Astrid Sehested

Cerebellar mutism: review of the literature.

PurposeCerebellar mutism is a common complication of posterior fossa surgery in children. This article reviews current status with respect to incidence, anatomical substrate, pathophysiology, risk factors, surgical considerations, treatment options, prognosis and prevention.MethodsWe reviewed all peer-reviewed English publications on cerebellar mutism between the years of 1985 and 2009. The majority were found by searching for ‘cerebellar mutism’ and ‘posterior fossa syndrome’ in PubMed. Additional cases were identified by cross-checking reference lists.ResultsThe overall incidence of postoperative cerebellar mutism is 11–29%, and patients with medulloblastomas and/or brainstem invasion are at a greater risk of developing it than those with other kinds of tumors and/or without brainstem invasion. Permanent sequelae in the form of both motor- and non-motor-related speech deficits are common, especially when the right cerebellar hemisphere is involved. The mutism is caused by bilateral pertubation of the dentate nuclei and their efferent pathways, which emphasizes the need to explore surgical methods that spare these structures. The pathophysiological mechanisms of delayed onset and resolution of cerebellar mutism are not clear, but axonal damage, edema, perfusional defects and metabolic disturbances may be involved.ConclusionThe incidence of cerebellar mutism is well documented in children with medulloblastoma, but precise figures for those with astrocytoma and ependymoma are lacking. Further anatomical, functional imaging and neuropsychological studies are needed to clarify the pathophysiological mechanisms in order to define preventive measures during surgery. Randomized, controlled trials of the effects of different medication and post-operative speech therapy are necessary for improving treatment.

Fetal Growth, Preterm Birth, Neonatal Stress and Risk for CNS Tumors in Children: A Nordic Population- and Register-Based Case-Control Study

Background: The peak incidence of central nervous system (CNS) tumors in childhood indicates that intrauterine or neonatal characteristics are potential risk factors or symptoms of early onset of disease. Methods: We conducted a registry-based case-control study nested in the childhood populations of Denmark, Finland, Sweden, and Norway on the association between indicators of fetal growth and neonatal stress and childhood CNS tumor risk diagnosed during the period 1985-2006. Each of the 3,443 cases was matched individually on date of birth, sex, and country to five controls sampled randomly from population registries. Information on birth characteristics was obtained from national birth registries. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) by conditional logistic regression analyses. Results: We observed a U-shaped relation between risk for CNS tumors and birthweight, at >4.5 kg (OR, 1.27; 95% CI, 1.03-1.55) and <2.0 kg (OR, 1.50; 95% CI, 1.13-1.99), the latter being attenuated after adjustment for gestational age. Moreover, small-for-gestational age (OR, 1.28; 95% CI, 0.98-1.66) and large-for-gestational age (OR, 1.26; 95% CI, 1.02-1.55) were both associated with CNS tumors. The OR for preterm births was increased per 1-week decrease in gestational age (OR, 1.58; 95% CI, 1.04-2.44). Increased ORs were also observed for head circumference >38 cm (1.80; 95% CI, 1.18-2.74), 5-minute Apgar score <7 (1.44; 95% CI, 0.98-2.12), and breech presentation (1.33; 95% CI, 1.04-1.69). The observed associations varied little by histologic subgroup. Conclusions: This study supports intrauterine or neonatal onset of childhood CNS tumors. The findings provide insight into the natural history of childhood CNS tumors indicating an early onset or, alternatively, potentially harmful exposures in the neonatal period that might be preventable. Cancer Epidemiol Biomarkers Prev; 19(4); 1042–52. ©2010 AACR.

Incidence of Childhood Central Nervous System Tumors in the Nordic Countries

The incidence rates of childhood central nervous system (CNS) tumors in the Nordic countries remain among the highest in the world. Large geographical and temporal variations in the incidence rates of CNS tumors have been reported. Increasing incidence rates would be a public health concern, as they might indicate increased exposure to environmental risk factors.

