Children with epilepsy demonstrate macro- and microstructural changes in the thalamus, putamen, and amygdala.

PURPOSE: Despite evidence for macrostructural alteration in epilepsy patients later in life, little is known about the underlying pathological or compensatory mechanisms at younger ages causing these alterations. The aim of this work was to investigate the impact of pediatric epilepsy on the central nervous system, including gray matter volume, cerebral blood flow, and water diffusion, compared with neurologically normal children. METHODS: Inter-ictal magnetic resonance imaging data was obtained from 30 children with epilepsy ages 1-16 (73% F, 27% M). An atlas-based approach was used to determine values for volume, cerebral blood flow, and apparent diffusion coefficient in the cerebral cortex, hippocampus, thalamus, caudate, putamen, globus pallidus, amygdala, and nucleus accumbens. These values were then compared with previously published values from 100 neurologically normal children using a MANCOVA analysis. RESULTS: Most brain volumes of children with epilepsy followed a pattern similar to typically developing children, except for significantly larger putamen and amygdala. Cerebral blood flow was also comparable between the groups, except for the putamen, which demonstrated decreased blood flow in children with epilepsy. Diffusion (apparent diffusion coefficient) showed a trend towards higher values in children with epilepsy, with significantly elevated diffusion within the thalamus in children with epilepsy compared with neurologically normal children. CONCLUSION: Children with epilepsy show statistically significant differences in volume, diffusion, and cerebral blood flow within their thalamus, putamen, and amygdala, suggesting that epilepsy is associated with structural changes of the central nervous system influencing brain development and potentially leading to poorer neurocognitive outcomes.

In-depth investigations of adolescents and adults with holoprosencephaly identify unique characteristics.

PurposeWith improved medical care, some individuals with holoprosencephaly (HPE) are surviving into adulthood. We investigated the clinical manifestations of adolescents and adults with HPE and explored the underlying molecular causes.MethodsParticipants included 20 subjects 15 years of age and older. Clinical assessments included dysmorphology exams, cognitive testing, swallowing studies, ophthalmic examination, and brain magnetic resonance imaging. Genetic testing included chromosomal microarray, Sanger sequencing for SHH, ZIC2, SIX3, and TGIF, and whole-exome sequencing (WES) of 10 trios.ResultsSemilobar HPE was the most common subtype of HPE, seen in 50% of the participants. Neurodevelopmental disabilities were found to correlate with HPE subtype. Factors associated with long-term survival included HPE subtype not alobar, female gender, and nontypical facial features. Four participants had de novo pathogenic variants in ZIC2. WES analysis of 11 participants did not reveal plausible candidate genes, suggesting complex inheritance in these cases. Indeed, in two probands there was a history of uncontrolled maternal type 1 diabetes.ConclusionIndividuals with various HPE subtypes can survive into adulthood and the neurodevelopmental outcomes are variable. Based on the facial characteristics and molecular evaluations, we suggest that classic genetic causes of HPE may play a smaller role in this cohort.

Improved Medical Student Engagement with EHR Documentation following the 2018 Centers for Medicare and Medicaid Billing Changes.

BACKGROUND: Medical student note writing is an important part of the training process but has suffered in the electronic health record (EHR) era as a result of student notes being excluded from the billable encounter. The 2018 CMS billing changes allow for medical student notes to be used for billable services provided that physical presence requirements are met, and attending physicians satisfy performance requirements and verify documentation. This has the potential to improve medical student engagement and decrease physician documentation burden. METHODS: Our institution implemented medical student notes as part of the billable encounter in August 2018 with support of our compliance department. Note characteristics including number, type, length, and time in note were analyzed before and after implementation. Rotating medical students were surveyed regarding their experience following implementation. RESULTS: There was a statistically significant increase in the number of student-authored notes following implementation. Attending physicians' interactions with student notes greatly increased following the change (4% of student notes reviewed vs. 84% of student notes). Surveyed students reported that having their notes as part of the billable record made their notes more meaningful and enhanced their learning. The majority of surveyed students also agreed that they received more feedback following the change. CONCLUSION: Medical students are interested in writing notes for education and feedback. Inclusion of their notes as part of the billable record can facilitate their learning and increase their participation in the note writing process.

Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation.

Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally completed by the fifth week of gestation. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE in living humans. This has led to better classification of types of HPE, identification of newer subtypes, and understanding of the pathogenesis. Currently, there are four generally accepted subtypes of HPE: alobar, semilobar, lobar, and middle interhemispheric variant. These subtypes are defined primarily by the degree and region of neocortical nonseparation. Rather than there being four discrete subtypes of HPE, we believe that there is a continuum of midline neocortical nonseparation resulting in a spectrum disorder. Many patients with HPE fall within the border zone between the neighboring subtypes. In addition, there are patients with very mild HPE, where the nonseparation is restricted to the preoptic (suprachiasmic) area. In addition to the neocortex, other midline structures such as the thalami, hypothalamic nuclei, and basal ganglia are often nonseparated in HPE. The cortical and subcortical involvements in HPE are thought to occur due to a disruption in the ventral patterning process during development. The severity of the abnormalities in these structures determines the severity of the neurodevelopmental outcome and associated sequelae.

Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microophthalmia.

We report on a patient with trisomy 21, microophthalmia, neonatal diabetes mellitus, hypopituitarism, and a complex structural brain anomaly who was a member of a large bilineal family with eye anomalies. The patient inherited a different mutation in PAX6 from each parent and is the only known living and second reported patient with compound heterozygosity for mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development and has roles in pancreatic and pituitary development. Clinical evaluation of the propositus and his parents demonstrated the effects of mutations of differing severity in multiple individuals.

Utility of prenatal MRI in the evaluation and management of fetal ventriculomegaly.

OBJECTIVE: Fetal ventriculomegaly may occur in isolation or as part of a broader syndrome. We aimed to determine the added value of magnetic resonance imaging (MRI) for informing the pre-natal and postnatal care of pregnancies complicated by ventriculomegaly (VM). STUDY DESIGN: Retrospective analysis of all cases of prenatally diagnosed VM referred to the fetal center at Lucile Packard Children's Hospital Stanford 1/1/2009-6/1/2014 were reviewed. Ultrasound (US) and MRI findings were reviewed, and the added yield of MRI evaluated. RESULTS: A total of 91 cases of fetal VM were identified and 74 (81%) underwent MRI. In 62/74 (84%) cases, additional CNS or non-CNS findings, not seen on US, were discovered on MRI, of which 58 were CNS-related. Forty-six (62%) of the additional findings were considered clinically relevant, of which 45 were CNS-related. CONCLUSION: Fetal MRI identifies additional, clinically relevant CNS and non-CNS findings in a majority of cases of VM following initial US.

Factor analysis of neuroanatomical and clinical characteristics of holoprosencephaly.

The objective of this study is to better understand the relationship between neuroradiologic and clinical characteristics in holoprosencephaly (HPE) using the multivariate analysis called factor analysis. HPE is a brain malformation characterized by incomplete cleavage of the cerebral hemispheres and deep gray structures. We performed evaluations on 89 children with HPE that included their history, developmental assessment, and physical examination. Ten clinical variables included in factor analysis were the grade of spasticity, dystonia, choreoathetosis, hypotonia, mobility, upper extremity/hand function, expressive language, feeding/swallowing difficulty, endocrinopathies, and temperature dysregulation. Five neuroimaging variables graded by pediatric neuroradiologists were the grade of HPE (from least to most severe: lobar, semilobar, and alobar) and the degree of non-separation of caudate, lentiform, thalamic, and hypothalamic nuclei. Factor analysis using principle component extraction and varimax rotation was utilized. Four significant factors were identified: (1) neuroimaging/developmental factor, (2) motor factor, (3) hypothalamic/oromotor factor, and (4) hypotonia factor. These four factors accounted for 65.2% of the variance. In this factor analysis of HPE patients, we were able to reduce the large number of clinical and radiological variables into four factors. These factors and the constructs underlying them provide structure to the data and provide key parameters for future studies involving neurodevelopmental outcomes in HPE.

Links between abnormal brain structure and cognition in holoprosencephaly.

Converging information on medical issues, motor ability, and cognitive outcomes is essential when addressing long-term clinical management in children with holoprosencephaly. This study considered whether adding more informative structural indices to classic holoprosencephaly categories would increase prediction of cognitive outcomes. Forty-two children with holoprosencephaly were examined to determine the association of deep gray nuclei abnormalities with cognitive abilities and the effect of motor skill deficits on cognitive performance. Additionally, a cognitive profile was described using the Carter Neurocognitive Assessment, an experimental diagnostic instrument designed specifically for young children with severe neurodevelopmental dysfunction. Findings indicated that nonseparation of the deep gray nuclei was significantly associated with the cognitive construct of vocal communication, but not with the cognitive constructs of social awareness, visual attention, or auditory comprehension. Importantly, motor skill deficits did not significantly affect performance on the Carter Neurocognitive Assessment. This study is the first investigation to provide a descriptive overview of specific cognitive skills in this group of children. The results also strongly suggest that this feature of the brain's structure does not predict all aspects of neurodevelopmental function. These findings contribute a critical component to the growing body of knowledge regarding the medical and clinical outcomes of children with holoprosencephaly.

