Epileptogenic Tubers Are Associated with Increased Kurtosis of Susceptibility Values: A Combined Quantitative Susceptibility Mapping and Stereoelectroencephalography Pilot Study.

BACKGROUND AND PURPOSE: Prior studies have found an association between calcification and the epileptogenicity of tubers in tuberous sclerosis complex. Quantitative susceptibility mapping is a novel tool sensitive to magnetic susceptibility alterations due to tissue calcification. We assessed the utility of quantitative susceptibility mapping in identifying putative epileptogenic tubers in tuberous sclerosis complex using stereoelectroencephalography data as ground truth. MATERIALS AND METHODS: We studied patients with tuberous sclerosis complex undergoing stereoelectroencephalography at a single center who had multiecho gradient-echo sequences available. Quantitative susceptibility mapping and R2* values were extracted for all tubers on the basis of manually drawn 3D ROIs using T1- and T2-FLAIR sequences. Characteristics of quantitative susceptibility mapping and R2* distributions from implanted tubers were compared using binary logistic generalized estimating equation models designed to identify ictal (involved in seizure onset) and interictal (persistent interictal epileptiform activity) tubers. These models were then applied to the unimplanted tubers to identify potential ictal and interictal tubers that were not sampled by stereoelectroencephalography. RESULTS: A total of 146 tubers were identified in 10 patients, 76 of which were sampled using stereoelectroencephalography. Increased kurtosis of the tuber quantitative susceptibility mapping values was associated with epileptogenicity (P = .04 for the ictal group and P = .005 for the interictal group) by the generalized estimating equation model. Both groups had poor sensitivity (35.0% and 44.1%, respectively) but high specificity (94.6% and 78.6%, respectively). CONCLUSIONS: Our finding of increased kurtosis of quantitative susceptibility mapping values (heavy-tailed distribution) was highly specific, suggesting that it may be a useful biomarker to identify putative epileptogenic tubers in tuberous sclerosis complex. This finding motivates the investigation of underlying tuber mineralization and other properties driving kurtosis changes in quantitative susceptibility mapping values.

Imaging Characteristics of CNS Neuroblastoma-FOXR2: A Retrospective and Multi-Institutional Description of 25 Cases.

BACKGROUND AND PURPOSE: The 5th edition of the World Health Organization Classification of CNS tumors defines the CNS neuroblastoma FOXR2 in the group of embryonal tumors. Published clinical outcomes tend to suggest a favorable outcome after resection, craniospinal irradiation, and chemotherapy. This multicenter study aimed to describe imaging features of CNS neuroblastoma-FOXR2, which have been poorly characterized thus far. MATERIALS AND METHODS: On the basis of a previously published cohort of tumors molecularly classified as CNS neuroblastoma-FOXR2, patients with available imaging data were identified. The imaging features on preoperative MR imaging and CT data were recorded by 8 experienced pediatric neuroradiologists in consensus review meetings. RESULTS: Twenty-five patients were evaluated (13 girls; median age, 4.5 years). The tumors were often large (mean, 115 [ SD, 83] mL), showed no (24%) or limited (60%) perilesional edema, demonstrated heterogeneous enhancement, were often calcified and/or hemorrhagic (52%), were always T2WI-hyperintense to GM, and commonly had cystic and/or necrotic components (96%). The mean ADC values were low (687.8 [SD 136.3] × 10-6 mm2/s). The tumors were always supratentorial. Metastases were infrequent (20%) and, when present, were of nodular appearance and leptomeningeal. CONCLUSIONS: In our cohort, CNS neuroblastoma FOXR2 tumors showed imaging features suggesting high-grade malignancy and, at the same time, showed characteristics of less aggressive behavior. There are important differential diagnoses, but the results of this study may assist in considering this diagnosis preoperatively.

Natural history of MRI brain volumes in patients with neuronal ceroid lipofuscinosis 3: a sensitive imaging biomarker.

