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Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.

Background Colony-stimulating factor-1 receptor (CSF1R)-related leukoencephalopathy is a rapidly progressive neurodegenerative disease for which there is currently no cure. Hematopoietic stem cell transplantation (HSCT) has been proposed as a disease-modifying treatment. Objective The objective of this study was to determine the effect of HSCT on disease progression. Methods We collected all available clinical data from a cohort of 7 patients with CSF1R-related leukoencephalopathy who underwent HSCT at our institutions. Clinical data included detailed neurological examination by a board-certified neurologist, serial cognitive screens, formal neuropsychological evaluations, and serial brain magnetic resonance imaging (MRI). Results Our patients had an average disease duration of 27.6 months at the time of transplant, and we have 87 months of total posttransplant follow-up time (median, 11; range, 2-27). One patient died in the periprocedural period. The remaining patients showed a variable response to treatment, with 6 of 7 patients trending toward stabilization on motor examination, cognitive scores, and/or MRI abnormalities, especially with white matter lesion burden. Conclusions This is the largest series of patients with CSF1R-related leukoencephalopathy receiving HSCT. We conclude that HSCT can stabilize the disease in some patients. Variability in patient responsiveness suggests that measures of disease heterogeneity and severity need to be considered when evaluating a patient's candidacy for transplant. HSCT appears to be the first disease-modifying therapy for CSF1R-related leukoencephalopathy. This milestone may serve as a foothold toward better understanding the disease's pathomechanism, thus providing new opportunities for better disease-specific therapies. © 2021 International Parkinson and Movement Disorder Society.

ObjectiveTo quantify benchmark treatment outcomes that may be enabled by newborn screening surveillance for X-linked adrenoleukodystrophy (ALD), we report neurocognitive, neuropsychiatric, and MRI change for boys who underwent hematopoietic stem cell transplant (HSCT) at initial stages of demyelination, prior to neurocognitive signs of disease.MethodsRetrospective chart review identified 36 patients whose cerebral ALD was detected and treated early, with lesion severity less than 5 on the ALD-specific MRI scoring system. Median age at transplant was 7.3 years (range, 4.0–16.1). Progression of radiologic disease on MRI in the 2 years following HSCT was examined relative to the severity of the initial lesion for 33 patients, and longitudinal neurocognitive and neuropsychiatric outcomes were studied for 30 patients.ResultsPatients whose pretransplant lesion extended beyond the splenium of the corpus callosum and adjacent periventricular white matter (MRI severity score >2) demonstrated lower posttransplant neurocognitive scores, more neuropsychiatric symptoms, and more disease progression on MRI than patients with a less severe lesion. Changes from baseline neurocognitive functioning were greater at 2 years posttransplant as compared to 1 year. There was greater variance and risk of lesion progression as pretransplant MRI severity increased.ConclusionTo realize the full benefits of newborn screening, clinicians must detect very small demyelinating lesions during surveillance and intervene quickly. Novel interventions that reduce risks inherent in allogeneic transplantation are needed. Trial endpoints should include direct neurocognitive assessment and extend at least 2 years posttreatment to provide the greatest sensitivity to detect neurocognitive morbidity.

Dysregulation of RAS or its major effector pathway is the molecular mechanism of RASopathies, a group of multisystemic congenital disorders. Neurologic complications are especially challenging in the management of the rare RASopathy cardiofaciocutaneous (CFC) syndrome. This study evaluated clinical neurologic and neurodevelopmental features and their associations with CFC syndrome gene variants.A multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained.The overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity.Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.

In the most common variant of childhood cerebral adrenoleukodystrophy (cALD), demyelinating brain lesions are distributed predominately in parieto-occipital white matter. Less frequently, lesions first develop in frontal white matter. This matched cohort study examined whether outcomes after standard treatment with hematopoietic cell transplantation (HCT) differ in patients with early stage frontal lesions as compared to parieto-occipital lesions. Retrospective chart review identified seven pediatric patients with frontal cALD lesions and MRI severity score

Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked ABCD1 gene, resulting in the inability to transport acylated very long chain fatty acids (VLCFAs) into the peroxisome for degradation. VLCFAs subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe progressive demyelinating form of ALD, cerebral ALD, resulting in regions of demyelination observed on brain magnetic resonance imaging that are associated with a “garland ring” of gadolinium contrast enhancement. Gadolinium enhancement indicates blood-brain barrier (BBB) disruption and an active inflammatory disease process. Only hematopoietic cell transplant (HCT) has been shown to halt neurologic progression, although the mechanism of disease arrest is unknown. We evaluated imaging- and transplant-related biomarkers in 66 males who underwent HCT. In 77% of patients, gadolinium contrast resolved by 60 days post-HCT. We determined that time to neutrophil recovery and extent of donor chimerism correlated significantly with time to contrast resolution post-HCT. Graft failure was associated with a significantly slower rate of contrast resolution (P < .0001). Time to neutrophil recovery remained significant in multivariate analysis with other biomarkers (P = .03). Our data suggest that robust donor myeloid recovery is necessary for timely repair of the BBB.

