Unilateral Cerebellar Hypoplasia with Different Clinical Features

Cerebellum (2011) 10:49–60 DOI 10.1007/s12311-010-0225-2 ORIGINAL PAPER Unilateral Cerebellar Hypoplasia with Different Clinical Features Gulcin Benbir & Simay Kara & Beyza Citci Yalcinkaya & Geysu Karlıkaya & Beyhan Tuysuz & Naci Kocer & Cengiz Yalcinkaya Published online: 22 October 2010 # Springer Science+Business Media, LLC 2010 Abstract Unilateral cerebellar hypoplasia (UCH) is a rare pathological condition characterized by the loss of volume in cerebellar hemispheres ranging from mild asymptomatic to severe symptomatic cases. As the designation of UCH remains problematic, the underlying etiopathogenesis also lacks explanation. We investigated the patients admitted to Departments of Child Neurology, Neurology, and Genetics between the years 1992 and 2010 and detected 12 patients All authors declare that there is no financial support or any conflicts of interest. G. Benbir : C. Yalcinkaya (*) Cerrahpasa Medical Faculty, Department of Neurology, Division of Pediatric Neurology, Istanbul University, 34098 Istanbul, Turkey e-mail: cengiz@istanbul.edu.tr S. Kara Department of Radiology, Acıbadem Hospital, Fulya, Istanbul, Turkey B. C. Yalcinkaya Department of Neurology, Acıbadem Hospital, Fulya, Istanbul, Turkey G. Karlıkaya Department of Neurology, Acıbadem University, Istanbul, Turkey B. Tuysuz Cerrahpasa Medical Faculty, Department of Pediatric Genetics, Istanbul University, Istanbul, Turkey N. Kocer Cerrahpasa Medical Faculty, Department of Radiology, Division of Neuroradiology, Istanbul University, Istanbul, Turkey with unilateral cerebellar volume loss, with the exclusion of all other cerebellar pathologies. The ages of patients ranged between 6 months to 55 years. Five patients had a delay in developmental milestones, and one of these was diagnosed with neurofibromatosis type 1. Two patients had epileptic seizures, one patient had peripheral facial paralysis as a component of Moebius syndrome, and four patients were incidentally diagnosed during etiological work-up for headache. The clinical outcomes of patients varied from healthy subjects to marked developmental impairment. Radiologically, five patients had severe disproportionate UCH, six had moderate disproportionate, and one had mild proportionate UCH. Cerebellar peduncles were affected in all, and vermis was partly hypoplastic in eight patients. Brainstem was involved in four patients, and seven patients showed involvement of white matter and/or corpus callosum. Imaging features supported that patients with severe disproportionate UCH also displayed additional cerebral and commissural changes, which were related to ischemic or vascular injuries, implying a prenatally acquired disruption. In the presence of such a wide spectrum of clinical and radiological features, a prenatally acquired lesion and, thus, a disruption seem to be more explanatory rather than a primary developmental process or malformation in the etiopathogenesis of unilateral cerebellar hypoplasia. Keywords Unilateral cerebellar hypoplasia . Cerebellar disruption . Moebius syndrome . Neurofibromatosis type 1 . Dyke–Davidoff–Mason syndrome Introduction Unilateral cerebellar hypoplasia (UCH) is a rare pathological condition characterized by the loss of volume in 50 cerebellar hemisphere ranging from mild asymptomatic to severe symptomatic cases [1]. Although often symmetric, the obviously acquired cerebellar lesions seen in very prematurely born infants have been reported to be unilateral in some cases. The designation of unilateral cerebellar hypoplasia, on the other hand, is problematic and lacks etiopathogenetic explanation [2, 3]. The definition of UCH suggests a primary developmental process describing the volume loss in cerebellum. On the other hand, it was recently suggested that UCH is a prenatally acquired lesion but not a true developmental malformation [4–7]. Prenatal unilateral vascular hemorrhage was first proposed to explain asymmetric cerebellar hypoplasia. The exclusion of cerebellar hemorrhage by prenatal ultrasound in few cases raised the possibility of ischemic disruptions as causative events, as well [3, 8]. Disruptions are commonly due to exogeneous factors such as infections; however, some genetic (intrinsic) factors such as coagulopathies may also predispose to disruption [9]. Clinical spectrum in patients with unilateral cerebellar hypoplasia was reported to vary from asymptomatic cases to severe developmental delay, hypotonia, ataxia, and abnormal ocular movements [10]. Unilateral cerebellar hypoplasia has also been reported in association with other cerebral malformations or some syndromes such as Moebius [11] or Prader–Willi [12]. Cerebellar disruptions presenting different morphological patterns have been defined likely to represent a morphological spectrum caused by the same disruptive pathogenetic mechanism. Although cerebellar disruptions potentially mimic cerebellar malformations, their pathogenesis has been suggested to be completely different [13]. In this paper, we report 12 patients with unilateral cerebellar hypoplasia and