Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain abnormalities and changes in cognitive functioning.

The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5-22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12-point rating scale at multiple time points throughout follow-up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U-fibers. We found a significant decline (p < 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (p = 0.17). Each point increment in the 12-point MRI rating scale was associated with a significant decline (3.1-6.0 points) in all the IQ index scores (p < 0.05). The majority of long-term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood-brain barrier in order to treat this CNS phenotype.

Brain volume in infants with metopic synostosis: Less white matter volume with an accelerated growth pattern in early life.

Metopic synostosis patients are at risk for neurodevelopmental disorders despite a negligible risk of intracranial hypertension. To gain insight into the underlying pathophysiology of metopic synostosis and associated neurodevelopmental disorders, we aimed to investigate brain volumes of non-syndromic metopic synostosis patients using preoperative MRI brain scans. MRI brain scans were processed with HyperDenseNet to calculate total intracranial volume (TIV), total brain volume (TBV), total grey matter volume (TGMV), total white matter volume (TWMV) and total cerebrospinal fluid volume (TCBFV). We compared global brain volumes of patients with controls corrected for age and sex using linear regression. Lobe-specific grey matter volumes were assessed in secondary analyses. We included 45 metopic synostosis patients and 14 controls (median age at MRI 0.56 years [IQR 0.36] and 1.1 years [IQR 0.47], respectively). We found no significant differences in TIV, TBV, TGMV or TCBFV in patients compared to controls. TWMV was significantly smaller in patients (-62,233 mm3 [95% CI = -96,968; -27,498], Holm-corrected p = 0.004), and raw data show an accelerated growth pattern of white matter in metopic synostosis patients. Grey matter volume analyses per lobe indicated increased cingulate (1378 mm3 [95% CI = 402; 2355]) and temporal grey matter (4747 [95% CI = 178; 9317]) volumes in patients compared to controls. To conclude, we found smaller TWMV with an accelerated white matter growth pattern in metopic synostosis patients, similar to white matter growth patterns seen in autism. TIV, TBV, TGMV and TCBFV were comparable in patients and controls. Secondary analyses suggest larger cingulate and temporal lobe volumes. These findings suggest a generalized intrinsic brain anomaly in the pathophysiology of neurodevelopmental disorders associated with metopic synostosis.

A diffusion tensor imaging analysis of white matter microstructures in non-operated craniosynostosis patients.

PURPOSE: In 7 to 15-year-old operated syndromic craniosynostosis patients, we have shown the presence of microstructural anomalies in brain white matter by using DTI. To learn more about the cause of these anomalies, the aim of the study is to determine diffusivity values in white matter tracts in non-operated syndromic craniosynostosis patients aged 0-2 years compared to healthy controls. METHODS: DTI datasets of 51 non-operated patients with syndromic craniosynostosis with a median [IQR] age of 0.40 [0.25] years were compared with 17 control subjects with a median of 1.20 [0.85] years. Major white matter tract pathways were reconstructed with ExploreDTI from MRI brain datasets acquired on a 1.5 T MRI system. Eigenvalues of these tract data were examined, with subsequent assessment of the affected tracts. Having syndromic craniosynostosis (versus control), gender, age, frontal occipital horn ratio (FOHR), and tract volume were treated as independent variables. RESULTS: ʎ2 and ʎ3 of the tracts genu of the corpus callosum and the hippocampal segment of the cingulum bundle show a ƞ2 > 0.14 in the comparison of patients vs controls, which indicates a large effect on radial diffusivity. Subsequent linear regressions on radial diffusivity of these tracts show that age and FOHR are significantly associated interacting factors on radial diffusivity (p < 0.025). CONCLUSION: Syndromic craniosynostosis shows not to be a significant factor influencing the major white matter tracts. Enlargement of the ventricles show to be a significant factor on radial diffusivity in the tracts corpus callosum genu and the hippocampal segment of the cingulate bundle. CLINICAL TRIAL REGISTRATION: MEC-2014-461.

Presymptomatic treatment of classic late-infantile neuronal ceroid lipofuscinosis with cerliponase alfa.