PURPOSE: Grey matter (GM) atrophy due to neuronal loss is a striking feature of patients with CLN3 disease. A precise and quantitative description of disease progression is needed in order to establish an evaluation tool for current and future experimental treatments. In order to develop a quantitative marker to measure brain volume outcome, we analysed the longitudinal volumetric development of GM, white matter (WM) and lateral ventricles and correlated those with the clinical course. METHODS: One hundred twenty-two MRI scans of 35 patients (21 females; 14 males; age 15.3 ± 4.8 years) with genetically confirmed CLN3 disease were performed. A three-dimensional T1-weighted sequence was acquired with whole brain coverage. Volumetric segmentation of the brain was performed with the FreeSurfer image analysis suite. The clinical severity was assessed by the Hamburg jNCL score, a disease-specific scoring system. RESULTS: The volumes of supratentorial cortical GM and supratentorial WM, cerebellar GM, basal ganglia/thalamus and hippocampus significantly (r = - 0.86 to - 0.69, p < 0.0001) decreased with age, while the lateral ventricle volume increased (r = 0.68, p < 0.0001). Supratentorial WM volume correlated poorer with age (r = - 0.56, p = 0.0001). Supratentorial cortical GM volume showed the steepest (4.6% (± 0.2%)) and most uniform decrease with strongest correlation with age (r = - 0.86, p < 0.0001). In addition, a strong correlation with disease specific clinical scoring existed for the supratentorial cortical GM volume (r = 0.85, p = < 0.0001). CONCLUSION: Supratentorial cortical GM volume is a sensitive parameter for assessment of disease progression even in early and late disease stages and represents a potential reliable outcome measure for evaluation of experimental therapies.

Spectrum of Neuroradiologic Findings Associated with Monogenic Interferonopathies.

The genetic interferonopathies are a heterogeneous group of disorders thought to be caused by the dysregulated expression of interferons and are now commonly considered in the differential diagnosis of children presenting with recurrent or persistent inflammatory phenotypes. With emerging therapeutic options, recognition of these disorders is increasingly important, and neuroimaging plays a vital role. In this article, we discuss the wide spectrum of neuroradiologic features associated with monogenic interferonopathies by reviewing the literature and illustrate these with cases from our institutions. These cases include intracerebral calcifications, white matter T2 hyperintensities, deep WM cysts, cerebral atrophy, large cerebral artery disease, bilateral striatal necrosis, and masslike lesions. A better understanding of the breadth of the neuroimaging phenotypes in conjunction with clinical and laboratory findings will enable earlier diagnosis and direct therapeutic strategies.

A Diagnostic Algorithm for Posterior Fossa Tumors in Children: A Validation Study.

BACKGROUND AND PURPOSE: Primary posterior fossa tumors comprise a large group of neoplasias with variable aggressiveness and short and long-term outcomes. This study aimed to validate the clinical usefulness of a radiologic decision flow chart based on previously published neuroradiologic knowledge for the diagnosis of posterior fossa tumors in children. MATERIALS AND METHODS: A retrospective study was conducted (from January 2013 to October 2019) at 2 pediatric referral centers, Children's Hospital of Philadelphia, United States, and Great Ormond Street Hospital, United Kingdom. Inclusion criteria were younger than 18 years of age and histologically and molecularly confirmed posterior fossa tumors. Subjects with no available preoperative MR imaging and tumors located primarily in the brain stem were excluded. Imaging characteristics of the tumors were evaluated following a predesigned, step-by-step flow chart. Agreement between readers was tested with the Cohen κ, and each diagnosis was analyzed for accuracy. RESULTS: A total of 148 cases were included, with a median age of 3.4 years (interquartile range, 2.1-6.1 years), and a male/female ratio of 1.24. The predesigned flow chart facilitated identification of pilocytic astrocytoma, ependymoma, and medulloblastoma sonic hedgehog tumors with high sensitivity and specificity. On the basis of the results, the flow chart was adjusted so that it would also be able to better discriminate atypical teratoid/rhabdoid tumors and medulloblastoma groups 3 or 4 (sensitivity = 75%-79%; specificity = 92%-99%). Moreover, our adjusted flow chart was useful in ruling out ependymoma, pilocytic astrocytomas, and medulloblastoma sonic hedgehog tumors. CONCLUSIONS: The modified flow chart offers a structured tool to aid in the adjunct diagnosis of pediatric posterior fossa tumors. Our results also establish a useful starting point for prospective clinical studies and for the development of automated algorithms, which may provide precise and adequate diagnostic tools for these tumors in clinical practice.

Discrepant longitudinal volumetric and metabolic evolution of diffuse intrinsic Pontine gliomas during treatment: implications for current response assessment strategies.

