Temporal Dynamics of MOG Antibodies in Children With Acquired Demyelinating Syndrome.

BACKGROUND AND OBJECTIVE: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course. METHODS: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG-positive. RESULTS: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG-negative. DISCUSSION: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk.

Treatment of Infantile Spasm Syndrome: Update from the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society of Neuropediatrics.

OBJECTIVES: The manuscript serves as an update on the current management practices for infantile spasm syndrome (ISS). It includes a detailed summary of the level of current evidence of different treatment options for ISS and gives recommendations for the treatment and care of patients with ISS. METHODS: A literature search was performed using the Cochrane and Medline Databases (2014 to July 2020). All studies were objectively rated using the Scottish Intercollegiate Guidelines Network. For recommendations, the evidence from these studies was combined with the evidence from studies used in the 2014 guideline. RECOMMENDATIONS: If ISS is suspected, electroencephalography (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatment should be evaluated clinically and electroencephalographically after 14 days. The preferred first-line treatment for ISS consists of either hormone-based monotherapy (AdrenoCorticoTropic Hormone [ACTH] or prednisolone) or a combination of hormone and vigabatrin. Children with tuberous sclerosis complex and those with contraindications against hormone treatment should be treated with vigabatrin. If first-line drugs are ineffective, second-line treatment options such as ketogenic dietary therapies, sulthiame, topiramate, valproate, zonisamide, or benzodiazepines should be considered. Children refractory to drug therapy should be evaluated early for epilepsy surgery, especially if focal brain lesions are present. Parents should be informed about the disease, the efficacy and adverse effects of the medication, and support options for the family. Regular follow-up controls are recommended.

Infantile Idiopathic Intracranial Hypertension: A Case Study and Review of the Literature.

Idiopathic intracranial hypertension, or pseudotumor cerebri, is an increase in cerebrospinal fluid pressure of unknown etiology. It is mostly seen in adults, less frequently in adolescents, rarely in younger children. Only 5 infants meeting idiopathic intracranial hypertension criteria have been mentioned in the literature. We report a case of a previously healthy 9-month-old boy who presented with irritability, decreased appetite, and a bulging fontanelle. Computed tomography (CT) head imaging and cerebrospinal fluid studies revealed normal results. The patient's symptoms transiently resolved after the initial lumbar puncture, but 11 days later, his fontanelle bulged again. A second lumbar puncture revealed an elevated opening pressure of 35 cmH2O and led to a diagnosis of idiopathic intracranial hypertension in accordance with the modified Dandy Criteria. Treatment with acetazolamide at a dose of 25 mg/kg/d was initiated and the patient remained symptom-free for 6 weeks, followed by another relapse. His acetazolamide dose was increased to 37 mg/kg/d, with no further relapses to date. A diagnosis of idiopathic intracranial hypertension is challenging in infants, because the patients cannot yet verbalize typical idiopathic intracranial hypertension-related symptoms such as positional headaches, diplopia, or pulsatile tinnitus. Furthermore, it is more difficult to assess papilledema in that age group. If undetected and untreated, idiopathic intracranial hypertension may result in permanent visual deficits. Little is known about idiopathic intracranial hypertension in infants, and age-specific treatment guidelines are lacking. We discuss this rare case of infantile idiopathic intracranial hypertension and provide a review of the literature, including an overview of disease characteristics and outcomes of idiopathic intracranial hypertension in this very young age group.

Gadolinium Brain Deposition after Macrocyclic Gadolinium Administration: A Pediatric Case-Control Study.

