An Exploratory Analysis of Physical Examination Subtypes in Pediatric Athletes With Concussion.

OBJECTIVE: Pediatric athletes with concussion present with a variety of impairments on clinical assessment and require individualized treatment. The Buffalo Concussion Physical Examination is a brief, pertinent clinical assessment for individuals with concussion. The purpose of this study was to identify physical examination subtypes in pediatric athletes with concussion within 2 weeks of injury that are relevant to diagnosis and treatment. DESIGN: Secondary analysis of a published cohort study and clinician consensus. SETTING: Three university-affiliated sports medicine centers. PARTICIPANTS: Two hundred seventy children (14.9 ± 1.9 years). INDEPENDENT VARIABLES: Orthostatic intolerance, horizontal and vertical saccades, smooth pursuits, vestibulo-ocular reflex, near-point convergence, complex tandem gait, neck range of motion, neck tenderness, and neck spasm. MAIN OUTCOME MEASURES: Correlations between independent variables were calculated, and network graphs were made. k-means and hierarchical clustering were used to identify clusters of impairments. Optimal number of clusters was assessed. Results were reviewed by experienced clinicians and consensus was reached on proposed subtypes. RESULTS: Physical examination clusters overlapped with each other, and no optimal number of clusters was identified. Clinician consensus suggested 3 possible subtypes: (1) visio-vestibular (horizontal and vertical saccades, smooth pursuits, and vestibulo-ocular reflex), (2) cervicogenic (neck range of motion and spasm), and (3) autonomic/balance (orthostatic intolerance and complex tandem gait). CONCLUSIONS: Although we identified 3 physical examination subtypes, it seemed that physical examination findings alone are not enough to define subtypes that are both statistically supported and clinically relevant, likely because they do not include symptoms, assessment of mood or cognitive problems, or graded exertion testing.

A Review of the Multi-Systemic Complications of a Ketogenic Diet in Children and Infants with Epilepsy.

Ketogenic diets (KDs) are highly effective in the treatment of epilepsy. However, numerous complications have been reported. During the initiation phase of the diet, common side effects include vomiting, hypoglycemia, metabolic acidosis and refusal of the diet. While on the diet, the side effects involve the following systems: gastrointestinal, hepatic, cardiovascular, renal, dermatological, hematologic and bone. Many of the common side effects can be tackled easily with careful monitoring including blood counts, liver enzymes, renal function tests, urinalysis, vitamin levels, mineral levels, lipid profiles, and serum carnitine levels. Some rare and serious side effects reported in the literature include pancreatitis, protein-losing enteropathy, prolonged QT interval, cardiomyopathy and changes in the basal ganglia. These serious complications may need more advanced work-up and immediate cessation of the diet. With appropriate monitoring and close follow-up to minimize adverse effects, KDs can be effective for patients with intractable epilepsy.

Newborn Screening for Spinal Muscular Atrophy in New York State: Clinical Outcomes From the First 3 Years.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, largely on the basis of the availability and efficacy of newly-approved disease modifying therapies. New York State (NYS) started universal newborn screening for SMA in October 2018. The authors report the findings from the first 3 years of screening. METHODS: Statewide neonatal screening was conducted using DNA extracted from dried blood spots using a real-time quantitative polymerase chain reaction (qPCR) assay. Retrospective follow-up data were collected from 9 referral centers across the state on 34 infants. RESULTS: In the first three years since statewide implementation, nearly 650,000 infants have been screened for SMA. 34 babies screened positive and were referred to a neuromuscular specialty care center. The incidence remains lower than previously predicted. The majority (94%), including all infants with 2-3 copies of SMN2, have received treatment. Among treated infants, the overwhelming majority (97%; 29/30) have received gene replacement. All infants in this cohort with 3 copies of SMN2 are clinically asymptomatic post-treatment based on early clinical follow-up data. Infants with 2 copies of SMN2 are more variable in their outcomes. Electrodiagnostic outcomes data from a subgroup of patients (n=11) for whom pre- and post-treatment data demonstrated either improvement or no change in CMAP amplitude at last clinical follow-up compared to pre-treatment baseline. Most infants were treated before 6 weeks of age (median = 34.5 DOL; range 11-180). Delays and barriers to treatment identified by treating clinicians followed two broad themes: medical and non-medical. Medical delays most commonly reported were presence of AAV9 antibodies and elevated troponin I levels. Non-medical barriers included delays in obtaining insurance as well as insurance policies regarding specific treatment modalities. DISCUSSION: The findings from the NYS cohort of newborn screen-identified infants are consistent with other reports of improved outcomes from early diagnosis and treatment. Additional biomarkers of motor neuron health including electromyography can potentially be helpful in detecting pre-clinical decline.

