Childs Nerv Syst DOI 10.1007/s00381-010-1328-2
REVIEW PAPER
Cerebellar mutism Review of the literature Thora Gudrunardottir & Astrid Sehested & Marianne Juhler & Kjeld Schmiegelow
Received: 20 October 2010 / Accepted: 22 October 2010 # Springer-Verlag 2010
Abstract Purpose Cerebellar 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. Methods We 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. Results The 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. T. Gudrunardottir : A. Sehested : K. Schmiegelow (*) Department of Pediatrics, The University Hospital Rigshospitalet, 2100 Copenhagen, Denmark e-mail:
[email protected] M. Juhler Department of Neurosurgery, The University Hospital Rigshospitalet, 2100 Copenhagen, Denmark K. Schmiegelow The Faculty of Medicine, Institute of Gynecology, Obstetrics and Pediatrics, University of Copenhagen, 2200 Copenhagen, Denmark
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. Conclusion The 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. Keywords Cerebellar mutism . Brain tumor . Posterior fossa surgery . Children . Speech disorder . Review
Introduction Cerebellar mutism was first described by Rekate et al. in 1985 [1], and since then over 400 cases have been reported in the literature. Cerebellar mutism is most commonly seen after resection of posterior fossa tumors in children [2, 3], but it may also occur following trauma [4, 5], vascular incidents [6–14] or infections [15–19]. Many different terms have been used to describe, report and refer to this kind of mutism in the literature, the most common ones being ‘cerebellar mutism’ (CM),[6, 9, 15, 20–31] ‘transient cerebellar mutism’ (TCM) [17, 32–37], and ‘mutism and subsequent dysarthria’ (MSD) [10, 38, 39]. The term ‘cerebellar mutism syndrome’ (CMS) [40–44], is a synonym for the posterior fossa syndrome, and many authors use two or more of these terms interchangeably in their articles [40, 42, 43, 45, 46].
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Clinical characteristics The term cerebellar mutism refers to muteness that follows lesions of the cerebellum as opposed to the cerebrum or the lower cranial nerves. Its unique features are delayed onset (1–6 days) and limited duration (1 day–4 months) followed by a recovery period where speech is marked by dysarthria [34]. Mean time of onset is 1.7 days and average duration is 7–8 weeks [26, 45]. Recovery is spontaneous [3, 47] and can occasionally be rapid (a few days) [45] and complete [48], but the majority of patients are left with long-term speech and language dysfunction such as ataxic dysarthria, dysfluency and slowed speech rate [3, 34, 35, 38, 39, 45, 48, 49]. Although initially described as an isolated finding [1], cerebellar mutism usually presents itself as the hallmark characteristic of the more complex posterior fossa syndrome [50–52], where patients are faced with a host of other neurological problems such as ataxia, hypotonia, cranial nerve palsies, hemiparesis [53, 54], and emotional lability [54]. These deficits appear to have separate anatomical substrates [55–58], but the areas in question lie close to one another and can all be disturbed by posterior fossa surgery (see section ‘Surgical damage to adjacent areas and correlated symptoms’).
from the lateral hemispheres of the cerebellum itself as well as from the primary and supplementary motor area (SMA) of the cerebrum via the pons. Their efferents then ascend through the superior and middle peduncle and upper part of the brainstem, cross over to the contralateral ventro-lateral nucleus of the thalamus (VL thalamus) and terminate in the motor cortex and prefrontal cortex [64, 67] (Fig. 1). The dentate nuclei are mutually connected across the midline (Mollaret’s triangle) and indirectly through ipsilateral pathways between the dentate nuclei and the inferior olivary nucleus [68]. This complex system involves both initiation of voluntary movement and higher cognitive functions [62, 67, 69]. The most common explanation of cerebellar mutism emphasizes the role of bilateral injury to the dentate nuclei [1, 48, 60, 70–74], but mutism can result from injuries anywhere along the path: it has been reported after bilateral thalamotomy for Parkinson’s disease and in patients with lesions in the SMA [64, 73], as well as those with bilateral edema in the brachium pontis/conjunctivum [54, 55] or superior cerebellar peduncles [61]. Studies have
Incidence Several recent prospective studies have reported the incidence of cerebellar mutism after posterior fossa surgery in children to be 11–29% [3, 34, 38, 58–60]. Older studies generally present much lower numbers, which may, at least partly, be caused by failure to recognize and/or register the syndrome [11], but this could also reflect a true rise in incidence. Advances in imaging and surgical techniques, along with demonstration of the importance of macroradical resection for the survival of children with especially medulloblastoma and ependymoma, have enabled and encouraged surgeons to perform more radical resections than before. Thus, cerebellar mutism can be viewed as part of the price to be payed for increased survival of children with posterior fossa tumors [25].
