Posterior fossa syndrome: Review of the behavioral and emotional aspects in pediatric cancer patients.

Medulloblastoma, the most common malignant brain tumor of childhood, occurs in the posterior fossa, the part of the intracranial cavity that contains the brainstem and the cerebellum. The cerebellum is involved in many complex aspects of human behavior and function, and when it is disrupted or insulted, this can lead to significant sequelae in children with posterior fossa tumors. A constellation of impairing and distressing symptoms, including mutism, ataxia/hypotonia, and emotional lability, develops in approximately 25% of children after the surgical resection of posterior fossa tumors. These symptoms may impede treatment and frequently require intervention in order for children to be able to participate in their care. The eventual recovery of speech occurs for most, but with slowly improving dysarthria over many months. Behavioral changes and emotional lability also occur. This phenomenon has been classified differently by different investigators over the past 35 years. For the purposes of this article, the term posterior fossa syndrome is used to refer to the neuropsychiatric and behavioral features that compose this condition. The current review summarizes the development of the clinical understanding of this phenomenon with a focus on near- and long-term psychosocial and psychiatric implications. Also, clinical examples of the presentation, management, and lasting implications of this syndrome are provided. This review is intended to be a resource for clinicians who treat affected children. Cancer 2017;123:551-559. © 2016 American Cancer Society.

Cerebellar mutism syndrome: cause and rehabilitation.

PURPOSE OF REVIEW: Mutism of cerebellar origin may occur in the context of various causes but is most frequent in children after resection of a large midline cerebellar tumour. In this review, the endeavour to reach a consensus on name and definition of postoperative mutism of cerebellar origin and associated symptoms is highlighted. In addition, progress in understanding of cause and risk factors for the syndrome is discussed as well as the rehabilitation issues. RECENT FINDINGS: Consensus on the term cerebellar mutism syndrome (CMS) has been reached. The exact pathogenesis of CMS remains unclear. Recently, attention was drawn to the hypothesis that thermal injury might be an important mechanism in the pathogenesis of CMS. Diffusion tensor imaging tractography was found to visualize the damage to relevant pathways that are associated with persistent impairments after recovery of CMS. There is still no established treatment for CMS to date. SUMMARY: By reaching a consensus on terminology and description of CMS, a firm basis has been created for future research. The pathogenesis of CMS seems multifactorial and important risk factors have been found. However, CMS cannot be effectively prevented yet and no established or specific treatment is available, apart from very general rehabilitation and cognitive interventions.

Cerebellar mutism syndrome in children with brain tumours of the posterior fossa.

BACKGROUND: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined. METHODS: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre-operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles. DISCUSSION: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02300766 , date of registration: November 21, 2014.

Novel LINS1 missense mutation in a family with non-syndromic intellectual disability.

Newer sequencing technologies decipher molecular variations and increase the knowledge of pathogenesis of complex diseases like intellectual disability (ID), affecting 2-3% of the population. We report a novel family with a missense mutation in LINS1 as a cause for non-syndromic ID. Clinical exome sequencing for ID related genes carried out for a male with dysmorphism, mutism, and cognitive delay was uninformative. Subsequently, "pathogenic" and "likely pathogenic" variants associated with other inherited disorders were searched for as secondary findings. Further, PCR-RFLP carried out in other family members confirmed the result. A novel missense variant (c.937G>A) in exon 5 of LINS1 was detected in the proband. His affected elder brother was homozygous and the parents were heterozygous respectively, for the mutation. No mutation was observed in his unaffected sister. Mutations in LINS1 were suspected in this non-syndromic ID case with mutism. LINS1 alterations affect ELAV1 expression and result in reduction in the commissural axonal growth, thus affecting peripheral and central neuronal function. LINS1 acts in association with ß-catenin to influence WNT1 signaling. It is hypothesized that mutations in LINS1 may alter HuR expression during neural differentiation, leading to ID in humans. © 2017 Wiley Periodicals, Inc.

Austistic Children: Bodily Factors in the Use of Language.

This paper addresses factors other than symbolic capacity that can influence the use of language by children on the autism spectrum. Chief among the issues considered are the influence of bodily experience on the articulation of words and the influence of fantasies concerning bodily relationships on the construction of words and sentences. It is suggested that such considerations may shed light on the behavior of those children on the autism spectrum whose symbolic capacity is greater than might be assumed from their use of language, and also on that of some children with selective mutism.

Secondary cerebro-cerebellar and intra-cerebellar dysfunction in cerebellar mutism syndrome.