Macroglossia Associated With Clobazam Administration: A Case Report and Literature Review.

Clobazam is a benzodiazepine derivative used as an antiepileptic agent for the treatment of focal and generalized seizures and drug-resistant epilepsy associated with Lennox-Gastaut Syndrome. While somnolence and mood-related side effects are commonly observed, acute macroglossia following initiation of Clobazam therapy has not been previously reported in the medical literature. In this case report, we present a female pediatric patient who developed significant tongue swelling with protrusion beyond the oral cavity after initiation of Clobazam for treatment-resistant epilepsy. Symptoms were unresponsive to antihistamines and steroids but resolved gradually in the days following discontinuation of Clobazam with no lingering sequelae.

Levetiracetam-induced aggression and acute behavioral changes: A case report and literature review.

Levetiracetam is a second-generation antiepileptic medication used to treat a wide range of partial and generalized seizure disorders. While Levetiracetam is generally well-tolerated, mild mood-related side effects (e.g., anxiety, agitation, and depression) have been observed in a minority of patients in the days following initiation of therapy or changes in dosing. The development of acute aggression requiring termination of Levetiracetam therapy has been rarely reported in the medical literature but poses a limiting effect on treatment options for refractory epilepsy in pediatric patients. In this report, we present a teenage male patient with a history of seizure disorder who developed sudden, severe behavioral abnormalities and aggression following increases in his Levetiracetam dosing. His symptoms resolved rapidly after return of his medication dosing to baseline, with no further sequelae noted. Our observations suggest that Levetiracetam remains a safe and effective first-line antiepileptic whose adverse behavioral side effect profile can be properly managed with close patient monitoring and dose titration.

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment.

Pediatric-onset multiple sclerosis (POMS) is a rare neuroinflammatory and neurodegenerative disease that has a significant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good specificity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions significantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been significantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (fingolimod and teriflunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-ß and glatiramer acetate) are also commonly used and result in a significant reduction in inflammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efficacy therapies such as dimethyl fumarate and high-efficacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efficacy DMTs generally provide additional reduction in inflammatory activity when compared with the first-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efficacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials.

Imaging Predictors of Neurologic Outcome After Pediatric Arterial Ischemic Stroke.

BACKGROUND AND PURPOSE: To assess whether initial imaging characteristics independently predict 1-year neurological outcomes in childhood arterial ischemic stroke patients. METHODS: We used prospectively collected demographic and clinical data, imaging data, and 1-year outcomes from the VIPS study (Vascular Effects of Infection in Pediatric Stroke). In 288 patients with first-time stroke, we measured infarct volume and location on the acute magnetic resonance imaging studies and hemorrhagic transformation on brain imaging studies during the acute presentation. Neurological outcome was assessed with the Pediatric Stroke Outcome Measure. We used univariate and multivariable ordinal logistic regression models to test the association between imaging characteristics and outcome. RESULTS: Univariate analysis demonstrated that infarcts involving uncinate fasciculus, angular gyrus, insular cortex, or that extended from cortex to the subcortical nuclei were significantly associated with poorer outcomes with odds ratios ranging from 1.95 to 3.95. All locations except the insular cortex remained significant predictors of poor outcome on multivariable analysis. When infarct volume was added to the model, the locations did not remain significant. Larger infarct volumes and younger age at stroke onset were significantly associated with poorer outcome, but the strength of the relationships was weak. Hemorrhagic transformation did not predict outcome. CONCLUSIONS: In the largest pediatric arterial ischemic stroke cohort collected to date, we showed that larger infarct volume and younger age at stroke were associated with poorer outcomes. We made the novel observation that the strength of these associations was modest and limits the ability to use these characteristics to predict outcome in children. Infarcts affecting specific locations were significantly associated with poorer outcomes in univariate and multivariable analyses but lost significance when adjusted for infarct volume. Our findings suggest that infarcts that disrupt critical networks have a disproportionate impact upon outcome after childhood arterial ischemic stroke.

Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy.

PURPOSE: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018. METHODS: Screening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion. RESULTS: During the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy. CONCLUSION: Newborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.

Evaluation of the Effects of Clobazam on Seizure Control and Quality of Life in Children With Lennox-Gastaut Syndrome: A Pilot Study.