Anatomical substrate of cerebellar mutism Most authors agree that bilateral interruption of the dentato–thalamo–cortical pathway (DTC) is the principal cause of cerebellar mutism [20, 26, 31, 39, 40, 42, 55, 58, 60–66]. The two dentate nuclei are symmetrically located in the paravermal regions of lobules VI and VII of the cerebellum, and give rise to this particular cerebello– cerebral connection. The dentate nuclei receive afferents
Fig. 1 Schematic illustration of the dentato–thalamo–cortical pathway. From the cerebellum, nucleus dentatus efferents ascend through the middle and superior cerebellar peduncle of the brain stem, cross over in brachium conjunctivum to the opposite VL thalamus and terminate in the SMA of the cortex. Republished with permission [64]
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It is well known that lesions of the anterior lobe of the cerebellum can result in truncal ataxia and hypotonia, while lesions of the posterior lobe can produce appendicular ataxia, hypotonia and tremor [67] (Fig. 2), but whether the hemiparesis and lower cranial nerve dysfunction so frequently observed in the posterior fossa syndrome are primarily due to brainstem injury or damage to the dentate nuclei/DTC pathway (or possibly both) remains to be elucidated. The cerebellum is, however, not only important for balance and coordination of motor function; it is intricately involved in higher cognitive processes (the cerebellar hemispheres) and
regulation of affect (the vermis) [56, 57, 62, 83]. There is a clear lateralization of function, with the left cerebellar hemisphere being responsible for spatial and executive tasks and the right one for language tasks [51, 57] (Fig. 2). Furthermore, damage to the dentate nuclei, the vermis, and the right cerebellar hemisphere result in significant reductions of various aspects of the patients’ intelligence quotient (IQ), and may lead to adverse neuropsychological outcomes [62, 83]. Thus, damage to these structures as observed on magnetic resonance imaging (MRI) scans can be used to predict the degree of post-operative neurological and neuropsychological impairment in children treated for posterior fossa tumors [62]. The parts of cerebellar lobules V and VI that overlap the superior dentate nuclei on both sides are related to working memory and motor function, while the inferior vermis that occupies the space between the two dentate nuclei is important for emotional processing and normal neurobehavioural function. The parts of lobules VI and VII that overlap the inferior part of the left dentate nucleus are responsible for executive functions, while the corresponding ones on the right hand side are important languagage areas. There is, furthermore, a large, additional language area lateral to the dentate in lobule VI of the right cerebellar hemisphere [57] (Fig. 2). This corresponds to the initial observation that patients with an incision of the vermis alone tend to get transient cerebellar mutism, while the ones with an additional partial excision of the right hemisphere are at risk of developing an intrinsic language disturbance [58] that has been referred to by some as ‘mutism and subsequent dysarthria’ [38, 84], and carries a much worse prognosis [51, 85, 86].
