G20 AS Manejo odontopediátrico del paciente con hipoplasia del cuerpo calloso by Luis Antonio Santana Martinez

UNIVERSIDAD AUTÓNOMA DE ZACATECAS “FRANCISCO GARCÍA SALINAS” UNIDAD ACADÉMICA DE ODONTOLOGÍA

Especialidad en odontopediatría Seminario de casos clínicos

“MANEJO ODONTOPEDIÁTRICO DEL PACIENTE CON HIPOPLASIA DEL CUERPO CALLOSO”

Reporte de caso clínico

Asesores: CDO Ma. Del Socorro Sotelo Camacho MgSc Heraclio Reyes Rivas

Alumna:

Shurgan Anastasiia

Mayo 2019

ÍNDICE

1.0

Resumen…………………………………………....3

2.0

Introducción…………………………………….......4

3.0

Marco teórico………………………………............5 3.1 Anatomía y fisiología……………………….....5 3.2 Embriología………………………………….....5 3.3 Epidemiologia…………………………………..5 3.4 Clasificación………………………………….…6 3.5 Etiología…………………………………….…..6 3.6 Manifestaciones clínicas……………………...6 3.7 Diagnóstico………………………………….....8 3.8 Tratamiento…………………………………….8

4 Caso clínico……………………………………….….10 5 Conclusiones…………………..……………………..14 6 Bibliografía.……………………..…………………….15

Anastasiia Shurgan, Ma. Del Socorro Sotelo Camacho, Heraclio Reyes Rivas, Jesús Alberto Luengo Fereira, Cristal Yurixie Díaz Rosas.

Resumen Introducción: Las malformaciones del cuerpo calloso (CC) son de los trastornos cerebrales más frecuentes, resultante de anomalías del desarrollo de las fibras que conectan ambos hemisferios cerebrales. Se observa en 1 de cada 4,000 nacimientos, afectando principalmente al sexo masculino y se diagnóstica posnatalmente. Las personas con alteraciones en CC representan un reto en el ámbito odontológico. Pero a pesar de su discapacidad psicomotora pueden ser abordados con el uso de técnicas conductuales y personalización del plan de tratamiento según las necesidades y grado de afectación que presenta cada paciente. Reporte de caso: Paciente femenino de 6 años de edad con diagnóstico de hipoplasia del cuerpo calloso en el istmo, acude a la clínica de Especialidad en Odontopediatría (UAO/UAZ), por presentar procesos infecciosos en órganos dentales 51-61, sin manifestación de dolor y sin recibir medicación alguna. Al examen clínico y radiográfico se evidencia presencia de lesiones cariosas, pulpitis irreversible, fistulas y desgaste de bordes incisales y oclusales por la presencia de bruxismo. Debido a la condición de la paciente se decide realizar rehabilitación odontológica iniciando por la eliminación de focos infecciosos extracción de resto radicular y órganos dentarios necrosados, tratamientos pulpares con Vitapex, IRM e ionómero de vidrio, colocación de las coronas de acero-cromo y mantenedores del espacio. Para la atención todas las sesiones fueron centradas en el manejo de conducta con la aplicación de diversas técnicas direccionadas a la desensibilización, disminuyendo así considerablemente los niveles de ansiedad del paciente, logrando una amplia cooperación de la misma. Conclusión: Pacientes con hipoplasia del cuerpo calloso representan un reto para un odontopediatra debido a cantidad del daño presente, junto con los trastornos conductuales y falta de comprensión. Sin embargo pueden ser exitosamente tratados con uso de las técnicas de desensibilización, dejando la anestesia general como última opción debido a sus riesgos. Palabras clave: Pacientes con necesidades especiales, hipoplasia del cuerpo calloso, caries dental, bruxismo, manejo de conducta.

Introducción El cuerpo calloso es la estructura que consiste de una masa de la sustancia blanca de fibras transversales que conectan los hemisferios cerebrales. Esta comisura es fundamental en el proceso de integración de las funciones sensoriales, motores y cognitivos (Integración de información sensorial compleja, lenguaje, pensamiento abstracto). Anormalidades de esta estructura son las más frecuentes malformaciones cerebrales. Clínicamente pueden presentar alteración de la coordinación y el tono muscular, que como una consecuencia afecta a la succión y masticación, presencia de parafunciones (sobre todo bruxismo, que se relaciona con estados de estrés y ansiedad), convulsiones, déficit neuropsiquiátrico de grado variable, autismo, trastornos del razonamiento abstracto, resolución de problemas y en la comprensión lingüística. Es frecuente encontrar retraso mental, desórdenes del comportamiento e integración social, déficit de atención e hiperactividad o muestra de los comportamientos depresivos en este tipo de pacientes. Por eso las personas con alteraciones en el CC representan un reto en el ámbito odontológico. Pero a pesar de su discapacidad psicomotora pueden ser exitosamente abordados. Es muy importante anotar que el enfoque clínico para este tipo de pacientes debe basarse en las técnicas de manejo de conducta y enfoque físico. Y cada plan de tratamiento debe ser individualizado según las necesidades y grado de afectación psicomotora que presenta cada paciente. El objetivo general es desensibilizar, lograr aceptación y cooperación durante procedimientos odontológicos necesarios. La intervención odontológica debe iniciarse con los tratamientos de invasión mínima, aumentando la complejidad de tratamientos ejecutados (siempre y cuando no hablamos de una urgencia). Hay que establecer una buena comunicación tanto con el paciente como con sus cuidadores. Hacer una completa historia clínica médica y odontológica, para obtener toda la información necesaria para abordar al paciente. Estructurar y planificar bien el plan del tratamiento. Acordar y explicar a los familiares del paciente que la salud bucal y los tratamientos preventivos pueden mejorar mucho la calidad de vida de ellos.

Marco Teórico

Anatomía y fisiología El cuerpo calloso (CC) es la comisura mayor del cerebro, una masa de la sustancia blanca formada por fibras transversales que conectan ambos hemisferios cerebrales 1. Está presente sólo en mamíferos placentarios, es un cúmulo de fascículos nerviosos en forma de C que conectan ambos hemisferios cerebrales, está compuesto por un número entre 200 y 800 millones de fibras de axones lo que corresponde a 2-3 % de todas las fibras corticales y tiene 10 cm de largo aproximadamente 2,3. Cuerpo calloso está constituido por cuatro porciones: rostrum, rodilla, cuerpo y esplenio 4.El septum pellucidum se relaciona con esta estructura en dirección cefálica y está irrigado por la arteria cerebral anterior 5,6 Funciones fisiológicas están mediadas por influencias excitatorias e inhibitorias en transferencia interhemisférica. Incluye movimientos bilaterales, integración bilateral sensorial e información visual, especialización de lenguaje, emociones, comportamiento, memoria y funciones cognitivas superiores 7. Estudios demuestran que un aumento de su grosor en niños, se ha relacionado con la inteligencia, la velocidad de procesamiento y las habilidades de resolución de problemas. Por otra parte, en ancianos, se ha encontrado que los cambios que afectan la integridad del cuerpo calloso se relacionan con disminución de la función cognitiva. Mientras otros autores relacionan trastornos de cuerpo calloso con algunas formas de comportamiento tipo obsesivo-compulsivo, y relación con esquizofrenia 8, 9, 10,11. Embriología Embriológicamente, se deriva de la lámina terminalis en la porción del tubo neural cefálico al neuroporo rostral; su formación se produce a partir de la 11 a 15 semanas de gestación y hasta el cuarto mes de gestación sólo se forma la parte más rostral del cuerpo calloso, la porción caudal lo hace después del quinto mes. La maduración continúa en el período postnatal con aumentos de tamaño observados en la edad adulta temprana y la mielinización se completa durante la pubertad 12,13,14. Epidemiologia Las malformaciones del CC son las malformaciones cerebrales más frecuentes, resultantes de anomalías en el desarrollo de las fibras que conectan ambos

hemisferios cerebrales. Los avances en neuroimagen de los últimos años han dado la posibilidad de detectar y diagnosticar más casos de anomalías estructurales del CC, lo que ha llevado a un aumento de su prevalencia. Los resultados de un estudio realizado en California entre 1983 y 2003, registraron una prevalencia de trastornos del CC de 1,8 cada 10.000 nacimientos. Sin embargo, otros estudios más recientes sugieren que la agenesia del CC se da por lo menos en 1 de cada 4.000 nacimientos, y el 3-5% de individuos con algún tipo de anomalía neurológica tienen también una lesión estructural en el CC - Su ausencia congénita (agenesia) puede ocurrir en una gran variedad de condiciones que interrumpen el desarrollo temprano de las fibras del CC. También se ha demostrado que estos desórdenes se dan con más frecuencia en los hombres. Esta mayor prevalencia masculina podría atribuirse al gran número de síndromes ligados al cromosoma X, que podrían estar íntimamente relacionados con las anomalías estructurales del CC 15, 16, 17,18. Clasificación La clasificación más reciente está basada en la línea sagital media, que nos indica 3 grandes clases. -hipoplasia cuando CC esta informalmente delgado o con el grosor disminuido solamente en el parte posterior. -Hipoplasia con displasia- cuando malformación de la forma sobrepasa las fronteras de región posterior. -Agenesia completa del cuerpo calloso 19. Etiología En los pacientes en los que no se identifica la causa específica de la alteración del cuerpo calloso se han descrito reordenamientos cromosómicos como delecciones, Translocaciones, por ejemplo del (1) (q43), del (2)(q12q14), del(2)(q31q33), del(6)(q23), t(2;15)(p21;q13), del(X)(p22.3), del(18)(q21qter)] y duplicaciones como las siguientes: dup(6)(p25), dup(6)(q25qter), dup(8)(p21pter), dup(8)(p11p23.1), entre otras 20. Existen circunstancias que aumentan la probabilidad de la apariencia de la agenesia del cuerpo calloso como las trisomías 8 y 18; también se ha relacionado el aumento de su presentación con el síndrome de alcoholismo fetal o la relación con la invasión del saco fetal por virus o bacterias; además, puede ser un hecho consecuente con otros procesos neurológicos como la existencia de un quiste que bloquea el desarrollo de esta estructura 21. Manifestaciones clínicas Los niños y adolescentes con trastornos aislados del CC pueden presentar desde una clínica completamente asintomática hasta cualquiera de las siguientes características:

- Anomalías faciales como, micrognatia, pabellones auriculares rotados hacia atrás y anomalías oculares. - Déficits motores como hipotonía, espasticidad, coordinación motora alterada e incluso parálisis cerebral. La epilepsia y las convulsiones son más frecuentes en este tipo de niños y adolescentes. Los investigadores también han descrito problemas de succión temprana, masticación, deglución y reflujo esofágico. - Los retrasos en el desarrollo son muy comunes, con una prevalencia de 60-80%. Algunos niños pueden presentar retrasos motores, lingüísticos y cognitivos. - Déficits o anormalidades sensoriales, siendo los problemas de visión los más frecuentes. También se han descrito déficits auditivos. Además, entre un 46 y 56% de los niños tienen reacciones anormales al tacto y al dolor. Se describió que tenían una sensibilidad excesiva a sensaciones táctiles particulares y una tolerancia inesperadamente alta al dolor. - En la mayoría de los casos, tienen una inteligencia dentro de los límites de la normalidad, pero algo más baja que la media. Tienen dificultades para integrar información de múltiples fuentes, razonamiento complejo, pensamiento abstracto, resolución de problemas y generalizar. Debido a estas dificultades, no pueden planificar y ejecutar eficazmente tareas multidimensionales, y a veces incluso actividades diarias. En cuanto al rendimiento escolar, con la fuerte participación de los padres, estos niños completan con éxito la escuela infantil. Algunos de estos niños suelen tener problemas para mantener la atención y permanecer quietos, se distraen fácilmente y experimentan dificultades en tareas que exigen atención y concentración. Estas últimas manifestaciones recuerdan al trastorno por déficit de atención e hiperactividad (TDAH) 22. - Uno de los dominios más examinados en estos pacientes es el lenguaje. Estos pacientes tienen dificultades en la comprensión de los idiomas, prosodia vocal, expresiones faciales y gestos. Además, tienen una gran dificultad para mantener una conversación; cambian de tema constantemente y hacen comentarios "sin sentido". Otra característica notable es la disminución de la comprensión del humor 23. - Los padres y los educadores describen a niños y adolescentes con lesiones en el cuerpo calloso como felices y amistosos, pero a veces inmaduros para su edad o incluso socialmente ingenuos. Además, carecen de autoconciencia y la capacidad de reconocer sus propias limitaciones. Estos niños también pueden contar historias incorrectas o falsas, pero creen que lo que dicen es cierto. - Los trastornos emocionales se han observado como condiciones de menor severidad, como depresión, ansiedad o cambios rápidos del estado de ánimo. También hay similitudes estructurales entre los trastornos callosos y algunos trastornos psiquiátricos. Por ejemplo, varios estudios han encontrado alteración de

la morfología del CC en adolescentes con esquizofrenia y niños con trastorno bipolar, incluyendo cambios en su tamaño y forma. Además, se encontró que los niños maltratados (y especialmente aquellos con trastorno de estrés postraumático), sometidos a investigaciones del cerebro por RM, habían reducido la mielinización y el diámetro de sus fibras en comparación con sujetos sanos en el cuerpo medial y posterior del CC, región que contiene proyecciones interhemisféricas de estructuras cerebrales involucradas en circuitos que median el procesamiento de estímulos emocionales y diversas funciones de memoriadisturbios asociados con una historia de trauma. El tamaño del CC total y sus subregiones fue menor que en los sujetos control. Además, se encontró un CC reducido en mujeres con episodios repetidos de abuso sexual en la infancia, especialmente a los 9-10 años. Estos trastornos por lo general coexisten con otras malformaciones cerebrales y demuestran que los factores ambientales pueden influir en el desarrollo calloso posnatal 24,25. En algunos recién nacidos prematuros se ha visto un retraso en el desarrollo neurológico relacionado con el tamaño del CC. Se han observado reducciones de su volumen, sobre todo más evidentes en la parte posterior y estas anormalidades suelen persistir y tener consecuencias neurológicas a largo plazo. - La dislexia es un trastorno en la capacidad de leer, en la que se confunden o se altera el orden de letras, sílabas o palabras. El estudio de la morfología del CC en la dislexia ha obtenido resultados variables, pero en la mayoría se podía evidenciar una relación positiva entre la capacidad de lectura y el volumen del CC. Diagnóstico El diagnóstico prenatal solo puede realizarse para los casos de agenesia total del cuerpo calloso. Se realiza mediante una ecografía o resonancia magnética a partir de la semana 20 de gestación. Para el asesoramiento prenatal, es muy importante identificar los casos de agenesia del cuerpo calloso aislada o asociada a síndromes genéticos, debido a que un 72,2 % de los pacientes con agenesia aislada presentan neurodesarrollo normal, pero sólo el 7 % de los casos asociados a síndromes genéticos tienen buen pronóstico con respecto a tener un neurodesarrollo adecuado 26,27,28,29. El diagnóstico posnatal puede llevarse a cabo mediante la realización de ecografía, tomografía computarizada o resonancia magnética cerebral. Es ideal que en cualquier escenario diagnóstico, prenatal o posnatal, se utilice la resonancia ya que tiene mayor sensibilidad y especificidad, principalmente para encontrar anomalías anatómicas asociadas 29. Tratamiento No existe un tratamiento específico. A pesar de eso, está indicado un tratamiento de rehabilitación teniendo en cuenta que a pesar de la ausencia congénita del cuerpo calloso, o disminución de su grosor están íntegros los procesos de

plasticidad neural que llevan a que en algunos casos se compense la reducción de la transferencia de información 30,31. El tratamiento debe iniciarse lo antes posible para aprovechar la plasticidad del sistema nervioso; además, hay que tener en cuenta que el objetivo de la rehabilitación es mejorar el funcionamiento global del paciente, las cuales incluyen: terapia del habla, fisioterapia, psicomotricidad, terapia ocupacional o educativa, acompañado de formación de los padres y asesoramiento a los profesores31.

Caso clínico

Nombre: D.S.S.M. Sexo: Femenino. Edad: 6 años 2 meses. Originario: Zacatecas, Zacatecas. Motivo de la consulta: ¨Abscesos en los dientes¨. Padecimiento actual: Paciente femenino, de 6 años de edad con diagnóstico de hipoplasia de cuerpo calloso, acude a la CLIO con presencia de fistulas en la mucosa vestibular en proyección de OD # 51, 61 con una evolución de 4 meses. Asintomáticos, sin medicación previa. Antecedentes personales patológicos: En periodo neonatal tuvo muchos vómitos. Ha sido hospitalizada por 2 días con herpangina a los 2 meses de edad. Por presencia de retraso psico-motor; sostuvo su cabeza a los 5 meses y empezó a caminar a los 18 meses, por lo que acudieron con neurólogo, y fue cuando le detectaron la hipoplasia del cuerpo calloso en la zona de istmo. En tres años de edad estuvo hospitalizada con bronconeumonía. Paciente es alérgica a la penicilina. Tiene inflamaciones intestinales recurrentes. Antecedentes familiares patológicos: La mamá y hermano son alérgicos al polvo, frutos rojos, humedad. Mamá, abuela materna y papá padecen diabetes. Abuela materna sufre de cardiopatías. Antecedentes odontológicos: Su primer visita al odontólogo fue cuando tenía 5 años, por dolor. Se realizó pulpotomia en OD # 85. Antecedentes odontológicos familiares: Presencia de la caries, enfermedad periodontal y maloclusiones. Conducta de la niña: Definitivamente negativa. Clasificación de los padres: Ansiosos.

Riesgo a Caries: Alto. Peso: 30 kilos. Talla: 133cm. Relación peso/edad- normal según la OMS. IMC: 17.0 (por encima del promedio). Circunferencia cefálica: 57cm- aumentado. Análisis facial: Cabello delgado, de inserción alta. Ojos asimétricos (lado derecho está más alto que izquierdo). Labios delgados, cierran con tensión. Línea media facial no coincide. Mentón con forma afilada, rígido. Perfil ligeramente convexo. Tercio inferior disminuido. Orejas grandes de implantación baja. CráneoDolicefálico. Tipo facial – leptoprosópico. Cuello sin tumefacciones y ganglios palpables, con movilidad normal. Miembros y dorso libres de lesiones y cicatrices. Análisis Intraoral: Dentición temporal completa y primeros molares inferiores en erupción (girados). En la mucosa vestibular en proyección de OD # 51 y 61 se observan 2 fistulas. Paladar profundo en forma ojival. Mandíbula y maxila en la forma de herradura. En OD # 51,61 con presencia de las fistulas, resto radicular de OD # 85. Diagnóstico presuntivo pulpitis irreversible de OD # 75, 64. Caries de OD # 84,74. Desgaste patológico de los OD # 52, 53, 62, 63, 74, 73, 83 por bruxismo. Examen Funcional: Respiradora bucal, Masticación unilateral por presencia del dolor. Oclusión: Espacios primates y fisiológicos- ausentes. Línea media desviada. Relación canina: lado derecho - clase 1, lado izquierdo -clase 2.Planos terminales mesiales en ambos lados. Se anexan estudios de laboratorio. Biometría Hemática completa: Todos los valores dentro de la norma a excepción de los siguientes: HCM: resultado-27.50 pg.

Valor de referencia - 28-33pg.

Linfocitos: resultado-64%.

Valor de referencia – 16- 45%.

Monocitos: resultado-4%.

Valor de referencia – 5-9%.

Linfocitos absolutos: resultado- 5184 uL. Valor de referencia-704-4500uL. Tiempo de protrombina: resultado- 11.3 seg. Valor de referencia-12,0- 14.0seg.

Análisis radiográfico:

Figura 1 Se observa resto radicular del OD # 85, y zona radiolúcida en la región periapical, que corresponde a reabsorción ósea.

Figura 2

Se aprecia en la radiografía periapical zona radiolúcida en el tercio apical, que corresponde a reabsorción radicular, aproximadamente de 1/3 de la raíz de los OD # 51,61. Zonas radiolúcidas extensas en las cámaras pulpares de los mismos órganos dentarios y en tabla ósea de órganos dentarios anteriores.

Diagnósticos: Diagnostico medico general: Hipoplasia del cuerpo calloso del istmo. Diagnostico odontológico: Necrosis pulpar de OD # 51(620), 61(620). Resto radicular en OD # 85. Pulpitis irreversible en OD # 52 (620), 62 (620), 53 (620), 63 (620), 64 (320), 75 (420). Caries en OD # 74 (320), 84 (320). Bruxismo. Plan de Tratamiento: 1 cita: Historia clínica, valoración, toma de radiografías, técnica de cepillado. 2 cita: Extracción de OD # 51 y 61. 3 cita: Pulpotomia en OD # 75. 4 cita: Extracción del resto radicular de OD # 85. 5 cita: Colocación de las coronas de acero cromo en OD # 74,75. 6 cita: Preparación del OD # 84, toma de impresión, confección y cementación de corona Ansa invertida. 7 cita: Pulpotomia en OD # 64. 8 cita: Pulpectomia en OD # 53, 52. 9 cita: Pulpectomia en OD # 62,63. 10 cita: Colocación de coronas de acero cromo en OD # 53,52. 11 cita: Colocación de coronas de acero cromo en OD # 62,63. 12 cita: Profilaxis, valoración para tratamiento ortopédico. Tratamientos ejecutados: 12.03.2019: Revisión, llenado de historia clínica, técnica de cepillado, toma de Radiografías en OD # 85 y 51, 52, 61,62. Uso de técnica Decir-Mostrar-Hacer. Refuerzo positivo. 20.05.2019: Extracción de OD # 51, 61. Uso de restricción física, musicoterapia.

27.03.2019: Pulpotomia con ZnO Eugenol e IRM en OD # 75. Uso de restricción física, musicoterapia, aromaterapia, técnica control de voz. 29.03.2019: Extracción del resto radicular en # 85. Uso de restricción física, aromaterapia, musicoterapia, refuerzo positivo. 09.04.2019: Colocación de las coronas del acero-cromo en OD # 74,75. 10.04.2019: Preparación del OD # 84; toma de impresión, confección y cementación de la corona Ansa invertida. Uso de restricción física, aromaterapia, musicoterapia, refuerzo positivo. 08.05.2019: 2 pulpectomias en OD # 62,63 con Vitapex y ionómero de vidrio. Uso de restricción física, aromaterapia y musicoterapia, refuerzo positivo. 21.05.2019: 2 pulpectomias en OD # 53,63 y pulpotomia en OD # 64.Uso de restricción física, musicoterapia y refuerzo positivo. 22.05.2019: Colocación de las coronas de acero-cromo en OD # 52, 53, 62, 63, 64. Extracción de OD # 84 por presencia del 3 grado de movilidad. Se planifica colocación de la prótesis removible unilateral. Conclusiones: Los niños que padecen hipoplasia del cuerpo calloso pueden presentar clínicamente variables manifestaciones bucales. Unos de los más frecuentes son: desgaste patológico por el bruxismo, paladar ojival, colapsos maxilares, anomalías de anatomía pulpar, presencia de los dientes supernumerarios o ausencias congénitas, erupción tardía, múltiples lesiones cariosas. Esa cantidad de daño presente junto con los trastornos conductuales y falta de comprensión nos podrán llevar a decisión de llevar tratamiento bajo anestesia general. Aun así es un deber de cada odontopediatra de tomar esta opción como la última por ofrecer, debido a sus riesgos. Sin embargo el reto en estos casos es adquirir la cooperación del paciente y saber modificar la conducta, ser flexible en su plan de tratamiento y tener una buena comunicación tanto con el niño, como con sus padres o cuidadores. Que la información brindada por ellos nos podrá dar ideas en qué manera abordar al paciente y cuales técnicas de desensibilización usar. El enfoque terapéutico debe basarse en los cambios de la dieta, hábitos de higiene bucal, y explicación de la importancia de la salud bucal a los padres, para poder ofrecer la rehabilitación exitosa y completa que mejorará la calidad de vida del paciente.