aimed to discuss the possible underlying etiopathogenesis of UCH on the basis of clinical and neuroradiological findings. Patients and Methods Among all patients admitted to Division of Child Neurology in the Department of Neurology and Division of Genetics in the Department of Pediatrics between the years 1992 and 2010, we have detected 12 patients with unilateral cerebellar structural abnormality upon consultation with Division of Neuroradiology in the Department of Radiology. Clinical data and follow-up information were supplied by the corresponding physicians. Only the patients with unilateral cerebellar volume loss were included in this study, and all the other pathologies causing dysmorphic changes in cerebellum such as cerebellar cleft or asymmetric arachnoid cysts in posterior fossa were excluded. All patients had cranial multiplanar magnetic resonance imaging (MRI) investigations scanned in a 1–1.5-T mag- Cerebellum (2011) 10:49–60 netic resonance scanner. MRI exams of patients had at least T1 and T2 weighted images in two planes with a slice thickness of 3 to 5 mm. None of the patients had 3D images, and volumetric measurements were not available. For this reason, cerebellar volume was assessed by visual evaluation of the various MRI planes. The MR images of all 12 patients were independently evaluated by two experienced adult and pediatric neuroradiologists blind to clinical findings. We classified the hypoplasia in cerebellar hemispheres as “severe” when a cerebellar hemisphere was reduced in volume to <25%. This volume reduction was estimated by visual inspection of the various MRI planes, as volumetric measurements could not be performed. In case of a volume reduction between 25% and 50%, we used the term “moderate,” and hypoplasia affecting less than 50% of a cerebellar hemisphere was defined as “mild.” The term “disproportionate cerebellar hypoplasia” was used to describe cerebellar hypoplasia with abnormal cerebellar shape, and the term proportionate cerebellar hypoplasia was used to indicate normal cerebellar shape in the presence of hypoplasia [1, 14]. Results We detected a total of 12 patients with unilateral cerebellar hypoplasia. Only one of them was female, and 11 patients were male. The ages of the patients showed a wide range varying between 6 months to 55 years. The clinical presentations of patients are given in Table 1. In our series, five patients (patients 1, 3, 7, 9, and 12) were brought to our department due to a delay in developmental milestones, two of which had intrauterine growth retardation (patients 1 and 9). Of these five patients, one was diagnosed as neurofibromatosis type 1 (NF1, patient 7). The ages of these patients varied between 6 months to 9 years. Radiologically, three of these patients had severe disproportionate unilateral cerebellar hypoplasia, and two had moderate UCH (Figs. 1, 2, and 3). Three out of five patients (patients 1, 3, and 9) also showed associated cerebral abnormalities (Table 2). The clinical outcome was poor in these patients; they remained retarded with slow improvement by rehabilitation and symptomatic therapies. Two patients were admitted due to epileptic seizures, one of these (patient 2) had vision loss in addition to cerebellar symptoms, and the other patient showed severe aggressive and mutilistic behaviors (patient 8). Patient 2 had severe disproportionate UCH, with significant cerebral involvement, while patient 8 had mild hypoplasia, with mild cerebral involvement. Both patients showed a good clinical outcome with antiepileptic therapy and long-term rehabilitation program. They managed to have education with a rather good school performance. Patient no., age, sex Complaint Neurological examination Perinatal history Consanguinity Additional features Prognosis 1, 3 years, M Speech delay, weakness on the right extremities Treated for seizures, had phototherapy for newborn jaundice Clonic motor seizures in his right hand None Treated with complete blood transfusions and phototherapy for hyperbilirubinemia, mucosal and umbilical artery bleedings Poor with static disease status in spite of 2 years’ follow-up with special education program and physical therapy In 2nd grade with a good school performance after longterm rehabilitation therapy 3, 19 months, F Delay in walking C/S at 32nd gw due to fetal hypoxia secondary to preeclampsia and oligohydramnios, BW of 1,350 g C/S at 33rd gw due to chronic prenatal hypoxia and decreased intrauterine fetal movements, BW of 1,634 g, hospitalized in ICU for grades 2–3 respiratory distress syndrome and intraventricular hemorrhage Not known (adopted child) First degree 2, 9 years, M Right-sided spastic hemiparesis, speech limited to few words with lexical mistakes 90% vision loss on right eye, dysdiadochokinesia and dysmetria on left side, globally hyperactive DTR Not known (adopted child) None Moderate with static disease status 4, 3 years, M Asymmetry on face noticed at birth None Moebius syndrome Stable 5, 20 years, M Headache Normal 6, 54 years, M Tension type headache Normal Mother fell down at 7th month of gestation with no complications