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Characterizing Posterior Fossa Syndrome: A Survey of Experts

      Abstract

      Background

      Despite recent efforts, disagreement remains among frontline clinicians regarding the operational definition of a syndrome commonly referred to as posterior fossa syndrome or cerebellar mutism syndrome.

      Methods

      We surveyed experts in the clinical care of children with posterior fossa tumors to identify trends and discrepancies in diagnosing posterior fossa syndrome.

      Results

      All surveyed professionals conceptualized posterior fossa syndrome as a spectrum diagnosis. The majority agreed that mutism is the most important symptom for diagnosis. However, results highlighted ongoing discrepancies related to important features of posterior fossa syndrome.

      Conclusions

      Greater posterior fossa syndrome conceptual alignment among providers is needed to formulate specific diagnostic criteria that would further research and clinical care. The authors propose preliminary diagnostic criteria for posterior fossa syndrome that require refinement through careful clinical characterization and targeted empirical investigation.

      Keywords

      Introduction

      Contemporary treatment for medulloblastoma, the most common malignant pediatric brain tumor,
      • Northcott P.A.
      • Jones D.W.
      • Kool M.
      • et al.
      Medulloblastomics: the end of the beginning.
      involves surgical resection, cranial radiation therapy, and chemotherapy.
      • Gajjar A.
      • Chintagumpala M.
      • Ashley D.
      • et al.
      Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.
      Recent treatment advances have resulted in significant improvements in survival rates (70% to 85%),
      • Gajjar A.
      • Chintagumpala M.
      • Ashley D.
      • et al.
      Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial.
      shifting the focus of research toward improving quality of life. Following surgical resection, up to 29% of patients with medulloblastoma develop symptoms most commonly referred to as posterior fossa syndrome (PFS) or cerebellar mutism syndrome (CMS).
      • De Smet H.J.
      • Baillieux H.
      • Catsman-Berrevoets C.
      • De Deyn P.P.
      • Mariën P.
      • Paquier P.F.
      Postoperative motor speech production in children with the syndrome of ‘cerebellar’ mutism and subsequent dysarthria: a critical review of the literature.
      ,
      • Korah M.P.
      • Esiashvili N.
      • Mazewski C.M.
      • et al.
      Incidence, risks, and sequelae of posterior fossa syndrome in pediatric medulloblastoma.
      Patients with PFS experience speech and language changes, motor impairments, and emotional lability.
      • Gudrunardottir T.
      • Morgan A.T.
      • Lux A.L.
      • et al.
      Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results.
      Typically, symptom onset is delayed (one to six days postsurgery) and duration is limited (one day to four months).
      • Gudrunardottir T.
      • Sehested A.
      • Juhler M.
      • Schmiegelow K.
      Cerebellar mutism: review of the literature.
      However, many patients experience persistent cognitive, motor, and emotion regulation difficulties.
      • Gudrunardottir T.
      • Sehested A.
      • Juhler M.
      • Schmiegelow K.
      Cerebellar mutism: review of the literature.
      • Robertson P.L.
      • Muraszko K.M.
      • Holmes E.J.
      • et al.
      Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children’s Oncology Group.
      • Wolfe-Christensen C.
      • Mullins L.
      • Scott J.
      • McNall-Knapp R.
      Persistent psychosocial problems in children who develop posterior fossa syndrome after medulloblastoma resection.
      • Patay Z.
      Postoperative posterior fossa syndrome: unraveling the etiology and underlying pathophysiology by using magnetic resonance imaging.
      Patients treated for medulloblastoma with PFS evidenced poorer intellectual ability, processing speed, attention, working memory, and visuospatial skills at one, three, and five years postdiagnosis compared with similarly treated patients with medulloblastoma without PFS.
      • Schreiber J.E.
      • Palmer S.L.
      • Conklin H.M.
      • et al.
      Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study.
      There is disagreement among experts regarding the operational definition of PFS. Inconsistencies include the diagnostic label (PFS, CMS, cerebellar cognitive affective syndrome), a required period of mutism, and broader theoretical conceptualization (categorical or continuous). A diagnosis of PFS is typically made by an attending physician’s subjective yes-no report, without demonstration of inter-rater reliability and disagreement regarding diagnostic criteria among clinicians. Formulation of a universal definition has been proposed.
      • De Smet H.J.
      • Baillieux H.
      • Catsman-Berrevoets C.
      • De Deyn P.P.
      • Mariën P.
      • Paquier P.F.
      Postoperative motor speech production in children with the syndrome of ‘cerebellar’ mutism and subsequent dysarthria: a critical review of the literature.
      ,
      • Gudrunardottir T.
      • Morgan A.T.
      • Lux A.L.
      • et al.
      Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results.
      • Gudrunardottir T.
      • Sehested A.
      • Juhler M.
      • Schmiegelow K.
      Cerebellar mutism: review of the literature.
      • Robertson P.L.
      • Muraszko K.M.
      • Holmes E.J.
      • et al.
      Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children’s Oncology Group.
      ,
      • Schreiber J.E.
      • Palmer S.L.
      • Conklin H.M.
      • et al.
      Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study.
      The Posterior Fossa Society, a group of international experts in pediatric neuro-oncology, neurosurgery, radiology, and neuropsychology, constructed a definition of the syndrome using the nominal group technique. A consensus committee generated 10 diagnostic consensus statements based on published reviews. Group members (27 to 30 respondents) completed Delphi questionnaires that assessed opinions of PFS and level of agreement with proposed consensus statements. Subsequently, results were evaluated at a consensus conference. The final working definition identified delayed-onset mutism or reduced speech accompanied by emotional lability after cerebellar tumor resection in children as fundamental features of the syndrome.
      • Gudrunardottir T.
      • Morgan A.T.
      • Lux A.L.
      • et al.
      Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results.
      Mutism was noted to always be transient, although syndrome recovery may be prolonged.
      • Gudrunardottir T.
      • Morgan A.T.
      • Lux A.L.
      • et al.
      Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results.
      Notably, the Posterior Fossa Society used “post-operative pediatric CMS” as the diagnostic label.
      Given remaining diagnostic ambiguities surrounding PFS, the present study aimed to gather information from clinicians who specialize in treating children with posterior fossa tumors about their conceptualization of PFS. The goal in ascertaining information from clinical experts was to identify trends in diagnostic practice and reveal any potential remaining controversies.