Endocrine disorders associated with holoprosencephaly.

OBJECTIVE: To investigate the incidence of endocrinopathies in holoprosencephaly (HPE) and correlate the severity of the endocrinopathies with the neuroanatomic abnormalities. STUDY DESIGN: We reviewed the histories and medical records of 117 children with HPE for endocrinopathies and related treatments. Neuroimaging studies were graded for severity of HPE, hypothalamus non-separation, and pituitary abnormalities. RESULTS: Diabetes insipidus (DI) occurred in 70% of patients with classic HPE. The severity of the DI correlated with the grade of HPE and hypothalamic non-separation (p < 0.0001). Anterior pituitary dysfunctions were much less common. Hypothyroidism was identified in 11% of patients, hypocorticism in 7%, and growth hormone deficiency in 5%. Only one patient with middle interhemispheric variant of holoprosencephaly (MIH) had any of these disorders. CONCLUSIONS: Patients with HPE have a high incidence of DI that may be related to the failure of cleavage of hypothalamic nuclei. Anterior pituitary dysfunctions are much less common than DI.

Special requirements for electronic medical records in neurology.

Electronic medical records (EMRs) are being rapidly adapted in the United States with goals of improving patient care, increasing efficiency, and reducing costs. Neurologists must become knowledgeable about the utility and effectiveness of the important parts of these systems specifically needed for care of neurology patients. The field of neurology encompasses complex disorders whose diagnosis and management heavily relies on detailed medical documentation of history and physical examination, and often on specialty-specific ancillary tests and extensive neuroimaging. Small discrepancies in documentation or absence of an in-hand ancillary test result can drastically change the current workup or treatment decision of a complex patient with neurologic disease. We describe current models and opportunities for improvements to EMRs that provide utility and efficiency in the care of neurology patients.

Electroencephalography in holoprosencephaly: findings in children without epilepsy.

OBJECTIVE: To evaluate the electroencephalographic characteristics of patients with holoprosencephaly (HPE) without epilepsy. METHODS: We evaluated the electroencephalograms (EEGs) of 18 children with HPE who lacked a history of seizures. Neuroimaging studies were assessed for severity of HPE and thalamic non-separation and the presence of dorsal cysts and cortical malformations. RESULTS: Hypersynchronous theta activity occurred in 50 and 60% of EEGs during wakefulness or drowsiness/sleep, respectively, and correlated with the grade of thalamic non-separation (p<0.05). Hypersynchronous beta activity during sleep occurred in 41% of EEGs. Posterior amplitude attenuation occurred in 33% of EEGs and correlated with the presence of a dorsal cyst (p

Analysis of the cerebral cortex in holoprosencephaly with attention to the sylvian fissures.

BACKGROUND AND PURPOSE: Analysis of specific features in the brain of patients with holoprosencephaly (HPE) may clarify normal and abnormal brain development and help predict outcomes for specific children. We assessed sulcal and gyral patterns of cerebral cortex in patients with HPE and developed a method of grading brain development. METHODS: Neuroimaging studies (75 MR imaging, 21 CT) of 96 patients with HPE were retrospectively reviewed, with specific attention paid to the cerebral cortex. Thickness of cortex, width of gyri, and depth of sulci were assessed subjectively and by measurement. The angle between lines drawn tangential to the sylvian fissures ("sylvian angle") was measured in each patient with HPE and in 20 control patients. RESULTS: Thickness of cortex was normal in all 96 patients. Gyral shape and width and sulcal depth were normal in 80 patients. Twelve patients, all with very severe HPE and microcephaly, had reduced sulcal depth, diffusely in eight and limited to the anteromedial cortex in four with lobar HPE. Four patients had subcortical heterotopia, located anterior to the interhemispheric fissure, associated with shallow sulci in the overlying cortex. Sylvian fissures were displaced further anteriorly and medially as HPE became more severe, until, in the most severe cases, no sylvian fissures could be identified. Sylvian angle measurements corresponded closely with severity of HPE, being largest in the most severe and smallest in the least severe cases. All patients with HPE had sylvian angles significantly larger than the mean of 15 degrees measured in the control patients. CONCLUSION: The only true malformations of cortical development were subcortical heterotopia. However, diffuse and focal abnormal sulci were observed. We propose our sylvian angle measurement of extent of frontal lobe development as an objective means of quantifying the severity of HPE.

