Figure - available from: Acta Neurochirurgica
This content is subject to copyright. Terms and conditions apply.
a–i Brain perfusion SPECT with 99mTc-HMPAO in basal condition (a, b, c), after administration of i.v. midazolam (d, e, f), and in basal condition 30 days after the first one (g, h, i). Coronal (a, d, g) and sagittal (b, e, h) reconstructions clearly show progressive improvement of the perfusion on the left parietal and occipital lobes and on the right paramedian cerebellar region, from the first to the third SPECT. Three-dimensional reconstruction of basal ganglia (c, f, i) demonstrates a progressive increase of perfusion, which parallels the improvement of cerebral cortex perfusion. White and red are the maximum values of radioactivity scale and indicate hyperperfusion, while blue and green are the minimum values of the same scale and indicate hypoperfusion. Values of ROI are reported in Table S1
Source publication
Post-operative pediatric cerebellar mutism syndrome (PPCMS) is a clinical syndrome arising from cerebellar injury and characterized by absence of speech and other possible symptoms and signs. Rare reports described some benefit after administration of dopamine agonist therapy, but no treatment has proven efficacy. In this paper, we report on the dr...
Citations
... In some pediatric literature, a lorazepam challenge test and objective catatonia rating scales have been used to help support its diagnosis, with management including medical evaluation, discontinuation of causative medications, and treatment with benzodiazepines and/or ECT [2,14,76]. Of all the cases collected in the current review, only six received catatonia-specific treatment, fortuitously, with benzodiazepines, midazolam and clobazam [54], lorazepam [50], delorazepam along with risperidone 0.5 mg/ day [12], and midazolam [61], and two with zolpidem, a non-benzodiazepine GABAergic drug [53,83], leading to significant or complete improvements in the short term from the catatonic signs described (mutism, immobility, withdrawal, excitement, hypotonia, posturing, stereotypies, and rigidity), and remaining the same or with a very slight improvement in the rest of the CMS non-catatonic symptomatology (as also occurred in the case presented). As the consensus definition explains and several studies have shown, PPCMS is transient, with symptoms peaking a few days after surgery and gradually improving in the course of several days or weeks. ...
Objective
To ascertain the presence of catatonia in cases of pediatric postoperative cerebellar mutism syndrome (PPCMS).
Method
A systematic review of PPCMS case reports of patients aged 0–17 years with sufficient clinical information to extract catatonic phenomena was undertaken following PRISMA guidelines. Standardized catatonia rating scales were applied to selected cases retrospectively to ascertain whether diagnostic criteria for catatonia were met. A case known to the authors is also presented.
Results
Two hundred twenty-one suitable full-text articles were identified. Following screening and application of inclusion criteria, 51 articles were selected plus seven more from their references, reporting on 119 subjects. All cases met Bush and Francis (BF) diagnostic criteria for catatonia, 92.5% Pediatric Catatonia Rating Scale (PCRS), 52.9% ICD-11, and 44.5% DSM-5. All patients presented with mutism. The next most frequent signs were immobility/stupor (77.3%), withdrawal (35.3%), mannerisms (23.5%), and excitement/agitation (18.5%). Most cases presented with stuporous catatonia (75.6%). Catatonia most frequently occurred following resection of medulloblastoma (64.7%). Preoperative hydrocephalus occurred in 89 patients (74.8%).
Conclusion
Catatonia was frequent in this PPCMS sample, with a predominant stuporous variant; it should be considered in patients with PPCMS and assessed with reliable and validated instruments for prompt diagnosis and management.
... Cerebellar mutism is another speech disorder that is clinically manifested mostly by a temporary loss of speech output. The impairment occurs in the case of tumors in the cerebellum 53 or as a post-operative syndrome 27,54 . In this study, we also observed that some of the males 1-3 days post-op did not sing. ...
