This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
Jun. 07, 2021
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This article includes discussion of cerebellar mutism, cerebellar cognitive affective syndrome, mutism and subsequent dysarthria syndrome, oral pharyngeal apraxia and mutism, postoperative cerebellar mutism syndrome, posterior fossa cerebellar mutism syndrome, posterior fossa syndrome, postoperative mutism, and pseudobulbar syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
This update on cerebellar mutism adds current literature regarding the possible risk factors associated with cerebellar mutism as well as the ongoing efforts to mitigate those risk factors. Longer-term neurocognitive prognosis following the diagnosis of cerebellar mutism is also included.
• Cerebellar mutism is not necessarily a transient disease that improves spontaneously in time. Although the mutism resolves, patients are still likely to have varying degrees of dysarthria. Cerebellar symptoms are cranial neuropathies making this more a chronic condition.
• A consensus statement has defined cerebellar mutism with the intent of clearly identifying and unifying the multiple signs and symptoms that are associated with cerebellar mutism. Specifically, it explicitly cites this disease as being a postoperative consequence in children in the effort to further research and improve the quality of life for these patients.
• Damage to the dentato-thalamo-cortical fiber tracts and proximal efferent cerebellar pathways are being identified via imaging and metabolic studies in patients with cerebellar mutism.
• There is still no clear cause for cerebellar mutism. However, bilateral cerebellar damage, brainstem invasion/compression by tumor, and large tumor size are noted as risk factors in multiple papers.
• Patients with cerebellar mutism exhibit greater short- and long-term neurocognitive impairment that require close follow-up and intervention.
A child’s loss of speech after removal of a cerebellar tumor was initially described in 1958 (28). This complication of posterior fossa surgery was mentioned in the literature in the following decades (Fraioli and Guidetti 1975; 55; 106). This complication became more widely recognized after a landmark case series of 6 patients in 1985 (101). Since then, the descriptions of more than 200 cases have contributed to the understanding of this unique constellation of signs and symptoms that has come to be known as the posterior fossa or cerebellar mutism syndrome. This syndrome is characterized by partially reversible decreased production of speech and often mutism, frequently in association with diffuse cerebellar dysfunction (ataxia and axial hypotonia), and a variety of neurobehavioral affective disturbances consisting of prominent emotional lability with irritability and apathy (Fraioli and Guidetti 1975; 55; 106; 129; 101; 123; 12; 32; 40; 46; 83; 108; 23; 53; D’Avanzo et al 1993; 87; 09; 14; 65; 03; 27; 98; 121; 60; 74; 107; 19; 49; 59; 71; 120; 22; 35; 114; 48; 58; 124; 77; 117; 91; 93; 104).
Cerebellar mutism syndrome occurs most often after the surgical resection of posterior fossa tumors, the majority of which are medulloblastoma, but can be seen after trauma, hemorrhage, or ischemic injury involving the cerebellum or brainstem. The onset of symptoms is often delayed until 1 or 2 days after the surgery (129; 40; 83; 26; 98; 121; 107; 48). The first description of mutism after posterior fossa surgery was in regards to several patients who underwent stereotactic lesioning of the cerebellar dentate nucleus for treatment of dyskinesias (42). Wisoff and Epstein were the first to describe affected patients after midline posterior fossa tumor resection, but they emphasized the emotional features and considered the mutism as part of a syndrome they termed pseudobulbar palsy (129). Rekate and colleagues reported the syndrome in 6 children who underwent posterior fossa tumor surgery and were the first to refer to it as the cerebellar mutism syndrome (101). In the same year, Yonemasu noted the same complication in 4 patients who underwent surgery for cerebellar tumors (132). This postoperative constellation of signs has also been called the posterior fossa syndrome (113). In view of the finding that in many cases the mutism is followed by a period of dysarthric speech, it has also been described as mutism and subsequent dysarthria syndrome (20; 36; 35).
Given the multiple names and constellation of symptoms associated with mutism after cerebellar surgery a consensus statement was issued in 2016 by the Iceland Delphi Group introducing the term “post-operative pediatric cerebellar mutism syndrome (CMS)” in an effort to unify the literature. The consensus statement reads: “Post-operative pediatric CMS is characterized by delayed onset mutism/reduced speech and emotional lability after 4th ventricle tumor surgery in children. Additional common features include hypotonia and oropharyngeal dysfunction/dysphagia. It may frequently be accompanied by the cerebellar motor syndrome, cerebellar cognitive affective syndrome and brain stem dysfunction including long tract signs and cranial neuropathies. The mutism is always transient but recovery may not return to normal, and other deficits of cognitive, affective and motor function often persist” (51).
Postoperative cerebellar mutism generally does not occur as an isolated finding. The clinical manifestations of the syndrome consist of a core of signs and symptoms that include the abnormalities of speech or mutism, neurobehavioral or affective disturbances, diffuse cerebellar dysfunction, long tract findings, and cranial neuropathies. These primary signs and symptoms are stereotypical and are becoming increasingly recognized as the syndrome has been more widely reported.