      Methods

      Participants

      Potential participants included 56 surveyed professionals associated with the SJMB12 protocol initiated at St. Jude Children’s Research Hospital [NCT01878617] considered PFS experts based on regular clinical care of this population. SJMB12, an ongoing, prospective, frontline treatment protocol for medulloblastoma, includes 19 sites across multiple continents.

      Materials and procedures

      A brief online survey, depicted in Supplemental Table 1, was developed based on the extant research literature and consisted of 10 questions. Participants provided demographic information and were asked about their conceptualization of PFS. Last, they were asked to rank order the importance of symptoms related to speech/language, motor, and mood/affect impairments in diagnosing PFS.

      Results

      Participant characteristics

      Of the 56 professionals contacted, 32 (57%) responded to the survey. As shown in Supplemental Table 2, participants primarily consisted of neuro-oncologists (56%) and neuropsychologists (34%), with an average of 13.9 years’ clinical experience with the PFS population. The majority of respondents were from the United States, with an even distribution among different geographic regions. The remainder resided in Australia, New Zealand, and Canada.

      Examination of survey responses

      All participants conceptualized PFS as continuous (on a spectrum from mild to severe) as opposed to categorical (present or not present). Twenty-one respondents (66%) stated that there is a pathognomonic symptom of PFS, with 16 of those respondents (76%) identifying mutism. However, 66% of participants reported that a period of mutism is not necessary to diagnose PFS. Alternate pathognomonic symptom responses included other speech/language difficulties (limited phrase length, disordered speech production), apraxia, and emotional lability. Seventy-two percent reported using PFS and CMS interchangeably.
      Participants were asked to rank order 10 symptoms associated with PFS from most to least important. Each item was given a weighted value (1 to 10) based on level of importance reported by participants. The analysis was conducted using data from 31 respondents. The Figure depicts the weighted average of the 10 items. Generally, the presence of mutism was the most important symptom when diagnosing PFS. This was followed by other speech/language symptoms and emotion regulation symptoms. Motor impairments were ranked least important.
      Figure thumbnail gr1
      FIGURERank order of symptom importance (N = 31). The color version of this figure is available in the online edition.

      “Junior” and “senior” experts

      Owing to the wide range in years of experience among respondents, further analyses examined differences between “junior” and “senior” experts, using the median years working with patients with PFS (15) to divide the sample. Junior experts included professionals with one to 13 years of PFS experience (n = 15), and senior experts included those with 15 to 30 years’ experience (n = 17). Both groups ranked mutism as most important in diagnosing PFS. Senior experts rated all speech/language symptoms (mutism, dysarthria, limited phrase length, slowed speech, in order) as most important, followed by emotional lability and irritability. Motor impairments (ataxia, apraxia, dysmetria, and hemiparesis, in order) were ranked least important. Conversely, junior experts’ rankings intermixed speech/language and emotion regulation symptoms with respect to symptom importance, with emotional lability as the second most important.