Fig. 2 The topographic arrangement of functions in and around the vermis, dentate and fastigial nuclei. Language is lateralised to the right cerebellar hemisphere, executive functions and spatial processing to the left hemisphere and limbic/emotional functions to the vermis. Lesions of
the anterior lobe result in truncal ataxia and hypotonia, while lesion of the posterior lobe result in appendicular ataxia, hypotonia and tremor. DN = dentate nucleus, FN = fastigial nucleus, LH = left hemisphere, RH = right hemisphere
also confirmed the importance of brainstem involvement [3, 52, 59]. Centrally located, monoaminergic areas in the mesencephalon such as the periaqueductal gray matter [33, 75] and the substantia nigra have been implicated [76, 77], and pre-operative brainstem compression has recently been identified as a predictor of post-operative mutism [78]. Cerebello–cerebral diaschisis refers to a lack of excitatory impulses from the cerebellum caused by a cerebellar lesion, resulting in hypoperfusion, decreased oxygen consumption, hypometabolism and functional inhibition in anatomically connected supratentorial structures [7]. This phenomenon has repeatedly been observed in children with cerebellar mutism [46, 79–81], is thought to reflect impairment of the DTC pathway [38], and supports the theory about it being an important anatomical substrate of the deficit [82].
Surgical damage to adjacent areas and correlated symptoms
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Pathophysiology
Edema
The delayed onset and resolution of the mutism and other neurological deficits after neurosurgery are characteristic and well described, but the pathophysiological mechanisms involved are unclear. Although surgery is the primary event, the onset is not immediate, and at least partial recovery is the rule. If mutism is present immediately after surgery, bulbar dysfunction caused by damage to cranial nerve nuclei in the brainstem should be suspected rather than cerebellar mutism [3]. Secondary processes initiated by the tumor resection therefore seem to play a role (65), and these have been proposed to involve dynamic perfusional disturbances, edema, transient disturbances in neurotransmitter release and axonal injury.
The delayed onset of cerebellar mutism roughly correlates with the onset of post-operative swelling and edema [10, 27, 55, 70, 71], and computed tomography (CT), MRI and diffusion tensor imaging (DTI) studies have clearly associated mutism with bilateral edema in the superior cerebellar peduncles and/ or the pons or mesencephalon after posterior fossa tumor resection [55, 61]. However, the duration of mutism outlasts the time course of postoperative edema [28, 44], and the effect of systemic corticosteroids on the occurrence and/or duration of cerebellar mutism has not been investigated.
Cerebellar perfusional defects Although rare, vasospasms are known to occur in settings other than a subarachnoidal hemorrhage (SAH) [67]. They are usually followed by focal hypoperfusion and transient ischemia, and it has been suggested that this mechanism could be responsible for the development of cerebellar mutism, thereby explaining the delayed onset (vasospasms), type of disturbance (transient ischemia) and resolution (normalization of blood flow) [10, 21, 26, 47, 73, 87]. However, none of the authors elaborate on the precise effects of ischemia in this context, and in a study conducted in 1999, Doxey et al. [52] did not find any signs of ischemic damage on postoperative MRIs of 20 patients with cerebellar mutism. Likewise, surgical manipulation of the cerebellum [54], intra-operative coagulation of perforating vessels [71] and arterial embolic occlusion [88] have been proposed as possible causes of cerebellar hypoperfusion and transient ischemia leading to cerebellar mutism. Two small single photon emission computed tomography (SPECT) studies showed cerebellar hypoperfusion in mute patients with normalisation of blood flow as speech returns [88, 89], but others have been unable to confirm these findings [59]. Cerebral perfusional defects Cerebello–cerebral diaschisis does not explain the delayed onset or resolution of the mutism as such, but it does illustrate the mechanism whereby damage to the proximal DTC pathway manifests itself in the cerebrum [90]. The global, supratentorial hypoperfusion observed does involve left prefrontal language regions, and several cerebral blood flow studies have demonstrated that the return of speech coincides with improvement of blood flow in the cerebrum [24, 79, 80, 84, 91, 92]. This, in turn, is likely to reflect functional improvements of the DTC pathway.