Speech impairment is nearly always characterized by transient decreased production of speech and usually complete mutism. In many cases, comprehension of verbal language is reported to be normal, or at least much better than speech (122; 60; 107; 59). More pervasive communication deficits affecting comprehension as well as expressive language and indicated by inability to follow verbal commands were noted in a number of patients from 1 series (114). With recovery from the syndrome, a speech pattern characterized as ataxic dysarthria has been described in a large fraction of patients. A review of 134 cases from the literature reported that 106 patients (79%) had dysarthric speech after resolution of the mutism (48). This finding has led to the hypothesis that the mutism may represent the most severe form of dysarthria, in effect, an ataxic anarthria (121; 120; 22).
Dysmetria and ataxia frequently accompany cerebellar mutism syndrome. Ataxic dysarthria often becomes apparent as speech returns (114). Some degree of ataxia was present with cerebellar mutism syndrome in nearly all of the 107 patients with cerebellar mutism syndrome in a multicenter prospective study; the ataxia was reported to be severe in 44% of them (104). Hypotonia was noted to accompany the ataxia in all 8 patients in 1 series and has been presumed to be an aspect of diffuse cerebellar dysfunction (114).
Most patients with the syndrome have exhibited a spectrum of neurobehavioral abnormalities. Substantial emotional lability and irritability is commonly described (129; 25; 122; 98; 114). In 1 series, an almost stereotypical response with inconsolable shrill whining occurred in 11 of 12 patients (98). Striking apathy and lack of initiative or hypokinesis are also commonly reported (57; 122; 114).
A variety of other neurologic abnormalities have also been noted in patients with cerebellar mutism syndrome. In the absence of bulbar cranial nerve deficits, decreased oral intake or oromotor apraxia was described in a high percentage of patients (57; 40; 122; 27; 98; 49; 59; 114). Persistent eye closure for prolonged periods, with apparent inability to initiate spontaneous opening of the eyes and usually in the absence of oculomotor deficits, was noted in 2 series (98; 114). One case of cerebellar mutism with prominent eye closure was characterized by 4 distinct phases lasting more than 1 month and was associated with severe persistent cerebellar dysfunction (21). Transient mutism, ataxia, and pathologic laughter were described in a child with presumed parainflammatory cerebellitis (33). Cerebellar mutism syndrome typically occurs in the absence of significant cranial nerve deficits or long tract signs (83; 39), although pontine cranial nerve deficits (VI or VII) or hemiparesis were found in several series (122; 98; 121; 114). The abrupt onset of visual loss has been reported in association with cerebellar mutism syndrome (29). Transient urinary and fecal incontinence was associated with the syndrome in 5 of 8 patients in 1 series (114).
The neurologic deficits associated with cerebellar mutism syndrome, to a degree, have been transient in virtually all reported cases (38; 48). Although resolution of mutism is always seen most patients continue to have long-term, chronic neurologic sequelae. Associated neurologic complications such as worsening cerebellar function manifested by dysarthria, dysmetria, or gait difficulties remain as well as neurocognitive side effects. In a review of 134 patients with cerebellar mutism syndrome reported in the literature, the mutism resolved at a mean of 8.3 weeks, with a range of 4 days to 5 months (48). However, residual symptoms, especially the ataxia and speech problems with evolution of the mutism to an ataxic dysarthria is commonly reported (32; 40; 122; Van Calengergh et al 1995; 38; 66; 114; 48). A case-control study of children after cerebellar tumor resection demonstrated significantly more long-term residual ataxic dysarthria in those who had suffered cerebellar mutism syndrome than in those who had not (56). A critical review of 283 children with cerebellar mutism syndrome found that 99% displayed ataxic dysarthric motor speech deficits after recovery from the period of being totally mute (31).
In a multicenter prospective evaluation of cerebellar mutism syndrome among medulloblastoma patients, persistent ataxia and speech difficulties were present to a moderate or severe degree for as long as 1 year from diagnosis in 66% (ataxia) and 44% (speech) of the patients who were initially judged to have had a severe degree of the syndrome (104). More significant residual speech deficits and a trend toward more ataxia was also seen among the initially most severe of 11 cerebellar mutism syndrome patients in a reported series (125). Language abnormalities associated with the mutism syndrome can go beyond deficient speech and articulation. A pervasive communication deficit, affecting comprehension as well as expressive language, was also noted in a significant number of patients with cerebellar mutism syndrome on comprehensive language evaluation during recovery (114). Speech improved in 6 of 7 children who developed mutism after posterior fossa tumor resection but returned to normal in only 1 of them (117). Moreover, intellectual deficits that extend beyond strictly linguistic function have been noted in some patients recovering from cerebellar mutism syndrome. In 1 series, several of the 12 children recovering from cerebellar mutism syndrome had impairments in recent memory, attention span, problem-solving ability, and executive function on detailed neuropsychometric testing (98). As well, a significant fraction of patients with cerebellar mutism syndrome in the prospective medulloblastoma study were estimated to have persistent mild to moderate deficits of global cognitive function at 1 year from initial diagnosis of their tumors (104).