      Discussion

      Review of findings

      The current findings clarify particular aspects of the conceptualization of PFS while also demonstrating ongoing diagnostic disagreement. All experts conceptualized PFS as continuous, with presentations that range from mild to severe, despite research that routinely uses a dichotomous categorization (present or not present).
      • Wolfe-Christensen C.
      • Mullins L.
      • Scott J.
      • McNall-Knapp R.
      Persistent psychosocial problems in children who develop posterior fossa syndrome after medulloblastoma resection.
      ,
      • Schreiber J.E.
      • Palmer S.L.
      • Conklin H.M.
      • et al.
      Posterior fossa syndrome and long-term neuropsychological outcomes among children treated for medulloblastoma on a multi-institutional, prospective study.
      Mutism was overwhelmingly ranked the most important feature when considering a diagnosis. However, most reported a period of mutism as not necessary to diagnose PFS. Variability among all other responses was noted, and junior and senior experts seemed to conceptualize PFS differently. While both experts largely concentrated on speech/language changes when diagnosing PFS, junior experts seemed to equally consider emotion regulation symptoms that may include irritability and emotional lability, dysphoria, apathy, distress, inconsolability, tearfulness, and distractibility.
      • Lanier J.C.
      • Abrams A.N.
      Posterior fossa syndrome: review of the behavioral and emotional aspects in pediatric cancer patients.
      ,
      • Turkel S.B.
      • Shu Chen L.
      • Nelson M.D.
      • et al.
      Case series: acute mood symptoms associated with posterior fossa lesions in children.
      Taken together, these results may reflect the impact of the Posterior Fossa Society’s definition of CMS
      • Gudrunardottir T.
      • Morgan A.T.
      • Lux A.L.
      • et al.
      Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results.
      for junior experts, as they may be more inclusive of other important features as opposed to primarily speech/language changes.
      Consistent with the goals of the Posterior Fossa Society, elucidating areas of disagreement among experts in the conceptualization of PFS can help work toward greater alignment. However, future research is required to establish specific diagnostic criteria that can be used reliably across assessors. Given the current study’s findings, including “mutism” in the diagnostic label is counter to the syndrome definition, as mutism does not appear to be required for diagnosis. PFS is a broader term than CMS that reduces confusion surrounding inclusion of patients in this group who display significant speech/language changes but not complete mutism. Likewise, movement toward a dimensional diagnostic approach with severity ratings that better reflect conceptualization of PFS is needed, such as those used for intellectual disabilities (Mild, Moderate, Severe, Profound).
      World Health Organization
      The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines.
      Dichotomous methods result in a loss of information related to individual differences,
      • MacCallum R.C.
      • Zhang S.
      • Preacher K.J.
      • et al.
      On the practice of dichotomization of quantitative variables.
      which can hamper research progress. Dimensional diagnostic approaches would accelerate research investigating the etiology of PFS, improving prediction of lasting neuropsychologic impairment and identifying targeted interventions. In addition, diagnostic agreement would allow for examining associations between PFS and neuroimaging findings in a uniform clinical population that might guide surgical approaches to minimize the occurrence of this syndrome.
      • Patay Z.
      Postoperative posterior fossa syndrome: unraveling the etiology and underlying pathophysiology by using magnetic resonance imaging.

      Proposed diagnostic criteria for posterior fossa syndrome

      Based on survey results, the authors propose a set of “working” diagnostic criteria for PFS in the Table below, with the expectation that future clinical characterization and research will help evaluate and refine these criteria.
      TABLE.Proposed Diagnostic Criteria for Posterior Fossa Syndrome
      Criterion AAcquired cerebellar injury (e.g., postsurgical or stroke-related), with symptoms in Criteria B, and C or D, emerging within two weeks of injury
      Criterion B
      • Presence of one of the following speech and/or language deficits:
        • 1
          Mutism (inability to speak) or
        • 2
          Significant impairment in language as indicated by one or more of the following: reduced phrase length (speech limited to single words or two- to three-word phrases), agrammatism, atypical speech rate/rhythm (slowed, gaited, ballistic), and/or dysnomia
      Criterion CPresence of notable changes in mood/affect characterized by irritability (excessive tearfulness, crying, agitation, or anger), emotional lability (rapid changes in mood), and/or flat affect
      Criterion DPresence of motor dysfunction defined as apraxia (inability to execute purposeful movements on command, despite having the physical capacity to perform the movement), ataxia (difficulty coordinating muscle movements), dysmetria (undershoot or overshoot of intended position with the hand, arm, or leg), hypokinesia (abnormally diminished motor activity), and/or hemiparesis (weakness one side of the body)
      Note: Criteria A and B1 (mutism) are sufficient for a diagnosis of PFS. In the absence of B1 (mutism), Criteria A, B2, and C or D must be met for diagnosis of PFS.

      Limitations and future directions

      The current study had several strengths, including many years of experience among respondents with respect to frontline care of the target population and a rank order approach of symptoms identified in the extant literature. However, limitations include sampling issues, as respondents were largely neuro-oncologists or neuropsychologists, with less representation of other rehabilitation professionals. Furthermore, the sample size in the present study, although similar to that of the Posterior Fossa Society’s consensus study,
      • Gudrunardottir T.
      • Morgan A.T.
      • Lux A.L.
      • et al.
      Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results.
      was small. This line of research could greatly benefit from future work that explores conceptualization practices in a larger sample that includes a broader range of disciplines. In addition, the proposed diagnostic criteria are a starting place requiring refinement based on careful clinical characterization (e.g., to establish severity indicators and subtypes, such as PFS with or without emotion dysregulation, given different weight assigned to these symptoms as a function of years of clinical experience), as well as empirical investigation to establish reliability and predictive validity.

      Acknowledgments

      The authors thank the experts who participated in this study.
      Funding: This work was supported, in part, by the National Cancer Institute (St. Jude Cancer Center Support [CORE] Grant [ P30-CA21765 ]) and the American Lebanese Syrian Associated Charities (ALSAC). Authors do not have conflicts of interest.

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