Cerebellar agenesis - IOS Press

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Journal of Pediatric Neuroradiology 2 (2013) 163–167 DOI 10.3233/PNR-13060 IOS Press

Case Report

Cerebellar agenesis: An extreme form of cerebellar disruption in preterm neonates Andrea Porettia,b,c, Sarah Risenc,d, Avner Meodeda,c, Frances J. Northingtonc,e, Michael V. Johnstonc,d,f, Eugen Boltshdauserb and Thierry A.G.M. Huismana,c,* a

Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, USA b Department of Pediatric Neurology, University Children’s Hospital, Zurich, Switzerland c Neurointensive Care Nursery Group, The Johns Hopkins University School of Medicine, Baltimore, MD, USA d Kennedy Krieger Institute, Baltimore, MD, USA e Division of Neonatology, Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA f Departments of Neurology, Pediatrics and Physical Medicine and Rehabilitation, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

Received 14 June 2012 Revised 27 August 2012 Accepted 7 September 2012

Abstract. Cerebellar agenesis (CA) may result from both a genetically mediated as well as a disruptive etiology. In preterm neonates, the cerebellum is highly susceptible to injury. Different neuroimaging findings have been reported in disrupted cerebellar development in preterm neonates. We report the association of CA and severe periventricular leukomalacia in a 7-year-old girl with spastic tetraparesis, profound cognitive impairment, epileptic seizures and posthemorrhagic hydrocephalus who was born at 25 wk of gestation. The neuroimaging studies performed during the first wk of life had shown a normal structure of the cerebellum and brainstem confirming a disruptive, rather than a malformative etiology. CA is the most severe form of cerebellar disruption in preterm neonates. Differentiation between malformative and disruptive etiologies of CA is important for prognosis and genetic counseling of the affected children and their families. Keywords: Cerebellum, agenesis, prematurity, disruptive lesion

1. Introduction Differentiation between malformative and disruptive etiologies of cerebellar agenesis (CA) is important for prognosis and genetic counseling of the affected *Corresponding author: Thierry A.G.M. Huisman, Division Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The JohnsHopkins University School of Medicine, 600 North Wolfe Street, Nelson B-173, Baltimore, MD 21287-0842, USA. Tel.: +1 410 955 6454; Fax: +1 410 502 3633; E-mail: [email protected].

children and their families [1]. A malformation is defined as a morphological defect of an organ, part of an organ, or a larger region of the body resulting from an intrinsically abnormal developmental process [2]. A disruption is defined as a morphological defect of an organ, part of an organ, or a larger region of the body resulting from an extrinsic breakdown of, or an interference with, an originally normal developmental process [2]. Therefore, cerebellar disruptions are due to extrinsic events such as hemorrhages or infections affecting a normal developing cerebellum [1]. CA is

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a descriptive term implying complete absence of cerebellar structures [1,2–5]. Usually, minute remnants of cerebellar tissue (middle cerebellar peduncles, anterior vermal lobules, and/or flocculi) are present. In view of this observation, the term subtotal CA is also used [6]. The definition of CA is based on the morphological pattern and does not suggest the pathogenesis [1,2–5]. Indeed, CA may represent a malformation resulting from a genetically mediated pathomechanism (e.g. mutations in the pancreas transcription factor 1α gene, PTF1α) or a disruption (linked to intrauterine/neonatal injury with disappearance of the developing cerebellum) [1,7]. The term vanishing cerebellum has been introduced by Sener [6] to report on cerebellar disruptive lesions in children with Chiari II malformation [1]. Prenatal hindbrain herniation through the foramen magnum may cause parenchymal damages leading to resolution of a part (typically strong asymmetric) of the cerebellum. In disruptive CA, the cerebellum is vanishing completely secondary to a direct or indirect injury. We report on CA in an ex-preterm girl as the result of disruptive cerebellar development related to prematurity. To the best of our knowledge, CA was not reported so far as a form of cerebellar disruption in premature newborns.