Persistent psychosocial problems, including obsessive-compulsive disorder, withdrawal behavior, and general difficulties with social interaction, were reported to be significantly more frequent in medulloblastoma patients who had experienced postoperative cerebellar mutism (130). Neurocognitive data available in 12 of 28 children after medulloblastoma tumor resection at a mean of 4.5 years after surgery demonstrated mean IQ to be 16 points lower among the 5 children with cerebellar mutism syndrome (125). At 1, 3, and 5 years following diagnosis of medulloblastoma, children who were initially diagnosed with posterior fossa syndrome following their treatment for medulloblastoma had lower mean scores on measures of general intellectual ability, processing speed, broad attention, working memory, and spatial relations compared to those without diagnosis of posterior fossa syndrome. Attention and working memory were also noted to decline over time. The posterior fossa syndrome group had mean scores at least 1 standard deviation below the mean for intellectual ability, processing speed, and broad attention across all time points and for working memory by 5 years postdiagnosis (110).
A 6-year-old boy presented to the emergency room with a history of progressive headache, morning vomiting, and unsteadiness of gait that had been getting worse over the previous 2 to 3 weeks. He was also complaining of double vision that was worse on left lateral gaze. On examination, he was mildly lethargic, but mental status was otherwise normal. His visual acuity and fields were normal, but bilateral papilledema was present. He had a partial left sixth nerve palsy and a mild degree of truncal ataxia. On brain MRI, there was a 4 X 3.5 X 3.5 cm homogeneous, gadolinium-enhancing mass arising from the cerebellar vermis and within the fourth ventricle, obstructing its outflow and causing a moderate degree of hydrocephalus.
After placement of an external ventriculostomy, the boy underwent a suboccipital craniotomy and gross total resection of the tumor, which was seen to be adherent to the brainstem. The histopathological tumor diagnosis was medulloblastoma. Disease-staging evaluation revealed no spinal metastases or residual tumor on postoperative MRI, and CSF cytologic examination was negative for neoplastic cells. He was extubated quickly following the surgery and had no new neurologic deficits in the immediate postoperative period.
His headaches resolved, the sixth nerve palsy improved, and he was noted to be speaking normally in short sentences to his parents and nurses. His ventriculostomy was weaned over 5 days, and he did not require shunting.
Then, on the second postoperative day, he stopped talking entirely and became extremely irritable, vocalizing only with frequent whining or high-pitched crying. He appeared to follow some verbal commands but would not always do so during periods of irritability. He did not want to eat and appeared to have difficulty with the initiation of chewing and swallowing, but he had no aspiration of liquids or solids on a swallow study. These symptoms persisted more or less unchanged for 2 to 3 weeks, after which time, he started to speak a few single words and was becoming less irritable.
As his speech gradually improved over the subsequent 2 months while he was undergoing craniospinal irradiation, it became apparent that he had an ataxic dysarthria as well as mild truncal ataxia. After completion of radiation therapy, he began a course of adjuvant chemotherapy. His speech and language comprehension, along with his gait, continued to improve during the chemotherapy, and his parents considered that his speech articulation and content were nearly back to normal by 1 year from diagnosis. There was no evidence of recurrent tumor on routine surveillance imaging. However, on detailed neuropsychometric testing at that time, he was found to have mild deficits of language comprehension, auditory processing, and executive function.
Various hypotheses have been advanced to explain the pathogenesis of cerebellar mutism syndrome, but its etiology and neuroanatomic substrate remain uncertain. Most of the patients affected by this syndrome are children who have undergone resection of midline cerebellar or fourth ventricular tumors, the majority of which are medulloblastoma. In a review of all cases of well-documented cerebellar mutism, 117 of 134 (89%) had midline posterior fossa tumors, of which 65% were medulloblastomas (48). However, adult patients have developed cerebellar mutism syndrome, and it has also been reported preoperatively in association with a posterior fossa hemangioblastoma tumor after ischemic or hemorrhagic injury to the cerebellum or brainstem and after resection of intrinsic brainstem tumors or cavernomas (32; 131; 108; 89; 20; 30; 44; 36; 39; 61; 66; 85; 115; 80; 07; 62; 58; 05; 17; 43).
Various risk factors found in association with cerebellar mutism syndrome have been proposed as possible etiologic factors. The size of the posterior fossa tumor was noted to be either large or very large in nearly all of the 134 cases of cerebellar mutism syndrome (48). However, large size of tumor was shown to be a statistically significant predictor of mutism only among medulloblastoma tumors in 1 series in which 12 of 42 children with posterior fossa tumors developed cerebellar mutism syndrome (22). Contrary to this, in several large series, tumor size was not a risk factor for the development of cerebellar mutism syndrome (98; 121; 114; 104; 24; 111).