INTRODUCTION: Based on clinical observations, we hypothesized that in infiltrative high-grade brainstem neoplasms, such as diffuse intrinsic pontine glioma (DIPG), longitudinal metabolic evaluation of the tumor by magnetic resonance spectroscopy (MRS) may be more accurate than volumetric data for monitoring the tumor's biological evolution during standard treatment. METHODS: We evaluated longitudinal MRS data and corresponding tumor volumes of 31 children with DIPG. We statistically analyzed correlations between tumor volume and ratios of Cho/NAA, Cho/Cr, and NAA/Cr at key time points during the course of the disease through the end of the progression-free survival period. RESULTS: By the end of RT, tumor volume had significantly decreased from the baseline (P < .0001) and remained decreased through the last available follow-up magnetic resonance imaging study (P = .007632). However, the metabolic profile of the tumor tissue (Cho/Cr, NAA/Cr, and Cho/NAA ratios) did not change significantly over time. CONCLUSION: Our data show that longitudinal tumor volume and metabolic profile changes are dissociated in patients with DIPG during progression-free survival. Volume changes, therefore, may not accurately reflect treatment-related changes in tumor burden. This study adds to the existing body of evidence that the value of conventional MRI metrics, including volumetric data, needs to be reevaluated critically and, in infiltrative tumors in particular, may not be useful as study end-points in clinical trials. We submit that advanced quantitative MRI data, including robust, MRS-based metabolic ratios and diffusion and perfusion metrics, may be better surrogate markers of key end-points in clinical trials.

Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression.

BACKGROUND AND PURPOSE: Experimental therapies for ceroid lipofuscinosis, neuronal, 2 (CLN2), a genetic disorder of childhood associated with progressive brain atrophy, are currently being developed. Because quantitative descriptions of the natural course of brain volume loss are needed to evaluate novel therapies, we performed MR imaging volumetry of patients with CLN2 to identify a suitable MR imaging marker of disease progression. MATERIALS AND METHODS: Thirteen patients (8 females, 5 males) were recruited from a prospective natural disease cohort of patients with neuronal ceroid lipofuscinosis. Repeated MR imaging volumetric analysis (29 datasets) was performed by using the FreeSurfer Software Suite. Follow-up time ranged from 8 months to 5.3 years. MR imaging-segmented brain volumes were correlated to patient age and clinical scores. RESULTS: Segmented brain volumes correlated significantly with patient age (lateral ventricles, r = 0.606, P = .001; supratentorial cortical GM, r = -0.913, P < .001; supratentorial WM, r = -0.865, P < .001; basal ganglia/thalamus, r = -0.832, P < .001; cerebellar GM, r = -0.659, P < .001; cerebellar WM, r = -0.830, P < .001) and clinical scores (lateral ventricles, r = -0.692, P < .001; supratentorial cortical GM, r = 0.862, P < .001; supratentorial WM, r = 0.735, P < .001; basal ganglia/thalamus, r = 0.758, P < .001; cerebellar GM, r = 0.609, P = .001; cerebellar WM, r = 0.638, P < .001). Notably, supratentorial cortical GM showed a uniform decline across the patient cohort. During late stages of the disease when the clinical score was zero, segmented brain volumes still correlated with patient age; this finding suggests that MR imaging volumetry allows quantitative assessment of disease progression at stages when it cannot be detected by clinical assessment alone. CONCLUSIONS: Automated MR imaging volumetry, as a nonsubjective and highly sensitive tool, is feasible in CLN2 disease and provides a quantitative basis to evaluate novel experimental therapies.

Severe neurotoxicity following intrathecal methotrexate with nitrous oxide sedation in a child with acute lymphoblastic leukemia.

Systemic and intrathecal methotrexate is widely used in treatment protocols for childhood acute lymphoblastic leukemia. Its side effects vary in characteristics, intensity and time of onset, and depend on the administration route. Interactions with several drugs are known. Side effects of nitrous oxide sedation, often used for moderately painful procedures, typically occur after long time use and include neurological symptoms. We present a child who experienced a severe and long-lasting neurotoxicity after the third intrathecal application of methotrexate with short sedation by nitrous oxide during induction therapy for acute lymphoblastic leukemia. Symptoms completely resolved after 12 months.

MR imaging evaluation of inferior olivary nuclei: comparison of postoperative subjects with and without posterior fossa syndrome.