Mother on digoxin for mitral valve disease during pregnancy, vaginal delivery at 34th gw, BW of 1,950 g, stayed in ICU None 7, 2 years, M Delay in walking Hypotonic, psychomotor developmental delay, cafe au lait spots Abortion threat at 1st month of pregnancy treated by intramuscular injections of progesterone Head circumference below the 3rd percentile, mild exotropia on right eye, spastic hemiparesis on right side, poor vocabulary Right-sided peripheral type facial paralysis None Cerebellum (2011) 10:49–60 Table 1 Clinical characteristics of the patients University student with a sportive life and no health problem otherwise None None None Neurofibromatosis type 1 Medical doctor with active professional life Newly managed to walk few steps 51 52 Table 1 (continued) Patient no., age, sex Complaint Neurological examination Perinatal history Consanguinity Additional features Prognosis 8, 4 years, M Seizures, autoaggression, mutilation Psychomotor developmental delay None 9, 6 months, M Immaturity Hypotonic, depressed newborn reflexes Hearing loss secondary to otitis media Respiratory distress syndrome, neonatal sepsis, hypoglycemia, hyperbilirubinemia and phototherapy, pneumothorax, anemia, intracerebellar hemorrhage detected at subacute stage At pre-school education, seizures under control with treatment Clinical table improved with intensive care and antibiotic treatment, discharged with oral feeding 10, 55 years, M Normal None None 11, 9 years, M Headache, peripheric vertigo Headache Unwanted pregnancy, massive psychological stress during pregnancy Mother on fraxiparine treatment for MTHF mutation, oligohydramnios, intrauterine growth retardation, asphyxia at birth, C/S at 28th gw, BW of 540 g, stayed in ICU Reported to be unremarkable None None None 12, 10 months, M Delay in sitting Hyperactive DTR, mild developmental motor delay None None Healthy subject with active life Healthy boy with good performance at school Stable Normal Abortion threat at 2nd month of pregnancy; spontaneous vaginal delivery at 36th gw, BW of 2,500 g None Cerebellum (2011) 10:49–60 Cerebellum (2011) 10:49–60 53 Fig. 1 Axial T2 weighted images (T2WI) of patient 1 showing the absence of inferior and posterior parts of the left cerebellar hemisphere as unilateral disproportionate severe cerebellar hypoplasia (a), together with supratentorial periventricular gliosis (b) One patient with peripheral facial paralysis as a component of Moebius syndrome (patient 4) had no associated clinical features with an otherwise healthy motor and mental development. Radiologically, in addition to the absence of right-sided seventh cranial nerve and asymmetrically small pontomedullary brainstem structures on the right side, this patient had a severe hypoplasia of the right cerebellar hemisphere (Fig. 4). Four other patients (patients 5, 6, 10, and 11) were diagnosed incidentally during etiological work-up for headache. All of these patients had moderate hypoplasia of cerebellar hemispheres, and only patient 6 had a mild cerebral involvement with calcification on CT (Fig. 5). Patient 10 also had the signs of old cerebellar hemorrhage in left cerebellar hemisphere in addition to moderate disproportionate hypoplasia. These patients are in good health with active professional or educational lives. When we investigate the risk factors or prenatal insults that might have caused UCH, we could summarize our patients as follows. Fig. 2 Coronal and axial T2WI of patient 3 showing the absence of inferior and posterior parts of the left cerebellar hemisphere (a) and the absence of inferior temporal lobe on the left side with irregular borders of the left ventricle secondary to prominent loss of white matter and gliosis (b) Three children were born by cesarean section due to fetal hypoxia. They were all premature and had low birth weight (LBW); patient 1 was born at the 32nd gestational week with a birth weight of 1,350 g, patient 2 was born at the 33rd gestational week with a birth weight of 1,634 g, and patient 9 was born at the 28th gestational week with a birth weight of 540 g. Patients 2 and 9 had respiratory distress syndrome and diagnosed to have intraventricular hemorrhage and intracerebellar hemorrhage, correspondingly, during their stay in intensive care unit. Patient 5 also had an LBW of 1,950 g, who was born by spontaneous vaginal delivery at 34th gestational week and stayed in intensive care unit but discharged without any clinical symptoms. Another patient with an LBW of 2,500 g (patient 12) was also born by spontaneous vaginal delivery at the 36th gestational week. Of these five patients, three had severe disproportionate UCH (patients 1, 2, and 12), two (patients 5 and 9) had moderate disproportionate cerebellar hypoplasia, and all except one (patient 5) displayed additional cerebral involvement (Table 2). 