2. Case report A baby girl was born at 25 wk of gestation to a 31-year-old mother by a Caesarean section because of placental abruption, following a preterm rupture of membranes as complication of chorioamnionitis. Her

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birth weight was 720 g (10th-50th percentile) with a head circumference of 23.5 cm (50th-90th percentile). Apgar scores were 5/7/8 at 1, 5 and 10 min respectively. There were no dysmorphic features. A head ultrasound (US) on day 1 of life revealed bilateral germinal matrix hemorrhages with intraventricular extension, ventriculomegaly, and periventricular hemorrhagic infarction, but no cerebellar hemorrhages. The newborn developed focal seizures at day 1 of life. Treatment with phenobarbital and midazolam was initiated and could be stopped at day 5 of life. No recurrent seizures occurred. Over the first month of life, she developed a moderate posthemorrhagic hydrocephalus and an Omaya reservoir was placed followed by a ventriculo-peritoneal shunt on follow up. Despite the mildly limited US-image quality and lack of mastoidal fontanel images, US performed at 4.5 (Fig. 1A) and 6 (Figs. 1B and 1C) wk of age revealed an age appropriate normal cerebellum, vermis and pons. US at 9 wk showed however an abnormal hypoechogenic cerebellum (Fig. 2A) and a computed tomography at the age of 12 wk revealed a nearly empty posterior fossa without evidence of cerebellar structures (Fig. 2B). None of the US studies showed evidence of intracerebellar hemorrhage. Additional complications related to prematurity included bilateral retinopathy (right: stage 5, left: stage 4) and chronic lung disease. At 6 mo, she developed infantile spasms with classic hypsarrhythmia. On therapy with adrenocorticotropic hormone, the infantile spasms stopped, but recurred at 9 mo. Ketogenic diet was started with a significant reduction of the seizure frequency. At that time, spastic tetraparesis was noted.

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Fig. 1. Midline sagittal brain ultrasound image at the age of 4.5 wk (A) and midline sagittal (B) and coronal brain (C) ultrasound images at the age of 6 wk of an extreme preterm baby girl born at 25 wk of gestation show the normal hyperechogenic cerebellar vermis compared to adjacent structures (white arrows on A-C), normal echogenicity of the cerebellar hemispheres (arrow heads on C), and the present pontine prominence (white arrow heads on A, B) at 4.5 and 6 wk of age.


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Fig. 2. Midline sagittal brain ultrasound image at the age of 9 wk (A) shows a markedly hypoechogenic cerebellum and axial head computed tomography image at the age of 12 wk (B) demonstrates complete disappearance of the cerebellum.

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Fig. 3. Midsagittal T1- (A) and axial T2- (B) weighted magnetic resonance images at the age of 7 yr show complete absence of the cerebellum, a shallow pons, and large empty posterior fossa with marked dilatation of the fourth ventricle. Supratentorial axial T2-weighted magnetic resonance image (C) shows a high-grade volume loss of the hemispheric white matter, including a more focal cortical/subcortical defect in the left parieto-occipital region. Additionally, high-grade ex-vacuo dilatation of the ventricles is seen. A ventriculo-peritoneal shunt catheter is noted in the right posterior, lateral ventricle.

At the last follow-up at 7 yr, she was not able to sit, stand up, walk independently nor speak any comprehensive words. Her cognitive functions were profoundly impaired. She was blind and required feeds via a gastrostomy tube. She was maintained on the ketogenic diet with satisfactory seizure control. The head circumference was 46.5 cm (< 3rd percentile). Neurological examination

showed increased muscle tone and brisk tendon reflexes. Magnetic resonance imaging showed complete absence of the cerebellum, a shallow pons, and a small midbrain and medulla (Fig. 3). Additionally, a large, empty posterior fossa with dilatation of the partially herniating fourth ventricle was noted. The last finding may suggest a trapped fourth ventricle. However, the stable clinical

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presentation did not match a high-pressure situation and the near-complete absence of cerebellar tissue may explain the large fourth ventricle. Finally, a high-grade volume loss of the hemispheric white matter with a secondary high-grade ex-vacuo dilatation of the ventricles and a more focal cortical/subcortical defect in the left parieto-occipital region were noted (Fig. 3C).