PURPOSE: This is a prospective study of children with Lennox-Gastaut syndrome receiving clobazam as adjunctive therapy. This pilot study aims to examine medication effectiveness as it relates to seizure reduction, as well as improvement in parent-reported behavior and quality of life (QOL). METHODS: Ten patients with Lennox-Gastaut syndrome aged 3-11 years were enrolled in this 6-week, 4 phase study. Seizure frequency, QOL, and Aberrant Behavior Checklist questionnaires were evaluated at 0, 2, 6, and 10 weeks during the study. RESULTS: Patients showed improvement on indices of QOL, including physical activities (62.5%), well-being (37.5%), cognition (87.5%), social activities (37.5%), behavior (87.5%), general health (50%), and overall QOL (87.5%). The Quality of Life in Childhood Epilepsy (QOLCE) questionnaire revealed significant improvement in cognition (P = .008), social activities (P = .049), behavior (P = .038), and overall QOL (P = .018). The Aberrant Behavior Checklist exhibited a trend toward improvement in hyperactivity. CONCLUSION: There was improvement in all patients with documented baseline seizures (8/10), with 5 showing significant improvement (95%-100% reduction) and 3 showing minor improvement (7%-23% reduction). Statistically significant improvement in areas of cognition, social activities, behavior, and overall QOL were seen. An overall trend toward a positive well-being was seen in our patients with clobazam, as adjunct therapy for Lennox-Gastaut syndrome in children.

Alice in Wonderland Syndrome: A Historical and Medical Review.

Alice in Wonderland syndrome is a disorienting neurological condition that affects human perception to the senses of vision, hearing, touch, sensation, and the phenomenon of time. Individuals affected with Alice in Wonderland syndrome can experience alterations in their perception of the size of objects or their own body parts, known as metamorphopsias. It is known to occur in conditions including migraine, epilepsy, and certain intoxicants and infectious diseases. The name refers to Lewis Carrol's well-known children's book Alice's Adventures in Wonderland, in which the title character experiences alterations of sensation in which she felt that her body had grown too tall or too small, or parts of her body were changing shape, size, or relationship to the rest of her body. The syndrome was described in 1952 by Caro Lippman, and given its name in 1955 by John Todd. The metamorphopsias characteristic of this condition are also sometimes referred to as Lilliputian hallucinations, a reference to the fictional island of Lilliput in the novel Gulliver's Travels, written by Jonathan Swift in 1726. As such, many literary and medical publications have roots in the description of this syndrome. The purpose of this review is to summarize the literary and historical significance of Alice in Wonderland syndrome, as well as to provide the reader with a medical overview of the condition.

Ketogenic diet: Predictors of seizure control.

BACKGROUND: The ketogenic diet is an effective non-pharmacologic treatment for medically resistant epilepsy. The aim of this study was to identify any predictors that may influence the response of ketogenic diet. METHODS: A retrospective chart review for all patients with medically resistant epilepsy was performed at a tertiary care epilepsy center from 1996 to 2012. Patient- and diet-related variables were evaluated with respect to seizure reduction at 1, 3, 6, 9 and 12-month intervals and divided into four possible outcome classes. RESULTS: Sixty-three patients met inclusion. Thirty-seven (59%) reported >50% seizure reduction at 3 months with 44% and 37% patients benefiting at 6-month and 12-month follow up, respectively. A trend toward significant seizure improvement was noted in 48% patients with seizure onset >1 year at 12-month (p = 0.09) interval and in 62% patients with >10 seizure/day at 6-month interval (p = 0.054). An ordinal logistic regression showed later age of seizure to have higher odds of favorable response at 1-month (p = 0.005) and 3-month (p = 0.013) follow up. Patients with non-fasting diet induction were more likely to have a favorable outcome at 6 months (p = 0.008) as do females (p = 0.037) and those treated with higher fat ratio diet (p = 0.034). CONCLUSION: Our study reports the effectiveness of ketogenic diet in children with medically resistant epilepsy. Later age of seizure onset, female gender, higher ketogenic diet ratio and non-fasting induction were associated with better odds of improved seizure outcome. A larger cohort is required to confirm these findings.

Optimal Duration of Continuous Video-Electroencephalography in Term Infants With Hypoxic-Ischemic Encephalopathy and Therapeutic Hypothermia.

Continuous video-electroencephalography (EEG) is an important diagnostic and prognostic tool in newborns with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia. The optimal duration of continuous video-EEG during whole-body hypothermia is not known. We conducted a retrospective study of 35 neonates with hypoxic-ischemic encephalopathy undergoing whole-body hypothermia with continuous video-EEG. EEG ictal changes were detected in 9/35 infants (26%). Of these 9 infants, the seizures were initially observed within 30 minutes of EEG monitoring in 6 (67%), within 24 hours in 2 (22%), and during rewarming in 1 infant (11%). No new seizures were detected between 24-72 hours of therapeutic hypothermia. Background suppression was detected in 14 infants (40%) by 24 hours. In neonates with hypoxic-ischemic encephalopathy undergoing therapeutic hypothermia, continuous video-EEG has the highest diagnostic yield within the first 24 hours and during the rewarming phase. In the absence of prior seizures or antiepileptic therapy, limiting continuous video-EEG to these periods in resource-limited settings may reduce cost during therapeutic hypothermia.