54 Cerebellum (2011) 10:49–60 Fig. 3 Axial gradient echo images and coronal T2WI of patient 9 showing left cerebellar hemorrhage (a) and disproportionate severe hypoplasia of left cerebellar hemisphere (b) Three patients had a prenatal history of drug exposure by the use of mother during pregnancy. Two of these, patients 5 and 9, were also premature and had LBW, as described above. The mother of patient 5 was on digoxin therapy during the pregnancy for mitral valve disease, and the mother of patient 9 was on fraxiparine treatment for MTHF mutation. The other patient is that diagnosed with NF 1 (patient 7). The mother of patient 7 had intramuscular progesterone injections for abortion threat, only during the first month of pregnancy. Patient 7 had moderate hypoplasia without any additional cerebral involvement. As for the patient diagnosed with Moebius syndrome (patient 4), the mother had a minor trauma at the seventh month of gestation. This patient had severe hypoplasia without cerebral involvement (Fig. 4). The mother of patient 8 reported severe depression during pregnancy but denied any use of drugs. This patient had mild cerebellar and cerebral involvement. Of four patients with incidental diagnosis of UCH, three (patients 6, 10, and 11) had no remarkable perinatal history of any insult. The perinatal history of patient 5 was given above. These patients had moderate hypoplasia, with mild cerebral features only in patient 11. One patient (patient 3) was adopted, and for this reason, her perinatal history was not known. She had a severe disproportionate unilateral cerebellar hypoplasia with additional cerebral involvement (Fig. 3). Discussion Unilateral cerebellar hypoplasia is a very rare clinical entity. Bodensteiner and Johnsen [15] investigated 1,025 patients with cerebral palsy and reported that 33 patients had cerebellar involvement with only four patients having unilateral or focal loss of cerebellar tissue. There are also few case reports of unilateral absence of cerebellar hemisphere [4, 7, 10, 13, 16]. Pathogenesis of Unilateral Cerebral Hypoplasia Underlying pathogenesis of UCH could only be poorly defined. Johnson et al. described cerebellar injury as a complication of low birth weight in 13 children with cerebral palsy [2]. Since then, some studies have also reported at least some degree of cerebellar injury in children with cerebral palsy, who were the survivors of extreme LBW (less than 1,000 g) and extreme prematurity (less than 28th gestational week) [16, 17]. Extreme prematurity and LBW were therefore suggested to pose a high risk of perinatal cerebellar damage and linked to a variety of etiologic factors [2, 18]. However, although unilateral asymmetric defects were demonstrated on the lower parts of the cerebellar hemispheres, follow-up MRI studies revealed mostly symmetric involvement in these patients [19]. In our series, four patients had premature birth and LBW (patients 1, 2, 5, and 9), and the perinatal history was not known in one patient (adopted, patient 3). On the other hand, except patient 9, these patients did not have extreme prematurity or LBW as accused of cerebellar injury (see Table 1), and all of them had a clear asymmetric disproportionate hypoplasia of one cerebellar hemisphere. Embryologic development of mid-hindbrain is complex, beginning at about 3 weeks of gestation and continuing until 20 months of postnatal life. The disruption was related to developmental steps that take place in the growing cerebellum at 24–32 gestational weeks [20, 21]. Therefore, the selective vulnerability of the growing cerebellum during 24th to 32th gestational weeks with increased responsiveness to any kind of injury constitutes particular importance for the disruption of subsequent neurodevelopmental processes [22]. Although prematurity per se is an important Case nos., age, sex Cerebellar hemispheres and vermis Cerebellar peduncles and brainstem Cerebral hemispheres and corpus callosum 1, 3 years, M, EA Severe disproportionate absence of inferior–posterior of the left cerebellar hemisphere inferior part absent small vermis Left inferior and middle cerebellar peduncles thinner than the right side Multiple hyperintense gliotic areas at the level of corona radiata and centrum semiovale Posterior body of the corpus callosum and splenium thinner in compared to rostral parts Significant white matter volume loss, focal encephalomalacia, periventricular leukomalacia on left cerebral hemisphere Very thin Absence of inferior temporal lobe on the left; left cerebral hemisphere, especially the posterior part significantly atrophic; left cerebral peduncle hypoplastic; significant white matter volume loss on left hemisphere The posterior body of corpus callosum thin, splenium small No feature of cerebral hemispheres No feature of brainstem 2, 9 years, M, GB 3, 19 months, F, MT Severe disproportionate absence of inferior and posterior parts of the left cerebellar hemisphere Inferior part very hypoplastic small vermis Severe disproportionate absence of inferior and posterior parts, and hypoplasia on the anterior part of the left cerebellar hemisphere Left middle cerebellar peduncle almost absent No feature of brainstem Slightly thin superior left cerebellar peduncle; middle cerebellar peduncle significantly hypoplastic Hypoplastic inferior vermis 4, 3 years, M, IY 5, 20 years, M, CY 6, 54 years, M, NC 7, 2 years, M, TI 8, 