Transcranial direct current stimulation (tDCS) involves the application of weak electric current to the scalp. tDCS may influence brain functioning through effects on cortical excitability, neural plasticity, and learning. Evidence in adults suggests promising therapeutic applications for depression, and the adverse effect profile is generally mild. Early research indicates complex interactions between tDCS and concurrent cognitive and motor tasks. Further investigation is warranted to understand how tDCS impacts processes relevant to psychiatric conditions.

Patient: Female, 7-year-old Final Diagnosis: Stroke Symptoms: Aphasia Medication:— Clinical Procedure: — Specialty: Neurology Objective: Rare disease Background: Ischemic stroke can have a tremendously negative impact on the fitness and well-being of a child. Because endovascular interventions may be of benefit in the adult stroke population, many investigators have recently evaluated the safety and benefits of pharmacological and non-pharmacological options in the pediatric stroke population and compared pediatric patients to their adult counterparts. Some of these trials have had promising results, showing the positive effects of endovascular treatment in children with arterial acute ischemic stroke due to large-vessel occlusion (LVO). The 2015 American Heart Association/American Stroke Association guidelines suggest that mechanical thrombectomy with stent retrievers may be a consideration in some patients who are younger than 18 years and have severe LVO, when treatment (groin puncture) is initiated within 6 h of symptom onset. However, the method remains under-studied in this age group. Case Report: A 7-year-old girl presented with migraine-like headache, right arm and facial weakness, and expressive aphasia 9.5 h after symptom onset. Her PEDS-NIH stroke scale score was 4. Upon further investigations, she was found to have a left middle cerebral artery cryptogenic stroke with a distal left M1 clot, which was successfully treated with mechanical thrombectomy. Huge improvement was noticed during her subsequent physical examination. Conclusions: Endovascular therapy offers an exciting treatment option for the management of pediatric stroke. The extent of safety of mechanical thrombectomy among children who present with large-vessel occlusion over an extended time window remains unknown and warrants further investigations.

Objective Focal cortical dysplasia (FCD) is a common pathology in focal drug resistant epilepsy (DRE). Voxel based morphometric MRI analysis has been proposed as an adjunct to visual detection of FCD, which remains challenging given the subtle radiographic appearance of FCD. This study evaluates the diagnostic value of morphometric analysis program (MAP) in focal DRE with pathology-confirmed FCD. Methods Automated morphometric analysis program analysis generated z-score maps derived from T1 images, referenced to healthy adult or pediatric controls for each of 39 cases with pathology-confirmed FCD. MAP identified abnormal extension of gray matter into white matter (MAP-E) and blurring of the gray-white matter junction (MAP-J), independently of clinical data and other imaging modalities. MRI was visually reviewed by neuroradiologists as part of usual clinical care, and independently re-reviewed retrospectively by a neuroradiologist with >10-years’ experience in epilepsy MRI. Sensitivity and specificity were calculated for MRI, MAP, scalp-EEG, PET and SISCOM compared to resection area (RA). Results In this cohort of 39 histologically proven FCD cases, the sensitivity and specificity of MAP-J [64% (95% CI 48%–77%) and 96% (95% CI 93%–0.98%)] and MAP-E [74% (95% CI 59%–86%) and 94% (95% CI 91%–97%)] were higher than qualitative MRI review, SISCOM, and FDG-PET. Initial MRI review detected FCD in 17, expert review identified 26. Among cases not detected by initial MRI review, MAP-J correctly identified FCD in 12 additional cases and MAP-E in 13 cases. Among cases not detected by expert MRI review, MAP-J correctly identified 6 and MAP-E 8 cases. Excellent surgical outcome was achieved in 76% of patients. Significance MAP showed favorable sensitivity compared to visual inspection and other non-invasive imaging modalities. MAP complements non-invasive imaging evaluation for detection of FCD in focal DRE patients.

Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked ABCD1 gene resulting in the inability to transport acylated very long chain fatty acids (VLCFA) into the peroxisome for degradation. VLCFA subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe, progressive demyelinating form of ALD, cerebral ALD (cALD), resulting in regions of demyelination observed on brain magnetic resonance imaging (MRI) that are associated with a "garland ring" of gadolinium contrast enhancement. Gadolinium enhancement indicates blood-brain-barrier (BBB) disruption and an active inflammatory disease process. Only hematopoietic cell transplant (HCT) is accepted as therapy sufficient to halt neurologic progression and resolve the observed gadolinium enhancement, although the mechanism of disease arrest is unknown. We have previously shown that rapid donor neutrophil recovery after HCT facilitates MRI gadolinium resolution. We now show early (28 days post HCT) gadolinium resolution correlates well with improved neurologic outcomes measured 1-year post HCT. We recently developed a method to quantify gadolinium on imaging and calculate a gadolinium (Gad) volume given in cubic centimeters (cc). We evaluated Gad volume and other previously described imaging and transplant related biomarkers in 66 boys who underwent HCT. In univariate analysis we found day 28 gadolinium resolution was associated with the following pre-transplant parameters: less Gad volume (7.3 cc versus 2.7 cc, p=0.01), less Gad intensity (p=0.04) and less extensive demyelination as determined by the Loes MRI scoring system (p=0.03). In addition, resolution of Gad enhancement by day 28 was associated with lower pre-HCT plasma and cerebral spinal fluid chitotriosidase activity (p=0.04 for both), and faster neutrophil recovery post HCT (less than 16 days versus greater than 16 days, p=0.03). Multivariate analysis revealed that only less Gad volume was predictive of rapid gadolinium resolution at 28 days post HCT (p = 0.02). This is the first data to quantify the extent of cerebral inflammation in cALD as defined by Gad positivity and its resolution after HCT. Future studies should consider use of Gad volume prior to HCT as a useful biomarker for time to resolution.

Minnesota became the fourth state to begin newborn screening (NBS) for X-linked adrenoleukodystrophy (X-ALD) in 2017. As there is limited retrospective data available on NBS for X-ALD, we analyzed Minnesota's NBS results from the first year of screening. C26:0 lysophosphatidylcholine (C26:0-LPC) screening results of 67,836 infants and confirmatory testing (ABCD1 gene and serum VLCFA analysis) for screen positives were obtained. Fourteen infants (nine males, five females) screened positive for X-ALD and all were subsequently confirmed to have X-ALD, with zero false positives. The birth prevalence of X-ALD in screened infants was 1 in 4,845 and 1 in 3,878 males, more than five times previous reported incidences. Pedigrees of affected infants were analyzed, and 17 male (mean age of 17) and 24 female relatives were subsequently diagnosed with X-ALD. Phenotypes of these family members included self-reported mild neuropathy symptoms in two males and seven females, and childhood cerebral disease (ccALD) and adrenal insufficiency in one male. We observed fewer cases of ccALD and adrenal insufficiency than expected in male family members (5.9% of males for both) compared to previous observations. Together, these findings suggest that the spectrum of X-ALD may be broader than previously described and that milder cases may previously have been underrepresented. Other challenges included a high frequency of variants of uncertain significance in ABCD1 and an inability to predict phenotypic severity. We posit that thoughtful planning to address these novel challenges and coordination by dedicated specialists will be imperative for successful implementation of population-based screening for X-ALD.

A 38-year-old, right-handed woman presented to the epilepsy clinic for evaluation of recurrent spells. These spells are characterized by an aura of a “rushing” cephalic sensation and a sense of “spaciness” or “dizziness” followed by loss of awareness with subsequent amnesia for the event. During these events, the patient is observed by family to sit down and slump forward or fall, followed by hyperventilation and occasionally staring, for up to 3 minutes. There is no head turn, eye deviation, or abnormal body movements. Postictally, she reports generalized weakness without focality and confusion. The spells occurred sporadically for 8 years, but recently increased in frequency to 5 to 20 times per day. Triggers included lack of sleep, stress, and various food products. The patient reported some improvement with levetiracetam therapy at 1,500 mg twice daily.

Febrile infection-related epilepsy syndrome (FIRES) is a devastating epileptic encephalopathy with limited treatment options and an unclear etiology. Anakinra is a recombinant version of the human interleukin-1 receptor antagonist used to treat autoinflammatory disorders. This is the first report of anakinra for treatment of a child with super-refractory status epilepticus secondary to FIRES. Anakinra was well tolerated and effective. Cerebral spinal fluid analysis revealed elevated levels of proinflammatory cytokines before treatment that normalized on anakinra, suggesting a potential pathogenic role for neuroinflammation in FIRES. Further studies are required to assess anakinra efficacy and dosing, and to further delineate disease etiology. Ann Neurol 2016;80:939-945.