BACKGROUND: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare rapidly progressive neurodegenerative disorder, resulting in early death. Intracerebroventricular enzyme replacement therapy (ERT) with cerliponase alfa is now available and has shown to delay disease progression in symptomatic patients. It is yet unknown if cerliponase alfa can prevent disease onset in presymptomatic patients. RESULTS: We evaluated the effect of 2 years of intracerebroventricular ERT in two siblings with CLN2 disease, one symptomatic (age 47 months) and one presymptomatic (age 23 months) at treatment start, using the CLN2 Clinical Rating Scale (CLN2 CRS), Gross Motor Function Measure-66 (GMFM-66) for motor function, Bayley Scales of Infant and Toddler Development, 3rd Edition, Dutch (BSID-III-NL) for neurocognitive development, brain MRI, and visual evoked potentials (VEP), electroretinogram (ERG) and retinoscopy for visual function. On the CLN2 CRS patient 1 showed a decline from 3 to 2 in the combined motor and language score due to regression in language use (CLN2 CRS total score after 2 years of treatment: 8), whereas a decline of 2 or more points in the combined motor and language score would be expected without treatment. Patient 2 retained the maximum score of 3 in all 4 subdomains (CLN2 CRS total score after 2 years of treatment: 12). The GMFM-66 total score declined from 46 to 39 in patient 1 and showed an age-appropriate increase from 66 to 84 in patient 2. Cognitive-developmental age decreased from 24 to 11 months in patient 1, whereas an increase in cognitive-developmental age from 21 to 39 months was seen in patient 2. Cerebral and cerebellar atrophy observed on MRI in patient 1 at age 42 months (before treatment) was not observed in patient 2 at age 48 months (after 2 years of treatment). CONCLUSION: We show that cerliponase alfa is able to delay the onset of symptoms when treatment is started in a presymptomatic stage of CLN2 disease. Our results advocate the start of treatment at an early age before symptom onset, but should be confirmed in a larger cohort study.

Cervical Spinal Cord Compression and Sleep-Disordered Breathing in Syndromic Craniosynostosis.

BACKGROUND AND PURPOSE: Cerebellar tonsillar herniation arises frequently in syndromic craniosynostosis and causes central and obstructive apneas in other diseases through spinal cord compression. The purposes of this study were the following: 1) to determine the prevalence of cervical spinal cord compression in syndromic craniosynostosis, and 2) to evaluate its connection with sleep-disordered breathing. MATERIALS AND METHODS: This was a cross-sectional study including patients with syndromic craniosynostosis who underwent MR imaging and polysomnography. Measures encompassed the compression ratio at the level of the odontoid process and foramen magnum and the cervicomedullary angle. MR imaging studies of controls were included. Linear mixed models were developed to compare patients with syndromic craniosynostosis with controls and to evaluate the association between obstructive and central sleep apneas and MR imaging parameters. RESULTS: One hundred twenty-two MR imaging scans and polysomnographies in 89 patients were paired; 131 MR imaging scans in controls were included. The mean age at polysomnography was 5.7 years (range, 0.02-18.9 years). The compression ratio at the level of the odontoid process was comparable with that in controls; the compression ratio at the level of the foramen magnum was significantly higher in patients with Crouzon syndrome (+27.1, P < .001). The cervicomedullary angle was significantly smaller in Apert, Crouzon, and Saethre-Chotzen syndromes (-4.4°, P = .01; -10.2°, P < .001; -5.2°, P = .049). The compression ratios at the level of the odontoid process and the foramen magnum, the cervicomedullary angle, and age were not associated with obstructive apneas (P > .05). Only age was associated with central apneas (P = .02). CONCLUSIONS: The prevalence of cervical spinal cord compression in syndromic craniosynostosis is low and is not correlated to sleep disturbances. However, considering the high prevalence of obstructive sleep apnea in syndromic craniosynostosis and the low prevalence of compression and central sleep apnea in our study, we would, nevertheless, recommend a polysomnography in case of compression on MR imaging studies.

Neurological deficits are present in syndromic craniosynostosis patients with and without tonsillar herniation.

BACKGROUND: Children with syndromic craniosynostosis (sCS) have a higher incidence of cerebellar tonsillar herniation (TH) than the general population. In the general population, TH ≥ 5 mm below the foramen magnum is associated with typical neurological deficits but, in sCS, we do not know whether this degree of TH is required before such deficits occur. OBJECTIVE: This prospective cohort study aimed to determine the association between findings on neurological assessment and cerebellar tonsillar position. METHODS: Magnetic resonance imaging (MRI) was used to determine TH ≥ 5 mm and the presence of syringomyelia. In regard to the outcome of neurological deficits, these were categorized according to: A, cerebellar function; B, cranial nerve abnormalities; and C, sensory or motor dysfunction. RESULTS: Twenty of 63 patients with sCS (32% [95% confidence interval 21-45%]) had TH ≥ 5 mm and/or syringomyelia. There was no significant difference in proportion between individual forms of sCS: 16/34 Crouzon, 2/11 Muenke, 2/12 Apert, and 0/7 Saethre-Chotzen patients. Neurological deficits were prevalent (73% [95% confidence interval 60-83%]), and as frequent in patients with TH ≥ 5 mm and/or syringomyelia as those without. Surgery occurred in 3 patients overall, and only in Crouzon patients. CONCLUSION: Determining the effect of TH ≥ 5 mm on neurologic functioning in sCS patients is used to better determine when surgical intervention is warranted. However, we have found that neurological deficits are prevalent in sCS patients, irrespective of cerebellar tonsillar position, suggesting that such findings are developmental and, in part, syndrome-specific central nervous system features.

Cavum Septum Pellucidum in the General Pediatric Population and Its Relation to Surrounding Brain Structure Volumes, Cognitive Function, and Emotional or Behavioral Problems.