4 years, M, BK 9, 6 months, M, SE Severe disproportionate hypoplasia of the right cerebellar hemisphere Disorganized foliation in hypoplastic area inferiorly hypoplastic vermis Moderate disproportionate hypoplasia of the left cerebellar hemisphere; decreased foliation rotated inferior part of vermis Moderate disproportionate hypoplasia of the right cerebellar hemisphere; radiations maloriented clockwise; calcification in the right cerebellar hemisphere in CT vermis without any feature Moderate disproportionate hypoplasia of the right cerebellar hemisphere Right half of pontomedullary brainstem asymmetrically small; 7th cranial nerve absent on right The inferior left cerebellar peduncle slightly thin No feature of brainstem Slightly thin inferior middle cerebellar peduncles No feature of brainstem No feature of CC No feature of cerebral hemispheres No feature of CC No feature of cerebral hemispheres No feature of CC Slightly thin middle, significant hypoplastic inferior right cerebellar peduncle No feature of brainstem No feature of cerebral hemispheres Slightly hypoplastic left inferior cerebellar peduncle No feature of brainstem Slightly thin superior and middle; significantly hypoplastic inferior left cerebellar peduncle Slightly dilated ventricles, decrease in white matter volume No feature Slightly dilated ventricles; delayed myelination Small splenium 55 Rotated and slightly hypoplastic inferior vermis Moderate proportionate hypoplasia of the left cerebellar hemisphere No feature of vermis Moderate disproportionate hypoplasia and hemorrhage of the left cerebellar hemisphere Inferior right cerebellar peduncle absent Cerebellum (2011) 10:49–60 Table 2 Neuroradiological features of the patients Posterior part of corpus and splenium thin Inferiorly migrated tentorium on the left side No feature of CC Absent inferior and middle peduncles, thin superior peduncle No feature of brainstem 12, 10 months, M, YRT 11, 9 years, M, TG Moderate disproportionate posterior– inferior–lateral left cerebellar hypoplasia and focal hemorrhage Vermis inferiorly small, left side rotated posteriorly Severe proportionate hypoplasia of left cerebellar hemisphere Small inferior posterior part of vermis No feature of brainstem Left lateral ventricles minimally dilated; left cerebral hemisphere migrated to inferior No feature of CC Small pons Absent inferior peduncle, thin middle and superior peduncule Right half of medulla slightly small and ischemic Thin middle peduncle Slightly rotated vermis Moderate disproportionate right cerebellar hypoplasia Inferior right side of vermis was small 10, 55 years, M, AK Cerebellar peduncles and brainstem Cerebellar hemispheres and vermis Case nos., age, sex Table 2 (continued) Thin No feature of cerebral hemispheres Cerebellum (2011) 10:49–60 Cerebral hemispheres and corpus callosum 56 risk factor for the disruption of cerebellar development [22], increased responsiveness of the developing cerebellum to injury during this particular time could also be affected by many other insults, including infection, toxins, radiation, hypoxia [23], hemorrhage [18, 20, 22], infarction [2, 24], or crossed diaschisis [25]. Any of these insults could result in cerebellar disruption and hence hypoplasia. In our series, other than prematurity and LBW as risk factors, two patients had fetal hypoxia (patients 1 and 2), two were exposed to drugs used by their mothers (patients 5 and 9), one patient had intraventricular hemorrhage (patients 2), and one patient had cerebellar hemorrhage (patient 9). All these patients with perinatal insults had a premature birth and/or LBW. In addition to these, three other patients in our series had prenatal accidents of unknown significance; one patient had intrauterine minor trauma as his mother fell down at the seventh month of gestation without any complication (patient 4), and two patients were survivors of abortion threat early in gestational weeks (patients 7 and 12). These patients completed their gestational weeks with vaginal delivery at term. In the presence of intrauterine cerebellar injury due to any type of insult, it has been reported that fetus could still complete gestational weeks with normal delivery. On the other hand, vascular disruptions or occlusions in cerebellar vasculature, such as primitive longitudinal artery or territories of basilar artery in primitive posterior circulation, early in gestational days (around 30–40 days) have been shown to initiate cerebellar tissue loss [11]. Although the drug exposure could not be definitely blamed for the cerebellar hypoplasia, especially in the absence of any associated neuroradiological abnormality, vascular undersupply, as a possible effect of drugs [21, 26], could still be the cause of cerebellar hypoplasia. Although the typical symmetric loss of cerebellar volume, in contrast to what we encountered here in our patients, makes a local event like hemorrhage or infarction unlikely, such vascular disruptions or occlusions could clearly explain asymmetric unilateral cerebellar hypoplasia [19, 20]. As destructive events interfere with the development of genetically