3. Discussion A disruption implies the interference of extrinsic factors with a normal developmental process causing morphological defects [2]. Based on its protracted development (extending from 4 wk of gestation until at least 20 mo of postnatal age) [8] and exponential growth (3.5 fold increased volume and 30-fold increased surface between 24 and 40 wk of gestation) [9], the developing cerebellum is highly susceptible to disruptive injuries [1,10]. Accordingly, it is not surprising that extremely preterm newborns are at high risk for disruptions of the cerebellar development [1,2,7,11–13]. Cerebellar injuries in the premature infants may be grouped into 2 categories: (a) primarily destructive injuries within the cerebellum including hemorrhages and ischemic infarctions and (b) injuries impairing primarily the cerebellar development due to direct (e.g. hemosiderin-blood products) or remote (impaired transsynaptic trophic effects) affection of the cerebellum [9]. The second broad category does not result only in an “arrested” cerebellar development, but also in an additional tissue loss (atrophy) [11,14]. In our patient, a primarily destructive (hemorrhagic or ischemic) cerebellar lesion was not seen in the perinatal or early postnatal period. The impressive cerebellar volume loss may well have resulted from several factors: damage due to hemosiderin in the context of intraventricular hemorrhage and the remote effects related to periventricular leukomalacia (PVL). To our knowledge, this child is the first one with CA in a preterm infant due to a disruptive lesion. Hemosiderin is a common agent adversely affecting the cerebellar development of very low birth weight (VLBW) preterm infants. Symmetric loss of cerebellar tissue was reported over weeks in 28 VLBW preterms without cerebellar, but intraventricular hemorrhages and infratentorial presence of blood products [14]. In our patient, all the follow-up images did not detect acute or chronic blood products within the posterior fossa. Disruption of the cerebellar development in preterms is frequently associated with PVL, raising the possibility

that both pathologies may be due to the same pathogenetic mechanisms such as hypoxic-ischemia and infection/inflammation [13,15]. Severe PVL was reported to be associated with CA in a girl who was born at term by uncomplicated delivery following an uneventful pregnancy [1]. However, it is also possible that CA may be secondary to the severe loss of supratentorial white matter. Transsynaptic effects involving the neuronal connections between cerebrum and cerebellum are believed causative. Unilateral cerebral brain injuries are associated with significantly decreased volume of the contralateral cerebellar hemisphere and unilateral cerebellar injuries are associated with a significantly decreased volume in specific regions (dorsolateral prefrontal, premotor, sensorimotor, and midtemporal grey and white matter) of the uninjured contralateral cerebral hemisphere [11]. Additionally, infants with bilateral diffuse PVL have symmetric bilateral decrease in cerebellar volume [11]. These findings are consistent with both crossed cerebro-cerebellar and cerebellar-cerebro diaschisis due to interruption(s) of the cerebro-cerebello/ cerebello-cerebro pathways. It is remarkable that in our patient the cerebellum vanished quickly (within 3 wk). A significant reduction of the cerebellar volume in a preterm neonate was reported within 3 wk of birth (Fig. 1) [14]. It is well known that apoptosis is much more active in developing than adult neurons suggesting that apoptosis might have profound effects on the rapidly developing cerebellum of preterms [9]. In our patient, the cerebellum appeared normal until the sixth week of postnatal age. A late onset of cerebellar disruption has been observed previously in preterm infants [14]. The causes of an early vs. late onset of cerebellar disruption are unclear. It may be hypothesized that disruptive injuries indirectly affecting the cerebellum have a later onset than injuries directly affecting the cerebellum. Of interest is that not only the cerebellum “vanished”, but that the pontine prominence also disappeared. The pontine prominence is present only if a significant part of cerebellum is present. This may be explained by the fact that the ventral pontine prominence consists of transverse fibers arched like a bridge across the median plane converging along each side into the middle cerebellar peduncles. However, it is remarkable that the vast majority of hereditary diseases causing cerebellar atrophy do not lead to a significant reduction of the pontine size, even in advanced stages [12]. Absence or significant reduction of the pontine prominence is typically present in children with a prenatal onset of degenerative