Transient dysregulation of neurotransmitter release Siffert et al. [44] proposed that alterations in neurotransmitter levels and synaptic or transsynaptic degeneration of connecting structures might explain the lag between injury and onset of mutism, but so far no studies have tested the validity of this theory [50]. Axonal injury Surgical manipulation and traction along ascending fiber pathways are likely to be important pathogenic factors [21, 24, 26, 41, 66, 71, 93, 94], and a recent MRI and DTI study concluded that functional disruption of the white matter bundles containing efferent axons within the superior cerebellar peduncles is a critical pathophysiological component of the posterior fossa syndrome and thereby cerebellar mutism [61]. More specifically, McMillan et al. [78] have proposed that axonal, cytoskeleton, or organelle damage due to surgical manipulation and traction together with the release of the tumor’s compressive force and ensuing axon distortion and dysfunction could be responsible for both the delayed onset and resolution of the mutism. Other possible recovery mechanisms include neuronal plasticity [66, 85, 95] and reassignment of speech function elsewhere in the cortical processing network after permanent cerebellar injury [96], but these theories also await thorough exploration. A recent study of the neuroradiographic features of the cerebellar mutism syndrome found considerably more atrophy/gliosis of the total cerebellum, vermis and brainstem at 1 year post-operatively in children with medulloblastoma that had suffered from cerebellar mutism syndrome, as compared to ones that had not. This correlated with a poorer functional outcome, both motorically and cognitively speaking [97].
Risk factors Several risk factors for the development of cerebellar mutism have been identified, the most significant one being
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brainstem involvement by the tumor [3, 52, 66]. Additional factors are midline (vermal and fourth ventricle) location and tumor type, rendering medulloblastomas by far the most likely to cause cerebellar mutism in the pediatric population [37, 38, 45], with the reported incidence being two to three times higher than for astrocytoma and ependymoma [39, 40, 45, 98, 99]. In the two largest studies to date the incidence of cerebellar mutism in children with medulloblastoma was almost 25%, and if the tumor invaded the brainstem the incidence rose to 44% [3, 52]. As mentioned earlier brainstem compression has recently been identified as a predictor of post-operative mutism [78], but whether brainstem compression and brainstem involvement are independent or related risk factors cannot be stated with certainty, as they are defined differently in the different articles. Previous studies did not find a statistically significant relationship between younger age at diagnosis [3, 38], radical tumor removal [3, 52] and the development of the mutism, although a more recent one did [100]. Similarly, Catsman-Berrevouets et al. found a vermal incision to be an independent risk factor for the development of cerebellar mutism regardless of tumor type, and tumor size to be a significant risk factor for medulloblastomas only, but larger and more recent studies have not confirmed these findings [3, 52, 66]. Hydrocephalus and post-operative meningitis were previously thought to be of significance [4, 27] but this has subsequently been disproved [38, 45, 54]. Other CNS infections, gender, length of vermal incision, type of neurosurgeon (pediatric vs. adult neurosurgeon), and edema/swelling in the cerebellum show no statistically significant correlation with the development of cerebellar mutism [3, 38, 55]. Since blood transfusions are known to increase the risk of vasospasms, hypoperfusion and ischemia in adults with SAH they have been suggested as a potential risk factor for the development of cerebellar mutism, but this has not been directly investigated [63].
correlate with functional prognosis, in the sense that patients whos symptoms persist for more than 4 weeks are at a greater risk of still suffering from speech and language dysfunction at 1 year postoperatively than those whos symtoms last less than 4 weeks [3, 83]. Chemotherapy and radiotherapy are causally unrelated to cerebellar mutism as it precedes these things, but the anticancer treatment may have an adverse effect on the recovery process [66, 85].