normal primordia [19, 27, 28], a prenatally acquired lesion and, thus, a disruption seem to be more explanatory rather than a primary developmental process or malformation in the pathogenesis of unilateral cerebellar hypoplasia [4–6]. On the other hand, some syndromes have been reported to be associated with unilateral cerebellar hypoplasia. In our series, two patients had syndromic diagnosis. One of these had the diagnosis of Moebius syndrome (patient 4), who had a history of a minor intrauterine trauma. The most common finding in Moebius syndrome is brainstem hypoplasia [29, 30], which was similarly explained by the disruption theory, as symmetric tegmental infarctions in the Cerebellum (2011) 10:49–60 57 Fig. 4 Coronal and axial T2WI of patient 4 with Moebius syndrome showing disproportionate severe hypoplasia of right cerebellar hemisphere (a) and the absence of right-sided seventh cranial nerve with asymmetrically small right-sided pontomedullary brainstem (b) fetal or neonatal brainstem were related to an episode of hypoperfusion from the basilar artery [31]. In the literature, there is another case of unilateral cerebellar hypoplasia in a patient with Moebius syndrome [11, 32] that was explained to result from a vascular disruption involving basilar artery. The other patient with a syndromic diagnosis in our series was patient 7 with NF 1, who also had a prenatal history of abortion threat at first month of gestation. Although posterior fossa tumors and cerebellar hamartomas are common in neurofibromatosis type 1, cerebellar hypoplasia was reported only in one case report [33]. However, the presence of asymmetric disproportionate cerebellar hypoplasia was not reported in association with this syndrome, and it would be speculative to relate this radiological feature to the syndrome or something else. The association of UCH could not be necessarily explained by the genetic expression of NF 1 itself. On the other hand, it is not rare to see a vascular anomaly in NF 1, affecting any part of the body, but mainly the cerebral, thoracic, and abdominal arteries. A systemic vasculopathy with an increased susceptibility of fragile vessels was proposed in patients with this syndrome [34], which may therefore support our theory of vascular disruption. The other syndromes associated with cerebellar hypoplasia in the literature are Dyke– Davidoff–Mason syndrome, oculoauriculovertebral spectrum, and Aicardi’s syndrome [35–37]. In these cases, a prenatal vascular occlusion was similarly proposed pathogenetically to result from a developmental defect of the arterial system in the Willis polygon, which also supports the vascular insult in cerebellar disruption and hypoplasia. Finally, we should report that three of our patients had no history of perinatal risk factors (patients 6, 10, and 11), and the perinatal history of the other patient (patient 3) was not known as she was adopted. Although any causative risk factors could be obtained from these patients’ perinatal and past medical history, a vascular disruption of unknown causes could also be the etiopathological explanation of unilateral cerebellar hypoplasia in these patients, as well [38, 39]. Fig. 5 Axial CT images of patient 6 showing right cerebellar calcification (a) and axial T2WI images of the same patient showing malrotated mild hypoplasia of right cerebellar hemisphere with disoriented folia (b); axial T2WI of patient 10 presenting with headache showing disproportionate right cerebellar hypoplasia diagnosed incidentally (c) 58 Clinical and Radiological Characteristics of Unilateral Cerebral Hypoplasia The patients with UCH could present with a wide variety of symptoms or show no or few symptoms due to some compensatory mechanisms [4, 7, 10, 40, 41]. The most common findings reported so far are developmental and speech delay, hypotonia, ataxia, and abnormal ocular movements. Mental status was demonstrated as an important element of prognosis [10, 42]. Epilepsy was also a common finding in association with cerebellar lesions in premature patients with LBW [3]. In our series, five patients had a delay in developmental milestones (patients 1, 3, 7, 9, and 12), two patients had epileptic seizures (patients 2 and 8), and one patient had peripheral facial paralysis (patient 4). Detailed clinical features of patients are given in Table 1. Clinical and radiological features in cerebellar hypoplasia do not seem to show any correlation. The relationship of main clinical features and radiological findings is drawn schematically in Fig. 6. The detailed cranial MRI features of the patients are summarized at Table 2. As previously reported in the literature [21], inferior and posterolateral Fig. 6 Schematic illustration of clinico-radiological correlation; inner circle, mild UCH; middle circle, moderate UCH; outer circle, severe UCH; left upper quadrant, patients with epilepsy; right upper quadrant, patients with MMR; right lower quadrant, patient with facial paralysis; left lower quadrant, patients evaluated for headache; P+, proportionate with additional features; P−, proportionate without additional