Decreasing prevalence of cerebral palsy in birth cohorts in South Carolina using Medicaid, disability service, and hospital discharge data, 1996 to 2009.

AIM: Since cross-sectional trends of 8-year-old cerebral palsy (CP) birth prevalence based on record review were stable from 1985 to 2002 in Metropolitan Atlanta, we examined birth cohort trends using administrative data sets promptly. METHOD: Among 755 433 live births from 1996 to 2009 in South Carolina, 2080 received CP diagnosis by age 4 years from linked Medicaid claims with International Classification of Diseases, Ninth Revision codes 343.X (contributing 1061 [51%] unique cases), hospital discharge data (57 [3%] unique cases), and Department of Disabilities and Special Needs program (64 [3%] unique cases). Trends were assessed using negative binominal regression. RESULTS: Including 3.7 percent of cases who died before age 4 years, CP prevalence per 1000 live births decreased significantly from 3.6 in 1996 to 2.1 in 2006 (-3.0% average annual change; 95% confidence interval -4.4 to -1.6). The overall prevalence was 2.8 per 1000 live births, 46.0 per 1000 very-low-birthweight (VLBW) live births, and 53.0 per 1000 VLBW 1-year survivors. Disparities and downward trends persisted across subgroups with higher rates among non-Hispanic black infants than non-Hispanic white and among males compared to females. INTERPRETATION: Downward CP prevalence rates and persistent disparities remain in South Carolina. Further research should validate this methodology, including early deaths, and develop broad surveillance systems to inform clinical practices and etiology. WHAT THIS PAPER ADDS: Birth cohort cerebral palsy (CP) prevalence decreased in South Carolina from 1996 to 2009. CP prevalence was higher in very-low-birthweight infants, non-Hispanic blacks, and males. Three administrative data sets captured 2080 patients with CP in South Carolina. Medicaid claims contributed 51% of unique cases of CP to the cohort. CP diagnoses included 76 patients who died before age 4 years.

DISMINUCIÓN DE LA PREVALENCIA DE PARÁLISIS CEREBRAL EN COHORTES DE NACIMIENTO EN CAROLINA DEL SUR UTILIZANDO MEDICAID, SERVICIO DE DISCAPACIDAD Y DATOS DE ALTA HOSPITALARIA, 1996-2009: OBJETIVO: Debido a que las tendencias transversales de la prevalencia de nacimientos con parálisis cerebral (PC), a los 8 años de edad, basadas en revisión de los registros, se mantuvieron estables desde 1985 hasta 2002 en el área metropolitana de Atlanta, se examinaron las tendencias de cohorte de nacimientos utilizando conjuntos de datos administrativos. MÉTODO: Entre 755.433 nacidos vivos de 1996 a 2009 en Carolina del Sur, 2080 recibieron el diagnóstico de PC a los 4 años de edad basados en prestaciones vinculados a Medicaid usando códigos de la Clasificación Internacional de Enfermedades, Noveno. Códigos de revisión 343.X (contribuyendo 1061 [51%] casos únicos), datos de alta hospitalaria (57 [3%] casos únicos) y programa del Departamento de Discapacidades y Necesidades Especiales (64 [3%] casos únicos). Las tendencias se evaluaron mediante regresión binominal negativa. RESULTADOS: Incluyendo el 3,7% de los casos que murieron antes de los 4 años, la prevalencia de PC por 1000 nacidos vivos disminuyó significativamente de 3,6 en 1996 a 2,1 en 2006 (-3,0% de variación anual promedio; intervalo de confianza del 95% [-4,4 a -1,6]). La prevalencia general fue de 2,8 por 1000 nacidos vivos, 46,0 por 1000 nacidos vivos con muy bajo peso al nacer (VLBW, por sus siglas en inglés) y 53,0 por 1000 sobrevivientes a 1 año VLBW. Las disparidades y las tendencias decrecientes persistieron en los subgrupos con tasas más altas entre los bebés negros no hispanos que entre los blancos no hispanos y entre los varones en comparación con las mujeres. INTERPRETACIÓN: Las tasas de prevalencia de PC en descenso y las disparidades persistentes permanecen en Carolina del Sur. Las investigaciones adicionales deben validar esta metodología, incluidas las muertes tempranas, y desarrollar sistemas de vigilancia amplios para informar las prácticas clínicas y la etiología.