BACKGROUND AND PURPOSE: Posterior fossa syndrome is a severe postoperative complication occurring in up to 29% of children undergoing posterior fossa tumor resection; it is most likely caused by bilateral damage to the proximal efferent cerebellar pathways, whose fibers contribute to the Guillain-Mollaret triangle. When the triangle is disrupted, hypertrophic olivary degeneration develops. We hypothesized that MR imaging patterns of inferior olivary nucleus changes reflect patterns of damage to the proximal efferent cerebellar pathways and show association with clinical findings, in particular the presence or absence of posterior fossa syndrome. MATERIALS AND METHODS: We performed blinded, randomized longitudinal MR imaging analyses of the inferior olivary nuclei of 12 children with and 12 without posterior fossa syndrome after surgery for midline intraventricular tumor in the posterior fossa. The Fisher exact test was performed to investigate the association between posterior fossa syndrome and hypertrophic olivary degeneration on MR imaging. The sensitivity and specificity of MR imaging findings of bilateral hypertrophic olivary degeneration for posterior fossa syndrome were measured. RESULTS: Of the 12 patients with posterior fossa syndrome, 9 had bilateral inferior olivary nucleus abnormalities. The 12 patients without posterior fossa syndrome had either unilateral or no inferior olivary nucleus abnormalities. The association of posterior fossa syndrome and hypertrophic olivary degeneration was statistically significant (P < .0001). CONCLUSIONS: Hypertrophic olivary degeneration may be a surrogate imaging indicator for damage to the contralateral proximal efferent cerebellar pathway. In the appropriate clinical setting, bilateral hypertrophic olivary degeneration may be a sensitive and specific indicator of posterior fossa syndrome.

Cerebral magnetic resonance imaging findings in adults with haemolytic uraemic syndrome following an infection with Escherichia coli, subtype O104:H4.

PURPOSE: Infections with Enterohaemorrhagic Escherichia coli typically occur in children causing haemolytic uraemic syndrome (HUS) and neurological symptoms in 20-50 %. Little information is available on the morphology of brain manifestations in adults. The purpose of this study was to identify a characteristic magnetic resonance imaging (MRI) pattern during the outbreak of a novel mutation of Escherichia coli O104:H4. METHODS: Patients were recruited from two hospitals between May and July 2011. The MRI protocol included standard anatomical, diffusion-weighted, and susceptibility-sensitive sequences. RESULTS: A total of 104 MRIs of 57 (32 female, 25 male) patients (mean 45.5 ± 18.4 years) showed abnormal signal intensity on 51 MRIs (49 %). Bilateral thalamus (39 %), bilateral pons (35 %), centrum semiovale and splenium of corpus callosum (33 %) were most often involved. Acute lesions were reversible in 81 % of cases. There was no statistically significant association between symptom onset and the MRI findings (P = 0.2). CONCLUSIONS: Neuroimaging findings in this adult patient cohort were non-specific and similar to previous findings in children. A characteristic neuroimaging pattern of an infection with Escherichia coli O104:H4 was not identified. However, bilateral symmetric T2 hyperintense lesions of the thalami and dorsal pons characterized by restricted diffusion suggest a metabolic toxic effect of the disease on the brain.

Reversible, irreversible and effective transverse relaxation rates in normal aging brain at 3T.

Quantitative transverse relaxation rates in normal aging brain are essential to investigate pathologies associated with iron accumulation and tissue degeneration. Since absolute values depend on imaging methods and magnetic field strengths, continuous evaluation of specific reference values remains requisite. Multi-echo turbo spin echo and multi-echo gradient recalled echo imaging sequences were applied to 66 healthy subjects (18-84years) at 3T to quantify the irreversible (R2), effective (R2*) and reversible (R2'=R2*-R2) transverse relaxation rates. Representative regions-of-interest (ROIs) were determined automatically in gray matter (GM) and white matter (WM) on T1-weighted scans. Phantom experiments of different sized iron-oxide particles were conducted to explore the correlation of R2' related to R2 for the evaluation of the size of iron deposits. R2 decreased with age for the majority of ROIs, but increased for putamen, head of caudate nucleus and nucleus accumbens. R2* and R2' increased with age in deep GM structures except for the thalamus. R2* and R2' showed a distinct dependency on fiber orientation in exemplary WM regions. R2', R2 and R2* were strongly linear proportional to age-related iron content in deep GM with slopes of 0.88, 0.18 and 1.08 in [1/s/mg Fe per 100g wet tissue] and intercepts of 1.69, 9.25 and 10.69 in [1/s], respectively. Linear and non-linear curve fitting of R2' vs. R2 in phantoms revealed increased slopes with increasing particle size. In vivo, averaged R2' vs. R2 data points of patients with Parkinson's disease and progressive supranuclear palsy were above the fitted curves of healthy subjects suggesting larger sized iron deposits in these neurodegenerative diseases. Decreased R2 with age may reflect physiological tissue degeneration, whereas increased R2* and R2' with age most likely denote physiological iron accumulation. The low intercept of R2' vs. iron content suggests a nearly sole sensitivity of R2' to iron in deep GM, potentially allowing a more specific estimation of the iron content than R2 or R2*. Since R2* and R2' depend on the fiber orientation, their feasibility to estimate iron content in WM is challenging. The analysis of R2' related to R2 may provide valuable information about the size of iron deposits.