Injury, tumors, ischemia, and lesions in the cerebellum show the involvement of this region in human speech. The association of the cerebellum with learned birdsong has only been identified recently. Cerebellar dysfunction in young songbirds causes learning disabilities, but its role in adult songbirds has not been established. The aim of this study was to investigate the role of the deep cerebellar nuclei (DCN) in adult birdsong. We created bilateral excitotoxic lesions in the DCN of adult male zebra finches (Taeniopygia guttata) and recorded their songs for up to 4 months. Using magnetic resonance imaging (MRI) and immunohistochemistry, we validated the lesion efficacy. We found that the song duration significantly increased from 14 weeks post-op; the increase in duration was caused by a greater number of introductory notes as well as a greater number of syllables sung after the introductory notes. On the other hand, the motif duration decreased from 8 weeks after DCN lesions were induced, which was due to faster singing of syllables, not changes in inter-syllable interval length. DCN lesions also caused a decrease in the fundamental frequency of syllables. In summary, we showed that DCN lesions influence the temporal and acoustic features of birdsong. These results suggest that the cerebellum influences singing in adult songbirds.
... Contemporary treatment for CMS remains supportive, as attempts to provide adjuncts such as fluoxetine [63], zolpidem [64], bromocriptine [65,66] and midazolam [67] have, in a small case reports and series, shown efficacy but remain off-licence in their use. Recently, it has been observed that despite multidisciplinary interventions, the functional outcome in these children is less favorable than previously described [68]. ...
Background
Cerebellar mutism (CM) is characterized by a significant loss of speech in children following posterior fossa (PF) surgery. The biological origin of CM remains unclear and is the subject of ongoing debate. Significant recovery from CM is less likely than previously described despite rigorous multidisciplinary neuro-rehabilitational efforts.
Methods
A national multi-centered retrospective review of all children undergoing PF resection in four midsized Canadian academic pediatric institutions was undertaken. Patient, tumor and surgical factors associated with the post-operative development of CM were reviewed. Retrospective identification of PF surgery patients including those developing and those that did not (internal control).
Results
The study identified 258 patients across the 4 centers between 2010 and 2020 (mean age 6.73 years; 42.2% female). Overall, CM was experienced in 19.5% of patients (N = 50). Amongst children who developed CM histopathology included medulloblastoma (35.7%), pilocytic astrocytoma (32.6%) and ependymoma (17.1%). Intraoperative impression of adherence to the floor of the 4th ventricle was positive in 36.8%. Intraoperative abrupt changes in blood pressure and/or heart rate were identified in 19.4% and 17.8% of cases. The clinical resolution of CM was rated to be complete, significant resolution, slight improvement, no improvement and deterioration in 56.0%, 8.0%, 20.0%, 14.0% and 2.0%, respectively. In the cohort of children who experienced post-operative CM as compared to their no-CM counterpart, proportionally more tumors were felt to be adherent to the floor of the 4th ventricle (56.0% vs 49.5%), intraoperative extent of resection was a GTR (74% vs 68.8%) and changes in heart rate were noted (≥ 20% from baseline) (26.0% vs 15.9%). However, a multiple regression analysis identified only abrupt changes in HR (OR 5.97, CI (1.53, 23.1), p = 0.01) to be significantly associated with the development of post-operative CM.
Conclusion
As a devastating surgical complication after posterior fossa tumor surgery with variable clinical course, identifying and understanding the operative cues and revising intraoperative plans that optimizes the child’s neurooncological and clinical outcome are essential.
... A recent systematic review mentioned a single case reports in which drugs such as fluoxetine, zolpidem, or bromocriptine were used to successfully relieve CMS symptoms a day after administration [6]. Moreover, Nicita et al. [7] reported on a patient who temporarily improved following intravenous midazolam administration. In the present paper, we also found midazolam effective in the transient improvement of CMS symptoms. ...
... It works by increasing ionotropic GABA-ergic stimulation, an inhibitor of neural activity. Nicita et al. [7] suggested that the efficacy of midazolam may be grounded in its inhibitory effect on the thalamic region to enhance further signaling from the cerebellum through DTC to the cortex. To date, no other proposed mechanism of action than the one presented in Nicita et al. [7] has been established. ...