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11 Shantanu H. Joshi, Katherine L. Narr, Owen R.Philips, Keith H. Nuechterlein, Robert F. Asarnow, Arthur W, Toga, Roger P. Woods Statistical shape analysis of the corpus callosum in Schizofrenia. NeuroImage 2013:64:547-559. 12 Singh S, Garge S. Agenesis of the corpus callosum. Journal of Pediatric Neurosciences. 2010; 5(1):83-85. 13 LK P. Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement. Journal of Neurodevelopmental Disorders. 2011; 3(1), 3–27. 14 Siffredi V, Anderson V, Leventer RJ, Spencer-Smith MM. Neuropsychological profile of agenesis of the corpus callosum: a systematic review, Developmental Neuropsychology.2013 38:1, 36-57. 15 Doherty, D., Tu, S., Schilmoeller, K., & Schilmoeller, G.: Health-related issues in individuals with agenesis of the corpus callosum. Child: Care, Health, and Development 2006; 3: 333–342. 16 Burton, B Agenesis of the corpus callosum. En Kuman, P. y Burton, B. (Mc Graw Hill Medical). 2008. Congenital Malformations. 17 L. Valls Masot, G. Blasco Solá, J. Puig Alcántara, S. Remollo Friedemann, S. Pedraza Gutiérrez. Lesiones del cuerpo calloso: diagnóstico diferencial mediante técnicas convencionales y avanzadas de resonancia magnética. 2012. Sociedad Española de Radiología Médica. Congreso Nacional en Granada. 18 D’Ercole C, Girard N, Cravello L, Boubli L, Potier A, Raybaud C, Blanc B. Prenatal diagnosis of fetal corpus callosum agenesis by ultrasonography and magnetic resonance imaging. Prenat Diagn 1998; 18: 247–53. 19 Chiappedi M, Bejor M. Corpus callosum agenesis and rehabilitative treatment. Italian Journal of Pediatrics. 2010; 36:64. 20 Glass HC, Shaw GM, Ma C, Sherr EH. Agenesis of the corpus callosum in California 1983-2003: A population-based study. Am J Med Genet A. 2008; 146A (19):2495-500. 21 Schell-Apacik CC, Wagner K, Bihler M, Ertl-Wagner B, Heinrich U, Klopocki E, et al. Agenesis and dysgenesis of the corpus callosum: clinical, genetic and neuroimaging findings in a series of 41 Patients. Am J Medic Genet 2008; 146A (19):2501-2511. 22 Labadi B., Beke AM. Mental state understanding in children with agenesis of the corpus callosum. 2017 Obstetrics and Gynecology Clinic No. 1, Semmelweis University, Budapest, Hungary.

23 Barkovich J., Norman Anomalies of the Corpus Callosum: Correlation with further anomalies of the brain.1988. AJR; 151: 171-179. 24 Unterberger I., Bauer R., Walser G., Bauer G. (2016) Corpus callosum and epilepsies. European Journal of Epilepsy. April 2016 Volume 37, pages 55-60. 25 P. Volpe, D. Paladini, M. Resta, A. Stanziano, M. Salvatore, M. Quarantelli, V. De Robertis. 2006. Characteristics, associations and outcome of partial agenesis. 26 Zaldibar, B, Ruiz B., Basterrechea J, Bermejo M. Rehabilitación psicomotriz en la agenesia del cuerpo calloso. Rehabilitación. 1999; 33(4): 236-242. 27 Da Silva S, Queiroz A, Niza, N, Da Costa, L, Ries L. Pediatric neurofunctional intervention in agenesis of the corpus callosum: a case report. Revista Paulista De Pediatria. 2014; 32(3): 252-256. 28 Mangione R, Fries N, Godard P, Capron C, Mirlesse V, Lacombe D, et al. Neurodevelopmental outcome following prenatal diagnosis of an isolated anomaly of the corpus callosum. Ultrasound Obstet Gynecol. 2011; 37:290–295. 29 Francesco P, Maria-Edgarda B, Giovanni P, Dandolo G, Giulio B. Prenatal diagnosis of agenesis of corpus callosum: what is the neurodevelopmental outcome? Pediatr Int. 2006; 48:298–304. 30 Hübner M, Ramírez R, Nazer J. Malformaciones congénitas. Santiago de Chile: Editorial Universitaria; 2005. 31 Hanna RM, Marsh SE, Swistun D, et al. Distinguishing 3 classes of corpus callosal abnormalities in consanguineous families. 2011 Neurology 76:373–382.

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE

Corpus callosum abnormalities: neuroradiological and clinical correlations AQEELA H AL-HASHIM1,2 | SUSAN BLASER3 | CHARLES RAYBAUD3 | DAUNE MACGREGOR11 Department of Neurology, The Hospital for Sick Children, Toronto, ON, Canada. 2 Department of Neuroscience, King Fahad Medical City, Riyadh, Saudi Arabia. 3 Department of Neuroradiology, The Hospital for Sick Children, Toronto, ON, Canada.Correspondence to Aqeela Al-Hashim at Department of Neurology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada. E-mail: Aqeela.alhashim@sickkids.ca This article is commented on by Palmer on pages 430–431 of this issue. PUBLICATION DATA

Accepted for publication 6th October 2015. Published online 9th December 2015. ABBREVIATIONS

ACC Agenesis of the corpus callosum CCA Corpus callosum abnormalities CMA Chromosomal microarray OMIM Online Mendelian Inheritance in Man

AIM To study neuroradiological features in pediatric patients with corpus callosum abnormalities, using new functional subtyping for the corpus callosum, and to correlate the features with the clinical presentation.METHOD We performed a retrospective review of 125 patients with radiologically identified abnormalities of the corpus callosum seen between 1999 and 2012. The study reviewed clinical features, genetic etiology, and chromosomal microarray (CMA) results. We used a new functional classification for callosal abnormalities based on embryological and anatomical correlations with four classes: complete agenesis, anterior agenesis (rostrum, genu, body), posterior agenesis (isthmus, splenium), and complete hypoplasia (thinning).We also studied the presence of extracallosal abnormalities.RESULTS The new functional callosal subtyping did not reveal significant differences between the various subtypes in association with neurological outcome; however, the presence of cardiac disease was found more frequently in the group with complete agenesis. Thirty- seven per cent (46/125) had identifiable causes: of these, 48% (22/46) had a monogenic disorder, 30% (14/46) had a pathogenic chromosomal copy-number variant detected by CMA or karyotype, and 22% (10/46) had a recognizable clinical syndrome for which no confirmatory genetic test was available (namely Aicardi syndrome/septo-optic dysplasia and Goldenhar syndrome). The diagnostic yield for a significant CMA change was 19%. The presence of Probst bundles was found to be associated with a better neurodevelopmental outcome.INTERPRETATION The functional classification system alone ‘without clinical data’ cannot predict the functional outcome. The presence of extracallosal brain abnormalities and an underlying genetic diagnosis predicted a worse neurodevelopmental outcome. This study highlights the importance of CMA testing and cardiac evaluation as part of a routine screen.

The corpus callosum is the major interhemispheric fiber bundle in the brain.1 Corpus

callosum abnormalities (CCA) have an estimated prevalence of 0.3% to 0.7% in patients undergoing neuroimaging2 in the general population and 2% to 3% in a developmentally challenged population.3 In humans, the development of the corpus callosum begins by week 8 of fetal life. The portion of the lamina terminalis immediately adjacent to the tela choroidea on the midline becomes thicker (the lamina reuniens) and forms the primordium of the septal area.4 The early pioneer fibers cross at week 9 in the lamina reuniens. The progression of these fibers is facilitated by commissural cellular glial guidance tunnels that support the pioneer axons to cross at about weeks 12 to 13 of fetal life to form the corpus callosum.4 While the anterior commissure, hippocampal commissure, and splenium develop across the lamina reuniens, the anterior callosum (circumscribing the septum pellucidum) has its own developmental process and crosses through the meninges of the interhemispheric fissure.4 Given the complexity of corpus callosum formation, the causes of commissural agenesis can be multiple and are usually associated with other diverse defects. Terminology about CCA is variable. Previous studies have differentiated patients into those with (complex) or without additional brain malformations (isolated) or into partial (absence from birth of at least one, but not all, regions of the corpus callosum) or complete agenesis (total absence from birth of all the anatomically defined regions of the corpus callosum);5 however, no previous study has, to our knowledge, used an embryology-based functional anatomical classification system. With advances in neuroimaging and use of diffusion tensor imaging-based tractography, investigators have ÂŠ 2015 Mac Keith Press DOI: 10.1111/dmcn.12978 475

separated transcallosal fiber tracts for their specific cortical projections and can distinguish between fibers associated with prefrontal, premotor (combined with supplementary motor), primary motor, primary sensory, parietal, temporal, and occipital cortical regions.6 The purpose of this study was to use this new functional anatomical classification system and to evaluate whether the neurodevelopmental outcome varies depending on the malformed area: namely, whether patients with anterior callosal agenesis have more motor abnormalities or patients with posterior agenesis have more visual disturbances. We studied for the presence of brain malformations other than CCA, including cortical dysgenesis, neuronal migration disorders, and brainstem abnormalities. We divided patients into those with isolated CCA and those with additional brain malformations.

METHOD We ascertained children with CCA by searching the data- base of the Neuroradiology

Department at the Hospital for Sick Children, Toronto, for patients seen from 1999 to 2012. Patients were referred for neuroimaging either for neurodevelopmental concerns or as a follow-up of antenatal concerns. We obtained institutional review board approval. Patientsâ&#x20AC;&#x2122; electronic charts were retrospectively reviewed for the following variables: patient demographics, date of the magnetic resonance imaging study, presence of prematurity, epilepsy, fine motor developmental delay, gross motor delay, social delay, speech delay, hearing and visual impairment, behavioral problems, dysmorphic features, head circumference, tone abnormality, other organ involvement (including eye; ear, nose, and throat; heart; gastrointestinal; musculoskeletal), genetic etiology, and the result of chromosomal microarray (CMA) testing (Tables SI and SII, online supporting information). Neuropsychological reports were not available for a significant proportion of patients. One hundred and forty-eight pediatric patients were found with CCA but only 125 from 1 day to 18 years of age were included. Eleven patients with insufficient clinical data were excluded and an additional 12 patients were also excluded upon neuroimaging review (nine patients with major brain malformations, for example holoprosencephaly or schizencephaly, in which the CCA was a secondary rather than primary phenomenon, and three patients with poor imaging quality). Clinical information was obtained from clinic reports of pediatric neurology or genetics (Table SI, online supporting information). All patients had magnetic resonance imaging of the brain on a 1.5T to 3T scanner. Images were reviewed by a pediatric neuroradiologist independent of the original interpretation of the scans and who was blinded to their clinical evaluation. We adopted a new functional anatomical subtyping of the corpus callosum in which we divided the corpus callosum into anterior and posterior regions. The anterior part includes the rostrum, genu, and body, and carries mainly pre-motor and frontal association fibers. The posterior part is composed of the isthmus (carrying the primary sensori- motor fibers) and the splenium (carrying mainly parieto- occipital fibers). We divided the CCA into four groups (Figure 1) for the neuroimaging findings in the different subtypes, as follows. (1) Complete agenesis of corpus callosum (ACC): there is complete absence of all callosal fibers. This accounted for 52% (65/125) of our cohort. (2) Ante- rior ACC: the rostrum, genu, and body are missing or severely hypoplastic, and only the splenium is present. This type is very rare and was found in only 2% (3/125) of the cohort. Because of the small sample size, it is difficult to draw any significant conclusions about this group. (3) Pos- terior agenesis: the splenium fibers are missing or severely hypoplastic, this was found in 30% (37/125) of the cohort. (4) Complete hypoplasia: defined as complete thinning of the corpus callosum. This was found in 16% (20/125).