Quantitative t2 measurements in juvenile and late infantile neuronal ceroid lipofuscinosis.

PURPOSE: The two most prevalent forms of neuronal ceroid lipofuscinosis (NCL) are the juvenile form (Batten disease, CLN3) and late infantile form (Jansky-Bielschowsky disease, CLN2). The aim of this study was to compare quantitative T2-values of brain tissue in CLN2 and CLN3 patients with reference values from age-matched normal subjects. METHODS: Twenty-three CLN2 (n = 6) and CLN3 (n = 17) patients (m:f = 11:12) underwent MRI examination including a multiecho T2 sequence. Quantitative T2-values were measured in six defined regions of interest (ROIs) in the calculated quantitative T2 maps within the white matter (WM) and gray matter (GM). The extracted quantitative T2-values were compared with reference values from healthy children and young adults. Informed consent was obtained from the patients or their parents for all patients. RESULTS: Statistical analysis revealed elevated quantitative T2-values in nearly all ROIs placed in the WM of the CLN2 patients. In contrast to this finding, no significant differences were found for the quantitative T2-values of the CLN3 patients compared to the age-matched healthy controls in any of the defined WM ROIs. Both groups exhibited no significant alterations of the quantitative T2-values in the GM ROIs compared to the healthy subjects. CONCLUSION: Alterations of quantitative T2-values in the cerebral WM may not be a reliable sign to confirm the diagnosis in CLN3 patients but could prove valuable for diagnosis confirmation, follow-up examinations, and longitudinal monitoring of the disease progression in CLN2 patients.

Cerebral neoplasms in L-2 hydroxyglutaric aciduria: 3 new cases and meta-analysis of literature data.

SUMMARY: Increasing evidence suggests that patients with L2-HGA have a predisposition to cerebral neoplasms. This may be related to the pathologic accumulation of L2-HG because high amounts of 2-HG have been found in brain neoplasms that have IDH1 mutations. Our experience, on the basis of 11 previously unreported cases of L2-HGA, 3 of which developed cerebral neoplasms during the course of the disease, also supports an association between L2-HGA and cerebral neoplasms. We conducted a meta-analysis of published data, and we identified 295 patients (including our 11 patients) with L2-HGA. In 14 patients, the metabolic disorder was associated with cerebral neoplasms, suggesting an approximately 5% prevalence rate of CNS neoplasms in patients with L2-HGA; nonetheless, it may still be an underestimate. L2-HGA is an important disease "model" that provides further evidence to support the recently proposed pathogenetic role of 2-HG in the development of cerebral neoplasms.

Quantitative diffusion-weighted and dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging analysis of T2 hypointense lesion components in pediatric diffuse intrinsic pontine glioma.

