In this review, we analyzed 23 studies published between 1997 and 2014 that reported neurodevelopmental outcomes of prematurity-related cerebellar injury. We rigorously searched three major databases. We selected studies only published in English; therefore, it is possible that relevant studies printed in other languages may have been missed. Due to the heterogeneity in research methodology used among the studies, meta-analyses could not be performed. For example, gestational age at birth varied widely between studies (from 22 to 36 weeks). It is well known that cerebellar injury and perinatal complications are inversely related to gestational age at birth. Therefore, the wide-ranging neurodevelopmental impairments reported by the different studies could be due in part to the variable gestation age of the study cohorts, where impairments may be more prevalent in samples with a lower gestational age at birth compared to those with a higher gestational age. Hence, the reader should interpret the findings reported in this review of literature with caution. Nevertheless, to provide greater synthesis of the results, we stratified the studies into three categories of prematurity-related cerebellar injury. It is important to note that the study group assignment was entirely based on the information provided in the published reports, which could have introduced bias when information was not reported. Nonetheless, to our knowledge, this is the first review to extensively summarize the neurodevelopmental and functional consequences of early life cerebellar injury in ex-preterm survivors using a structured approach.

About half of the studies reviewed included information from neonatal cranial ultrasound. MRI was the most common brain imaging modality and was used by all studies except three that reported only HUS findings [23–25]. Most studies used a prospective longitudinal design and serial MRI was performed in only three studies [28, 29, 42]. Longitudinal serial imaging studies spanning the neonatal to adolescent period, coupled with standardized outcomes evaluations during childhood and/or adolescence, are currently lacking. Such studies are needed to determine to what extent neonatal imaging findings and subsequent neurodevelopmental impairments described herein are transient or persistent in nature. Understanding the long-term consequences of prematurity-related cerebellar underdevelopment is essential for determining the best clinical services for optimal development. Despite the heterogeneity among the analyzed studies, this review highlights a common, cross-cutting theme that prematurity-related cerebellar injury is associated with non-desirable motor and non-motor outcomes.

Motor Outcomes

Overall, neuromotor impairments were associated with severe direct CBI with a prevalence varying from 15 to 100 % [11, 22–25, 29, 31, 32]. Although less consistent, a similar trend was observed in studies evaluating cerebellar volume in the presence of cerebral injury; reduced cerebellar volume was associated with less favorable motor outcomes [34, 35, 40]. Despite the well-established role of the cerebellum in motor function, only 39 % (9/23) of studies evaluated motor performance using standardized developmental assessments and most did not differentiate between gross and fine motor deficits. The majority of studies relied on a formal neurologic examination which is more likely to detect major neurologic dysfunction, but may be less sensitive to the more subtle motor deficits.

Cognitive Outcomes

The results of this review demonstrate that prematurity-related CBI occurs on a continuum of severity and is associated with wide-ranging and far-reaching long-term neurocognitive impairments and disabilities. This review highlights a strong association between cerebellar volumetric growth impairment and cognitive disabilities as well as executive dysfunction secondary to direct and indirect CBI [34, 36, 38, 41–43]. These data corroborate previous reports from other pediatric populations including older children following cerebellar tumor resection who develop higher order cognitive deficits such as difficulties with task organization and problem solving [44, 45]. Moreover, a broad range of cognitive dysfunction including impairments in visuospatial processing, executive function, and memory has been reported in adults with cerebellar lesions [46].

Language Outcomes

Although a cerebellar role in language deficits has been increasingly reported in adults following cerebellar vascular lesions [47, 48], to date, very few studies in ex-preterm children following early life CBI have examined the association between the cerebellum and early language development. Available evidence [22, 32] suggests that direct CBI, and more specifically injury to the vermis [22], is associated with language deficits in ex-preterm children. Similarly, larger hemorrhagic lesions affecting the cerebellar vermis have been implicated in language deficits among term-born infants [49]. Interestingly, these findings differ from the lateralized right cerebellar hemispheric language pathway that has been reported in adults using functional MRI studies [50]. These intriguing topographic differences associated with injury to the immature versus the mature cerebellum deserve further investigation. Taken together, available evidence links direct CBI with expressive and receptive language deficits in preschool- and school-aged children; however, future studies are needed to better delineate the type of language deficits and their regional cerebellar topology.

Social-Behavioral Outcomes

Although behavioral problems are prevalent among survivors of preterm birth [14, 51, 52], behavioral outcomes in ex-preterm survivors of CBI were relatively unexplored in the studies included in this review. Only three studies examined the relationship between behavioral difficulties and direct/indirect CBI [22, 42] and two of them found strong associations between behavioral problems and cerebellar injury/underdevelopment [22, 42]. Moreover, socialization difficulties and early autistic features were also found to be highly prevalent and primarily related to vermian injury [22]. This atypical social-behavioral functioning in ex-preterm children following early life CBI is strongly suggestive of an autism spectrum disorders profile. Interestingly, similar associations between social/behavior dysfunction and the vermis have been described in young children with cerebellar malformations [53]. Converging evidence from other study populations has suggested that regional cerebellar vermis volume may be a substrate for autism spectrum disorders [46, 54].