... Nicita et al. [7] suggested that the efficacy of midazolam may be grounded in its inhibitory effect on the thalamic region to enhance further signaling from the cerebellum through DTC to the cortex. To date, no other proposed mechanism of action than the one presented in Nicita et al. [7] has been established. While there is no sufficient evidence in the literature to indicate the efficacy of midazolam in the CMS treatment unequivocally, it is believed that based on the GABA-ergic action of BDZ, further research would be warranted. ...
Cerebellar mutism syndrome (CMS) is a postsurgical complication that occurs within days following posterior fossa surgery. It manifests with a speech impediment, emotional lability, or cognitive and motor abnormalities. So far, therapy for CMS consists of logopedic and neurological rehabilitation, with limited data on the efficacy of pharmacological treatment. Recently, a single case report suggested benzodiazepines' (BDZ) efficacy in relieving CMS symptoms. In this paper, we report on a pediatric patient with a transient improvement of CMS symptoms after an intravenous administration of midazolam. A 12-year-old girl was operated on for a 4th ventricle tumor. Following surgical tumor resection, performed through a telovelar approach, the patient revealed dysarthria and ataxia, suggesting CMS. Control MRI has been performed, with prior intravenous midazolam injection. Within minutes following the BDZ injection, the patient's speech markedly improved. Within 2 h, the patient returned to her previous neurological condition. We presume that BDZ can positively act in CMS, which, however, still needs better evidence to support that hypothesis. A low dosage of intravenous midazolam was found effective. We found oral midazolam less effective than intravenously administered one. Further research is needed to prove the efficacy of benzodiazepines in alleviating CMS symptoms and to study the underlying mechanism.
... With fluoxetine, zolpidem, and bromocriptine, the beneficial effect appears at least 24 h after the first administration of the drug and usually complete recovery takes few months. On the contrary, Nicita et al. described a resolution of postoperative CMS within few minutes after intravenous administration of midazolam in a 17-year-old boy after resection of a fourth-ventricle choroid plexus papilloma [26]. The clinical amelioration was confirmed by improvement in perfusion on SPECT in various regions of the brain. ...
... The authors hypothesized that the positive results obtained with midazolam administration on CMS symptoms observed in their patient were due to an inhibitory effect of this drug on the direct and indirect basal ganglia pathways that regulate the excitatory output of the thalamus. The final result is a reduction of inhibition of the thalamus via the striatum, an outcome similar to what is obtained with bromocriptine administration [26]. ...
PurposeCerebellar mutism syndrome (CMS) represents a major complication affecting many children that undergo surgery for posterior fossa lesions. Etiology and pathophysiology are still not fully understood. CMS deeply influences quality of life and recovery of these patients. An effective treatment has not been defined yet. This case-based review aims at analyzing the available evidence and knowledge to better delineate this phenomenon and to determine whether CMS can be successfully treated with pharmacological therapy.Methods
Systematic research and retrieval of databases were conducted analyzing all papers where medical treatment of CMS was reported. A summary of the latest understanding and reports regarding definition, clinical manifestations, pathophysiology, management, and outcome of CMS has been conducted.ResultsConsensus on definition of this syndrome is lacking. CMS is the term accepted by the Posterior Fossa Society in 2016. Pathophysiology is still poorly understood but the most likely mechanism is injury along proximal components of the efferent cerebellar pathway. Nine papers describing positive effects of pharmacological therapy for CMS have been identified. Fluoxetine, zolpidem, bromocriptine, and midazolam are the drugs that seem to alleviate symptoms of CMS and improve recovery. To date, cognitive rehabilitation and physiotherapy are the only treatment options available.ConclusionCMS has deep impact on affected children and their families. Despite attempts to identify preventive measures and treatment, cases still occur on a regular basis. Pharmacological treatments have been proposed to help reduce the symptoms of CMS with some promising results, but reports are limited; therefore, further studies are needed.