The middle interhemispheric variant of holoprosencephaly.

BACKGROUND AND PURPOSE: The middle interhemispheric variant of holoprosencephaly (MIH) is a rare malformation in which the cerebral hemispheres fail to divide in the posterior frontal and parietal regions. We herein describe the structural abnormalities of the brain in a large group of patients with MIH, compare these features with those of classic holoprosencephaly (HPE), and propose a developmental mechanism, based on current knowledge of developmental neurogenetics, by which MIH develops. METHODS: Brain images obtained in 21 patients with MIH (MR images in 16 patients and high-quality X-ray CT scans in five patients) were retrospectively reviewed to classify cerebral abnormalities. The cerebral parenchyma, hypothalami, caudate nuclei, lentiform nuclei, thalami, and mesencephalon were examined for the degree of midline separation (cleavage) of the two hemispheres. The orbits, olfactory apparati, and presence or absence of a dorsal cyst were also assessed. RESULTS: In all patients, by definition, midportions of the cerebral hemispheres were continuous across the midline, with an intervening interhemispheric fissure. The sylvian fissures were abnormally connected across the midline over the vertex in 18 (86%) of 21 patients. Two patients had relatively normal-appearing sylvian fissures; one had unilateral absence of a sylvian fissure owing to substantial subcortical heterotopia. Heterotopic gray matter or dysplastic cerebral cortex was also seen in 18 (86%) of 21 patients. MIH differed from classic HPE as follows. 1) In all subjects, the midline third ventricle separated the hypothalamus and lentiform nuclei. 2) The caudate nuclei were separated by the cerebral ventricles in 17 (89%) of the 19 [corrected] patients in whom they could be assessed. 3) The most commonly affected basal nucleus was the thalamus (non-cleavage in seven [33%] of 21 cases, abnormal alignment in 1 [5%]). 4) Three (18%) of the 17 [corrected] patients in whom the mesencephalon could be assessed showed some degree of mesencephalic non-cleavage. 5) No patients had hypotelorism (four had hypertelorism, the remainder manifested normal intraocular distances). Dorsal cysts were present in five (25%) of the 20 patients in whom they could be assessed (dorsal cysts could not be assessed after shunt surgery), and as in classic HPE, were associated with severe thalamic non-cleavage in three of these five patients. CONCLUSION: MIH appears to cause non-cleavage of midline structures in a completely different pattern than does classic HPE. In MIH, impaired induction or expression of genetic factors appears to influence the embryonic roof plate, whereas in classic HPE, induction or expression of the embryonic floor plate seems to be affected.

Unilateral schizencephaly and contralateral polymicrogyria associated with umbilical cord mass.

We report a 6-month-old boy with diffuse hypertonia and developmental delay who had unilateral separated-lip schizencephaly and contralateral polymicrogyria. The contralateral polymicrogyria was associated with an incomplete clefting in that hemisphere. An umbilical cord hamartoma is presumed to have caused hypoperfusion to the early developing brain, resulting in bilateral lesions.

Hydranencephaly owing to twin-twin transfusion: serial fetal ultrasonography and magnetic resonance imaging findings.

We report a newborn girl with hydranencephaly. In the setting of a monochorionic twin pregnancy, one twin's demise was detected by ultrasonography at 18 weeks of gestation, apparently the result of a twin-twin transfusion. In the surviving twin, the evolution of ventriculomegaly, first noted at 18 weeks, to hydranencephaly at 27 weeks is documented by serial sonograms. These findings were confirmed with fetal and postnatal magnetic resonance imaging.

Frontal lobe seizures and uveitis associated with acute human parvovirus B19 infection.

We report a 5-year-old girl who developed repeated episodes of behavioral alterations shortly after human parvovirus B19 infection and uveitis. Video-electroencephalographic study demonstrated that these brief episodes were frontal lobe seizures. Seizures responded promptly to antiepilepsy medications. Further diagnostic testing did not reveal any rheumatologic disorders. Human parvovirus B19 infections in children are more commonly associated with febrile seizures and meningoencephalitis. Our case demonstrates that, rarely, it may be associated with the development of partial epilepsy.

Short duration of benign partial epilepsy in infancy.