Research involving transcranial direct current stimulation (tDCS) in child and adolescent psychiatry is limited. Early, short-term studies have found tDCS to be safe and well-tolerated in youth with neurodevelopmental disorders (attention-deficit hyperactivity disorder, autism, learning disorders). Preliminary data suggest potential utility in symptom reduction and improving cognitive function. Further careful research considering implications for the developing brain is necessary.

Transcranial direct current stimulation (tDCS) involves the application of weak electric current to the scalp. tDCS may influence brain functioning through effects on cortical excitability, neural plasticity, and learning. Evidence in adults suggests promising therapeutic applications for depression, and the adverse effect profile is generally mild. Early research indicates complex interactions between tDCS and concurrent cognitive and motor tasks. Further investigation is warranted to understand how tDCS impacts processes relevant to psychiatric conditions.

ObjectiveTo assess the variation in baseline and seizure onset zone interictal high-frequency oscillation (HFO) rates and amplitudes across different anatomic brain regions in a large cohort of patients.MethodsSeventy patients who had wide-bandwidth (5 kHz) intracranial EEG (iEEG) recordings during surgical evaluation for drug-resistant epilepsy between 2005 and 2014 who had high-resolution MRI and CT imaging were identified. Discrete HFOs were identified in 2-hour segments of high-quality interictal iEEG data with an automated detector. Electrode locations were determined by coregistering the patient's preoperative MRI with an X-ray CT scan acquired immediately after electrode implantation and correcting electrode locations for postimplant brain shift. The anatomic locations of electrodes were determined using the Desikan-Killiany brain atlas via FreeSurfer. HFO rates and mean amplitudes were measured in seizure onset zone (SOZ) and non-SOZ electrodes, as determined by the clinical iEEG seizure recordings. To promote reproducible research, imaging and iEEG data are made freely available (msel.mayo.edu).ResultsBaseline (non-SOZ) HFO rates and amplitudes vary significantly in different brain structures, and between homologous structures in left and right hemispheres. While HFO rates and amplitudes were significantly higher in SOZ than non-SOZ electrodes when analyzed regardless of contact location, SOZ and non-SOZ HFO rates and amplitudes were not separable in some lobes and structures (e.g., frontal and temporal neocortex).ConclusionsThe anatomic variation in SOZ and non-SOZ HFO rates and amplitudes suggests the need to assess interictal HFO activity relative to anatomically accurate normative standards when using HFOs for presurgical planning.

A 74-year-old woman with Parkinson disease was admitted to the hospital for evaluation of dizziness and falls. She had undergone bilateral subthalamic nucleus (STN) implantation of a deep brain stimulator (DBS) 4 years prior to presentation (Activa PC Neurostimulator, model 37601, Medtronic, Minneapolis, MN). Symptoms resulting from Parkinson disease including rigidity and tremor were reasonably controlled with the bilateral STN DBS in addition to carbidopa-levodopa 25–100 mg every 2 hours while awake and 25–100 mg extended release at bedtime. On admission, her vital signs were normal. She was alert and oriented and in no distress, with diffuse moderate rigidity. The next day, on routine nursing assessment, she was found to have tachypnea, tachycardia, and confusion. These assessments were performed every 6 hours; hence onset of her clinical decompensation occurred somewhere between 28 and 34 hours after admission.

Freely available software, derived from the past 2 decades of neuroimaging research, is significantly more flexible for research purposes than presently available clinical tools. Here, we describe and demonstrate the utility of rapidly deployable analysis software to facilitate trainee-driven translational neuroimaging research. A recipe and video tutorial were created to guide the creation of a NeuroDebian-based virtual computer that conforms to current neuroimaging research standards and can exist within a HIPAA-compliant system. This allows for retrieval of clinical imaging data, conversion to standard file formats, and rapid visualization and quantification of individual patients’ cortical and subcortical anatomy. As an example, we apply this pipeline to a pediatric patient’s data to illustrate the advantages of research-derived neuroimaging tools in asking quantitative questions “at the bedside.” Our goal is to provide a path of entry for trainees to become familiar with common neuroimaging tools and foster an increased interest in translational research.