Cerebellar mutism: definitions, classification and grading of symptoms

Dear editor, We would like to thank Dr. Frassanito and Dr. Massimi for their interesting and valuable comments on our review article on cerebellar mutism, particularly in sharing their own operative experience [1]. However, their interpretation of the incidence of cerebellar mutism syndrome, following surgery for cerebellar ependymoma in von Hoffs article, seems to be based on a misunderstanding regarding definitions of two different problems related to the cerebellum in this article—“postoperative cerebellar mutism” versus “postoperative cerebellar syndrome”. von Hoff et al. define the “cerebellar syndrome” as a motoric triad of ataxia, nystagmus, and dysmetria, grade it as mild, moderate, or severe as proposed by Riva et al. in 1991 [2] and refer to it as a general measure of cerebellar damage. They do not relate it to the wellrecognized posterior fossa/cerebellar mutism syndrome as such. Thus, a closer look at Table 1 reveals that the incidence of postoperative cerebellar mutism was in fact 0 [3]. The same motoric cerebellar syndrome is described in a group of patients as a measure of pre-operative clinical status in another article by Callu et al from 2009. The incidence of ataxia, nystagmus and dysmetria before surgery was 31%, while the incidence of post-operative mutism was 8% [4]. In both series, the telovelar approach was used from year 2004 and onwards, but only in patients whose tumor was located in the inferior part of the vermis. This was recommended after recognizing the role that splitting of the vermis plays in post-operative intellectual impairment [5]. This discussion highlights the confusion that exists in the literature regarding classification and definitions. We have defined “cerebellar mutism” as muteness following lesion of the cerebellum as opposed to the cerebrum or the lower cranial nerves. It is further characterized by delayed onset, limited duration, and (usually) long-term linguistic sequelae [6]. A common synonym is “transient cerebellar mutism” [7]. The “posterior fossa syndrome” is a broad term that usually includes cerebellar mutism as its main feature, but also encompasses motoric problems such as ataxia, hypotonia, cranial nerve palsies together with neurobehavioral abnormalities such as emotional lability, poor oral intake, decreased spontaneous initiation of movements, and impaired eye opening [8]. The “cerebellar mutism syndrome” was initially used as a synonym for isolated cerebellar mutism [9, 10], but has more recently in T. Gudrunardottir :A. Sehested :K. Schmiegelow (*) Department of Pediatrics, University Hospital Rigshospitalet, Copenhagen, Denmark e-mail: kschmiegelow@rh.dk

Radiation therapy and concurrent topotecan followed by maintenance triple anti‐angiogenic therapy with thalidomide, etoposide, and celecoxib for pediatric diffuse intrinsic pontine glioma

Despite major treatment attempts, the prognosis for pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. Gliomas are highly vascularized tumors, suggesting that the prevention of vessel formation by anti‐angiogenic treatment might be effective.

A new NFIA:RAF1 fusion activating the MAPK pathway in pilocytic astrocytoma

Pilocytic astrocytoma (PA) is one of the most common brain cancers among children and activation of the Mitogen-Activated Protein Kinase (MAPK) pathway is considered the hallmark. In the majority of cases, oncogenic BRAF fusions or BRAF V600E mutations are observed, while RAF1 or NF1 alterations are more rarely found. However, in some cases, no apparent cancer driver events can be identified. Here, we describe a novel fusion between the transcription factor nuclear factor 1A (NFIA) and Raf-1 proto-oncogene (RAF1) in a 5-year old boy with PA. The novel fusion was identified as part of a comprehensive genomic tumor profiling. We show that the NFIA:RAF1 fusion results in constitutive Raf1 kinase activity, leading to activation of downstream MEK1/2 cascade and increased proliferation of cancer cells. The NFIA:RAF1 fusion displayed distinct subcellular localization towards the plasma membrane indicative of Raf-1 activation, in contrast to both wild type NFIA and Raf-1, which were localized in the nucleus and cytoplasm, respectively. In conclusion, our data support the existence of rare oncogenic RAF1 fusions with constitutive Raf-1 activity. This highlights the need for broad genetic testing in order to refine diagnostics of PA and to unravel potential treatment options, e.g. with MEK inhibitors.

Cerebellar mutism: incidence, risk factors and prognosis

Dear Editor, We have, with interest, read the review article by Tasdemiroğlu et al. in Childs Nervous System on postoperative cerebellar mutism and autistic spectrum disorder [1]. Although this is not the first paper that locates some of the language problems characteristic for autism to anatomical aberrations in the cerebellum [2, 3], its focus on the similarities between the autistic language problems and postoperative cerebellar mutism is intriguing. However, we have recently reviewed cerebellar mutism [4] and wish to correct some important inaccuracies in the paper of Tasdemiroğlu et al. First, the incidence of cerebellar mutism it not 5.7–8.5% as stated by Tasdemiroğlu et al., but at least twice as high, with incidence figures ranging from 11 to 29% [5–10]. Second, recovery from postmutistic dysarthria is not complete within 1–3 months as stated by Tasdemiroğlu et al. Thus, three recent long-term follow-up studies have shown that speech rarely normalizes and that dysarthria tends to persist [7, 11–13]. Finally, hydrocephalus [5, 14, 15], postoperative meningitis [5, 10] and the length of the vermian incision [16] are no longer considered to be risk factors for cerebellar mutism, whereas the role of tumour size remains uncertain, since published data have reached divergent conclusions [5, 15]. In contrast, known risk factors for cerebellar mutism are brainstem involvement by the tumour [10, 14, 17], midline location [5, 10] and tumour type [5, 14].