features; D+, disproportionate with additional features; D−, disproportionate without additional features Cerebellum (2011) 10:49–60 parts of cerebellum were affected more than other parts, probably related to the rostrocaudal developmental feature. Most patients had disproportionate cerebellar hypoplasia, and only one had mild hypoplasia, while others had moderate to severe cerebellar hypoplasia. Patients with severe disproportionate unilateral cerebellar hypoplasia also displayed significant commissural changes related to ischemic or vascular injuries. Patients with syndromerelated unilateral cerebellar hypoplasia had less cerebral changes than others. Moreover, we have noticed that of five patients with poor prognosis (patients 1, 3, 7, 9, and 12), all except one (patient 12) had the involvement of white matter and/or morphological changes in corpus callosum. On the other hand, only three out of seven patients with good prognosis had involvement of corpus callosum. This might be an important factor in estimating the prognosis. Four patients in our series (patients 5,6,10, and 11) were examined for headache and incidentally diagnosed to have moderate disproportionate unilateral cerebellar hypoplasia. Headache as a presenting symptom was also reported in cerebellar hypoplasia and Arnold–Chiari malformations [1]. None of our patients had Arnold–Chiari malformation or any other associated cerebral abnormality, except for patient 11 who had thin corpus callosum posteriorly. All these patients had an unremarkable perinatal history, except for one patient with intrauterine drug exposure, prematurity and LBW, as previously discussed (patient 5). On the other hand, all without any exception had a normal neurological examination and perfect prognosis. A surprisingly well preserved motor functioning was previously reported in patients with cerebellar agenesis [38]. It was proposed that in the presence of intact loops within cerebro-cerebellar system, the patients could remain asymptomatic [39]. Another study has emphasized the importance of vermis in the emergence of symptoms and suggested that the involvement of cerebral hemispheres sparing vermis has a favorable outcome [43]. In our series, however, the sparing of vermis did not seem to have any influence on prognosis. There are some limitations in our study; the sample size is relatively small and precluded formal statistical analyses; prenatal imaging data were merely present; cerebellar volume measurements were done by visual inspection of the various MRI planes as described in the “Patients and Methods” section but not by volumetric measurements; and the time frame of follow-up and the parameters used to describe prognosis were variable. Conclusion Cerebellar malformations are rare clinical entities, and attention in the literature was recently drawn by the vast advances in neuroimaging studies. Unilateral cerebellar Cerebellum (2011) 10:49–60 hypoplasia is not a newly diagnosed entity, but problematic in its classification and underlying pathogenesis. However, under the light of these data, we may suggest that unilateral asymmetric cerebellar hypoplasia is probably caused by a prenatal vascular insult secondary to a variety of etiologies, ultimately resulting in a disruption in cerebellar development. This hypothesis should better be exemplified by other case reports from this point of view and linked to pathogenetic experimental studies in a way to expand our current knowledge. In addition, for patients with asymptomatic unilateral cerebellar hypoplasia, neuroimaging studies such as diffusion tensor imaging and fiber tractography could reveal important information about cerebrocerebellar circuits and be useful in our better understanding of cerebellum and its functions. 59 16. 17. 18. 19. 20. 21. 22. References 1. Patel S, Barkovich AJ. Analysis and classification of cerebellar malformations. AJNR. 2002;23:1074–87. 2. Johnsen SD, Tarby TJ, Lewis KS, Bird R, Prenger E. Cerebellar infarction: an unrecognised complication of very low birthweight. J Child Neurol. 2002;17:320–4. 3. Boltshauser E. Cerebellum—small brain but large confusion: a review of selected cerebellar malformations and disruptions. Am J Med Genet. 2004;126:376–85. 4. Boltshauser E, Steinlin M, Martin E, Deonna TH. Unilateral cerebellar aplasia. Neuropediatrics. 1996;27:50–3. 5. Dhillon AS, Chapman S, Milford DV. Cerebellar defect associated with Schimke immuno-osseous dysplasia. Eur J Pediatr. 2001; 160:372–4. 6. Mancini J, Lathel V, Hugonenq C, Charbol B. Brain injuries in early foetal life: consequences for brain development. Dev Med Child Neurol. 2001;43:52–5. 7. Erdogan N, Kocakoc E, Bekar D, Ozturk O. Unilateral absence of cerebellar hemisphere: a case report. Neuroradiology. 2002;44:49– 51. 8. Robins JB, Mason GC, Watters J, Martinez D. Case report: cerebellar hemi-hypoplasia. Prenat Diagn. 1998;18:173–7. 9. Poretti A, Leventer RJ, Cowan FM, Rutherford MA, Steinlin M, Klein A, et al. Cerebellar cleft: a form of prenatal cerebellar distruption. Neuropediatrics. 2008;39:106–12. 