... Transient ischemia encompassing the dento-thalamo-cortical pathways or cerebellar deep nuclei due to vasospasm or cytotoxic edema is a possible cause. Involvement of the basal ganglia in cerebellar mutism is suggested by the sudden resolution of the syndrome when midazolam is administered; this is supposed to produce indirect cortical excitation by inhibiting the thalamocortical pathway via the striatum [129]. ...
Evidence reported in recent decades increasingly confirms that both the cerebellum and the basal ganglia, which are primarily involved in movement control, also have a significant role in a vast range of cognitive and affective functions. Evidence from pathology indicates that the disorders of some aspects of language production which follow damage of the cerebellum or respectively basal ganglia, i.e., disorders of speech, word fluency, and sentence construction, have identifiable neuropsychological profiles and that most manifestations can be specifically attributed to the dysfunctions of mechanisms supported by one or the other of these structures. The cerebellum and the basal ganglia are reciprocally interconnected. Thus, it is plausible that some disorders observed when damage involves one of these structures could be remote effects of abnormal activity in the other. However, in a purely clinical-neuropsychological perspective, primary and remote effects in the network are difficult to disentangle. Functional neuroimaging and non-invasive brain stimulation techniques likely represent the indispensable support for achieving this goal.
... Mutism cases are related in the age range from two to ten years. Moreover, it is known as the most common histological type of tumor of the posterior fossa is medulloblastoma [3,4]. ...
... However, given a close relationship with posterior fossa surgery, it is more likely to involve initial parts (e.g., dentate nucleus or superior cerebellar peduncle). The pathophysiological basis of akinetic mutism has not been fully elucidated and there are several controversies [4][5][6]. ...
Pediatric akinetic mutism syndrome is a clinical disease resulting from cerebellar injury and characterized by the absence of speech or reduced speech, emotional lability, there may also be hypotonia, oropharyngeal dysfunction/dysphagia, bladder and intestinal incontinence, or other behavioral disorders and neurological signals. It is described as the most recurrent complication in children, after posterior fossa tumor surgery, mainly related to cerebellar midline injuries. An increasing number of research and prospective reviews have provided valuable information on cerebellar mutism syndrome in recent years. The purpose of this review was to elucidate the pathophysiological basis and the predictive factors for this syndrome. Most cases of mutism are due to injury cerebellar tracts and cerebellar-cerebral circuits, involving particularly distinct points of the dentate-thalamus-cortical and dentato-rubro-thalamus-cortical. Advanced neuroimaging techniques, such as tractography and perfusion studies, have contributed to demonstrating changes in these pathways in patients with pediatric cerebellar mutism.
... There has also been a discussion of using dopamine, low-dose mannitol, and vasoactive medications such as nimodipine to enhance perfusion and avoid vasospasm. Bromocriptine [46] (and in one case, midazolam [47]) has also been used, presumably in an attempt to mitigate inhibition of cortical activity by altering neuro-modulation at the level of thalamic nuclei, thus circumventing the ultimate results of "diaschisis." Some authors have also reported success with fluoxetine [48] and zolpidem [49]. ...
Purpose
Cerebellar mutism syndrome (CMS) is a serious source of morbidity following posterior fossa surgery in the pediatric population. However, methods for effectively decreasing its incidence and impact remain unclear. It is our aim to examine the impact of adjusting surgical factors, namely the use of a telovelar approach and avoidance of cavitronic ultrasonic aspirator, on the incidence of CMS in our population as well as outlining potential pre-, intra-, and postoperative factors that may contribute to its development.
Methods
Retrospective review was performed to identify patients undergoing posterior fossa surgery for resection of a medulloblastoma. Demographic, surgical, and postoperative data were collected. These data were analyzed for possible correlations to the risk of developing CMS via univariate analysis. For factors found to be significant, a multivariate analysis was performed to assess their independence.