Genomic diagnostics leading to the identification of a TFG-ROS1 fusion in a child with possible atypical meningioma

Meningiomas are rare in children. They are highly complex, harboring unique clinical and pathological characteristics, and many occur in patients with neurofibromatosis type 2. Hereby, we present a case of a two-year-old boy presented with a diagnostically challenging intraventricular tumor. It was incompletely resected 6 times over 14 months but kept progressing and was ultimately deemed unresectable. Histologically, the tumor was initially classified as schwannoma, but extensive international review concluded it was most likely an atypical meningioma, WHO grade II. Comprehensive genomic profiling revealed a TFG-ROS1 fusion, suggesting that ROS1-signaling pathway alterations were driving the tumor growth. In light of this new information, the possibility of a diagnosis of inflammatory myofibroblastic tumor was considered; however the histopathological results were not conclusive. This specific molecular finding allowed the potential use of precision medicine and the patient was enrolled in the AcSé phase 2 trial with crizotinib (NCT02034981), leading to a prolonged partial tumor response which is persisting since 14 months. This case highlights the value of precision cancer medicine in children.

T-cell ALL in ataxia telangiectasia cured with only 7 weeks of anti-leukemic therapy.

A 20-month-old girl diagnosed with T-cell acute lymphoblastic leukemia was treated according to the Nordic NOPHO ALL2000 protocol. The patient developed severe immunosuppression and experienced life-threatening adenovirus infection, which was treated with ribavirin and cidofovir. α-fetoprotein was 20- to 30-fold elevated, and genetic analysis confirmed the diagnosis of ataxia telangiectasia. Despite receiving only 7 weeks of anti-leukemic therapy, she has stayed in first remission now 8 years after the diagnosis. We speculate that this could be because of increased chemosensitivity of ATM-mutated leukemic cells, adenovirus causing a direct oncolytic effect, and/or high levels of endogenous cortisol during her severe infection.

Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

Medulloblastomas are the most common, and often fatal, paediatric brain tumours that feature high genomic instability, frequent infection by human cytomegalovirus (HCMV) and resistance to radiation and chemotherapy. The causes of the pronounced chromosomal instability and its potential links with HCMV infection and/or resistance to genotoxic therapies remain largely unknown. To address these issues, here we have combined immunohistochemical analysis of a series of 25 paediatric medulloblastomas, complemented by medulloblastoma cell culture models including experimental HCMV infection. Using eight established immunohistochemical markers to assess the status of the DDR machinery, we found pronounced endogenous DNA damage signalling (γH2AX marker) and robust constitutive activation of both the ATM‐Chk2 and ATR‐Chk1 DNA damage checkpoint kinase cascades, yet unexpectedly modest p53 tumour suppressor activation, across our medulloblastoma cohort. Most tumours showed high proliferation (Ki67 marker), variable oxidative DNA damage (8‐oxoguanine lesions) and formation of 53BP1 nuclear ‘bodies’, the latter indicating (along with ATR‐Chk1 signalling) endogenous replication stress. The bulk of the clinical specimens also showed expression of HCMV immediate early and late proteins, in comparative analyses using three immunohistochemical protocols. Cell culture experiments validated the chronic endogenous replication stress in medulloblastoma cell lines and showed sharply differential, intriguing responses of normal cells and medulloblastoma cells to HCMV infection, including differential subcellular mislocalization and enhancement of replication stress‐related 53BP1 body formation, the latter in cell‐non‐autonomous manner. Overall, our results strongly indicate that in human medulloblastomas, the DDR checkpoint barrier is widely activated, at least in part due to replication stress. Furthermore, we propose that unorthodox p53 defects other than mutations may allow high proliferation despite the ongoing checkpoint signalling and that the highly prevalent HCMV may impact the medulloblastoma host cell replication stress and DNA repair. Collectively, the scenario we report here likely fuels genomic instability and evolution of medulloblastoma resistance to standard‐of‐care genotoxic treatments.