Posterior fossa tumors were determined to have been totally resected in 64 of 134 patients with cerebellar mutism syndrome in a review (extent of resection unreported in the remainder) (48). In another single institution report, the absence of residual tumor on postoperative MRI was a predictor of cerebellar mutism, which had an incidence of 29% among 51 children after resection of a medulloblastoma (67). However, the extent of resection did not correlate with development of cerebellar mutism syndrome in several series (98; 114; 104; 24; 111).
Incision of the inferior cerebellar vermis was proposed as the critical component of the pathophysiology of cerebellar mutism syndrome in 1 series of 60 patients who underwent midline posterior fossa tumor surgery (27). Although the surgical approach was not reported in as much detail, general consensus is that the great majority of midline tumors, most of which are medulloblastoma, are resected by incision through or resection of the inferior vermis, and only a small percentage of patients develop mutism. This establishes an argument against vermian incision as a risk factor (98; 22; 114; 133).
One literature review reported that postoperative hydrocephalus that required placement of a ventriculoperitoneal shunt developed in 42 of 134 patients with cerebellar mutism syndrome (31%) (48). This has been advanced as a possible risk factor for cerebellar mutism syndrome. Hydrocephalus that required CSF diversion appeared to be a significant factor in a small series in which 5 of 5 patients with cerebellar mutism syndrome, but only 4 of 10 without cerebellar mutism syndrome, required a ventriculoperitoneal shunt (122). Postoperative hydrocephalus was present in 3 of 4 patients with mutism in another report (66), but in many series, no significant correlation has been demonstrated (108; 27; 98; 114; 102).
Postoperative meningitis was suggested as a possible risk factor in the development of cerebellar mutism syndrome (57; 40) but was actually present in only 9 of 134 patients with cerebellar mutism syndrome (6%) in a literature review (48). Similarly, postoperative CNS infection correlated with the occurrence of cerebellar mutism syndrome among high-risk medulloblastoma patients evaluated in a large prospective Children’s Oncology Group study, although it was present in only 5 of 85 patients with mutism (104). Postoperative meningitis did not appear to correlate with cerebellar mutism syndrome in several series (101; 122; 98; 121; 38; 22).
The occurrence of brainstem involvement by tumor was a factor found to significantly correlate with the development of cerebellar mutism syndrome in the Children’s Oncology Group medulloblastoma study (104). Several series have shown some correlation of brainstem involvement and the development of mutism (40; 122; 98; 76; 99; 111). This association of cerebellar mutism syndrome with brainstem involvement by tumor could be a clue to a possible neuroanatomic substrate for the syndrome.
A prospective Italian study found that abnormal language prior to surgery was a strong risk factor for the development of cerebellar mutism (34). All 7 of 34 children who developed cerebellar mutism (20%) after posterior fossa tumor surgery had preoperative language impairment; no child with normal preoperative language developed mutism.
The midline cerebellar location of tumor in the majority of cases of cerebellar mutism syndrome has suggested that the cerebellum is anatomically important in the pathogenesis. Certainly, the cerebellum plays an important role in regulating and coordinating speech, but it has traditionally been considered to primarily control articulation and not the production of speech. Dysarthria is well known to result from lesions in a variety of cerebellar locations, including unilateral hemispheric lesions, midline vermal lesions, or lesions of the deep cerebellar nuclei (70). Mutism is frequently associated with truncal or appendicular ataxia in cerebellar mutism syndrome, and an ataxic dysarthria is reported in a large percentage of patients when the mutism resolves (83; 121; 120; 22; 114; 48).
However, increasing evidence indicates that the role of the cerebellum extends beyond the motor domain. A spectrum of nonmotor cognitive deficits, some of which are reminiscent of features of cerebellar mutism syndrome, has been described in patients with a variety of cerebellar diseases or injuries. This has been called cerebellar cognitive affective syndrome and is characterized by disturbances of executive function, visual-spatial disorganization, and nonarticulation language problems, including mild anomia and agrammatism. Personality changes with blunting or disinhibition of affect are also seen (41; 109; 126). Other cognitive disturbances have been found after surgical procedures on the cerebellum in children (06).
These clinical observations are supported by experimental neuroanatomic studies in primates and by functional imaging in humans, showing cerebellar involvement in extramotor functions. Using a retroviral detector in monkeys, a direct connection was demonstrated between dentate nuclei and the nonmotor prefrontal cortex, a region known to be involved in spatial working memory and future behavior-planning (78). Functional imaging with PET and fMRI methodology showed cerebellar activation in complex human cognitive operations such as puzzle-solving, sensory discrimination, and visual attention in the complete absence of motor activity. Moreover, this localization was in discrete areas of the cerebellum independent of those activated by motor activity (41; 64; 45; 10). A role for the cerebellum in mediating emotional behavior was demonstrated by the alleviation of aggressive behaviors in isolation-reared primates after the production of various cerebellar lesions (96; 18). Functional connections have also been identified between cerebellar and limbic structures, further strengthening a hypothesis that the cerebellum can modulate behavior and emotion (13; 52).
