Summary The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have ...been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.
To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS.
Multicenter retrospective study.
A total of 144 children and adolescents (median age 8 ...years, range 0.7-17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years range 0.1-8.5). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later.
While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality.
This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections.
Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage ...with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes.
Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion.
This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center's experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.
We have previously demonstrated that pediatric‐onset multiple sclerosis (POMS) negatively impacts the visual pathway as well as motor processing speed. Relationships between MS‐related diffuse ...structural damage of gray and white matter (WM) tissue and cortical responses to visual and motor stimuli remain poorly understood. We used magnetoencephalography in 14 POMS patients and 15 age‐ and sex‐matched healthy controls to assess visual gamma (30–80 Hz), motor gamma (60–90 Hz), and motor beta (15–30 Hz) cortical oscillatory responses to a visual‐motor task. Then, 3T MRI was used to: (a) calculate fractional anisotropy (FA) of the posterior visual and corticospinal motor WM pathways and (b) quantify volume and thickness of the cuneus and primary motor cortex. Visual gamma band power was reduced in POMS and was associated with reduced FA of the optic radiations but not with loss of cuneus volume or thickness. Activity in the primary motor cortex, as measured by postmovement beta rebound amplitude associated with peak latency, was decreased in POMS, although this reduction was not predicted by structural metrics. Our findings implicate loss of WM integrity as a contributor to reduced electrical responses in the visual cortex in POMS. Future work in larger cohorts will inform on the cognitive implications of this finding in terms of visual processing function and will determine whether the progressive loss of brain volume known to occur in POMS ultimately contributes to both progressive dysfunction in such tasks as well as progressive reduction in cortical electrical responses in the visual cortex.
We used magnetoencephalography in 14 pediatric‐onset multiple sclerosis (POMS) patients and 15 age‐ and sex‐matched healthy controls to assess visual gamma (30–80 Hz), motor gamma (60–90 Hz), and motor beta (15–30 Hz) cortical oscillatory responses to a visual‐motor task. 3T MRI was used to: (a) calculate fractional anisotropy (FA) of the posterior visual and corticospinal motor WM pathways and (b) quantify volume and thickness of the cuneus and primary motor cortex. Visual gamma band power was reduced in POMS and was associated with reduced FA of the optic radiations but not with loss of cuneus volume or thickness.
Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The ...objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients.
Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials.
Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm
) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm
, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm
; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients.
Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.
Background:
Pediatric acquired demyelinating syndromes (ADSs) are monophasic (mono-ADS) in 70% of cases and represent the first attack of multiple sclerosis (MS) in 30%. Secondhand tobacco smoke ...(SHS) exposure has been implicated as a risk factor for adult-onset MS. Little is known about whether SHS presents an additive risk beyond genetic factors and other environmental exposures associated with pediatric MS.
Methods:
This study examined SHS exposure in 216 children with mono-ADS and 81 children with MS. Interactions between SHS, HLA-DRB1*15 alleles, serum 25-hydroxyvitamin D concentrations, and serological evidence of remote Epstein–Barr virus (EBV) exposure were evaluated.
Results:
SHS exposure was more common in children with MS (37% exposed) compared to mono-ADS (29.5% exposed). Compared to mono-ADS, SHS exposure was not an independent risk factor for MS. When both SHS exposure and HLA-DRB1*15 were present, the odds for MS increased (odds ratio (OR) = 3.7; 95% confidence interval (CI): 1.17–11.9) compared to mono-ADS. Interactions between SHS and vitamin D or EBV did not associate with MS.
Conclusion:
Exposure to SHS is a risk factor for central nervous system (CNS) demyelination. Results suggest that SHS exposure and HLA-DRB1*15 interact to increase risk for MS in children diagnosed with mono-ADS.
Objective: To determine the ages at acquisition of developmental milestones, loss of motor function, and clinical symptoms in Alexander disease. Methods: Patients with confirmed cerebral Alexander ...disease were included. Data abstraction of developmental and disease-specific milestones was performed from medical records, physical exams, and questionnaires. Mixed effects logistic regression was used to determine if key clinical features were associated with milestone achievement, controlling for patient age. Results: 51 patients with cerebral/infantile Alexander disease were evaluated at a mean age of 10.96 years (range 2.29-31.08 years). Developmental milestones in Alexander disease were often achieved but delayed. Ambulation was achieved in 44 subjects (86%); 34 (67%) subjects walked independently (mean age 1.9 years, range 0.91-3.25 years) and an additional 10 (20%) subjects walked with assistance (mean age 3.9 years, range 1.8-8 years) but did not progress to independent ambulation. Developmental delay was the earliest and most prevalent symptom (N = 48 94%, mean age 0.58 years), compared to an initial seizure (N = 41 80%, mean age 2.80 years), and macrocephaly (N = 28 55%, mean age 4.04 years), P < .0001 between these ages of onset. Loss of independent ambulation occurred in 11 of the 34 (32%) children who had acquired ambulation (range 3.41-15.10 years). Presence of seizures or macrocephaly did not predict the achievement or loss of ambulation. Conclusions: The clinical triad of developmental delay, seizures, and macrocephaly are not universally present in cerebral Alexander disease. Clinicians should have a high index of suspicion for Alexander disease in patients with mild delays and a first seizure.