It has previously been reported that benign partial epilepsy in infancy constitutes up to 29% of the epilepsies presenting in the first 2 years of life. To determine the proportion of benign partial epilepsy in our epilepsy population, we retrospectively reviewed 331 patients with greater than two afebrile seizures in the first 2 years of life between 1993 and 2000. Inclusion criteria were (1) partial seizures with or without secondary generalization, (2) normal development, (3) no other neurologic abnormalities, (4) normal interictal electroencephalograms (EEGs), and (5) good response to treatment. Exclusion criteria included seizures that (1) were caused by acute central nervous system insult, (2) occurred only within the first month of life, and (3) lasted longer than 30 minutes. Of 331 patients, 22 (6.6%) fulfilled the criteria with a minimum of 2 years and a mean of 4 years of follow-up off antiepilepsy drug treatment. Six (27%) had complex partial seizures, and 16 (73%) had complex partial seizures with secondary generalization. Neuroimaging studies were normal in all patients. Of the 6 patients with ictal EEGs, 3 had a temporal lobe focus, 1 had an occipital lobe focus, and the remaining 2 had dual foci. Median onset was 4.0 months (range 0.8-9.3). Seizures remitted within 4 months in 20 (91%). Mean duration of seizure persistence was 2.1 months (range 0-8.3) and was longer in treated patients. Median age at last seizure was 6.4 months (range 2-18). Nineteen were treated with antiepilepsy drugs. At last follow-up (mean duration of 52.2 months), all patients were seizure free and off antiepilepsy drugs. Benign partial epilepsy in infancy is an epilepsy syndrome of short duration and is easily recognized using accepted classification criteria. Benign partial epilepsy in infancy appears to be an idiopathic localization-related epilepsy with a favorable prognosis. The incidence in our population is not as common as previously reported. Based on our findings, we suggest weaning of antiepilepsy drugs 6 months after seizure onset.

Holoprosencephaly: genetic, neuroradiological, and clinical advances.

Recent advances in genetics and neuroimaging have greatly contributed to our understanding of the spectrum of midline brain and craniofacial malformations known as holoprosencephaly. This review summarizes our current understanding of the epidemiology and molecular-genetic bases of these malformations, as well as recent neuroradiological and clinical studies, which have revealed that the manifestations of holoprosencephaly are far more variable than previously appreciated. We also discuss the implications for and importance of accurate diagnosis, prognosis, management of common medical problems, and counseling for affected families.

Evaluation and management of children with holoprosencephaly.

Recent advances in genetics and neuroimaging have greatly contributed to our understanding of the spectrum of midline brain and craniofacial malformations known as holoprosencephaly. Neuroradiologic studies have provided detailed characteristics of four major types of holoprosencephaly: alobar, semilobar, lobar, and middle interhemispheric variant. Clinical studies in children with these types of holoprosencephaly have revealed a wide range of survival and neurologic outcomes. Motor and developmental dysfunctions correlate with the severity of the brain malformation in holoprosencephaly. These findings have implications in the management of medical problems associated with holoprosencephaly and overall prognostication.

The impact of an online social network with wireless monitoring devices on physical activity and weight loss.

BACKGROUND: Online social networks (OSNs) are a new, promising approach for catalyzing health-related behavior change. To date, the empirical evidence on their impact has been limited. PURPOSE: Using a randomized trial, we assessed the impact of a health-oriented OSN with accelerometer and scales on participant's physical activity, weight, and clinical indicators. METHODS: A sample of 349 PeaceHealth Oregon employees and family members were randomized to the iWell OSN or a control group and followed for 6 months in 2010-2011. The iWell OSN enabled participants to connect with "friends," make public postings, view contacts' postings, set goals, download the number of their steps from an accelerometer and their weight from a scale, view trends in physical activity and weight, and compete against others in physical activity. Both control and intervention participants received traditional education material on diet and physical activity. Laboratory data on weight and clinical indicators (triglycerides, high-density lipoprotein, or low-density lipoprotein), and self-reported data on physical activity, were collected at baseline, 3 months, and 6 months. RESULTS: At 6 months, the intervention group increased leisure walking minutes by 164% compared with 47% in the control group. The intervention group also lost more weight than the controls (5.2 pounds compared with 1.5 pounds). There were no observed significant differences in vigorous exercise or clinical indicators between the 2 groups. Among intervention participants, greater OSN use, as measured by number of private messages sent, was associated with a greater increase in leisure walking and greater weight reduction over the study period. CONCLUSIONS: The study provides evidence that interventions using OSNs can successfully promote increases in physical activity and weight loss.