The midline posterior fossa location of tumors has focused attention on the cerebellar vermis as a possible critical structure in the development of the syndrome. From a review of the operative approach to posterior fossa tumor surgery at a single institution, Dailey and colleagues found a correlation between cerebellar mutism syndrome and splitting the inferior cerebellar vermis, which they postulated as an etiology (27). Kellog and Piatt reported a surgical approach to fourth ventricular tumors without splitting the vermis that avoided mutism. This was cited as support for vermian injury as the cause of the syndrome (63). In another series, no cerebellar mutism syndrome was reported among 16 patients who underwent resection of fourth ventricular tumors by a telovelar surgical approach that avoided splitting vermian structures (37). A combined transventricular and supracerebellar infratentorial approach preserving the vermis avoided the mutism syndrome in 4 patients with giant posterior fossa tumors that involved the tectum and the 4th ventricle (54). Conversely, in other series, the presence or length of vermian incision did not correlate with the development of mutism (98), and cerebellar mutism syndrome has occurred in the absence of splitting the vermis (30; 133). Siffert and colleagues reported continuing to see patients with postoperative mutism despite a change in practice to avoid splitting the vermis, and no correlation between the development of cerebellar mutism syndrome and vermian involvement by tumor was found in a large multicenter prospective study of cerebellar mutism syndrome (104). Moreover, as has been previously reasoned, if direct injury to the cerebellar vermis were responsible for the mutism syndrome, it seems likely that it would occur even more frequently because the majority of patients with a midline posterior fossa tumor undergo its resection by a midline incision of this structure (98). Moreover, the onset of the syndrome, typically 1 to 2 days after the surgery, also speaks against operative vermian injury or resection as a mechanism (98).
Surgical approaches using a vermian incision has been associated with cerebellar mutism and a subsequent low IQ (27; 22; 103; 50; 100).
Several investigators have postulated the dentato-thalamo-cortical pathways as the anatomical substrate of cerebellar mutism (32; 26; 44; 98; 38; 68). These pathways project both to and from the dentate nucleus of cerebellum on either side, crossing in the superior and middle cerebellar peduncle, through the brainstem to the contralateral red nucleus and thalamus and on to the premotor and supplementary motor cortex (Adams and Victor 1993; 88). There is evidence that injury anywhere along the dentato-thalamo-cortical pathways can produce mutism. However, the proximal segment of the dentato-thalmo-cortical pathway appears to be clinically most relevant, as tumors and surgical resection occur within the region of this pathway (03; 105; Law et al 2012). The proximal efferent cerebellar pathway consisting of the dentate nucleus, the superior cerebellar peduncle, and the mesencephalic tegmentum appear to be involved on imaging of patients with cerebellar mutism (122; 98; 126; 82; 100; 79; 88).
Injury of the dentate-thalamo cortical pathway is thought to lead to cerebello-cerebral diaschisis. This causes hypoperfusion and decreased metabolic activity in the corresponding cerebral cortex due to lack of excitatory stimulation from the cerebellum. Perfusion and diffusion tensor imaging studies have demonstrated this connection (Germanò et al 1998; 105; 82; 79; 116).
Children have become mute after injury to the brainstem, in which the proximal portions of the dentato-thalamo-cortical tracts travel. Mutism has occurred after surgical treatment of a pontine cavernous hemangioma or brainstem tumor (89; 122; 44) or after brainstem stroke (80). Brainstem involvement by tumor correlated with the development of cerebellar mutism syndrome in several series, including the multicenter medulloblastoma study, and could localize dysfunction to the brainstem within the dentato-thalamo-cortical pathways (98; 121; 104). A higher incidence of brainstem tumor invasion was also found in a series of 11 of 28 patients with cerebellar mutism syndrome after medulloblastoma surgery (125). In a prospective case-control study of 26 children, 13 with cerebellar mutism and 13 without cerebellar mutism after posterior fossa surgery, postoperative MRI signal abnormalities were observed more often in the superior cerebellar peduncles and midbrain in children with mutism than in controls (82). On DTI, there was lower fractional anisotropy of water in white matter tracts in bilateral superior cerebellar peduncles and bilateral fornices in the cerebellar mutism cohort, reflecting more interruption of white matter tracts in these areas.
Diffusion abnormalities in the proximal efferent cerebellar pathway have been associated with the development of cerebellar mutism, particularly bilateral involvement of the proximal efferent cerebellar pathway (15). Another group noted bilateral diffusion abnormalities about the surgical cavity and likely involving the dentate nucleus as being a risk factor (24). The superior cerebellar peduncles may also demonstrate abnormalities in diffusion-weighted images as well as on FLAIR in those with cerebellar mutism (119). Hypertrophic olivary degeneration can be demonstrated on MRI in patients with cerebellar mutism. This finding is thought to be caused by denervation injury of Mollaret triangle and further implicates the proximal efferent cerebellar pathways as the causative site of injury (15; 95).