Statistics Our variables were categorical. We calculated proportions and associations using chi square

testing and Fisher’s exact test (whenever the sample size was <10 at any given cell) to calculate p values and odds ratios (OR). Results having p<0.05 were considered significant. The p value was adjusted to 0.005 to account for multiple testing using Sidak correction. Calculations were performed using SPSS version 17 (IBM SPSS Statitics, IBM Inc., NY, USA).

RESULTSClassification and functional subtyping of corpus callosumThere were some associations between callosal subtype and clinical features. The presence of cardiac disease was found more in the group with complete agenesis (25% [16/65]; p=0.001). The following showed no statistically significant differences between callosal subtypes: dysmorphic features, visual impairment, fine motor delay, social delay, behavioral problems, other organ involvement, genetic etiology, and CMA testing. This study did not show that patients with posterior agenesis have more visual impairment as originally hypothesized (Table I). There was no significant association between complex versus isolated CCA and the different callosal subtypes (p=0.9).

Developmental and neurological features Among the 125 patients, 58% were male and 42% were female. A significant proportion had fine motor

What this paper adds

•

The yield of chromosomal microarray testing is high, even in cases of isolated callosal agenesis.

•

It highlights the significant association of cardiac anomalies in isolated and complete agenesis of the corpus callosum.

•

The functional anatomical classification system in isolation was not able to predict neurological outcome.

•

The presence of extracallosal and extra-central nervous system malformation together with the detection of a neurogenetic

476 Developmental Medicine & Child Neurology 2016, 58: 475–484

(a) Complete ACC (52%) (b) Anterior ACC (2%) APAP APAP

Figure 1: Different types of corpus callosum abnormality based on functional anatomical classification. (a) Sagittal T1 showin absent anterior and hippocampal commissures. (b) Sagittal T1 turbo spin echo showing agenesis of the rostrum and hypoplasi inversion recovery showing absent splenium with small interhemispheric lipoma. (d) Sagittal T2 turbo spin echo showing hyp with Apert syndrome. A, anterior; P, posterior.

developmental delay (77% [90/117]), gross motor delay (74% [86/116]), speech delay (74% [86/116]), and social delay (66% [77/116]). Behavioral abnormalities were reported in 49% (29/59) of the patients. Epilepsy was diagnosed in 36% (45/125) of patients and dysmorphic features were found in 61% (74/ 121). Fifty-one per cent (64/125) of patients had consistent ophthalmological review by a pediatric ophthalmologist. Visual impairment occurred in 40% (49/123) and was not different between the various corpus callosal subtypes; 35% (13/37) of patients with posterior agenesis CCA had visual impairment. Normal tone was found in 45% (54/ 121), with hypotonia in 36% (44/121) and hypertonia in 19% (23/121) of the patients. Macrocephaly or microcephaly were found in 23% of the patients, with normo- cephaly in 55% (65/119). The involvement of other organ systems apart from the brain was found in 81% (101/125). Systemic abnormalities in this patient cohort were as follows: eye (46%), ear, nose, and throat (27%), heart (21%), lung (13%), gastrointestinal (37%), genitourinary (34%), musculoskeletal (34%), endocrine (13%).

Genetic etiology and CMA testing Among patients with CCA, 53% (66/125) had a clinical genetics review, 70% (87/125) had a neurology review, and 33% (41/125) had combined genetic and neurology reviews. Thirty-seven per cent (46/125) had identifiable genetic causes. The following results were found among the patients with an underlying cause identified on clinical genetic review, chromosomal or single gene testing: 48% (22/46) had a monogenic disorder, 30% (14/46) had a pathogenic chromosomal change on CMA out of karyotype testing, and 22% (10/46)

had a clinical syndromic diagnosis for a condition where specific genetic testing was not available (namely Aicardi syndrome, septo-optic dysplasia, and Goldenhar syndrome). The commonest syndromic diagnoses in our cohort were Aicardi syndrome in seven patients, frontonasal dysplasia in five, septo-optic dysplasia in two, and Apert syndrome in two, for all patients with single gene disorders and recognizable syndromes (Table II). CMA testing was done in 29% (36/125) of the patients, and karyotyping in 22% (28/125). Thirty-one per cent (20/ 64) of patients had abnormal results but only 70% (14/20) were known pathogenic changes and 30% (6/20) were of unknown clinical significance. Fifty per cent (7/14) of pathogenic changes were detected by CMA and the remaining 50% (7/14) by karyotype. The chromosomal findings are listed in Table III. Seven of the copy number variants detected by CMA represented likely/known pathogenic variants; the remaining six were variants of uncertain clinical significance. Therefore, overall the diagnostic yield (likely and definite pathogenic variants) of CMA in our Corpus Callosum Abnormalities Aqeela H Al-Hashim et al. 477 Table I: Corpus callosal subtyping and clinical variables Anterior agenesis (%), n=3 Cardiac anomalies Present 100 Absent 0 EpilepsyPresent 0 Absent 100 Posterior agenesis (%), n=37 5 95 38 62 70 27 73 24 60 35 24 27 62 32 16 73 35 62 65 32 46 32 19 8 22 51 49

Complete agenesis (%), n=65 25 75 41 59 71 19 62 26 60 29 22 25 69 22 14 74 42 57 55 43 42 34 23 9 19 49 51 Complete hypoplasia (%), n=20 30 70 20 80 80 20 85 15 70 30 25 20 75 20 35 50 40 60 60 30 45 40 5 10 25 30 70 p Adjusted pa 0.0001 0.0010.2 0.70.8 1

0.6 1 0.9 1 0.9 1 0.5 0.9 0.1 0.7 0.9 1 0.7 1 0.6 0.9 0.1 0.7 0.4 0.9

Fine motor DD Present AbsentGross motor DD Present Absent Social DD Present 67 33 67 33 67 Absent Behavioral issues Present 33 Absent 0 Speech delay Present 100 Absent 0 Hearing impairment Present 33 Absent 67 Visual impairment Present 33 Absent 67 Dysmorphic features Present 67 Absent 33 Hypotonia, hypertonia Normal 33 Hypotonia 67 Hypertonia 0 CMA testing Positive 100 Negative 0 Extracallosal brain abnormalities Present 33Absent 67 33

Adjusted p value using S_ıda_k correction. DD, developmental delay; CMA, chromosomal microarray.

cohort was seven out of 36 (19%). The chromosomal abnormalities in 12 patients included genes previously associated with CCA;7 however, we report here a novel association of syndromic diagnoses and CCA in argini- nosuccinic aciduria, Schinzel–Giedion syndrome, and Baraitser–Winter syndrome. An underlying genetic etiology was highly associated with the presence of dysmorphic features (p=0.001) (Table SIII).

Isolated CCA versus extracallosal CNS abnormalities (complex)Extracallosal brain abnormalities were found in 46% (58/125) and were associated with a higher risk of

epilepsy (p=0.002), gross motor delay (p=0.011), and speech delay (p=0.035). CMA testing yield was comparable between patients without and with extracallosal CNS abnormalities, although one might suspect that patients with extracallosal CNS abnormalities would have had a higher probability of positive CMA. The presence of cardiac disease was higher in patients with an isolated callosal abnormality (p=0.001).

Additional neuroimaging features 478 Developmental Medicine & Child Neurology 2016, 58: 475â&#x20AC;&#x201C;484

Probst bundles (longitudinal callosal fascicles that fail to cross the midline) were found in 60% of our cohort (75/ 125). There was high association between the presence of Probst bundles and agenesis of the anterior callosal fibers, whether as part of anterior or complete ACC. Forty-two per cent of those patients had Probst bundles (53/125; p=0.001). In patients with a normal anterior callosum, only 3% had Probst bundles. There was a high association between the presence of Probst bundles and colpocephaly (p=0.001). Patients with better adaptive and social functions had a higher percentage of Probst bundles (p=0.017). The anterior commissure was absent in 35% (44/125), normal in 26% (33/125), and hypoplastic in 38% (48/125). Associated grey matter heterotopia was noted in 20% (25/ 125) while cortical dysgenesis was found in 14% (18/125). The presence of ventral posterior fossa abnormalities (mid brain, pons, and medulla) was higher than dorsal posterior fossa anomalies (21% and 15% respectively). Almost half of our cohort had colpocephaly (52%) while generalized Table II: Single gene disorder and recognizable syndromesaPatient Diagnosis Confirmatory test disorder syndrome

1 Goldenhar + syndromea

2 CHARGE + Syndromea

3 Orofacial digital NA + syndrome type 1

4 Apert De novo heterozygous reported + syndrome pathogenic variant in FGFR2 c.755C>G (p.Ser252Trp)

5 Fibrodysplasia De novo heterozygous reported + ossificans pathogenic variant in ACVR1 progressiva c.983G>A (p.Gly328Glu)

6 Crouzon De novo heterozygous reported + syndrome pathogenic variant in FGFR2 c.880T>C (p.Trp290Gly)

7 Aicardi + syndromea

8 Aicardi + syndromea

9 Cornelia de NA + Lange syndrome

10 Coffin–Siris NA + syndrome

11 Bilateral De novo heterozygous variant + hereditary predicted pathogenic deletion of neuroblastoma exons 15 and 16 in RB1

12 Frontonasal Not done + dysplasia

13 Aicardi + syndromea

14 Septo-optic + dysplasiaa

15 Apert NA + syndrome

16 Schinzel- NA + Giedion syndrome

17 Aicardi + syndromea

18 Arginosuccinic De novo compound + aciduria heterozygous variant predicted pathogenic in ASL c.35G>A (p.Arg12Gln); c.839delG resulting in frame shift mutation

19 Andermann De novo homozygous variant + syndrome predicted pathogenic in KCC3 c.745+2t>a presumably affects splicing in intron 6

20 Frontonasal Not done + dysplasia

21 Frontonasal Not done + dysplasia

22 Mowat–Wilson De novo heterozygous variant + syndrome reported pathogenic in ZEB2 c.3211T>C (p.Ser1071Pro)

23 Septo-optic + dysplasiaa

24 Frontonasal Not done + dysplasia

25 Schinzel– NA + Giedion syndrome

26 Aicardi + syndromea

27 Frontonasal Not done + dysplasia

RecognizedCCA Complex syndrome CCA ++ + + + Single gene Recognizable Isolated CCA +

+ + ++ ++ + + + Type of CCA Complete agenesis Posterior agenesis Complete agenesis Complete hypoplasia Posterior agenesis Complete hypoplasia Complete agenesis Complete agenesis Complete agenesis Complete hypoplasia Complete agenesis Complete agenesis Complete agenesis Complete hypoplasia Posterior agenesis Complete hypoplasia Complete agenesis Complete agenesis Complete agenesis Complete agenesis Complete agenesis Complete agenesis Complete agenesis Complete agenesis Complete agenesis Complete agenesis Complete agenesis

+ + +

+ + ++ ++ + + + + ++ + + + ++ ++ +++++ +++++ ++++

Corpus Callosum Abnormalities Aqeela H Al-Hashim et al. 479 Table II: Continued Singlegene Recognizable disorder syndrome ++ syndromea RecognizedCCA Complex syndrome CCA ++ Isolated CCA Type of CCA Complete agenesis Posterior agenesis Complete hypoplasia Complete agenesis Patient Diagnosis 28 FG syndrome Confirmatory test NA

29 Baraitserâ&#x20AC;&#x201C; NA Winter + ++ ++

syndrome 30 Frontonasal +31 Aicardi + dysplasia De novo heterozygous variant reported pathogenic in EFNB1 c.80C>G (p.Pro27Arg)

Recognizable clinical syndrome without a single genetic test, for example Goldenhar/Aicardi syndromes. CCA, corpus callosum abnormalities; NA, not available in our medical records but genetic testing already done in the referring center.

ventriculomegaly was noted in 26%. Cystic meningeal dysplasia was noted in 12%.