Long-Term Neurocognitive, Psychosocial, and Magnetic Resonance Imaging Outcomes in Pediatric-Onset Acute Disseminated Encephalomyelitis.

BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder that is usually self-limited. Recent studies have suggested ongoing neurological deficits and neurocognitive impairment in these patients. Little information on the correlation of clinical and neuroimaging markers in ADEM is available. We examined potential clinical factors (e.g., age of onset, acute symptom duration, magnetic resonance imaging [MRI] lesions) and their relation to neurocognitive and psychosocial outcomes. METHODS: This is a retrospective chart review of consecutive pediatric patients diagnosed with ADEM between 2006 and 2012. Patients were evaluated with standard neurological assessment, MRI of the brain, and neuropsychological evaluation. RESULTS: Twenty-three patients with ADEM with average age at neuropsychological assessment of 10.1 years (±3.50) were included. Five (22.7%) patients were impaired on three or more neurocognitive measures. Psychosocial problems were reported in 20%-40% of patients. Earlier age of onset was correlated with poorer sustained attention and psychosocial problems, whereas acute symptom duration and Expanded Disability Status Scale were not. MRI outcomes were correlated with psychosocial outcomes but not neuropsychological findings. CONCLUSIONS: Our findings suggest lingering cognitive and psychosocial deficits in children with a history of ADEM. Clinical features and MRI findings correlated more strongly with psychosocial outcomes than cognitive functioning. Further studies are needed to confirm relationships and other possible contributing factors to lingering deficits.

Cerebral paragonimiasis: an unusual manifestation of a rare parasitic infection.

BACKGROUND: Paragonimiasis is a parasitic disease that typically produces a subacute to chronic inflammatory disease of the lung. Although rare in the United States, paragonimiasis is sporadically observed in the immigrant population. Rarely, paragonimiasis can affect the nervous system. This infection is even more unusual in the pediatric population, and therefore can be challenging to diagnose. PATIENTS: Here we present a child with cerebral paragonimiasis. She presented with new onset seizures in the setting of a febrile illness. Magnetic resonance imaging of the brain with contrast revealed a ring-enhancing lesion within the right frontal lobe and a second lesion in the left parietal lobe extending from the cortex to the centrum semiovale. Extensive evaluation including stool ova and parasite analysis confirmed the diagnosis of Paragonimus westermani. She was treated with praziquantel and prednisone and improved both clinically and radiographically. CONCLUSIONS: Cerebral paragonimiasis is diagnosable and treatable and therefore is important to consider in the differential of immigrants presenting with cavitary lung lesions and central nervous system findings.

MRI segmentation analysis in temporal lobe and idiopathic generalized epilepsy.

BACKGROUND: Temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE) patients have each been associated with extensive brain atrophy findings, yet to date there are no reports of head to head comparison of both patient groups. Our aim was to assess and compare between tissue-specific and structural brain atrophy findings in TLE to IGE patients and to healthy controls (HC). METHODS: TLE patients were classified in TLE lesional (L-TLE) or non-lesional (NL-TLE) based on presence or absence of MRI temporal structural abnormalities. High resolution 3 T MRI with automated segmentation by SIENAX and FIRST tools were performed in a group of patients with temporal lobe epilepsy (11 L-TLE and 15 NL-TLE) and in15 IGE as well as in 26 HC. Normal brain volume (NBV), normal grey matter volume (NGMV), normal white matter volume (NWMV), and volumes of subcortical deep grey matter structures were quantified. Using regression analyses, differences between the groups in both volume and left/right asymmetry were evaluated. Additionally, laterality of results was also evaluated to separately quantify ipsilateral and contralateral effects in the TLE group. RESULTS: All epilepsy groups had significantly lower NBV and NWMV compared to HC (p < 0.001). L-TLE had lower hippocampal volume than HC and IGE (p = 0.001), and all epilepsy groups had significantly lower amygdala volume than HC (p < = 0.004). In L-TLE, there was evidence of atrophy in both ipsilateral and contralateral structures. CONCLUSIONS: Our study revealed that TLE and IGE patients demonstrated similar overall tissue-specific brain atrophy, although specific structures differences were appreciated. L-TLE also appeared to behave differently than NL-TLE, with atrophy not limited to the ipsilateral side.