BACKGROUND AND PURPOSE: Focal anaplasia characterized by T2 hypointensity, signal-intensity enhancement on postcontrast T1-weighted MR imaging and restricted water diffusion has been reported in a patient with juvenile pilocytic astrocytoma. We identified T2(HOF) with these MR imaging characteristics in children with DIPG and hypothesized that these represent areas of focal anaplasia; and may, therefore, have increased perfusion properties and should be characterized by increased perfusion. Thus, we used DSC to investigate our hypothesis. MATERIALS AND METHODS: We retrospectively reviewed the baseline MR imaging scans of 86 patients (49 girls, 37 boys; median age, 6.1 years; range, 1.1-17.6 years) treated for DIPG at our hospital (2004-2009). T2(HOF) with the described MR imaging characteristics was identified in 10 patients. We used a region of interest-based approach to compare the ADC, FA, rCBV, rCBF, and rMTT of T2(HOF) with those of the typical T2(HRT). RESULTS: The ADC of T2(HOF) with the specified MR imaging characteristics was significantly lower than that of T2(HRT) (range, 0.71-1.95 µm(2)/ms versus 1.36-2.13 µm(2)/ms; P < .01); and the FA (range, 0.12-0.34 versus 0.07-0.24; P = .03) and rCBV (range, 0.4-2.62 versus 0.23-1.57; P = .01) values of T2(HOF)s were significantly higher. CONCLUSIONS: Our data suggest that T2(HOF) in DIPG may represent areas of focal anaplasia and underline the importance of regional, rather than global, tumor-field analysis. T2(HOF) may be the ideal target when stereotactic biopsy of tumors that present with an inhomogeneous T2 signal intensity is considered.

Attenuation of cerebral venous contrast in susceptibility-weighted imaging of spontaneously breathing pediatric patients sedated with propofol.

BACKGROUND AND PURPOSE: SWI is known for its detailed visualization of the cerebral venous system and seems to be a promising tool for early detection of cerebrovascular pathologies in children, who are frequently sedated for MR imaging. Because sedation influences cerebral hemodynamics, we hypothesized that it would affect cerebral venous contrast in SWI. MATERIALS AND METHODS: SWI (125 examinations) of 26 patients (age, 2-16 years) was reviewed in this study. Images were acquired of patients sedated with propofol. Reviewers classified the images by weak or strong venous contrast. Physiologic data, such as etCO(2), BP, age, and CBF by arterial spin-labeling, were monitored and collected during MR imaging. A generalized estimating equation approach was used to model associations of these parameters with venous contrast. RESULTS: EtCO(2) and CBF were found to correlate with venous contrast, suggesting that patients with high etCO(2) and CBF have weak contrast and patients with low etCO(2) and CBF have strong contrast. BP was also found to correlate with the venous contrast of SWI, suggesting that patients with high BP have strong venous contrast. No significant correlations were found for any other physiologic parameters. CONCLUSIONS: We found that the venous contrast in SWI is affected by propofol sedation in spontaneously breathing patients. We also found that low etCO(2), low CBF, and high BP are associated with strong venous contrast. Reviewing SWI data in light of physiologic measures may therefore help prevent potential misinterpretations of weak venous contrast in SWI examinations under propofol sedation.

Cerebellocerebral diaschisis is the likely mechanism of postsurgical posterior fossa syndrome in pediatric patients with midline cerebellar tumors.

BACKGROUND AND PURPOSE: PFS occurs in approximately 25% of pediatric patients receiving surgery for midline posterior fossa tumors. Increasing evidence suggests that PFS represents a complex supratentorial cortical dysfunction related to surgery-induced disruption of critical cerebellocerebral connections. The purpose of this study was to determine whether a consistent surgical damage pattern may be identified in patients with PFS by early postoperative anatomic imaging analysis of the pECP and to test whether DSC can detect corresponding changes in cerebral cortical perfusion to indicate a secondary, remote functional disturbance, which could suggest a diaschisis-like pathomechanism. MATERIALS AND METHODS: Eleven patients with postoperative PFS were evaluated retrospectively and were paired with age- and sex-matched control subjects in whom PFS did not develop. MR imaging work-up included DSC within 3 to 4 weeks after surgery as well as early postoperative anatomic imaging to evaluate components of the pECP. RESULTS: DSC showed significant decreases in CBF within frontal regions (P < .05) and a trend to global cerebral cortical hypoperfusion in patients with PFS. Logistic regression analysis suggested a strong (potentially predictive) relationship between bilateral damage to pECP and the development of PFS (P = .04). CONCLUSIONS: Our data suggest that the primary cause of PFS is the bilateral surgical damage to the pECP. This leads to a trans-synaptic cerebral cortical dysfunction (a form of bilateral crossed cerebellocerebral diaschisis), which manifests with DSC-detectable global, but dominantly frontal, cortical hypoperfusion in patients with patients with PFS compared with age- and sex-matched control subjects.