Diffusion tensor imaging (DTI) and tractography map white matter fiber tracts on MRI. Reduced cerebello-thalamo-cortical volumes in postoperative patients with medulloblastomas evaluated via DTI correlated with poorer motor outcomes for patients (86). Other studies utilizing DTI found decreased fiber tract organization (reduced fractional anisotropy) within the bilateral superior cerebellar peduncles that persisted beyond a year post development of cerebellar mutism (88; 75). Decreased fronto-cerebellar association fibers volumes were also seen in patients with cerebellar mutism along with diminished fiber signal from the superior cerebellar peduncles and midline cerebellar structures in patients with cerebellar mutism, suggesting a link for the neurocognitive sequelae seen in patients with cerebellar mutism (116). These clinical observations and imaging data suggest that mutism after posterior fossa tumor surgery could involve dentato-thalamo-cortical pathways and most likely the dentate, superior cerebellar peduncle, and/or brainstem portions.
Bilateral cerebellar injury appears to be most likely to induce cerebellar mutism. The relationship of left dominant cerebral hemisphere and its connections with the right cerebellum via the dentato-thalamo-cortical pathway, however, has been shown to be associated with acquisition of cerebellar mutism (Law et al 2012) and also permanent dysarthria (81). There is also evidence that left-handed patients may be more susceptible to postoperative cerebellar mutism. In 1 study, 6 out of 17 patients that developed cerebellar mutism were left-handed whereas only 1 patient out of 34 not affected was (Law et al 2012).
With regard to mechanism of injury in cerebellar mutism syndrome, Wisoff and Epstein postulated that edema developing in supranuclear afferent pathways, caused by intraoperative retraction of these structures, was the pathophysiology of the syndrome (129). This hypothesis could also account for the delayed onset after surgery and partially transient nature of the syndrome, reflecting the time interval for development and regression of edema. The development of delayed edema by this same mechanism, but in the cerebellum itself, was also hypothesized by Ozek and colleagues, who recommended avoidance of constant retraction of bilateral cerebellar structures as a way to prevent the syndrome (89). A retrospective study demonstrated a statistically significant greater degree of preoperative pons compression and greater increase in postoperative pons diameter on MRI in 13 of 51 children who developed cerebellar mutism syndrome after resection of a posterior fossa midline tumor (76). The authors postulated that the greater compression may make white matter tracts in brainstem more vulnerable to injury after surgical manipulation, and that the relatively sudden release of this greater force at surgery may increase predisposition to axonal distortion and injury.
Postoperative vasospasm causing ischemia also has been proposed as a mechanism of injury that could account for the period of latency before the onset of symptoms (40; 83). On a SPECT scan, hypoperfusion was detected in the cerebellar hemisphere in a patient with mutism and then normalized after resolution of the mutism (38). The bilateral edema in middle cerebellar peduncles in many of the patients with cerebellar mutism syndrome was thought to be consistent with ischemia from vasospasm in these structures as a pathophysiologic mechanism of cerebellar mutism syndrome (98). Sagiuchi reported decreased blood flow in both cerebellar hemispheres (as well as in both thalami and frontal lobes) on SPECT scan after resection of a right cerebellar hemispheric medulloblastoma. This normalized after improvement of the patient’s mutism, providing support for a mechanism of delayed edema or ischemia in the cerebellum as a cause of cerebellar mutism syndrome (105). The hypoperfusion in the thalami and frontal lobes provides support for cerebellar connections to these structures, which are known to undergo changes in perfusion and metabolism with changes in the metabolism of the contralateral cerebellar hemisphere (105). In 11 case-controlled pediatric patients with cerebellar mutism after posterior fossa tumor resection, this concept of “crossed cerebellocerebral diaschisis,” presumed to be caused by bilateral cerebellar injury in cerebellar mutism, was strengthened by the recent demonstration of significantly decreased blood flow by MR dynamic perfusion studies in the bilateral frontal cortex (79). FDG PET/CT demonstrated hypometabolism in the right cerebellar hemisphere and left frontal lobe in 1 patient, demonstrating this relationship (47).
Whatever the mechanism, it seems clear that injury/damage, and not just transient functional change, occurs in the cerebellum and/or its connecting pathways following cerebellar mutism syndrome. A review of the experience of a single institution, where many medulloblastoma patients are referred and treated, found significantly more brainstem and cerebellar atrophy on MRI done 1 year after surgery among 11 of 28 children with cerebellar mutism syndrome following medulloblastoma resection (125). It has been demonstrated that gross-total or near-total tumor resection improves long-term survival in medulloblastoma (08; 134). This has put the onus on neurosurgeons to attempt more radical tumor resections, possibly a contributing factor in the increased incidence of the syndrome. The role played by changes in surgical technique that may facilitate more extensive resections, such as the intraoperative laser and the Cavitron ultrasonic nebulizer, is still uncertain. However, it was noted by the senior author of the report that demonstrated late cerebellar atrophy that limiting the use of the Cavitron has resulted in a marked reduction of cerebellar mutism syndrome at his institution (92; 125). Another group has also implicated the Cavitron (16).