Purpose To determine whether signal intensity (SI) in T1 sequences as a potential indicator of gadolinium deposition increases after repeated administration of the macrocyclic gadolinium-based contrast agents (GBCAs) gadoteridol and gadoterate meglumine in a pediatric cohort. Materials and Methods This retrospective case-control study of children with brain tumors who underwent nine or more contrast material-enhanced brain magnetic resonance (MR) imaging studies from 2008 to 2015 was approved by the local ethics board. Informed consent was obtained for MR imaging. Twenty-four case patients aged 5-18 years and appropriate control patients with nonpathologic MR neuroimaging findings (and no GBCA administration), matched for age and sex, were inculded. SI was measured on unenhanced T1-weighted MR images for the following five regions of interest (ROIs): the dentate nucleus (DN), pons, substantia nigra (SN), pulvinar thalami, and globus pallidus (GP). Paired t tests were used to compare SI and SI ratios (DN to pons, GP to thalamus) between case patients and control patients. Pearson correlations between relative signal changes and the number of GBCA administrations and total GBCA dose were calculated. Results The mean number of GBCA administrations was 14.2. No significant differences in mean SI for any ROI and no group differences were found when DN-to-pons and GP-to-pulvinar ratios were compared (DN-to-pons ratio in case patients: mean, 1.0083 ± 0.0373 [standard deviation]; DN-to-pons ratio in control patients: mean, 1.0183 ± 0.01917; P = .37; GP-to-pulvinar ratio in case patients: mean, 1.1335 ± 0.04528; and GP-to-pulvinar ratio in control patients: mean, 1.1141 ± 0.07058; P = .29). No correlation was found between the number of GBCA administrations or the total amount of GBCA administered and signal change for any ROI. (Number of GBCA applications: DN: r = -0.254, P = .31; pons: r = -0.097, P = .65; SN: r = -0.194, P = .38; GP: r = -0.175, P = .41; pulvinar: r = -0.067, P = .75; total amount of administered GBCA: DN: r = 0.091, P = .72; pons: r = 0.106, P = .62; SN: r = -0.165, P = .45; GP: r = 0.111, P = .61; pulvinar: r = 0.173, P = .42.) Conclusion Multiple intravenous administrations of these macrocyclic GBCAs in children were not associated with a measurable increase in SI in T1 sequences as an indicator of brain gadolinium deposition detectable by using MR imaging. Additional imaging and pathologic studies are needed to confirm these findings. © RSNA, 2017 Online supplemental material is available for this article.

Probable pseudotumor cerebri complex in 25 children. Further support of a concept.

BACKGROUND: Cerebrospinal fluid (CSF) opening pressure (OP) of ≥28 cm H2O is now considered a diagnostic criterion for Pseudotumor cerebri syndrome (PTCS) in children. However, it has been proposed that a diagnosis of "probable" PTCS can be made with an OP < 28 cm H2O if other diagnostic criteria are met. We report a group of children with probable PTCS. METHODS: Retrospective analysis of 25 children diagnosed with PTCS but with a CSF OP below 28 cm H2O. Eleven patients were identified during a nation-wide, prospective, active hospital-based surveillance, and additional 14 patients from our own institution. An extensive chart review of these cases was performed in order to identify signs and symptoms supportive of PTCS. RESULTS: Of these 25 patients 23 were treated with acetazolamide. Five children required escalation of medical treatment. Findings supportive of PTCS in the absence of an abnormal OP were: papilledema (n = 24), abducens nerve palsy (n = 7), without papilledema in one of them, headache (n = 15). Six patients had a relapse. A second lumbar puncture (LP) documented an opening pressure of >30 cm H2O in seven children. MRI findings supportive of PTCS were seen in eight patients. CONCLUSIONS: The diagnosis of probable PTCS as a subgroup of PTCS can be convincingly made in children with an OP < 28 cm H2O. Results of opening pressure measurement always need to be interpreted within the whole clinical context. Treatment decisions in patients with "probable" PTCS should follow the same stage-based principles as for "proven" PTCS.

Treatment of Infantile Spasms: Report of the Interdisciplinary Guideline Committee Coordinated by the German-Speaking Society for Neuropediatrics.

Objectives This report aims to define treatment goals, to summarize the evidence level (EL) of different treatment options for infantile spasms (IS), both in terms of efficacy and adverse effect, and to give recommendations for the management of IS. Methods The Cochrane and Medline (1966-July 2014) databases were searched. Literature known to the guideline working group and identified through citations was also considered. The results of previously published guidelines were taken into account in our analysis. Rating the level of evidence followed the Scottish Intercollegiate Guidelines Network. Recommendations If IS are suspected, electroencephalogram (EEG) should be performed within a few days and, if confirmed, treatment should be initiated immediately. Response to first-line treatments should be evaluated clinically and electroencephalographically after 14 days.Adrenocorticotropic hormone, corticosteroids, and vigabatrin are the first-line drugs for the treatment of IS. In children with tuberous sclerosis complex, vigabatrin is the treatment of first choice. Ketogenic diet, sulthiame, topiramate, valproate, zonisamide, and benzodiazepines can be used when first-line drugs have proved ineffective. Children refractory to drug therapy should be evaluated for epilepsy surgery, especially if focal brain lesions are present.Regular follow-up controls, including EEG (preferably sleep EEG) and standardized developmental assessment are recommended.