REDUÇÃO NA PREVALÊNCIA DE PARALISIA CEREBRAL EM COORTES DE NASCIMENTO DA CAROLINA DO SUL USANDO MEDICAID, SERVIÇO DE INCAPACIDADES, E DADOS DE ALTAS HOSPITALARES, 1996-2009: OBJETIVO: Como tendências transversais de prevalência de nascimentos com paralisia cerebral (PC) com base em registros de 8 anos permaneceram estáveis de 1985 a 2002 na região metropolitana de Atlanta, examinamos tendências de coortes de nascimento usando bases de dados administrativos imediatos. MÉTODO: Em 755.433 nascidos vivos de 1996 a 2009 na Carolina do Sul, 2080 receberam diagnóstico de PC até a idade de 4 anos a partir de guias Medicaids com Códigos 343.X Segundo a Classificação Internacional de Doenças, nona revisão (contribuíram 1061 [51%] casos únicos), dados de altas hospitalares (57 [3%] casos únicos), e do programa do Departamento de Incapacidade e Necessidades especiais (64 [3%] casos únicos). As tendências foram avaliadas usando regressão binomial negativa. RESULTADOS: Incluindo 3,7 por cento de casos que foram a óbito antes de 4 anos de vida, a prevalência de PC por 1000 nascidos vivos diminuiu significativamente de 3,6 em 1996 a 2,1 em 2006 3 (-3,0% mudança média anual; intervalo de confiança 95% [-4,4 a -1,6]). A prevalência geral foi 2,8 por 1000 nascidos vivos, 46,0 por 1000 nascidos vivos com peso aos nascimento muito baixo (PNMB), e 53,0 por 1000 PNMB sobreviventes após 1 ano. Disparidades e tendências descendentes persistiram entre subgrupos com maiores taxas entre lactentes negros não-hispânicos e entre meninos em comparação com meninas. INTERPRETAÇÃO: Taxas descendentes de prevalência de PC e disparidades persistentes continuam a ser observadas na Carolina do Sul. Pesquisas devem validar esta metodologia, incluindo mortes precoces, e desenvolver sistemas de vigilância mais amplos para informar práticas clínicas e etiologias.

Birth Settings and the Validation of Neonatal Seizures Recorded in Birth Certificates Compared to Medicaid Claims and Hospital Discharge Abstracts Among Live Births in South Carolina, 1996-2013.

Objective Neonatal seizures in the first 28 days of life often reflect underlying brain injury or abnormalities, and measure the quality of perinatal care in out-of-hospital births. Using the 2003 revision of birth certificates only, three studies reported more neonatal seizures recorded among home births ​or planned out-of-hospital births compared to hospital births. However, the validity of recording neonatal seizures or serious neurologic dysfunction across birth settings in birth certificates has not been evaluated. We aimed to validate seizure recording in birth certificates across birth settings using multiple datasets. Methods We examined checkbox items "seizures" and "seizure or serious neurologic dysfunction" in the 1989 and 2003 revisions of birth certificates in South Carolina from 1996 to 2013. Gold standards were ICD-9-CM codes 779.0, 345.X, and 780.3 in either hospital discharge abstracts or Medicaid encounters jointly. Results Sensitivity, positive predictive value, false positive rate, and the kappa statistic of neonatal seizures recording were 7%, 66%, 34%, and 0.12 for the 2003 revision of birth certificates in 547,177 hospital births from 2004 to 2013 and 5%, 33%, 67%, and 0.09 for the 1998 revision in 396,776 hospital births from 1996 to 2003, and 0, 0, 100%, -0.002 among 660 intended home births from 2004 to 2013 and 920 home births from 1996 to 2003, respectively. Conclusions for Practice Despite slight improvement across revisions, South Carolina birth certificates under-reported or falsely reported seizures among hospital births and especially home births. Birth certificates alone should not be used to measure neonatal seizures or serious neurologic dysfunction.

Subcortical DNET in a Patient With an Enzymatic Deficiency: A Rare Case and Review of the Literature.

PURPOSE: This case report describes a toddler with a medical history of biotinidase deficiency who presented with atypical seizures due to a brain tumor. METHODS: This is a case report. RESULTS: Electroencephalogram revealed a frontal lobe mass, with magnetic resonance imaging confirmation of a mass extending from the frontal lobe into the genu and anterior corpus callosum. She underwent a near-total resection, and pathology identified a dysembryoplastic neuroepithelial tumor. The patient is now seizure free and clinically doing well. CONCLUSIONS: Children with biotinidase deficiency and atypical seizures should receive a full electroencephalogram evaluation, as brain tumors continue to be on the differential for seizures in this patient population.

Recording of Neonatal Seizures in Birth Certificates, Maternal Interviews, and Hospital Discharge Abstracts in a Cerebral Palsy Case-Control Study in Michigan.

We evaluated the recording of neonatal seizures in birth certificates, hospital discharge abstracts, and maternal interviews in 372 children, 198 of them with cerebral palsy, born in Michigan hospitals from 1993 to 2010. In birth certificates, we examined checkbox items "seizures" or "seizure or serious neurologic dysfunction"; in hospital discharge abstracts ICD-9-CM codes 779.0, 345.X, and 780.3; and in maternal interviews a history of seizures or convulsions on day 1 of life recalled 2-16 years later. In 27 neonates, 38 neonatal seizures were recorded in 1 or more sources, 17 in discharge abstracts, 20 in maternal interviews, but just 1 on a birth certificate. The kappa coefficient (κ) between interviews and discharge abstracts was moderate (κ = 0.55), and substantial (κ = 0.63) if mothers noted use of antiepileptics. Agreement was higher (κ = 0.71 vs κ = 0.29) in term births than in preterm births. Birth certificates significantly underreported neonatal seizures.

Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease.

While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI-743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase γ deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGam™ (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population.

Initial experience in the treatment of inherited mitochondrial disease with EPI-743.

Inherited mitochondrial respiratory chain disorders are progressive, life-threatening conditions for which there are limited supportive treatment options and no approved drugs. Because of this unmet medical need, as well as the implication of mitochondrial dysfunction as a contributor to more common age-related and neurodegenerative disorders, mitochondrial diseases represent an important therapeutic target. Thirteen children and one adult with genetically-confirmed mitochondrial disease (polymerase γ deficiency, n=4; Leigh syndrome, n=4; MELAS, n=3; mtDNA deletion syndrome, n=2; Friedreich ataxia, n=1) at risk for progressing to end-of-life care within 90 days were treated with EPI-743, a novel para-benzoquinone therapeutic, in a subject controlled, open-label study. Serial measures of safety and efficacy were obtained that included biochemical, neurological, quality-of-life, and brain redox assessments using technetium-99m-hexamethylpropyleneamine oxime (HMPAO) single photon emission computed tomography (SPECT) radionuclide imaging. Twelve patients treated with EPI-743 have survived; one polymerase γ deficiency patient died after developing pneumonia and one patient with Surf-1 deficiency died after completion of the protocol. Of the 12 survivors, 11 demonstrated clinical improvement, with 3 showing partial relapse, and 10 of the survivors also had an improvement in quality-of-life scores at the end of the 13-week emergency treatment protocol. HMPAO SPECT scans correlated with clinical response; increased regional and whole brain HMPAO uptake was noted in the clinical responders and the one subject who did not respond clinically had decreased regional and whole brain HMPAO uptake. EPI-743 has modified disease progression in >90% of patients in this open-label study as assessed by clinical, quality-of-life, and non-invasive brain imaging parameters. Data obtained herein suggest that EPI-743 may represent a new drug for the treatment of inherited mitochondrial respiratory chain disorders. Prospective controlled trials will be undertaken to substantiate these initial promising observations. Furthermore, HMPAO SPECT imaging may be a valuable tool for the detection of central nervous system redox defects and for monitoring response to treatments directed at modulating abnormal redox.

Extrahippocampal gray matter loss and hippocampal deafferentation in patients with temporal lobe epilepsy.

PURPOSE: Medial temporal epilepsy (MTLE) is associated with extrahippocampal brain atrophy. The mechanisms underlying brain damage in MTLE are unknown. Seizures may lead to neuronal damage, but another possible explanation is deafferentation from loss of hippocampal connections. This study aimed to investigate the relationship between hippocampal deafferentation and brain atrophy in MTLE. METHODS: Three different MRI studies were performed involving 23 patients with unilateral MTLE (8 left and 15 right) and 34 healthy controls: (1) voxel-based morphometry (VBM), (2) diffusion tensor imaging (DTI) and (3) probabilistic tractography (PT). VBM was employed to define differences in regional gray matter volume (GMV) between controls and patients. Voxel-wise analyses of DTI evaluated differences in fractional anisotropy (FA), mean diffusivity (MD) and hippocampal PT. Z-scores were computed for regions-of-interest (ROI) GMV and peri-hippocampal FA and MD (to quantify hippocampal fiber integrity). The relationship between hippocampal deafferentation and regional GMV was investigated through the association between ROI Z scores and hippocampal fiber integrity. RESULTS: Patients with MTLE exhibited a significant reduction in GMV and FA in perihippocampal and limbic areas. There was a decrease in hippocampal PT in patients with MTLE in limbic areas. A significant relationship between loss of hippocampal connections and regional GMV atrophy was found involving the putamen, pallidum, middle and inferior temporal areas, amygdala and ceberellar hemisphere. DISCUSSION: There is a relationship between hippocampal disconnection and regional brain atrophy in MTLE. These results indicate that hippocampal deafferentation plays a contributory role in extrahippocampal brain damage in MTLE.

Imaging, anatomical, and molecular analysis of callosal formation in the developing human fetal brain.