DISCUSSION Consistent with the broad range of genetic factors involved in CCA, the behavioral and neurological consequences of CCA are wide ranging. One approach to defining clinical subsets of a population of patients with CCA is to catego- rize individuals according to specific neuroanatomical findings and relate these to specific neurological symptoms within those groups. Matching specific symptoms to a functionally corresponding corpus callosum subtype did not reveal significant association at a clinical level. The group with posterior agenesis did not have a higher proportion of visual impairment as initially hypothesized given the involvement of parieto-occipital fibers. Perhaps the lack of evidence of an association is due to the lack of power to detect anything but gross differences, or due to the lack of an ophthalmology review in 49% of the patients who might have had subtle abnormalities, or in relying on very simple clinical scales; however, using a sophisticated tech- nique like tachistoscopic presentation of visual stimuli as shown by visual evoked potentials may demonstrate unique patterns of visual field deficits in laboratory tasks, intact comparisons of simple stimuli, and impaired comparisons of complex stimuli in these patients.8 The largest subset of patients in our cohort was the group with complete agenesis (52%), similar to a study by Bedeschi et al.9 that reported 47% with complete ACC versus 53% with partial ACC. This is in contrast to a study by Taylor and David10 that reported a prevalence of complete agenesis (71%) versus partial agenesis (29%), although their methods were not comparable to our study because they used computed tomographic scanning. Schell-Apacik et al.11 reported a significant proportion of developmental delay in 89%, speech delay in 88%, and seizure disorders in 62% of 41 patients with ACC. The proportion of patients with extracallosal neuroradiological findings was higher than in our study. A higher prevalence of ACC predominance in males has been reported in some studies.12,13 In our cohort, 58% were male and 42% were female. Cardiac anomalies were found in 25% of our cohort, comparable to the results in

the study by Bedeschi et al.9 (27%). Our study is the first to show, to our knowledge, that patients with isolated CCA and those with complete agenesis have a higher rate of cardiac anomalies (p=0.001). Our study also highlights the importance of including a cardiac review in the assessment of patients with apparently isolated CCA. A recent systematic review14 assessed the rate of neurodevelopmental outcome in 132 infants (16 studies) with isolated ACC. The authors reported neurodevelopmental outcome as normal, borderline, moderate disability, or severe disability. In complete ACC, the respective figures for the last three outcomes were 74%, 14%, and 11%, whereas for isolated partial ACC they were 66%, 7%, and 28%.14 A recent prospective study15 of 11 children with isolated ACC using neuropsychological assessment showed intelligence levels in the normal to low range in 73% and borderline in 27%. Half of these children had academic difficulties requiring rehabili- tation services. Behavioral issues were reported in 43%. In our cohort, we found 49% with behavioral issues, but we did not conduct neuropsychological evaluations. ACC has been associated with several syndromes with autosomal dominant, autosomal recessive, or X-linked modes of inheritance.11,16 An Online Mendelian Inheri- tance in Man (OMIM) search for â&#x20AC;&#x2DC;Agenesis of the corpus callosum and syndromeâ&#x20AC;&#x2122; resulted in 412 entries. Bedeschi et al.9 studied 63 cases of ACC with neuropsychiatric disorders and found that 33% had a recognizable syndrome. Schell-Apacik et al.11 studied 41 patients with ACC and found that 32% had genetic syndromes. Thirty-seven per cent of our cohort had identifiable diagnoses including single gene disorders, copy number variants, or a recognizable syndrome. This result is comparable to or just slightly higher than what have been reported; the group with single gene disorders is the commonest and the list will expand in the future with the use of exom sequencing. Our study showed that CMA should be a best practice standard in CCA and not limited to those with additional brain malformations or systemic comorbidities. There is no statistically significant difference between those with com480 Developmental Medicine & Child Neurology 2016, 58: 475â&#x20AC;&#x201C;484 Corpus Callosum Abnormalities Aqeela H Al-Hashim et al. 481 Table III: Microdeletion/duplication syndromes Type of genetic Patient test Human genome assembly RecognizedPathogenic CC critical Complex Isolated CCA CCA subtype 32 Oligonucleotide CMA

Hg18 Parental studies not available Likely pathogenic deletion + Complete agenesis 33 Oligonucleotide CMA Hg18 Hg18 14q12q21.1(29, 342, 794->37, 696, 839) X1dn De novo 609408182138, 602403, 611358, 162200, 606245 Pathogenic Recognized deletion deletion ++ Anterior agenesis 34 Oligonucleotide CMA 17q11.2q12(25, 012, 105-29, 590, 451)x1 Parental studies not available Pathogenic Not deletion recognized Complete hypoplasia 35 Karyotype, CTG band 46, xy, del(5) (p15.1p15.3) Parental studies not available Pathogenic Recognized + deletion deletion Complete hypoplasia resolution 550 36 Oligonucleotide CMA Hg19 13q13.2-q31.2(34, 580, 420-89, 240, 042)x1dn De novo 230 OMIM morbid map genes SPG20, RFXAP, SMAD9, FREM2, COG6, FOX01, SLC25A15, TNFSF11, HTR2A, SUCLA2, ITM2B, RB1, LPAR6, PHF11, RCBTB1, RNASEH2B, ATP7B, ALG11, DIA, PH3, ATXN805, CLN5,

EDNRB and SL1TRX1 Pathogenic Not + deletion recognized Posterior agenesis 37 Karyotype, CTG band 46, xy.ish del(x) (p22.3)(DXY5129-, KAL-)unbalanced translocation between xp2.31 and 11q25 Parental studies not available Pathogenic Recognized + deletion deletion Posterior agenesis resolution 550 38 Oligonucleotide CMA Hg18 14q32.33(104, 472, 421-105, 050, 817)93 Parental studies not available Duplication + of unknownclinicalsignificance Complete agenesis 39 Oligonucleotide CMA Hg18 8q11.1-q11.2(47, 061, 921->48, 703, 290)93 Parental studies not available Duplication of unknown clinical significance + Complete agenesis 40 Karyotype, CTG band 46, xy, del(18) (q21.2q22.2)ins(18;4) (q21.2;q25q31.1) De novo De novo Pathogenic Recognized deletion deletion + Complete agenesis resolution 500 41 Karyotype, CTG

46, xy, inv dup(8) (p23.1p21) Pathogenic Recognized + duplication duplication Complete agenesis band resolution 550 Abnormality detected 6q22.31(123, 272, 156 Inheritance OMIM number vs UCS gene7 CCA â&#x20AC;&#x201C;124, 322, 360)x1, 6q23.1q23.2(130, 846, 741-131, 685, 322)x1, 7p21.1p15.3(19, 208, 927-20, 781, 916)x1, 7p21.3p21.1(8, 990, 160-17, 361, 999)x1

482 Developmental Medicine & Child Neurology 2016, 58: 475â&#x20AC;&#x201C;484 Table III: ContinuedType of genetic genome RecognizedPathogenic CC critical Complex Human Patient test assembly Abnormality detected Inheritance De novo OMIM number vs UCS gene7 CCA Isolated CCA CCA subtype 42 Karyotype, CTG band 46, XX del(1) (p36.1P36.2) Pathogenic Recognized + deletion deletion Complete agenesis resolution 450 43 Karyotype, CTG 47, XX, +18 De novo Pathogenic Known to + (trisomy 18) be Complete agenesis

band resolution 550 associated 44 Oligonucleotide Hg18 CMA 1p36.33p36.22(836, 343-11, 769, 179) x1dn, 14q21.2(41, 353, 432-42, 858, 823)93 De novo 607872 with CCA Pathogenic Recognized + Complete hypoplasia 45 Oligonucleotide Hg18 CMA 22q11.21(17, 015, 796->19, 770, 515)93 Parental studies not available Pathogenic Recognized + duplication duplication Complete agenesis 46 Oligonucleotide Hg19 CMA 17q21.31(41, 457, 342-41, 461, 699)x1 De novo 157140 Pathogenic Recognized deletion deletion + Posterior agenesis 47 Oligonucleotide Hg18 CMA 5p15.33-p14.3(74, 949-20, 321, 317)x1, 20p13-p11.23(18, 380->13, 137, 085)93 Parental studies not available OMIM morbid map genes 600857, 608893, 126455, 603848, 187270, 602568, 610150, 604275, 603335, 123450 Pathogenic Recognized + deletion + deletion duplication Anterior agenesis 48 Oligonucleotide Hg18 CMA Xq13.1(68, 435, 734- 69, 017, 748)x2, 2q21.1(131, 217, 776- 131, 632, 329)93 Maternal

2 Duplication + of unknownclinicalsignificance Posterior agenesis 49 Oligonucleotide Hg18 CMA 19q12(32, 544, 847- 33, 175, 489)93 Maternal Duplication of unknown clinical significance + Anterior agenesis 50 Oligonucleotide Hg18 CMA 15q11.2(21, 982, 546- 22, 653, 142)93 Parental studies not available Duplication of unknown clinical significance + Complete agenesis 51 Karyotype G banding 550 46, XY, del(18)(q21.1) [8]/46, XY [21] Parental studies not available Pathogenic Recognized + deletion deletion Posterior agenesis OMIM, Online Mendelian Inheritance in Man; UCS, uncertain clinical significance; CC, corpus callosum; CCA, corpus callosum abnormalities; CMA, chromosomal microarray. deletion deletion

plex brain malformations and the isolated cases of cytoge- netic abnormalities or CMA test. This is in contrast to a study that suggested a high risk of chromosomal abnormalities is confined to complex cases,17 but these authors only used karyotyping for genetic testing. There was no evidence of an association between CMA abnormalities and callosal subtypes; however, the small sample size might be a factor in this. The presence of extracallosal CNS malformation was found in 46% of our cohort whereas other studies have shown variable results: 83%,9 52%,18 and 46%.19 Our study reports a similar result to that of Hetts et al.20 who found an absent anterior commissure in 33% of their patients and in 25% of their group with hypoplasia. We found

73% of our patients had either an absent or hypoplastic anterior commissure.20 The association with Probst bundles was variable. One study reviewed patients from two hospitals and found one group with 18% Probst bundles and the other with 66%.20 Interestingly, our study showed that patients with Probst bundles have better adaptive and social function- ing, which illustrates the important role of Probst bundles as compensatory fibers. An abnormality of the corpus callosum was commonly associated with cortical malformations (51% of the group with ACC) and grey matter heterotopia (29% of the group with ACC).20 The lower percentages in our study (14% and 20% respectively) are probably due to exclusion of major cortical malformations in our cohort.