cerebellar disorders (e.g. pontocerebellar hypoplasia, congenital disorders of glycosylation), in prenatal cerebellar disruption (e.g. some forms of CA and vanishing cerebellum in myelomeningocele) and in cerebellar disruption in VLBW preterms [1,12]. In conclusion, our patient confirms that CA may result from a disruptive process and shows that the disruptive event may occur not only prenatally, but also postnatally in VLBW preterm neonates. It is important to be aware on the possible disruptive etiology of CA and differentiate between malformative and disruptive causes of CA because of prognosis and genetic counseling of the affected children and their families. References [1] Poretti A, Prayer D, Boltshauser E. Morphological spectrum of prenatal cerebellar disruptions. Eur J Paediatr Neurol 2009;13(5):397–407. [2] Reardon W, Donnai D. Dysmorphology demystified. Arch Dis Child Fetal Neonatal Ed 2007;92(3):225–9. [3] Sener RN, Jinkins JR. Subtotal agenesis of the cerebellum in an adult. MRI demonstration. Neuroradiology 1993;35(4): 286–7. [4] Glickstein M. Cerebellar agenesis. Brain 1994;117(5):1209–12. [5] Zafeiriou DI, Vargiami E, Boltshauser E. Cerebellar agenesis and diabetes insipidus. Neuropediatrics 2004;35(6):364–7.

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[6] Sener RN. Cerebellar agenesis versus vanishing cerebellum in Chiari II malformation. Comput Med Imaging Graph 1995;19(6):491–4. [7] Sellick GS, Barker KT, Stolte-Dijkstra I, Fleischmann C, Coleman RJ, Garrett C, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet 2004;36(12):1301–5. [8] Ten Donkelaar HJ, Lammens M. Development of the human cerebellum and its disorders. Clin Perinatol 2009;36(3):513–30. [9] Volpe JJ. Cerebellum of the premature infant: rapidly developing, vulnerable, clinically important. J Child Neurol 2009; 24(9):1085–104. [10] Limperopoulos C, du Plessis AJ. Disorders of cerebellar growth and development. Curr Opin Pediatr 2006;18(6):621–7. [11] Limperopoulos C, Soul JS, Haidar H, Huppi PS, Bassan H, Warfield SK, et al. Impaired trophic interactions between the cerebellum and the cerebrum among preterm infants. Pediatrics 2005;116(4):844–50. [12] Poretti A, Wolf NI, Boltshauser E. Differential diagnosis of cerebellar atrophy in childhood. Eur J Paediatr Neurol 2008; 12(3):155–67. [13] Shah DK, Anderson PJ, Carlin JB, Pavlovic M, Howard K, Thompson DK, et al. Reduction in cerebellar volumes in preterm infants: relationship to white matter injury and neurodevelopment at two years of age. Pediatr Res 2006;60(1):97–102. [14] Messerschmidt A, Brugger PC, Boltshauser E, Zoder G, Sterniste W, Birnbacher R, et al. Disruption of cerebellar development: potential complication of extreme prematurity. AJNR 2005;26(7):1659–67. [15] Srinivasan L, Allsop J, Counsell SJ, Boardman JP, Edwards AD, Rutherford M. Smaller cerebellar volumes in very preterm infants at term-equivalent age are associated with the presence of supratentorial lesions. AJNR 2006;27(3):573–9.