Few diseases blur the margins between their childhood and adult-onset varieties as much as optic neuritis. This report will review our state of knowledge of pediatric optic neuritis, as well as its ...relationship to the latest consensus definitions of neuroinflammatory disease. Current diagnostic and treatment options will be explored, as well as our potential to uncover an understanding of pediatric optic neuritis through systematic prospective studies. The risk of evolving multiple sclerosis is probably less than in adults, but pediatric optic neuritis is more likely to be an initial manifestation of acute disseminated encephalomyelitis. Steroids may hasten visual recovery, but they do not change visual outcome except in cases because of neuromyelitis optica. The role of puberty in modifying the presentation and risk associations is unknown. Prospective studies are required to resolve these diagnostic and management issues.
Optic neuritis (ON) in children is uncommon. There are limited prospective data for visual acuity (VA) outcomes, associated diseases, and neuroimaging findings. Prospective data from a large sample ...would be useful for counseling families on treatment decisions and prognosis.
To prospectively study children with a first episode of ON, describe VA after 6 months, and ascertain the network's (Pediatric Eye Disease Investigator Group and Neuro-Ophthalmology Research Disease Investigator Consortium) ability to enroll pediatric patients with ON prospectively.
This nonrandomized cohort study was conducted from September 20, 2016, to July 20, 2018, at 23 sites in the United States and Canada in pediatric ophthalmology or neuro-ophthalmology clinics. A total of 44 children (aged 3-15 years) presented with a first episode of ON (visual loss, pain on eye movements, or both) within 2 weeks of symptom onset and at least 1 of the following in the affected eye: a distance high-contrast VA (HCVA) deficit of at least 0.2 logMAR below age-based norms, diminished color vision, abnormal visual field, or optic disc swelling. Exclusion criteria included preexisting ocular abnormalities or a previous episode of ON.
Primary outcomes were monocular HCVA and low-contrast VA at 6 months. Secondary outcomes were neuroimaging, associated diagnoses, and antibodies for neuromyelitis optica and myelin oligodendrocyte glycoprotein.
A total of 44 children (mean age SD, 10.2 3.5 years; 26 boys 59%; 23 White individuals 52%; 54 eyes) were enrolled in the study. Sixteen patients (36%) had bilateral ON. Magnetic resonance imaging revealed white matter lesions in 23 children (52%). Of these children, 8 had myelin oligodendrocyte glycoprotein-associated demyelination (18%), 7 had acute disseminated encephalomyelitis (16%), 5 had multiple sclerosis (11%), and 3 had neuromyelitis optica (7%). The baseline mean HCVA was 0.95 logMAR (20/200), which improved by a mean 0.76 logMAR (95% CI, 0.54-0.99; range, -0.70 to 1.80) to 0.12 logMAR (20/25) at 6 months. The baseline mean distance low-contrast VA was 1.49 logMAR (20/640) and improved by a mean 0.72 logMAR (95% CI, 0.54-0.89; range, -0.20 to 1.50) to 0.73 logMAR (20/100) at 6 months. Baseline HCVA was worse in younger participants (aged <10 years) with associated neurologic autoimmune diagnoses, white matter lesions, and in those of non-White race and non-Hispanic ethnicity. The data did not suggest a statistically significant association between baseline factors and improvement in HCVA.
The study network did not reach its targeted enrollment of 100 pediatric patients with ON over 2 years. This indicates that future treatment trials may need to use different inclusion criteria or plan a longer enrollment period to account for the rarity of the disease. Despite poor VA at presentation, most children had marked improvement by 6 months. Associated neurologic autoimmune diagnoses were common. These findings can be used to counsel families about the disease.
For nearly two centuries, the ophthalmoscope has permitted examination of the retina and optic nerve-the only axons directly visualized by the physician. The retinal ganglion cells project their ...axons, which travel along the innermost retina to form the optic nerve, marking the beginning of the anterior visual pathway. Both the structure and function of the visual pathway are essential components of the neurologic examination as it can be involved in numerous acquired, congenital and genetic central nervous system conditions. The development of optical coherence tomography now permits the pediatric neuroscientist to visualize and quantify the optic nerve and retinal layers with unprecedented resolution. As optical coherence tomography becomes more accessible and integrated into research and clinical care, the pediatric neuroscientist may have the opportunity to utilize and/or interpret results from this device. This review describes the basic technical features of optical coherence tomography and highlights its potential clinical and research applications in pediatric clinical neuroscience including optic nerve swelling, optic neuritis, tumors of the visual pathway, vigabatrin toxicity, nystagmus, and neurodegenerative conditions.
PDF