Results
Seven of 65 patients (10.8%) developed CMS postoperatively. Factors found to be significantly associated with a higher risk of CMS were the degree of retraction utilized during the procedure (p = 0.0000) and incision of the vermis (p = 0.0294). Although they did not reach the threshold of statistical significance, tumor vascularity (p = 0.19), adoption of a transvermian approach (p = 0.19), and lack of intraoperative imaging (p = 0.17) exhibited strongly suggestive trends towards a correlation with CMS.
Discussion
In an effort to reduce the incidence and severity of CMS in our population, our institution adopted surgical practices that minimize tissue trauma and mitigate postoperative edema. This included the use of a telovelar over a transvermian approach to obviate the need for vermian incision, avoidance of the CUSA, and minimization of heavy retraction during surgery. This was successful in reducing the incidence of CMS from 39% in our medulloblastoma patients to 10.8%. The development of CMS after posterior fossa surgery appears to be a “two-hit” phenomenon requiring a combination of existing predisposition, surgical injury, and postoperative exacerbation. Therefore, it is critical to identify the factors involved at each stage and investigate treatments to target them appropriately.
... a cerebellar-induced decrease or loss of transmission of excitatory impulses from the deep cerebellar nuclei via the dentato-thalamo-cortical pathway to the anatomically and functionally connected supratentorial associative cortices. This view is supported by numerous ( 99m Tc-HMPAO or 99m Tc-ECD) SPECT studies revealing perfusion defects in distant, structurally undamaged supratentorial regions involved in cognition, behavior, and affect that paralleled the clinical course of cognitively and/or behaviorally disabled cerebellar patients (e.g., Van Mourik et al. 1996;Germano et al. 1998;Sagiuchi et al. 2001;Mariën et al. 2001Mariën et al. , 2003Mariën et al. , 2008Mariën et al. , 2009Mariën et al. , 2010Mariën et al. , 2013aBaillieux et al. 2010;De Smet et al. 2009;Catsman-Berrevoets and Aarsen 2010;Miller et al. 2010;De Smet et al. 2013;Nicita et al. 2017). For instance, Mariën et al. (2001Mariën et al. ( , 2003 reported a 5-year-old patient with a posterior fossa medulloblastoma who already presented with mild dysexecutive symptoms in the preoperative phase as reflected on 99m Tc-HMPAO SPECT by perfusion changes in the anatomoclinically suspected but structurally intact prefrontal brain regions. ...
... A recent study by Nicita et al. (2017) unveiled a spectacular effect of benzodiazepine treatment (midazolam) in a 17-year-old boy who underwent posterior fossa surgery for choroid plexus papilloma of the fourth ventricle. Four days post-surgery, he became dysarthric and less responsive. ...
Cerebellar mutism can be considered the hallmark feature of the cerebellar mutism syndrome (CMS), previously also frequently termed the posterior fossa syndrome (PFS). The syndrome consists of specific linguistic, cognitive, behavioral, and affective symptoms following acute posterior fossa damage in children and adults. Although the symptoms have been exceptionally associated with non-tumoral etiologies, CMS usually develops after a brief period of relatively normal functioning in the immediate postoperative phase following posterior fossa tumor surgery. The incidence of CMS in the pediatric population is estimated to range between 7% and 50%. Although similar symptoms have been occasionally reported in adults, CMS is typically viewed as a clinical condition affecting children.
An international consensus as to the definition of CMS was recently reached. However, this accepted definition specifically addresses the pediatric variant of the syndrome associated with posterior fossa surgery (postoperative pediatric CMS, POPCMS). In this chapter, the more general term CMS (instead of POPCMS) will be used to denote similar symptoms also occurring in adults, and with non-tumoral etiologies.
Although the semiology of CMS has extensively been described, the underlying pathophysiological mechanisms still remain largely unclear. This chapter presents a brief overview of the intriguing semiological combination of transient cerebellar mutism and cognitive, behavioral, and affective alterations following acute posterior fossa lesions. Furthermore, the most important pathophysiological hypotheses and the proposed therapeutic interventions are briefly discussed.