Surgical epilepsy conferences are an important part of the process of determining whether a patient is a candidate for resective epilepsy surgery. At these conferences, repeat review ( re-review ) of the magnetic resonance images (MRIs) of the patient's head often occurs. This study assessed how often radiologic re-review at a presurgical epilepsy conference resulted in a changed interpretation of the head MRI. Charts were reviewed for 239 patients who had been presented at presurgical epilepsy conferences between 2008 and 2012. Of the 233 patients whose MRIs were re-reviewed, resective surgery was performed in 94 patients (40.3%). Forty-one patients (17.6%) had a previously undiagnosed finding, and 18 of the 41 (43.9%) underwent resective surgery. For 4 of the 41 patients (9.8%) with a previously undiagnosed pertinent finding, re-review detected abnormalities that were not amenable to surgical resection (autoimmunity or significant bilateral pathology).

Dravet syndrome (DS) is an intractable pediatric epilepsy syndrome, starting in early childhood. This disorder typically manifests with febrile status epilepticus, and progresses to a multifocal epilepsy with febrile and non-febrile seizures with encephalopathy. Most cases are due to a mutation in the SCN1A gene. This article reviews treatments for DS, with an emphasis on pharmacotherapy. While many medications are used in treating the seizures associated with DS, these patients typically have medically refractory epilepsy, and polytherapy is often required. First-line agents include valproate and clobazam, although there are supportive data for topiramate, levetiracetam, stiripentol and the ketogenic diet. Other agents such as fenfluramine are promising therapies for Dravet syndrome. Sodium channel-blocking anticonvulsants such as carbamazepine and lamotrigine are generally contraindicated in this syndrome. Nonpharmacologic therapies (such as neurostimulation or surgery) are understudied in DS. Because DS is a global encephalopathy, pharmacologic treatment of non-epileptic manifestations of the disease is often necessary. Attention-deficit hyperactivity disorder is often encountered in patients with DS, and psychostimulants can be helpful for this indication. Other psychoactive drugs are less studied in this context. Extrapyramidal and gait disorders are often encountered in DS as well. While DS is a severe epileptic encephalopathy with a high (up to 15 %) mortality rate in childhood, careful pharmacologic management can improve these patients' clinical picture and quality of life.

A 1-day-old male infant is transferred to the neonatal intensive care unit with a large congenital skin defect of the inferior chest and abdomen extending in a butterfly distribution to the flanks (Figure 1). Figure 1. Well-demarcated butterfly-shaped lesion affecting skin, muscle, and fascia which spares the umbilicus. Photograph taken less than one day after birth. ### Prenatal and Birth Histories Apgar scores were 8 and 9 at 1 and 5 minutes, respectively. ### Physical Examination

A19-month-old girl of South Indian parents presented to a general pediatric clinic for evaluation of global developmental delay. The infant's father was the maternal uncle of the infant's mother; the maternal greatgrandparents were uncle and niece. The child was delivered at term by cesarean for fetal heart decelerations following an uneventful pregnancy to her primiparous 27-year-old mother. The perinatal course was unremarkable. The infant was able to roll at 3 months of age, but she did not sit independently until 10 months. At 9 months, she had axial hypotonia. By 15 months, she could wave, pull to a stand, and walk with both hands held. She used a pincer grasp at 9 months and ate finger foods at 15 months. At 19 months, she was not walking, even with support, and had stopped sitting, standing, or waving. She started saying

edited by Jean-Marie Saudubray, Georges van den Berghe, and John H. Walter, 684 pp., Springer, 2012, $209 In the 110 years since Sir Archibald Garrod described alkaptonuria, there has been an explosion in our knowledge of metabolic pathways and their derangements. In more recent times, the pace of discovery has quickened exponentially with advances in laboratory science and bioinformatics. For those of us who must sift through this embarrassment of riches for the tools to diagnose and treat our patients, the thicket of syndromes, enzymes, and substrates can be bewildering. The fifth edition of Inborn Metabolic Diseases promises to be highly useful for understanding and treating these disorders.

Neurological Complications of Systemic Cancer and Antineoplastic Therapy edited by Herbert B. Newton, Mark G. Malkin, 590 pp., Informa Healthcare, 2010, $199.95 Nothing offers more diagnostic challenges or therapeutic wrinkles for the consulting neurologist than the oncology unit. Patients have complex, multisystem disease. Therapies have narrow therapeutic windows and side effects that can range from the fulminant and devastating to the insidious and subtle. …

A 58-year-old man presented with daily hour-long spells of hypothermia, hyperhidrosis, and hypotension. Results of laboratory studies, including thyroid-stimulating hormone, free thyroxine, total/bioavailable testosterone, morning cortisol, and urine osmolality, were normal. MRI of the brain