Severe Cerebral Vasospasm and Childhood Arterial Ischemic Stroke After Intrathecal Cytarabine.

We report on 2 patients who developed widespread cerebral vasospasm and arterial ischemic strokes (AIS) after application of intrathecal (IT) cytarabine. In a 3-year-old child with acute lymphoblastic leukemia (ALL), left leg weakness, hyperreflexia, and clonus were noted 4 days after her first dose of IT cytarabine during the induction phase of her chemotherapy. Cerebral MRI revealed multiple acute cerebral ischemic infarcts and widespread cerebral vasospasm. A 5-year-old girl complained of right arm and leg pain and began limping 11 days after IT cytarabine. Symptoms progressed to right dense hemiplegia, left gaze deviation, headache, and speech arrest. MRI revealed 2 large cortical areas of diffusion restriction in the right frontal and left parietal lobes. Cerebral magnetic resonance angiography (MRA) showed irregular narrowing affecting much of the intracranial arterial circulation. Although the first child fully recovered from her neurologic symptoms, the second patient had persistent hemiplegia on follow-up. Including this report, there are now 4 pediatric ALL cases of severe cerebral vasospasm and AIS in the context of IT cytarabine administration, strongly suggesting a true association. Differential diagnosis and management issues are discussed. Along with the more widespread use of MRI and MRA, the true frequency of this severe adverse effect will become clearer in future. For any child with neurologic symptoms within hours or days of receiving IT cytarabine, a low threshold for cerebral imaging with MRI and MRA is recommended.

Presumed Arterial Gas Embolism After Breath-Hold Diving in Shallow Water.

Dive-related injuries are relatively common, but almost exclusively occur in recreational or scuba diving. We report 2 children with acute central nervous system complications after breath-hold diving. A 12-year-old boy presented with unilateral leg weakness and paresthesia after diving beneath the water surface for a distance of ∼25 m. After ascent, he suddenly felt extreme thoracic pain that resolved spontaneously. Neurologic examination revealed right leg weakness and sensory deficits with a sensory level at T5. Spinal MRI revealed a nonenhancing T2-hyperintense lesion in the central cord at the level of T1/T2 suggesting a spinal cord edema. A few weeks later, a 13-year-old girl was admitted with acute dizziness, personality changes, confusion, and headache. Thirty minutes before, she had practiced diving beneath the water surface for a distance of ∼25 m. After stepping out, she felt sudden severe thoracic pain and lost consciousness. Shortly later she reported headache and vertigo, and numbness of the complete left side of her body. Neurologic examination revealed reduced sensibility to all modalities, a positive Romberg test, and vertigo. Cerebral MRI revealed no pathologic findings. Both children experienced a strikingly similar clinical course. The chronology of events strongly suggests that both patients were suffering from arterial gas embolism. This condition has been reported for the first time to occur in children after breath-hold diving beneath the water surface without glossopharyngeal insufflation.

Delineation and diagnostic criteria of Oral-Facial-Digital Syndrome type VI.

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.

Clinical spectrum of the pseudotumor cerebri complex in children.

PURPOSE: Our aim was to improve diagnosis and management of pseudotumor cerebri (PTC; also known as idiopathic intracranial hypertension) in children. METHODS: We performed a comprehensive analysis of epidemiology, diagnostic work-up, therapy, and clinical follow-up in 53 consecutive patients. RESULTS: We identified several important aspects to be considered in the management of these children. First, patients may present without obvious symptoms at diagnosis. Second, bilateral papilledema might not or not yet be present in symptomatic patients. Third, measurement of cerebrospinal fluid (CSF) opening pressure may not always be reliable due to drugs used for sedation, which may alter intracranial pressure. Fourth, normal CSF pressure values in childhood are not well established and diagnosis might even be justified if pressure is <20 cm H(2)O. Fifth, associated conditions are frequent (at least in our cohort); however, in most cases, a causative link cannot be proven. Finally, disease relapse is a serious problem (20% in our group), which stresses the importance of standardized follow-up programs. CONCLUSIONS: PTC constitutes an important and possibly underrecognized disorder in children and adolescents. Considering the high percentage of possibly associated conditions in our study, a detailed diagnostic work-up is crucial to identify treatable underlying conditions.