The cerebellum is known to play a role in the pathogenesis of neurodevelopmental and neuropsychiatric conditions such as dyslexia, attention deficit hyperactivity disorder, schizophrenia, and autism [15, 46, 55, 56]. Taken together, converging lines of investigation point to an elevated increased risk among survivors of very premature infants for subsequent development of cognitive, learning, behavioral, and socio-affective disturbances. These data support an under-appreciated role for early life cerebellar injury in the high prevalence of long-term pervasive neurodevelopmental disabilities. Noteworthy, the degree to which these initial positive screen rates for autistic features are transient or reflective of true autism spectrum disorders remains to be determined. Ongoing studies are needed to examine the sensitivity, specificity, and predictive validity of early autism screeners in ex-preterm infants following a CBI.

Developmental Cerebellar Cognitive Affective Syndrome

Although previously thought to be exclusively involved in motor control, the cerebellum is now known to play a critical role in higher order cognitive and affective functions. Schmahmann and Sherman [57] were the first to describe the cerebellar cognitive affective syndrome characterized by a myriad of impairments in executive, visual spatial, linguistic, and affective function in adults [58, 59] and in older children [60–64] following cerebellar lesion. Relevant to the current review is an apparent ‘developmental’ form of cerebellar cognitive affective syndrome is survivors of prematurity-related CBI. The underpinnings of this developmental cerebellar cognitive affective profile suggest an overlap with the features of early autism described herein. Worthy of note is the fact that social-behavioral changes described in the cerebellar cognitive affective syndrome appear to be most prominent with injury to the cerebellar vermis and paravermian regions (described above). Higher order cognitive and social-behavioral deficits have also been described in children with cerebellar malformations [65]. Although most studies have reported non-specific global developmental delays, recent reports using comprehensive outcome evaluations suggest that visuospatial skills, language, and attention are also impaired in children with cerebellar malformations [53, 66, 67]. Moreover, as reported in children with prematurity-related CBI, smaller cerebellar volume was associated with lower motor and non-motor functioning in children with cerebellar malformations. In particular, smaller right cerebellar hemispheric volume was associated with lower expressive language and cognitive skills, while smaller vermian volume was associated with behavioral problems [68]. Collectively, these data suggest that a developmental cerebellar cognitive affective profile is present in children with both acquired and developmental cerebellar lesions.

Cerebellar Functional Topography

Although very few studies in this review described the topography of the cerebellar lesions, available data suggests that there appears to be a functional topography to cerebellar underdevelopment in ex-preterm survivors. Zayek et al. [25] reported that lesions confined to the lateral hemisphere, either unilaterally or bilaterally, were associated with cognitive impairment, while other studies found that injury that involved the vermis was associated with more extensive cognitive, language, and social-behavioral disturbances [22, 32]. Although the topography of neuromotor deficits was not directly explored in the studies reviewed herein, literature from adult populations suggests that motor abnormalities occur in the presence of midline and/or anterior lobe cerebellar lesions or malformations [47, 69]. The fastigial nuclei are important relays of the vestibulo-occular system. They are the most medially located cerebellar nuclei and, therefore, are more vulnerable in the event of vermian injury. Cerebellar strokes in adults are more frequent in the posterior inferior cerebellar artery (PICA) territory, which in turn has implicated the inferior part of the vermis and posterior sections of the cerebellar hemispheres [70]. There appears to be a similar predilection for infero-medial injury in prematurity-related CBI [6, 32], which may in part explain the predisposition for cognitive, language, and social impairments over motor problems in these infants.

Only one study in this review [26] performed regional cerebral parcellation and tissue segmentation in children with isolated direct CBI. This study showed regional decreases in cerebral cortical volume contralateral to unilateral CBI. These volume reductions were identified in apparently uninjured cerebral cortical regions and were highly significantly associated with language, motor, cognitive, and behavioral deficits. These results suggest that secondary impaired cerebral cortical volumetric growth following a direct contralateral CBI likely underlies the developmental impairments observed in these children. The authors postulated that transtentorial trophic withdrawal is associated with secondary growth impairment of cerebral cortical development after remote CBI. Remarkably, only about a third of the studies included in this review tentatively controlled for this crossed cerebellar diachisis effect by adjusting for cerebral volume or injury in their analyses [11, 22, 23, 25, 26, 29, 30, 36, 37]. Future studies combining advanced regional volume analyses of the cerebrum and cerebellum will help to better elucidate this phenomenon and its functional implications. Moreover, given the highly plastic properties of the cerebellum alongside its protracted developmental course, the potential role of early intervention to prevent secondary developmental disruption warrants further exploration.

Conclusion and Future Directions

This review highlights that cerebellar injury (direct or indirect) in very preterm born infants has far-reaching functional consequences among survivors. Collectively, the existing literature supports the notion of a developmental form of cerebellar cognitive affective syndrome in prematurity-related cerebellar injury. To date, cerebellar structure-function relationships have been explored almost exclusively using single measurement designs and primarily at a macrostructural level by qualitative evaluation of the cerebellar structure or 3-D volumetric MRI. Future prospective, longitudinal studies applying serial advanced quantitative MRI techniques such as diffusion tensor imaging (DTI), functional MRI, and 1H-MRS will provide critically important, currently unavailable insights at a microstructural, functional, and metabolic level. Likewise, ongoing research is needed in order to precisely delineate the relationship between prematurity-related cerebellar injury and the true prevalence of autism spectrum disorders. Collectively, this will allow clinicians to provide more informed prognostic counseling and anticipatory planning, as well as the development of more timely, tailored, and cost-effective models for early intervention that will lead to better allocation of resources.