Treatment There is no established treatment that facilitates recovery from cerebellar mutism. The effects of pharmacological intervention and/or speech therapy are sporadically reported in the literature, and randomized controlled trials are lacking. Medication Those who consider dopaminergic cell groups in monoaminergic pathways to be important recommend the use of bromocriptine because it is known to reverse the symptoms of akinetic mutism [76, 77], but it does not always have the desired effect on patients with cerebellar mutism [39]. The calcium antagonist nimodipine has been suggested to help prevent ischemia due to vasospasm [47], but this has not been systematically assessed. Speech therapy Speech rate has been used to investigate and evaluate the manifestations of cerebellar mutism, and the monitoring of it has proven to be particularly helpful when it comes to quantifying the severity of the disease and monitoring speech impairment in the post-mutistic phase [9, 60]. In contrast, there is a complete lack of trials that explore the efficacy of speech therapy as such during the recovery phase.
Prognosis It is difficult to predict the prognosis for the individual patient, and the course of recovery is extremely variable. In their review from 2001, Gelabert-Gonzales et al. [45] found that 68% of the patients were still suffering from motorspeech deficits a year after the resolution of mutism, and dysarthria is frequently a permanent sequela of cerebellar mutism [3, 34, 48, 49, 66]. It has also become clear that patients can suffer from non-motor-related speech disturbances even after speech returns, such as adynamic spontaneous speech production, impaired verbal fluency, word-finding difficulties and grammatical disturbances [82]. The duration of symptoms after surgery seems to
Prevention The traditional approach to tumors in the midline of the cerebellum and fourth ventricle involves the splitting the vermis and lateral retraction of the hemispheres to disclose the tumor bed. This, however, carries a high risk of causing cerebellar mutism together with some or all of the symptoms of the posterior fossa syndrome, which underlines the importance of exploring alternative operative approaches to the removal of midline cerebellar tumors. Supratentorial approaches to tumor removal in the brainstem and upper cerebellar hemispheres have been tried, but
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they too can bring about the same results due to lesions of the pons and/or superior cerebellar peduncles [96, 101]. Alternative strategies include piecemeal as opposed to en bloc removal of the tumor to minimize injury to the vermis [21], avoidance of damage to the right cerebellar hemisphere, which is deleterious to cognitive functioning [62], and using a telovelar approach, which offers access to the fourth ventricle without splitting the vermis [102]. Although radical removal of large tumors and tumors focally attached to critical areas in the fourth ventricle remains a challenge while using the telovelar approach [103, 104] it is comparable to the traditional transvermian method in terms of exposure of the ventricle [105, 106]. Whether or not this approach results in a lower incidence of cerebellar mutism is an important question; one series of 16 patients operated by the telovelar approach showed no cases of mutism [103], and another institution reported a relatively low rate after they stopped splitting the vermis [107]. At a third institution, surgical practice changed to include intraoperative electrophysiological monitoring, less aggressive retraction and the avoidance of ultrasonic aspiration, which resulted in seemingly fewer cases of cerebellar mutism [83]. These results highlight the importance of systematically comparing different surgical methods with respect to differences in survival and morbidity after posterior fossa operations.
Conclusion Cerebellar mutism is a frequent complication of posterior fossa surgery in children, and permanent sequelae are common. There is convincing evidence pointing to bilateral lesions of the dentate nuclei and their connections as being the anatomical substrate of the deficit. Little is still known about the precise mechanism of injury, the pathophysiology of delayed onset and resolution, the most effective speech therapy, and whether there is a role for pharmacological therapy or not. In order to further understand, prevent and treat the condition there is a need for continued systematic prospective study of surgical methods, associated neuroimaging findings, pharmacological treatment options and rehabilitation methods, together with focused investigation into the underlying causes of the mutism. Formal definitions of both cerebellar mutism and the posterior fossa syndrome are long due in this context, as are standardized methods of monitoring acute and late sequelae in the form of neurological and cognitive follow-up. Acknowledgements This study received financial support from The Childhood Cancer Foundation, Denmark. Kjeld Schmiegelow holds the Danish Childhood Cancer Foundation Professorship in Pediatric Oncology. The authors wish to thank Dr. Flemming Finn Madsen for his assistance in the preparation of the manuscript.
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