Limitations Given the nature of the retrospective study, detailed neuropsychological evaluation was not available to detect subtle abnormalities that might not have been found by clinical evaluation. The lack of genetic analysis in a high number of patients is another limitation. The proportion of comorbid conditions is high, reflecting a group of patients with complex medical problems followed at a tertiary healthcare center. This might increase the number of patients with severe disabilities, therefore making our results less generalizable.

CONCLUSION Developmental CCA appeared to be a common phenotype and implicate multiple overlapping pathways in their causa- tion. The functional classification system alone without clinical data cannot predict the functional outcome. The presence of extracallosal brain anomalies is not the only major predictive factor, and probably the underlying neurogenetic cause has a stronger effect on the clinical phenotype and outcome. Based on our findings we recommend clinical genetics review (and genetic testing targeted at a clinical diagnosis), CMA testing, and cardiac evaluation to be a best practice standard in patients with CCA, even in those with the isolated form. Future studies to be considered should use functional and tractography-based imaging to identify the role played by Probst bundles and other misrouted fibers in interhemispheric organization in patients with CCA. ACKNOWLEDGEMENTS The authors have stated that they had no interests that might be perceived as posing a conflict or bias.

SUPPORTING INFORMATION The following additional material may be found online: Table SI: Clinical characteristics.Table SII: Variables and missing data.Table SIII: Genetic etiology and other organ involvement.

REFERENCES 1. Aboitiz F, Montiel J. One hundred million years of interhemispheric communication: the history of the corpus callosum. Braz J Med Biol Res 2003; 36: 409–20. 2. Grogono JL. Children with agenesis of the corpus callosum. Dev Med Child Neurol 1968; 10: 613–16. 3. Jeret JS, Serur D, Wisniewski KE, Lubin RA. Clinico- pathological findings associated with agenesis of the corpus callosum. Brain Dev 1987; 9: 255–64. 4. Raybaud C. The corpus callosum, the other great forebrain commissures, and the septum pellucidum: anatomy, development, and malformation. Neuroradiology 2010; 52: 447–77. 5. Palmer EE, Mowat D. Agenesis of the corpus callosum: a clinical approach to diagnosis. Am J Med Genet C 2014; 166: 184–97. 6. Hofer S, Frahm J. Topography of the human corpus callosum revisited—comprehensive fiber tractography using diffusion tensor magnetic resonance imaging. NeuroImage 2006; 32: 989–94. 7. O’Driscoll MC, Black GC, Clayton-Smith J, Sherr EH, Dobyns WB. Identification of genomic loci contributing to agenesis of the corpus callosum. Am J Med Genet A 2010; 152: 2145–59. 8. Brown WS, Jeeves MA, Dietrich R, Burnison DS. Bilateral field advantage and evoked potential interhemispheric transmission in commissurotomy and callosal agenesis. Neuropsychologia 1999; 37: 1165–80. 9. Bedeschi MF, Bonaglia MC, Grasso R, et al. Agenesis of the corpus callosum: clinical and genetic study in 63 young patients. Pediatr Neurol 2006; 34: 186–93. 10. Taylor M, David AS. Agenesis of the corpus callosum: a United Kingdom series of 56 cases. J Neurol Neurosurg Psychiatry 1998; 64: 131–34. 11. Schell-Apacik CC, Wagner K, Bihler M, et al. Agenesis and dysgenesis of the corpus callosum: clinical, genetic and neuroimaging findings in a series of 41 patients. Am J Med Genet A 2008; 146: 2501–11. 12. Moes P, Schilmoeller K, Schilmoeller G. Physical, motor, sensory and developmental features associated with agenesis of the corpus callosum. Child Care Health Dev 2009; 35: 656–72. 13. Shevell MI. Clinical and diagnostic profile of agenesis of the corpus callosum. J Child Neurol 2002; 17: 896–900. 14. Sotiriadis A, Makrydimas G. Neurodevelopment after prenatal diagnosis of isolated agenesis of the corpus callosum: an integrative review. Am J Obstet Gynecol 2012; 206: 337.e1–5. 15. Moutard ML, Kieffer V, Feingold J, et al. Isolated corpus callosum agenesis: a ten-year follow-up after prenatal diagnosis (how are the children without corpus callosum at 10 years of age?). Prenat Diagn 2012; 32: 277–83. 16. Richards LJ, Plachez C, Ren T. Mechanisms regulating the development of the corpus callosum and its agenesis in mouse and human. Clin Genet 2004; 66: 276–89. 17. Li Y, Estroff JA, Khwaja O, et al. Callosal dysgenesis in fetuses with ventriculomegaly: levels of

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agreement between imaging modalities and postnatal outcome. Ultrasound Obstet Gynecol 2012; 40: 522– 29. 18. Volpe P, Paladini D, Resta M, et al. Characteristics, associations and outcome of partial agenesis of the corpus callosum in the fetus. Ultrasound Obstet Gynecol 2006; 27: 509–16.19. Santo S, D’Antonio F, Homfray T, et al. Counseling in fetal medicine: agenesis of the corpus callosum. Ultra- sound Obstet Gynecol 2012; 40: 513–21. 20. Hetts SW, Sherr EH, Chao S, Gobuty S, Barkovich AJ. Anomalies of the corpus callosum: an MR analysis of the phenotypic spectrum of associated malformations. AJR Am J Roentgenol 2006; 187: 1343–48.

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Hindawi Publishing Corporation BioMed Research InternationalVolume 2013, Article ID 265619, 14 pages http://dx.doi.org/10.1155/2013/265619

Review Article Congenital and Acquired Abnormalities of the Corpus Callosum: A Pictorial Essay Katarzyna Krupa and Monika BekiesinskaFigatowska Department of Diagnostic Imaging, Institute of Mother and Child, ul. Kasprzaka, 17a, 01211 Warsaw, Poland Correspondence should be addressed to Monika Bekiesinska-Figatowska; m.figatowska@mp.pl Received 2 April 2013; Revised 16 June 2013; Accepted 12 July 2013Academic Editor: Margaret A. Niznikiewicz Copyright © 2013 K. Krupa and M. Bekiesinska-Figatowska. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The purpose of this review is to illustrate the wide spectrum of lesions in the corpus callosum, both congenital and acquired: developmental abnormalities, phakomatoses, neurometabolic disorders, demyelinating diseases, infection and inflammation, vascular lesions, neoplasms, traumatic and iatrogenic injury, and others. Cases include fetuses, children, and adults with rich iconography from the authors’ own archive.

1. Introduction Corpus callosum is one of the three interhemispheric commissures (anterior commissure, hippocampal commissure and corpus callosum) and the greatest of them—it consists of approximately 190 000 000 axons [1]. Its role is interhemispheric connection and coordination. A good example of this role is an alien hand syndrome (AHS): anterior callosal injury (in case of stroke, trauma, and tumor) leads to interman- ual conflict with involuntary movements of nondominant hand. The callosal type of AHS can best be explained by the loss of interhemispheric connection, revealed during activities that require control of the dominant

hemisphere [2]. Another example is the role of the corpus callosum in the interhemispheric spread of epileptic activity and the efficacy of corpus callosotomy in cases of medically intractable epilepsy [3]. The patients that underwent callosotomy present a “disconnection syndrome” as well as subtle social and emotional deficits [1]. Transection of the anterior part of the callosal body during neurosurgical procedures aiming at the removal of tumors of the third or lateral ventricles leads to the deficits of memory, the dysexecutive cognitive and behavioral syndrome, disturbances in interhemispheric transfer of learning from one hand to the other, and an increase in reaction times [4]. In the anterior-posterior direction the corpus callosum is divided into rostrum, genu, body, isthmus, and splenium. The fibers in the rostrum connect fronto-basal cortex, in the genu—prefrontal cortex and anterior cingulate area, in the body—precentral (motor) cortex, insula, and cingulate gyri, in the isthmus—precentral and postcentral gyri (motor, somatosensory) and primary auditory areas, and in the splenium— posterior parietal, medial occipital, and medial temporal cortexes [5]. According to the newest theory the corpus callosum in its embryological development is fused of two separate parts: the anterior one, consisting of the rostrum, genu, and body and the posterior one—splenium. The place of the fusion is the isthmus. Callosal development is a very quick process and takes place in 13th week of gestational life. From this time on the corpus callosum grows mainly in the anterior direction, pushing the splenium posteriorly. It reaches its final shape in midgestation (week 20) but is still small and grows, initially by addition of fibers and later by myelination [5]. The target volume is reached at the age of 6–9 years. Myelination of the brain progresses from the center to the periphery, from bottom to top and from back to front. In newborns corpus callosum is not yet myelinated. In the 6th month after birth, when the cerebellum and genu of the internal capsule completed the process of myelination, the 2 BioMed Research International

(a) (b)

(c)

Figure 1: MRI of fetal brain. SSFSE sequence, T2-weighted images (T2WI). (a) Wide

hemispheric fissure, and “viking helmet” appearance of the lateral ventricles on a coronal image. (b) “Tear drop” configuration (colpocephaly) as a result of enlargement of occipital horns of the lateral ventricles in the axial projection. (c) “Sunray” appearance of brain sulci in the midsagittal plane.

corpus callosum is myelinated in part (splenium), although it has not yet reached its target volume. Callosal genu is myelinated a little bit later than splenium—in about 8th month. It is not until about the first year of life that the corpus callosum displays the typical signal intensity: hyperintense on T1-weighted images and hypointense on T2-weighted images. There are a few papers illustrating callosal pathology in the literature [6–8]. Continuing our work from the past [9] we present a more detailed review of congenital and acquired callosal changes in fetuses, children, and adults with rich iconography from the own archive.

2. Acquisition Parameters of Presented Images All the images were acquired with 1.5T scanners. Figures 9, 12, 21, 24, and 25 were obtained with Philips Gyroscan ACS-NT in the years 1999–2006. Figures 4, 18, 20, 22, 23, 28, 29, 30, and 34 (in adult patients) were acquired with one GE Signa HDxt scanner in the years 2008–2013 and the remaining figures (in children) were acquired with another GE Signa HDxt scanner in the years 2004–2013. The following acquisition parameters were used: (i) Philips Gyroscan ACS-NT (a) SE/T1-weighted images (T1WI): repetition time TR shortest, echo time TE 14 ms, flip angle FA 90 deg, number of acquisitions NEX 2, matrix MX 256 × 225, field of view FOV 25 cm, slice thickness/interslice gap ST 5.0/1.0 mm, (b) TSE/T2WI: TR shortest, TE 100 ms, FA 90deg, NEX 2, MX 512 × 512, FOV 25cm, ST 5.0/1.0 mm, (c) FLAIR: TR 6000 ms, TE 100 ms, FA 90 deg, NEX 2, MX 256 × 256, FOV 25 cm, ST 5.0/1.0 mm, BioMed Research International 3

Figure 2: FSE sequence, T2WI, sagittal plane. Partial callosal agenesis in the form of its shortening. Figure 3: FSE, T2WI, sagittal plane. Rudimentary unmyelinated callosal splenium in a 6month-old boy with semilobar holoprosencephaly. â&#x20AC;˘ (d) FFE/T2â&#x2C6;&#x2014;WI: TR shortest, TE 23 ms, FA 15 deg, NEX 2, MX 256 Ă&#x2014; 256, FOV

23cm, ST 5.0/ 1.0 mm, â&#x20AC;˘ (e) DWI: TR shortest, TE 42 ms, FA 90, NEX 1, ST 6.0/1.0 mm.