BACKGROUND: Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebro-cerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebro-cerebellar dysfunction may be related to chronic, rather than transient, symptomatology. METHODS: We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma. Surgical lesions were mapped to the infratentorial anatomy, and connectivity with cerebral cortex was tested for statistical dependence on extent of cerebellar outflow pathway injury. RESULTS: CMS diagnosis was associated with an increase in connectivity between the right cerebellar and left cerebral hemisphere, maximally between cerebellum and ventromedial prefrontal cortex (VM-PFC). Connectivity dependence on cerebellar outflow was significant for some speech nodes but not for VM-PFC, suggesting altered input to the cerebellum. Connectivity between posterior regions of cerebellar cortex and ipsilateral dentate nuclei was abnormal in CMS participants, maximally within the right cerebellar hemisphere. CONCLUSIONS: The functional abnormalities we identified are notably upstream of where causal surgical injury is thought to occur, indicating a secondary phenomenon. The VM-PFC is involved in several functions that may be relevant to the symptomatology of CMS, including emotional control and motor learning. We hypothesize that these abnormalities may reflect maladaptive learning within the cerebellum consequent to disordered motor and limbic function by the periaqueductal gray and other critical midbrain targets.

Abnormalities in auditory efferent activities in children with selective mutism.

Two efferent feedback pathways to the auditory periphery may play a role in monitoring self-vocalization: the middle-ear acoustic reflex (MEAR) and the medial olivocochlear bundle (MOCB) reflex. Since most studies regarding the role of auditory efferent activity during self-vocalization were conducted in animals, human data are scarce. The working premise of the current study was that selective mutism (SM), a rare psychiatric disorder characterized by consistent failure to speak in specific social situations despite the ability to speak normally in other situations, may serve as a human model for studying the potential involvement of auditory efferent activity during self-vocalization. For this purpose, auditory efferent function was assessed in a group of 31 children with SM and compared to that of a group of 31 normally developing control children (mean age 8.9 and 8.8 years, respectively). All children exhibited normal hearing thresholds and type A tympanograms. MEAR and MOCB functions were evaluated by means of acoustic reflex thresholds and decay functions and the suppression of transient-evoked otoacoustic emissions, respectively. Auditory afferent function was tested by means of auditory brainstem responses (ABR). Results indicated a significantly higher proportion of children with abnormal MEAR and MOCB function in the SM group (58.6 and 38%, respectively) compared to controls (9.7 and 8%, respectively). The prevalence of abnormal MEAR and/or MOCB function was significantly higher in the SM group (71%) compared to controls (16%). Intact afferent function manifested in normal absolute and interpeak latencies of ABR components in all children. The finding of aberrant efferent auditory function in a large proportion of children with SM provides further support for the notion that MEAR and MOCB may play a significant role in the process of self-vocalization.

Sluggish vagal brake reactivity to physical exercise challenge in children with selective mutism.

Cardiovascular response patterns to laboratory-based social and physical exercise challenges were evaluated in 69 children and adolescents, 20 with selective mutism (SM), to identify possible neurophysiological mechanisms that may mediate the behavioral features of SM. Results suggest that SM is associated with a dampened response of the vagal brake to physical exercise that is manifested as reduced reactivity in heart rate and respiration. Polyvagal theory proposes that the regulation of the vagal brake is a neurophysiological component of an integrated social engagement system that includes the neural regulation of the laryngeal and pharyngeal muscles. Within this theoretical framework, sluggish vagal brake reactivity may parallel an inability to recruit efficiently the structures involved in speech. Thus, the findings suggest that dampened autonomic reactivity during mobilization behaviors may be a biomarker of SM that can be assessed independent of the social stimuli that elicit mutism.

Cerebellar Mutism Syndrome: An Overview of the Pathophysiology in Relation to the Cerebrocerebellar Anatomy, Risk Factors, Potential Treatments, and Outcomes.

Cerebellar mutism syndrome (CMS) is one the most disabling postoperative neurological complications after posterior fossa surgery in children. CMS is characterized by a transient mutism with a typical onset demonstrated within 2 days postoperatively accompanied by associated ataxia, hypotonia, and irritability. Several hypotheses for the anatomical basis of pathophysiology and risk factors have been suggested. However, a definitive theory and treatment protocols have not yet been determined. Animal histological and electrophysiological studies and more recent human imaging studies have demonstrated the existence of a compartmentalized representation of cerebellar function, the understanding of which might provide more information on the pathophysiology. Damage to the dentatothalamocortical pathway and cerebrocerebellar diaschisis have been described as the anatomical substrate to the CMS. The risk factors, which include tumor type, brainstem invasion, tumor localization, tumor size, and vermal splitting technique, have not yet been clearly elucidated. The efficacy of potential pharmacological and speech therapies has been studied in small trials. Long-term motor speech deficits and associated cognitive and behavioral disturbances have now been found to be common among CMS survivors, affecting their development and requiring rehabilitation, leading to significant financial effects on the healthcare system and distress to the family. The aim of the present review was to outline the cerebellar anatomy and function and its connections in relationship to the pathophysiology and to refine the risk factors and treatment strategies for CMS.