Cerebellar mutism syndrome occurs most often following the resection of a large midline posterior fossa tumor. The great majority of these are medulloblastoma tumors in children. There are only reports and small case series of adults with cerebellar mutism reported (73). It seems likely that this age distribution is related to the higher incidence of posterior fossa tumors in childhood (38). In a literature review of 134 cases of cerebellar mutism syndrome, 119 cases (89%) were following resection of midline posterior fossa tumors; 85 (63%) were medulloblastomas, 24 (18%) were astrocytomas, and 19 were ependymomas (14%). The mean age of these patients was 9.2 years (range 2 to 61 years), and the ratio of male to female patients was 2.7:1 (48).
Cerebellar mutism syndrome has also occurred in adults and in settings other than tumor resection, including after traumatic or surgical vertebrobasilar injury, in the context of cerebellar or brainstem hemorrhage, and after resection of intrinsic brainstem tumors (32; 131; 108; 20; 30; 36; 39; 61; 66; 85; 115; 80; 62; 58), and with parainflammatory cerebellitis and acute disseminated encephalomyelitis (77; 93; 94). A prospective study of cerebellar mutism following posterior fossa surgery in 59 operations in adults did not find anyone with postoperative cerebellar mutism, though 16% had development or worsening of speech or motor complication (128).
A variable incidence of the syndrome after posterior fossa tumor surgery in children, ranging from 2% to 29%, has been reported in the literature and was derived mainly from single institution experiences (27; 98; 66; 59; 22; 35; 114; 48; 67). In a large multicenter study of pediatric medulloblastoma, the incidence was 24% among 450 patients (104). There is no known cultural or racial predilection to developing the syndrome. There is an ongoing multicenter prospective study in Europe that in addition to identifying risk factors, comorbidities, and differences in treatments, will also be exploring the role of genomic variants on the development, severity, and recovery from cerebellar mutism (127).
There are currently no known effective measures to prevent cerebellar mutism after posterior fossa surgery. Based on the hypothesis that incision or removal of the cerebellar vermis was a cause of cerebellar mutism syndrome, it has been proposed that an approach that avoided splitting the vermis could avoid mutism (27; 63; El–Bahy 2005). However, such an approach does not appear to prevent cerebellar mutism syndrome with any consistency (30; 98; 114; 133). The avoidance of prolonged intraoperative retraction was proposed as a means of preventing cerebellar mutism syndrome in view of the hypothesis that this might be a factor contributing to cerebellar mutism syndrome by producing delayed postoperative edema or ischemia in cerebellar or pericerebellar structures (129; 89). But avoidance of prolonged intraoperative retraction has not been shown to be effective in preventing cerebellar mutism syndrome. Better understanding of the pathophysiology of postoperative mutism is needed to reduce the incidence of this postoperative complication in the future.
A multicenter international retrospective study tried to identify modifiable factors associated with the development of cerebellar mutism in children with resection of posterior fossa tumors; however, no significant associations were seen with preresection surgical hydrocephalus treatment, prone position, ultrasonic aspirator use, external ventricular drain use, cerebellar vermis sparing approach, complete or near total resection, or treating center with postoperative cerebellar mutism (102). Risk factors for cerebellar mutism are fourth ventricular tumor with brainstem invasion and/or compression (22; 104; 67; 97; 111). Medulloblastoma is the most common tumor pathology associated with development of postoperative cerebellar mutism (22). Another group found along with brainstem invasion and/or compression that an increase of 0.5 degrees Celsius in mean body temperature in the first 4 postoperative days resulted in an almost 5-fold increased odds ratio of developing cerebellar mutism (99).
An imaging-based preoperative risk scoring system to stratify patients in terms of postoperative cerebellar mutism risk has been developed though has not yet been utilized prospectively or validated (72). Using the 6 identified predictors of primary location, bilateral middle cerebellar peduncle involvement, dentate nucleus invasion, and age at imaging of more than 12.4 years, patients were risk stratified into low, intermediate, and high risk of cerebellar mutism, with 88.8% accuracy. The hope was to provide preoperative risk stratification during surgical consent.
The differential diagnosis of decreased speech or mutism following posterior fossa surgery includes the inability to speak because of cranial nerve palsies. These would include deficits of facial nerve function with decreased lip mobility, deficits of bulbar cranial nerves with attendant oropharyngeal dysfunction, and deficits of hypoglossal nerve function with decreased tongue mobility. The absence of speech in children after posterior fossa surgery conceivably could be unrelated to organic injury to brain structures and instead could represent a psychological reaction in the child to the stress of the operation. This is a phenomenon well known in psychiatry as “elective mutism,” and has been described in various psychologically stressful settings (11). Indeed, it has been hypothesized that the mechanism of the cerebellar mutism syndrome is actually a functional disturbance reflecting a sense of betrayal and anger in children whose parents have allowed them to be subjected to a difficult and painful operation (40). However, the cerebellar mutism syndrome, as currently described and increasingly identified, has such distinctive and stereotypical features that it seems improbable to have an exclusively psychological basis. Moreover, when the fully realized mutism syndrome is present, it is unlikely not to be recognized as such.
