresis (PEX). Both method seemed to be effective. None of our patients died. All were cured. By five patients residual clinical symptoms could be found. CONCLUSION: The disease process, the relative incidence of each subtype of GBS is nearly similar to that in Western Europe and North America according to the literature. By the currently used immune therapy most of the pediatric patients recover fully within a short time.

[Acute transverse myelitis in childhood]. / Akut myelitis transversa gyermekkorban.

We reviewed the medical history, clinical signs, imaging studies, laboratory data and treatment effectiveness of our 10 patients presented with acute idiopathic transverse myelitis. We used the criteria of the Transverse Myelitis Consortium Working Group (2002). So we excluded all those cases by whom the cause of the inflammation could be detected (e. g. direct viral inflammatory disease, systemic autoimmune disease). Age of the patients at disease onset ranged from 3 to 15 years. The first clinical signs were pain in different locations, and urinary retention. Paraparesis or plegia reached its maximum within five days. By all patients spinal MRI and lumbar puncture were performed at admission. These results were interpreted together with the clinical signs, and therapy was started immediately. We used methylprednisolon pulse therapy. Within 10-30 days the patients started to walk. We have followed the children for 1.5-13 years. Few residual clinical signs were observed: by one child left sided spastic monoparesis persisted, by the other right sided latent monoparesis was stated, and by one partial urinary incontinence persisted. By the control spinal MRI persisting signal changes or atrophy were detected just by those two children who had residual clinical signs. In the follow-up period no clinical relapse occured. Neither did the brain or spinal MRI show new lesions. The quick diagnosis and the immediately started therapy determine mostly the clinical outcome of these children. We hope that our long follow-up period can help in better understanding the disease even in adult patients. In the future we try to join multicenter clinical studies.

[Severe intracranial hypotension in an adolescent with Marfan syndrome. Case report]. / Súlyos fokú spontán intracranialis hipotenzió Marfan-szindrómás serdülô esetében.

Spontaneous intracranial hypotension is a rare complication of connective tissue disorders. One of them is Marfan syndrome. It predisposes the patient to meningeal diverticula. Possibly after minor unrecognised head trauma or secondary to Valsalva manoeuvre cerebrospinal fluid leak from meningeal diverticula can happen. It causes postural headache. We describe a 15 year old adolescent female newly diagnosed with Marfan syndrome, who presented with intractable postural headache. Our patient's brain MRI showed bilateral frontal subdural effusion, narrow ventricles, downward displacement of the brainstem, enlarged cervical venous plexi, dural ectasias and wide nerve root sleeves. Radionuclide cisternography demonstrated CSF leaks at multiple sites. She could not be treated conservatively, but was successfully treated by epidural saline injections. Control brain and cervical MRI confirmed her healing, too. At the two and half year follow up visit, she was completely well. So we recommend this easy technique to be used before epidural autologous blood patches.

[Experience with levetiracetam in childhood epilepsy]. / Tapasztalatok a levetiracetamkezeléssel gyermekkori epilepsziákban.

OBJECTIVE: To evaluate the efficacy and tolerability of levetiracetam in children with drug resistant epilepsy from a retrospective study. METHODS: We report the result of a study of 85 pediatric patients (mean 10.5 years, range: 1-24) with refractory generalized and focal epilepsy, who received levetiracetam as add-on treatment. The average duration of epilepsy was eight years, and the patient were treated with mean of 6.0 antiepileptic drugs before levetiracetam was introduced. RESULTS: Ten patients (12%) became seizure-free, three (3%) responded with seizure reduction of more than 90%, 32 (38%) responded with seizure reduction of more than 50% following introduction of levetiracetam. No response to levetiracetam was reported in 34% (n: 29). Positive psychotropic effect was observed in 26 patient (30%). Mild to moderate side effects were reported in 11 patients (13%), consisting most frequently general behavioral changes, aggression, sleep disturbances, but they ceased after decreasing the dose of levetiracetam. Mental retardation was associated with poor response and associated with more side effects. CONCLUSION: Levetiracetam is a well tolerated new antiepileptic drug that may effectively improve seizures control as an add-on drug in resistant epilepsy in childhood with good tolerability.

[Phenotypic variants of A3243G mitochondrial DNA mutation in a Hungarian family]. / A mitokondriális DNS A3243G mutációja egy magyar családban.

The first Hungarian case with typical features of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) in a young girl is presented. MELAS is a multisystem disorder inherited by the mitochondrial DNA with onset typically in childhood. Our patient presented the first symptoms at the age of 6 years with recurrent vomiting, nausea and transient visual loss. Several stroke-like episodes followed gradually impairing motor abilities and mental development. Molecular analysis of the mitochondrial DNA confirmed a heteroplasmic A3243G transition. The maternal family members were also tested for the mutation in peripheral blood DNA. In the mother of the proband, who suffers from bilateral hypacusis the mutation was detected in 20% of heteroplasmy, while in one of her asymptomatic sisters the mutation was present in 10% only. The bilateral hypacusis of the mother may be associated with this mutation and seems to differentiate the pedigree reported here from others published in the literature.