(ii) GE Signa HDxt (adult brain)(a)SE/T1WI: TR 540ms, TE 9ms, NEX 2, MX 320 Ă&#x2014; 224, FOV 24 Ă&#x2014; 18 cm, ST 5.0/1.5 mm,(b) FSE/T2WI: TR 5000 ms, TE 88 ms, NEX 1.5, MX 384 Ă&#x2014; 384, FOV 24 Ă&#x2014; 24 cm, ST 5.0/1.5 mm (c)FLAIR: TR 8002ms, TE 126.8ms, TI 2000, NEX1,MX320Ă&#x2014;256,FOV24Ă&#x2014;24cm,ST 5.0/1.5 mm, Figure 4: FSE, T2WI, sagittal plane. Two separate parts of the corpus callosum in a 47year-old manâ&#x20AC;&#x201D;an incidental finding. Figure 5: FSE, T2WI, sagittal plane. Severe callosal hypoplasia in a 4-year-old boy with macrocephaly and the Dandy-Walker syndrome. Rudimentary anterior portion of CC.

(d) GRE/T2â&#x2C6;&#x2014;WI: TR 660 ms, TE 15 ms, NEX 2, MX 320 Ă&#x2014; 192, FOV 24 Ă&#x2014; 18 cm, ST 5.0/1.5 mm, (e)DWI: TR 8000ms, TE 98.5ms, NEX 1, MX 128 Ă&#x2014; 128, ST 5.0/0.0 mm, đ?&#x2018;? = 1000. (iii) GE Signa HDxt (children)(a) SE/T1WI: TR 540 ms, TE 9 ms, NEX 2, MX 320

× 224, FOV 24 × 18 cm, ST 5.0/1.5 mm,(b) FSE/T2WI: TR 5500 ms, TE 84 ms, NEX 1.5, MX 320 × 320, FOV 24 × 24 cm, ST 5.0/1.5 mm,(c) FLAIR: TR 8000 ms, TE 140.2 ms, TI 2000, NEX 1,MX320×320,FOV24×18cm,ST5.0/1.5mm, (d) GRE/T2∗WI: TR 660 ms, TE 15 ms, NEX 2, MX 320 × 192, FOV 24 × 18 cm, ST 5.0/1.5 mm, (e) SWI: TR 6750ms, TE 40ms, NEX 4, MX 256 × 512, FOV 26 × 26 cm, ST 3.0/0.0 mm,

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Figure 6: FSE, T2WI, axial plane. Agenesis of the corpus callosum with multilocular interhemispheric cyst and cortical heterotopia on the right side of the brain. Figure 7: SE sequence, T1WI, sagittal plane. Dorsal tubulonodular lipoma overlying the thick and shortened CC. Figure 8: Fetal MRI. SSFSE, T2WI, coronal plane. Agenesis of the septum pellucidum and of the corpus callosum. Figure 9: Fetal MRIâ&#x20AC;&#x201D;23rd week of gestation. SSFSE, T2WI, sagittal plane. Vein of Galen malformation (VOGM) causing callosal hypoplasia. . (f) DWI:TR6625ms,TE100.5ms,NEX2,MX160 Ă&#x2014; 160, ST 5.0/1.5 mm, đ?&#x2018;? = 1000, . (g) FSPGR/3D/T1WI: TR 8.1 ms, TE 3.6 ms, TI 450, NEX 1, MX 320 Ă&#x2014; 224,

FOV 24 Ă&#x2014; 24cm, ST 1.6/â&#x2C6;&#x2019;0.8 mm, . (h) CUBE/3D/FLAIR: TR 6000 ms, TE 130.7 ms, TI

1852,NEX1,MX224Ă&#x2014;224,FOV22Ă&#x2014;22cm,ST 1.4/â&#x2C6;&#x2019;0.7 mm.

3. Developmental Abnormalities 3.1.AgenesisandHypoplasia. Incompleteorabnormaldevel- opment leads to the most common pathology, which affects the organs in question: agenesis and hypoplasia. The characteristic appearance of callosal agenesis makes this anomaly easily and early recognizable on prenatal ultrasound and MRI: wide interhemispheric fissure (Figure 1(a)), upward bulging of the 3rd ventricle, parallel lateral ventricles away from the midlineâ&#x20AC;&#x201D;racing car sign (Figure 1(b)), widen- ing of the atria and occipital horns of the lateral ventricles (colpocephaly)â&#x20AC;&#x201D;â&#x20AC;&#x153;tear dropâ&#x20AC;? configuration on axial scans (Figure 1(b)), moose head or viking helmet appearance of the frontal horns (Figure 1(a)), and the sulci on the medial aspect of the hemispheres converging towards the 3rd ventricle due to lack of cingulate gyrusâ&#x20AC;&#x201D;sunray appearance (Figure 1(c)). MRI allows for visualization of the bundles of Probstâ&#x20AC;&#x201D; evidence that callosal fibers are not really agenetic but heterotopic, lying parasagittally on both sides and giving the lateral verticle appearance of moose head or viking helmet on coronal images. In contrast to patients after callosotomy, individuals with callosal agenesis show only weak evidence of a â&#x20AC;&#x153;disconnection syndromeâ&#x20AC;? which suggests that brain plasticity allows for forming alternative pathways of interhemispheric transfer in cases of this congenital anomaly [1]. One has to remember that as the three interhemispheric commissures develop

together, callosal agenesis is only rarely isolated: it is accompanied by hippocampal commissure

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(a) (b)

Figure 10: (a), (b) FLAIR sequence, axial plane. 12-year-old boy with NF1. Two

hyperintense lesions in the callosal spleniumâ&#x20AC;&#x201D;they were absent on the previous examination at the age of 10.

Figure 11: FSPGR sequence, 3D/T1WI, sagittal plane. Callosal hypoplasia in the BlochSulzberger syndrome. Partially empty sella is additionally seen. Figure 12: SE, T2WI, axial plane. Typical pattern of X-ALD with involvement of the callosal splenium and occipital and parietal lobes. Figure 13: FSE, T2WI, sagittal plane. 13-month-old boy with the Krabbe disease. Diffuse demyelination of the corpus callosum with relative sparing of its ventral and dorsal borders. Six months earlier the corpus callosum was intact.

agenesis and in 50% of cases also by anterior commissure agenesis or hypoplasia [5]. There are various forms of partial callosal agenesis. In the most frequent form the corpus callosum is simply shortened (Figure 2). Less frequently one can observe only a rudimentary part of the corpus callosum (genu or spleniumâ&#x20AC;&#x201D;Figure 3) or two separate parts (anterior and posterior) (Figure 4). Various degrees of callosal hypoplasia may be seen (Figure 5). Suspected defects of the corpus callosum should be confirmed by MRI because in 80% of cases they coexist with other CNS pathologies. Interhemispheric cyst is one of them. It may be communicating (upward bulging of the ventricular tela choroidea or a single cyst) or noncommunicating, the latter resulting from midline meningeal dysplasia. The noncommunicating cysts are usually multilocular and associated

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Figure 14: FSE, T2WI, sagittal plane. Leukoencephalopathy with vanishing white matterâ&#x20AC;&#x201D; corpus callosum is present but demyeli- nated to such an extent that practically indistinguishable from the cerebrospinal fluid on T2-weighted images. Figure 15: FSE, T2WI, sagittal plane. Four year-old boy with a mitochondrial disease, most likely MERFF. The lesions in the anterior part of the corpus callosum are progressive; 1.5 years earlier there was only a trace of T2 hyperintensity in the callosal genu.

with malformations of cortical development (Figure 6). Interhemispheric meningeal lipoma is also a form of midline meningeal dysplasia and may accompany congenital callosal anomalies (Figure 7) although dorsal tubulonodular lipoma can

also be found in people with normal corpus callosum. Callosal agenesis may be associated with septal agenesis (Fig- ure 8). Callosal abnormalities are found in a great number of other brain malformations, for example, Chiari II malformation, holoprosencephaly (Figure 3), Dandy-Walker syndrome (Figure 5), PHACE syndrome (posterior fossa anomalies, hemangioma, arterial lesions, cardiac abnormalities/aortic coarctation, eye abnormalities), and microcephaly [5]. For example the authors found the increased frequency of callosal abnormalities in cases of the Nijmegen breakage syndrome in which microcephaly is a hallmark of the disease [10, 11]. Isolated callosal anomalies are often asymptomatic and may remain undetected unless highly specialized neuropsychological tests are performed [9]. Underdevelopment of the corpus callosum may be caused by other congenital abnormalities which do not allow for its normal development. In our material there is a case of vein of Galen malformation diagnosed at the 23rd week of gestation, which resulted in callosal hypoplasia (Figure 9) [12].

3.2. Phakomatoses. Phakomatoses belong to congenital diseases in which callosal abnormalities are observed. Neurofi- bromatosis type 1 or von Recklinghausen disease is the most frequent of them, with the estimated incidence of 1:3000. Neurofibromatosis bright objects (UNO), called formerly unidentified bright objects (UBO), are T2 hyperintense and appear most often in the basal ganglia, brainstem, and posterior fossa. They are also found in the corpus callosum, mainly in the splenium (Figures 10(a) and 10(b)). UNO are rare before the age of 4 years; they increase in number and volume till the age of 10â&#x20AC;&#x201C;12 years and tend to resolve thereafter, so that after the age of 20 they are almost never seen. Usually they do not undergo malignant transformation but they can, so follow-up MRI studies are very important in NF1 patients [13]. Besides it has been shown that NF 1 children have a significantly larger corpus callosum while their IQ is significantly lower than in control subjects [14]. Enlargement of the rostral body, anterior and posterior midbody of the corpus callosum in these patients seems to be correlated with impairments in academic or visuospatial skills and motor coordination but may facilitate attention [1]. Higher incidence of callosal agenesis/dysgenesis is described in other neurocutaneous syndromes, among them are the Sturge-Weber syndrome, tuberous sclerosis complex, and Bloch-Sulzberger syndrome (Figure 11) [15].

4. Inborn Neurometabolic Diseases 4.1. X-Linked Adrenoleukodystrophy (X-ALD). X-ALD is an inborn disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues. It affects mainly the myelin in the central nervous

system, the adrenal cortex, and the Leydig cells in the testes. In the most typical form which accounts for approximately 80% of the cases demyelination involves callosal splenium and spreads symmetrically into occipital and parietal lobes (Figure 12) and then forward. In about 20% of patients the disease begins in the callosal genu and frontal lobes and spreads backward [16]. Contrast enhancement of the zone of active demyelination is usually observed which is uncommon in neurometabolic diseases and therefore characteristic of this disease.

5. Others The anterior part of the corpus callosum is involved in the Alexander disease. Callosal demyelination is observed in many neurometabolic diseases, for example, in globoid leukodystrophy (Krabbe disease) (Figure 13), metachromatic leukodystrophy, leukoencephalopathy with vanishing white

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(a) (b)

Figure 16: Multiple sclerosis: plaque in the isthmus of the corpus callosum (FSE, T2WI, sagittal plane (a)) with contrast enhancement after gadolinium administration (SE, T1WI after gadolinium administration, sagittal plane (b)).

Figure 17: DWI sequence, axial plane. Focal infarct of the callosal splenium as a result of vasculitis in the course of streptococcal meningitis. Figure 18: FSE, T2WI, sagittal plane. Callosal involvement in borreliosis. Figure 19: FSE, T2WI, sagittal plane. Callosal involvement in subacute sclerosing panencephalitis.

matter (Figure 14), and mitochondrial diseases (Figure 15). Lack of myelination of the corpus callosum is an element of the Pelizaeus-Merzbacher disease. In the course of neurometabolic diseases callosal agenesis is also observed, among others in nonketotic hyperglycin- emia, Menkes kinky hair disease, Hurler disease or maple syrup urine disease [17]. In other diseases from this group secondary changes occur within the corpus callosum. The example is phenylketonuria in which loss of volume and shape abnormalities are observed in the corpus callosum [18].