A complex set of axonal guidance mechanisms are utilized by axons to locate and innervate their targets. In the developing mouse forebrain, we previously described several midline glial populations as well as various guidance molecules that regulate the formation of the corpus callosum. Since agenesis of the corpus callosum is associated with over 50 different human congenital syndromes, we wanted to investigate whether these same mechanisms also operate during human callosal development. Here we analyze midline glial and commissural development in human fetal brains ranging from 13 to 20 weeks of gestation using both diffusion tensor magnetic resonance imaging and immunohistochemistry. Through our combined radiological and histological studies, we demonstrate the morphological development of multiple forebrain commissures/decussations, including the corpus callosum, anterior commissure, hippocampal commissure, and the optic chiasm. Histological analyses demonstrated that all the midline glial populations previously described in mouse, as well as structures analogous to the subcallosal sling and cingulate pioneering axons, that mediate callosal axon guidance in mouse, are also present during human brain development. Finally, by Northern blot analysis, we have identified that molecules involved in mouse callosal development, including Slit, Robo, Netrin1, DCC, Nfia, Emx1, and GAP-43, are all expressed in human fetal brain. These data suggest that similar mechanisms and molecules required for midline commissure formation operate during both mouse and human brain development. Thus, the mouse is an excellent model system for studying normal and pathological commissural formation in human brain development.

The transcription factor gene Nfib is essential for both lung maturation and brain development.

The phylogenetically conserved nuclear factor I (NFI) gene family encodes site-specific transcription factors essential for the development of a number of organ systems. We showed previously that Nfia-deficient mice exhibit agenesis of the corpus callosum and other forebrain defects, whereas Nfic-deficient mice have agenesis of molar tooth roots and severe incisor defects. Here we show that Nfib-deficient mice possess unique defects in lung maturation and exhibit callosal agenesis and forebrain defects that are similar to, but more severe than, those seen in Nfia-deficient animals. In addition, loss of Nfib results in defects in basilar pons formation and hippocampus development that are not seen in Nfia-deficient mice. Heterozygous Nfib-deficient animals also exhibit callosal agenesis and delayed lung maturation, indicating haploinsufficiency at the Nfib locus. The similarity in brain defects in Nfia- and Nfib-deficient animals suggests that these two genes may cooperate in late fetal forebrain development, while Nfib is essential for late fetal lung maturation and development of the pons.

White matter imaging in holoprosencephaly in children.

PURPOSE OF REVIEW: Holoprosencephaly is a disorder of forebrain development characterized by a failure of the brain to separate into two hemispheres during early development. It is now clear that many cases of holoprosencephaly are caused by alterations in the genetic programmes that pattern the nervous system. Less is known about how a holoprosencephalic brain either forms or fails to form connections between various brain structures. RECENT FINDINGS: Abnormalities in the corpus callosum, corticospinal tract, medial lemniscus and cerebellar peduncles can be seen in holoprosencephaly. Diffusion tensor imaging has been and will continue to be an important tool for imaging white matter in the brain, and will be reviewed here. Furthermore, recent evidence suggests that holoprosencephaly can be associated with delays or abnormalities in myelination. The functional implications of white matter abnormalities in children with holoprosencephaly is only beginning to be understood. SUMMARY: Modern neuroimaging has led to a better appreciation of the variability seen in holoprosencephaly, an anomaly known to have multiple etiologies. Recent reviews of the biology of holoprosencephaly identify the condition as a defect in dorsoventral patterning. More detailed white and grey matter structure-function studies are likely to shed light on how a brain with drastically altered composition and connectivity does or does not organize itself to accomplish increasingly complex developmental functions.

Holoprosencephaly in children: diffusion tensor MR imaging of white matter tracts of the brainstem--initial experience.

PURPOSE: To evaluate the dimensions of specific white matter tracts in the brainstems (region of brain thought to be least affected) of children with holoprosencephaly by using diffusion tensor magnetic resonance (MR) imaging and to correlate these abnormalities with forebrain malformation severity and neurologic deficit severity. MATERIALS AND METHODS: Thirteen patients with holoprosencephaly underwent diffusion tensor MR imaging, with which white matter color maps were generated. Type of holoprosencephaly was correlated with presence or absence of specific brainstem white matter tracts. Furthermore, patient rank based on cortico-ponto-spinal tract (CPST) and middle cerebellar peduncle (MCP) dimensions was correlated with holoprosencephaly type and neurodevelopmental score by using Spearman rank correlation analysis. RESULTS: Two patients had alobar holoprosencephaly, five had the semilobar type, one had the lobar type, and one had the middle-hemisphere-variant type. Four patients were excluded from analysis. In the two patients with alobar holoprosencephaly, the CPSTs were absent bilaterally. In all of the remaining patients except one, who had semilobar holoprosencephaly in which the CPSTs could not be identified at the level of the medulla oblongata, all tracts were present bilaterally. Holoprosencephaly type and neurodevelopmental score correlated strongly with CPST and MCP dimensions (P <.01) over and above the effect of age. CONCLUSION: In vivo identification of brainstem white matter tract abnormalities in patients with holoprosencephaly can be achieved by performing diffusion tensor MR imaging.

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.