Rhesus macaque as an animal model for posterior fossa syndrome following tumor resection.

BACKGROUND/AIMS: Posterior fossa tumors are the most common brain tumors in children. Surgeons usually remove these tumors via a midline incision through the posterior vermis of the cerebellum. Though often effective, this surgery causes hypotonia, ataxia, oculomotor deficits, transient mutism, difficulty in swallowing and nausea. To date, there is no animal model that mimics these complications. We found that the rhesus macaque is a good model for the consequences of this surgery. METHODS: We made a midline incision through the cerebellar vermis of one monkey to mimic the posterior fossa surgery. Then, we closely monitored the monkey for deficits following the surgery. RESULTS: In the first few days, the monkey exhibited nausea, hypotonia, ataxia, difficulty in swallowing and an absence of vocalization. At 28 days, we recorded eye movements and found severe deficits in the accuracy of rapid eye movements and smooth pursuit of a target. Additionally, the animal had trouble fixating and a rightward-beating nystagmus. Oculomotor signs persisted until we sacrificed the animal 99 days after surgery, but the other effects resolved by 37 days. CONCLUSION: Our surgery in a monkey caused the same postsurgical signs observed in humans. We expect to use this model to improve the posterior fossa surgery methods.

Video self-modeling, fading, and reinforcement: An effective treatment package for children with selective mutism.

Three children aged 8 with selective mutism were treated with an intervention package that consisted of video self-modeling, stimulus fading, and reinforcement behavioral techniques for up to 8 weeks. Parents, teachers, and the researcher conducted a comprehensive assessment of participants' verbal behavior across multiple settings and throughout baseline, intervention, post-intervention, and 1-month follow-up phases of the study. Findings indicated participants' verbal communicative behavior increased significantly during post-intervention, and their progress was maintained at 1-month follow-up.

The Selective Mutism Questionnaire: Data from typically developing children and children with selective mutism.

The core symptom of the anxiety disorder selective mutism (SM) is absence of speech in specific situations, such as at school. The most commonly used standardized instruments to assess speaking behavior are the parent-rated Selective Mutism Questionnaire (SMQ) and the teacher-rated School Speech Questionnaire (SSQ), scored from 0 to 3, indicating that speaking behavior never, seldom, often, and always occur. They were developed to assess severity of mutism and potential effects of treatment. However, prospective data on speaking behavior in typically developing children (TDs) are missing in the literature. The main aim of this study was to present data from TDs over time with previously reported data from children treated for SM, as a comparison. Participants were 64 children aged 3-9 years, 32 TDs who were a matched control group to 32 children with SM. At baseline, the mean SMQ and SSQ scores were ⩾2.5 in TDs and 0.5 in children with SM. The TDs did not show significant changes over time, while significantly increased speech was found in children with SM after treatment. Thus, our findings support the use of the SMQ/SSQ to assess baseline SM severity and to evaluate potential treatment effects in future studies.

Alemtuzumab significantly improves posterior fossa syndrome presented as a relapse of multiple sclerosis.

BACKGROUND: Posterior fossa syndrome (PFS) is a rare manifestation of ponto-mesencephalic lesions frequently reported in post-surgical pediatric tumors, rarely described as a consequence of vascular, infective or inflammatory lesions. OBJECTIVE: The aim of this article is to report the clinical and neuroradiological characteristics of a patient with an acute PFS presentation as a relapse in relapsing-remitting MS, significantly responsive to Alemtuzumab treatment. CASE REPORT: 24-year-old patient affected by multiple sclerosis developed motor-cognitive and behavioral syndrome related to an extensive ponto-mesencephalic lesion under Fingolimod treatment. CONCLUSION: Our case highlights the significant and rapid effect of Alemtuzumab therapy on both cognitive and motor symptoms occurring during a MS relapse with atypical neuroradiological localization.

Cerebellar mutism after spontaneous intratumoral bleeding involving the upper cerebellar vermis: a contribution to the physiopathogenic interpretation.