6. Acquired Demyelinating Diseases 6.1. Multiple Sclerosis (MS). Callosal involvement is typical of MS although it has never been included in the evolving diagnostic criteria of this disease [19]. The typical locations of demyelinating lesions in the course of MS are periventricular,

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Figure 20: FLAIR, axial plane. Old isolated infarct in the callosal splenium.

juxtacortical, infratentorial, or spinal cord. So callosal lesions should be regarded as periventricular. In the acute phase of demyelination the plaques demonstrate contrast enhancement (Figures 16(a) and 16(b)), increased diffusion-weighted imaging (DWI) signals, and increased apparent diffusion coefficient (ADC) [20]. Cognitive impairment in benign MS has been shown to be associated with the extent of corpus callosum damage [21]. and necrosis with subsequent atrophy. It is classically associated with chronic alcoholism but it has also been described in patients with malignancy and nutritional deficiencies. The lesions are T2- and FLAIR hyperintense which reflects edema and myelin damage. Necrosis in the chronic stage is reflected by T1-hypointensity but lesions may also regress [22].

7. Infection and Inflammation 7.1.StreptococcusMeningitis. Cerebrovascularinvolvementis common in group B streptococcus meningitis, especially in neonates, but also in older children. There are two main patterns of brain infarction: deep perforator arterial stroke to basal ganglia, thalamus, and periventricular white matter and focal cortical infarctions [23]. In our archive there is a case of this disease with the only focus in the callosal splenium (Figure 17). In this case, in contrast to the generally poor prognosis with severe disability or death, the outcome was good. 7.2. The Lyme Disease. The Lyme disease, caused by Bor- relia burgdorferi, belongs to infectious diseases that are most commonly mistaken for MS [24]. FLAIR and T2- hyperintense foci may be seen in the same localization which is typical of MS, including the corpus callosum (Figure 18). MRI alone is often misleading and the presence of anti-B. burgdorferi antibodies in the plasma or cerebrospinal liquid is an indication for antimicrobial treatment.

7.3. Subacute Sclerosing Panencephalitis (SSPE). SSPE is a progressive disease considered to be caused by persistent measles virus. In typical setting the lesions in the white matter are bilateral, asymmetric, and T2-hyperintense and involve the parietal and temporal lobes in the acute stage. As the disease progresses lesions become more prominent, and periventricular white matter, corpus callosum, and basal ganglia can be involved (Figure 19) [25].

8. Lesions of Vascular Origin 8.1. Ischemic. Corpus callosum has rich blood supply from the anterior communicating artery (via the subcallosal and medial callosal arteries which deliver

blood to the anterior part of the corpus callosum), the pericallosal artery which supplies the body, and the posterior pericallosal artery, a branch of the posterior cerebral artery, which feeds the splenium. Isolated callosal infarcts are therefore uncommon. If present, they affect callosal splenium more often than the body and genu (Figure 20) [26]. They rather accompany larger territorial infarcts (Figures 21(a) and 21(b)).

8.2. Vascular Malformations. Arteriovenous malformations of the corpus callosum account for 9–11% of all cerebral AVMs [7]. They are often asymptomatic and diagnosed in patients with intracranial, most frequently intraventricular, hemorrhages. The MRI pattern is typical with flow voids in the corpus callosum.

9. Tumors 9.1. Glioblastoma Multiforme. Glioblastoma multiforme (GBM) (WHO grade IV) is the most common and most aggressive malignant primary brain tumor. Callosal GBM, in addition to the corpus callosum, affects also both cerebral hemispheres resulting in the typical “butterfly glioma” appearance with solid intense contrast enhancement in the corpus callosum [27]. 9.2. Gliomatosis Cerebri. Gliomatosis cerebri, WHO grade III, does not form a solid tumor but diffusely infiltrates the brain tissue. The architecture of the brain is preserved but the affected portions of the brain are swollen. Loss of distinction between grey and white matter is observed. Usually bilateral widespread invasion with involvement of the corpus callosum is found (Figures 22(a) and 22(b)) [28]. In 80% of cases callosal genu is affected, in 60% the body, and in 40% the splenium. The lesions are T2-hyperintense; on T1-weighted images they display isointense or—rarer—hypointense signal intensity. Mass effect and contrast enhancement are minimal [29]. Disease. TheBignami disease is characterized by callosal demyelination 6.2. Marchiafava-Bignami MarchiafavaBioMed Research International 9

(a) FLAIR (b) DWIFigure 21: Acute stroke of the right occipital lobe involving callosal

splenium as well. (a) FLAIR, axial plane (b) FSE, T2WI, sagittal plane Figure 22: Gliomatosis cerebri. (a) FSE, T2WI, sagittal plane (b) SE, T1WI with contrast enhancement Figure 23: FSE, T2WI,

sagittal plane. 51-year-old man with a biopsy-proven oligoastrocytoma G2.

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Figure 24: FLAIR, axial plane. Lymphoma affecting callosal genu.

Figure 25: SE, T1WI after gadolinium administration. Lung cancer metastases to the corpus callosum and both cerebral hemispheres. Figure 26: DAI—acute phase visualized on DWI. Figure 27: FSE, T2WI, sagittal plane. Chronic lesions in a motor vehicle accident survivor in the posterior part of the corpus callosum—localization typical of DAI. Figure 28: GRE sequence, T2∗WI, axial plane. Hemosiderin deposits in the corpus callosum. Figure 29: FSE, T2WI, sagittal plane. 53-year-old man with epilepsy, after head trauma. Callosal genu is torn.

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Figure 30: FSE, T2WI, sagittal plane. Corpus callosum pierced by a valve. Figure 31: FSE, T2WI, coronal plane. Callosal injury as a result of multiple shunting procedures. Figure 32: FLAIR, axial plane. Posterior reversible encephalopathy syndrome (PRES) in a 60-year-old woman with renal carcinoma and severe hypertension. Figure 33: FSE, T2WI, sagittal plane. Dilated Virchow-Robin space in the callosal splenium. Figure 34: FSE, T2WI, sagittal plane. Callosal atrophy at the age of 85. Figure 35: FLAIR, sagittal plane. Hyperintense band in the ventral part of CC in a 58-yearold woman with uncontrolled hypertension.

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(a) (b)

Figure 36: FLAIR, axial plane. (a) Five year-old boy with active hydrocephalus. (b) Three months later the ventricles are narrower and normalization of callosal signal intensity is observed. (a) (b)

Figure 37: DWI sequence in axial plane. (a) Transient splenial lesion in a 9-year-old boy with school problems visualized as a hyperintense focus in the midline. (b) Six months later the lesion is absent.

9.3. Oligoastrocytoma. Oligoastrocytoma (mixed glioma) occurs in two main types: well-differentiated oligodendroglioma (WHO grade II) and its anaplastic variant (WHO grade III). The most frequent locations are the frontal lobes and these tumors

may involve the corpus callosum and extend through it to the contralateral hemisphere producing a “butterfly glioma” pattern (Figures 23(a) and 23(b)). Signal intensity may be mixed due to cystic elements and calcifica- tions; “dot-like” contrast enhancement is often seen although many tumors do not enhance [30].

9.4. Lymphoma. Primary CNS lymphoma accounts for approximately 16% of primary brain tumors. Most of them are non-Hodgkin’s and represent B-cell type. They are most often isointense-hypointense on T1-weighted images, hypointense on T2-weighted images and enhance homogeneously with gadolinium-based contrast media. In classic presentation the tumors involve the corpus callosum in a butterfly pattern (Figure 24). In patients with immunodeficiency lymphoma is more often multifocal, irregular, and heterogeneous in terms of signal intensity and ring enhancing [31].

9.5. Metastases. Corpus callosum may also be affected by metastases although it is reported to be rare. Callosal involvement is more frequent in case of infiltration by a lesion from the adjacent structures [8]. In our material there is a case of metastases of the lung cancer directly to the corpus callosum (Figure 25).

10. Traumatic and Iatrogenic Injuries The term “diffuse axonal injury” (DAI) refers to extensive traumatic lesions in white matter tracts. This kind of injury BioMed Research International is the result of traumatic shearing forces that occur when the head is rapidly accelerated, decelerated, or rotated. Motor vehicle accidents are the most frequent cause of DAI but it can also be a result of child abuse, for example, in shaken baby syndrome. Corpus callosum belongs to the most frequently injured parts of white matter. The splenium and the undersurface of the posterior body are mainly involved due to vicinity of the falx cerebri. The lesions are typically small (1–15 mm) and invisible on CT. MRI is a method of choice in their diagnosis. They are T2hyperintense but first of all show diffusion restriction with reduced ADC values (Figure 26) [32, 33]. Chronic lesions are seen as posttraumatic scars in the survivors (Figure 27). After hemorrhagic injury hemosiderin deposits may be seen in the corpus callosum (Figure 28). It may be also torn, as in Figure 29. Corpus callosum may be injured as a result of shunting procedures in patients with hydrocephalus (Figures 30 and 31) [34]. Posterior reversible encephalopathy syndrome (PRES) is a toxic-metabolic disease

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characterized by headache, con- fusion, seizures, and visual loss. It occurs in patients with malignant hypertension, eclampsia, hypercalcemia, receiving some drugs, for example, cyclosporine, after organ trans- plantation. That is why the condition may be considered as iatrogenic. The brain swelling is seen on MRI mainly in the posterior parts of the brain, including splenium of the corpus callosum. The symptoms tend to resolve after a period of time (Figure 32) [35].

11. Other/Miscellaneous Perivascular Virchow-Robin spaces may be seen in the corpus callosum as an incidental finding (Figure 33). Abnormally dilated Virchow-Robin spaces within callosum are observed in patients with mucopolysaccharidosis. Callosal atrophy is associated with aging (Figure 34). In Alzheimer’s disease (AD) callosal atrophy reflects loss of intracortical projecting neocortical pyramidal neurons and is more severe than in healthy subjects. The most significant atrophy in AD is noticed in callosal splenium. Callosal atrophy correlates with progression of dementia severity in AD patients [36]. Linear T2- and FLAIR hyperintensity of the ventral part of the corpus callosum is a frequent finding reflecting gliosis and is attributed in the literature to the elderly age, subcortical arteriosclerotic encephalopathy, and radiation therapy [8, 37]. In our experience this finding was also present in younger patients with uncontrolled hypertension and ischemic lesions in other localization, not only subcortical (Figure 35), in multiple sclerosis, PRES, and—transiently—in patients with hydrocephalus. The latter regressed after normalization of the ventricular width (Figures 36(a) and 36(b)). Transient splenial lesion is a term attributed to the ovoid or round focus in the central part of the callosal splenium that has been described in cases of epilepsy and encephalitis. These lesions show diffusion restriction and regress with time they are regarded as intracellular (intramyelinic) edema [8]. In our material there was a case of such a transient lesion in 13 a neurologically healthy boy referred to MRI due to “school problems” (Figures 37(a) and 37(b)). 12.

Conclusions

Being the largest brain commissure, the corpus callosum is related to cognitive functions, social skills, problem solving, and attention. Thanks to its multiplanar nature and high tissue resolution magnetic resonance imaging is a method of choice in the assessment of the corpus callosum and its congenital and acquired pathological lesions. It is a perfect diagnosing tool from the very beginning of life,

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that is, from the prenatal period. Visualization of callosal involvement helps to establish diagnosis in certain disease entities.

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