BACKGROUND AND PURPOSE: The cavum septum pellucidum, a cavity filled with CSF, is localized between the 2 lateral ventricles of the brain. The cavum is present in all neonates, but it typically closes within 5 months after birth. In some cases, this closure does not occur and a persistent or enlarged cavum septum pellucidum has been linked, in some studies, to psychiatric disorders. However, the clinical relevance in the general population is unknown. In this study, we examined the relationship between the cavum septum pellucidum and volumes of brain structures, cognitive function, and emotional and behavioral problems in children. MATERIALS AND METHODS: This study was embedded in the Generation R Study, a prospective cohort in Rotterdam, the Netherlands. MR imaging studies of 1070 children, 6-10 years of age, were systematically evaluated for the presence and length of a persistent cavum septum pellucidum. An enlarged cavum septum pellucidum was defined as a cavum length of ≥6 mm. Groups without, with persistent, and with enlarged cavum septi pellucidi were compared for brain structure volumes, nonverbal intelligence, and emotional and behavioral problems. RESULTS: The prevalence of cavum septi pellucidi in our sample was 4.6%. Children with an enlarged cavum septum pellucidum had a larger corpus callosum, greater thalamic and total white matter-to-total brain volume ratio, and smaller lateral ventricle volumes. We did not find a relationship between cavum septi pellucidi and cognitive function or emotional and behavioral problems. CONCLUSIONS: The cavum septum pellucidum is a normal structural brain variation without clinical implications in this population-based sample of school-aged children.

Does the Addition of a "Black Bone" Sequence to a Fast Multisequence Trauma MR Protocol Allow MRI to Replace CT after Traumatic Brain Injury in Children?

BACKGROUND AND PURPOSE: Head CT is the current neuroimaging tool of choice in acute evaluation of pediatric head trauma. The potential cancer risks of CT-related ionizing radiation should limit its use in children. We evaluated the role of MR imaging, including a "black bone" sequence, compared with CT in detecting skull fractures and intracranial hemorrhages in children with acute head trauma. MATERIALS AND METHODS: We performed a retrospective evaluation of 2D head CT and brain MR imaging studies including the black bone sequence of children with head trauma. Two experienced pediatric neuroradiologists in consensus created the standard of reference. Another pediatric neuroradiologist blinded to the diagnosis evaluated brain MR images and head CT images in 2 separate sessions. The presence of skull fractures and intracranial posttraumatic hemorrhages was evaluated. We calculated the sensitivity and specificity of CT and MR imaging with the black bone sequence in the diagnosis of skull fractures and intracranial hemorrhages. RESULTS: Twenty-eight children (24 boys; mean age, 4.89 years; range, 0-15.5 years) with head trauma were included. MR imaging with the black bone sequence revealed lower sensitivity (66.7% versus 100%) and specificity (87.5% versus 100%) in identifying skull fractures. Four of 6 incorrectly interpreted black bone MR imaging studies showed cranial sutures being misinterpreted as skull fractures and vice versa. CONCLUSIONS: Our preliminary results show that brain MR imaging complemented by a black bone sequence is a promising nonionizing alternative to head CT for the assessment of skull fractures in children. However, accuracy in the detection of linear fractures in young children and fractures of aerated bone remains limited.

The diagnostic accuracy of non-echo-planar diffusion-weighted imaging in the detection of residual and/or recurrent cholesteatoma of the temporal bone.

BACKGROUND AND PURPOSE: Non-EPI DWI is a promising alternative to second-look surgery for the detection of residual and/or recurrent cholesteatoma. We evaluated the diagnostic accuracy, expressed as a positive predictive value, of MR imaging for the detection of residual and/or recurrent cholesteatoma in our hospital. MATERIALS AND METHODS: Fifty-six MR imaging studies were performed from 2005 to 2010 in patients having previously undergone surgery for cholesteatoma. Pre- and postgadolinium T1-weighted, T2-weighted, and non-EPI DWI sequences were performed and correlated with clinical and intraoperative findings. Twenty-seven patients underwent second-look surgery; 7 were under close clinical follow-up. Twenty-two patients without evidence of cholesteatoma were under regular follow-up (range, 14-44 months). RESULTS: Non-EPI DWI sequences showed increased DW signal intensity in 36 patients. Of those, 27 had second-look surgery, confirming cholesteatoma in 25 patients; in 1 patient, an empyema was diagnosed, and in the other patient, no cholesteatoma was found at surgery. In 2 patients who had not undergone surgery, increased DW signal intensity was accompanied by hyperintense signal intensity on T1-weighted images, consistent with transplanted fat in the postoperative cavity. The positive predictive value for detection of cholesteatoma was 93% (25/27). CONCLUSIONS: Residual and/or recurrent cholesteatomas after primary cholesteatoma surgery can be accurately detected by increased DW signal intensity on non-EPI DWI. However, DWI without conventional sequences increased the risk of misdiagnosis in our patient setting because transplanted fat within the postoperative cavity may show increased DW signal intensity.