BACKGROUND: Transient mutism as a consequence of posterior fossa surgery is a well-known phenomenon. However, it has rarely been reported after focal nonsurgically induced cerebellar damage. CASE REPORT: We describe a 7-year-old child affected by a tumor arising from the quadrigeminal plate who developed transient cerebellar mutism after a spontaneous bleeding which extended to the upper cerebellar vermis. The recovery from mutism started about a week after the bleeding. At the time of the surgical treatment, 8 weeks after the spontaneous intratumoral bleeding, she was only dysarthric. DISCUSSION: To our knowledge, this is the first pediatric case of presurgical cerebellar mutism due to a hemorrhage of a neoplastic lesion. Moreover, the focality of bleeding allows the confirmation of the role played by the upper vermis in speech control as well as exclusion of surgically induced lesions commonly suggested as possible cause of the cerebellar mutism.

Increased left prefrontal activation during staring/mutism episodes in a patient with resistant catatonic schizophrenia: a near infrared spectroscopy study.

OBJECTIVE: To present the first near infrared spectroscopy (NIRS) study of a patient with resistant catatonic schizophrenia during residual episodes of catatonia-related symptoms. BACKGROUND: Functional imaging studies generally point to a decreased cortical activation in catatonic patients, with the notable exception of increased orbitofrontal/medial prefrontal activity elicited by negative stimuli. METHODS: Cortical activity of the left anterior prefrontal area was recorded with a Techen 4 x 4 NIRS apparatus. Four episodes of staring/mutism were recorded and averaged. Compared with normal activity, these episodes were characterized by increased cortical activation. CONCLUSIONS: Within its methodologic limitations, the present observation suggests that increased anterior prefrontal activation in catatonic patients is not specific to negative stimuli. Known functions of the anterior prefrontal cortex such as self monitoring, reallocation of attention, or conflict resolution might underlie these findings. These also attest to the potential of NIRS for functional imaging of vulnerable subjects.

Speech and language functions that require a functioning Broca's area.

A number of previous studies have indicated that Broca's area has an important role in understanding and producing syntactically complex sentences and other language functions. If Broca's area is critical for these functions, then either infarction of Broca's area or temporary hypoperfusion within this region should cause impairment of these functions, at least while the neural tissue is dysfunctional. The opportunity to identify the language functions that depend on Broca's area in a particular individual was provided by a patient with hyperacute stroke who showed selective hypoperfusion, with minimal infarct, in Broca's area, and acutely impaired production of grammatical sentences, comprehension of semantically reversible (but not non-reversible) sentences, spelling, and motor planning of speech articulation. When blood flow was restored to Broca's area, as demonstrated by repeat perfusion weighted imaging, he showed immediate recovery of these language functions. The identification of language functions that were impaired when Broca's area was dysfunctional (due to low blood flow) and recovered when Broca's area was functional again, provides evidence for the critical role of Broca's area in these language functions, at least in this individual.

Liver Transplant Can Resolve Severe Neuropsychiatric Manifestations of Wilson Disease: A Case Report.

Although liver transplant for decompensated cirrhosis secondary to Wilson disease is well accepted, the use of transplant for patients with severe neurologic manifestations of this condition remains controversial, and these can be perceived as a contraindication. Here, we describe a 45-year-old woman who presented with an incidental hepatocellular carcinoma at the time of transplant. The patient had severe neurologic manifestations of Wilson disease pretransplant, including dysarthria, hyperreflexia, asymmetrical ataxia, tremor, bradyphrenia, and shuffling gait. She underwent successful transplant from a hepatic and surgical standpoint, but her postoperative course was marked by protracted mutism, hypophonia, and fluctuating akinesia and immobility that did not respond promptly to withdrawal of calcineurin inhibitors or pramipexole but did respond robustly to amantadine. At 9 months posttransplant, there was marked neurologic improvement, and, at 18 months, she exhibited subtle memory and organizational difficulties but was fully ambulatory and otherwise completely functional. Our experience suggests that even patients with severe neurologic Wilson disease may recover after transplant, albeit slowly, demonstrating the need for a multidisciplinary approach, including pre- and posttransplant neurologic and neuropsychiatric consultations.

Postoperative motor speech production in children with the syndrome of 'cerebellar' mutism and subsequent dysarthria: a critical review of the literature.

Transient cerebellar mutism is a well-known clinical entity which may develop after surgery to the cerebellum. As the period of mutism is followed by motor speech deficits, the condition has also been termed the syndrome of (cerebellar) Mutism and Subsequent Dysarthria (MSD). In children, its incidence is estimated between 8% and 31%. Unfortunately, the literature provides contradictory information regarding motor speech production post-mutism. We therefore critically reviewed data on 283 childhood cases to chart the mode of recovery of motor speech production after the mute period. After applying stringent exclusion criteria, we found that 98.8% of the children displayed motor speech deficits. This percentage is much higher than commonly reported in the literature. In addition, recovery of speech appeared to be less favourable than previously ascertained. Future studies should investigate more carefully the patients' speech characteristics in order to be able to offer children an adequate and complete rehabilitation program.