10. Kilickesmez O, Yavuz N, Hoca E. Unilateral absence of cerebellar hemispheres: incidental diagnosis with magnetic resonance imaging. Acta Radiol. 2004;8:876–7. 11. Harbord MG, Finn JP, Hall-Craggs MA, Brett EM, Baraitser M. Moebius’ syndrome with unilateral cerebellar hypoplasia. J Med Genet. 1989;26:579–82. 12. Titomanlio L, De Brasi D, Romano A, Genesio R, Diano AA, Del Giudice E. Partial cerebellar hypoplasia in a patient with Prader– Willi syndrome. Acta Paediatr. 2006;95:861–3. 13. Poretti A, Prayer D, Boltshauser E. Morphological spectrum of prenatal cerebellar disruptions. Eur J Pediatr Neurol. 2009;13:397– 407. 14. Goasdoue P, Rodriguez D, Moutard ML, Robain O, Lalande G, Adamsbaum C. Pontoneocerebellar hypoplasia: definition of MR features. Pediatr Radiol. 2001;31:613–8. 15. Bodensteiner JB, Johnsen SD. Magnetic resonance imaging (MRI) findings in children surviving extremely premature 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. delivery and extremely low birthweight with cerebral palsy. J Child Neurol. 2006;21:743–7. Bodensteiner JB, Johnsen SD. Cerebellar injury in the extremely premature infant: a newly recognized but relatively common outcome. J Child Neurol. 2004;19:139–42. Johnsen SD, Bodensteiner JB, Lotze TE. Frequency and nature of cerebellar injury in the extreme premature survivor with cerebral palsy. J Child Neurol. 2005;20:60–4. Miall LS, Cornette LG, Tanner SF, Arthur RJ, Levene MI. Posterior fossa abnormalities seen on magnetic resonance brain imaging in a cohort of newborn infants. J Perinatol. 2003;23:396– 403. Boltshauser E. Cerebellar imaging—an important signpost in paediatric neurology. Child Nerv Syst. 2001;17:211–6. 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;26:1659– 67. Parisia MA, Dobyns WB. Human malformations of the midbrain and hindbrain: review and proposed classification scheme. Mol Genet Metab. 2003;80:36–53. Messerschmidt A, Prayer D, Brugger PC, Boltshauser E, Zoder G, Sterniste W, et al. Preterm birth and disruptive cerebellar development: assessment of perinatal risk factors. Eur J Pediatr Neurol. 2008;12:455–60. Lee C. Cerebellar alterations induced by chronic hypoxia: an immunohistochemical study using a chick embryonic model. Brain Res. 2001;901:271–6. Kraeloh-Mann I, Toft P, Lunding J, Andresen J, Pryds O, Lou HC. Brain lesions in preterms: origin, consequences and compensation. Acta Paediatr. 1999;88:897–908. Rollins NK, Wen TS, Dominguez R. Crossed cerebellar atrophy in children: a neurologic sequela of extreme prematurity. Pediatr Radiol. 1995;25:S20–5. de Souza N, Chaudhuri R, Bingham J, Cox T. MRI in cerebellar hypoplasia. Neuroradiology. 1994;36:148–51. Merks JH, van Karnebeek CD, Caron HN, Hennekam RC. Phenotypic abnormalities: terminology and classification. Am J Med Genet. 2003;123:211–30. Spranger J, Benirschke K, Hall JG, Lenz W, Lowry RB, Opitz JM, et al. Errors of morphogenesis: concepts and terms—recommendations of an International Working Group. J Pediatr. 1982;100:160–5. Pedraza S, Gamez J, Rovira A, Zamora A, Grive E, Raguer N, et al. MRI findings in Moebius syndrome: correlation with clinical features. Neurology. 2000;55:1058–60. Ouanounou S, Saigal G, Birchansky S. Moebius syndrome. AJNR. 2005;26:430–2. Sarnat HB. Watershed infarcts in the fetal and neonatal brainstem. An aetiology of central hypoventilation, dysphasia, Moebius syndrome and micrognathia. Eur J Paediatr Neurol. 2004;8:71– 87. Pitner SE, Edwards JE, Mccormick WF. Observations on the pathology of the Moebius syndrome. JNNP. 1965;28:362–74. Al-Hail H, Ruiz-Miyares F, Deleu D, Mesraoua B. Cerebellar hypoplasia and vertebral indentations in a case of neurofibromatosis type I. Rev Neurol. 2008;46:626–7. Saunauf B, Chevalier S, Jehan C, Courtheoux P, Gerard JL, Hanouz JL, et al. Neurofibromatosis type 1 and multiple traumatic cervical arterial injuries: a case report. Cases J. 2009;2:7199. Martinelli P, Maruotti GM, Agangi A, Mazzarelli LL, Bifulco G, Paladini D. Prenatal diagnosis of hemifacial microsomia and ipsilateral cerebellar hypoplasia in a fetus with oculoauriculovertebral spectrum. Ultrasound Obstet Gynecol. 2004;24:199– 201. Serrano-Gonzalez C, Prats Vinas JM. Unilateral aplasia of the cerebellum in Aicardi’s syndrome. Neurolgia. 1998;13:254–6. 60 37. Atalar MH, Icagasioglu D, Tas F. Cerebral hemiatrophy (Dyke– Davidoff–Mason syndrome) in childhood: clinicoradiological analysis of 19 cases. Pediatr Int. 2007;49:70–5. 38. Lemon RN, Edgley SA. Life without cerebellum. Brain. 2010;133:652–4. 39. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121:561–79. 40. Altman NR, Naidich TP, Braffman BH. Posterior fossa malformatinos. AJNR. 1992;13:691–724. Cerebellum (2011) 10:49–60 41. Mendelsohn DB, Hertzanu Y, Glass RBJ, Spiro F. Unilateral cerebellar hypoplasia. J Comput Assist Tomogr. 1983;7:1077– 8. 42. Poretti A, Limperopoulos C, Roulet-Perez E, Wolf NI, Rauscher C, Prayer D, et al. Outcome of severe unilateral cerebellar hypoplasia. Dev Med Child Neurol. 2010;52:718–24. 43. Tavano A, Grasso R, Gagliardi C, Triulzi F, Bresolin N, Fabbro F, et al. Disorders of cognitive and affective development in cerebellar malformations. Brain. 2007;130:2646–60.