The diagnosis of cerebellar mutism syndrome is made on the basis of the clinical constellation of signs and symptoms described in the clinical manifestations section of this article. Abbreviated speech and language evaluations to document the degree of language deficit at the onset and then at intervals during recovery from the mutism could be useful for prognosis. There are currently no established laboratory or brain imaging evaluations to confirm the diagnosis, although certain MRI abnormalities, such as edema in cerebellar peduncles or brainstem, have been noted in some cases of cerebellar mutism syndrome (122; 98).
The comprehensive characterization of the neurologic impairments seen in cerebellar mutism syndrome may include severe communication deficits of expressive and sometimes receptive language with evolution to dystaxic speech, severe global cerebellar dysfunction, emotional lability, and sometimes inattention, oromotor dyspraxia, and loss of bowel and bladder control. This rather global picture of neurologic dysfunction frequently necessitates an intensive program of rehabilitation that includes speech, occupational, and physical therapy for patients recovering from cerebellar mutism syndrome. One reported case described a child who developed cerebellar mutism syndrome with complete absence of speech for 2 weeks after resection of a posterior fossa tumor; but the child was abruptly able to sing along with a musical video, which seemed to trigger a rapid and sustained overall speech recovery (90). The nonbenzodiazepine hypnotic agent, zolpidem, is primarily used as a sedative, but there is some evidence for its efficacy in alleviating mutism and akinesia in other neurologic and psychiatric disorders. Zolpidem was reported to have increased arousal and accelerated recovery of speech via an uncertain mechanism in a child with postoperative cerebellar mutism (112). Another case report reported the resolution and recurrence of cerebellar mutism correlating with the administration and clearance of midazolam in 1 patient; the authors performed SPECT analysis on this patient’s brain and also demonstrated initially reduced blood flow to cerebral cortex that resolved on follow-up (84).
There is little experience with pharmacological management of the symptoms of cerebellar mutism syndrome. High-dose steroids were administered to several patients with cerebellar mutism syndrome with a thought to preventing the edema hypothesized as a cause of the syndrome, either from intraoperative retraction of cerebellar structures or from postoperative vasospasm; they were ineffective in reversing the symptoms (98). However, 2 children with postoperative cerebellar mutism syndrome were reported to have had accelerated improvement after treatment with fluoxetine, a serotonin-reuptake inhibitor antidepressant medication. This idea for therapy was based on the hypothesis that speech and language impairment in childhood autism is related to decreased serotonin in the cerebral cortex, resulting from interruption of the dentato-thalamo-cortical pathways. A subsequent case report of a child with cerebellar mutism responding to fluoxetine was published in 2012 (04). A patient who developed cerebellar mutism syndrome after resection of a low-grade fourth ventricular neuronal-glial tumor was reported to have improved dramatically with the administration of bromocriptine. This was hypothesized to have restored possible decreased brainstem dopaminergic outflow related to the mutism (01).
Despite the age of injury and the number of years after surgery, most patients were found to have made their most substantial improvements within the first year of cerebellar mutism. After 1 year subsequent dysarthria did not improve (56; 118). Most patients with postoperative cerebellar mutism go on to have some speech difficulties (117). Patients with tumors requiring only surgical resection and without brainstem invasion had the best recovery in 1 group’s experience (118). The same group found that patients presenting at diagnosis with associated combined procedural memory and defective neurocognitive function tend to have a more severe cerebellar mutism course and are less prone to complete recovery.
Additionally, the emotional toll that these deficits may cause or may be a direct consequence of cerebellar injury needs to be monitored with referral to a psychologist/psychiatrist, as needed. Patients should be referred for rehabilitation services focusing on speech and any other associated cerebellar/cranial nerve findings along with neurocognitive assessment and rehabilitation. These patients will likely need individualized education plans at school.
Fertility. There would be no expected influence of cerebellar mutism syndrome, per se, on fertility. Infertility incidence is increased in patients with medulloblastoma, the most common setting in which cerebellar mutism syndrome occurs, related to treatment with irradiation and chemotherapy.
Pregnancy complications. The cerebellar mutism syndrome has no particular relevance during pregnancy.
Anesthesia seems unlikely to be complicated by cerebellar mutism syndrome, unless there were to be uncommonly associated cranial nerve deficits, which could result in aspiration from loss of airway protection because of bulbar dysfunction.
Aimee A Sato MD
Dr. Sato of Seattle Children’s has no relevant financial relationships to disclose.See Profile
Roger J Packer MD
Dr. Packer of George Washington University and Children’s National Health System received honorariums from AstraZeneca and Novartis as an advisory board member.See Profile
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