Optic Nerve T2 Signal Intensity and Caliber Reflect Clinical Severity in Genetic Optic Atrophy.

BACKGROUND: Genetic optic atrophies comprise phenotypically heterogenous disorders of mitochondrial function. We aimed to correlate quantitative neuroimaging findings of the optic nerves in these disorders with clinical measures. METHODS: From a retrospective database of 111 patients with bilateral optic atrophy referred for genetic testing, 15 patients diagnosed with nonglaucomatous optic atrophy of genetic origin (7 patients with pathogenic variants in OPA1, 3 patients with Wolfram syndrome, and 5 patients with Leber hereditary optic neuropathy) who had accessible magnetic resonance (MR) images of the orbits and/or brain were analyzed. The primary outcome measures of T2 short Tau inversion recovery (STIR) signal and optic nerve caliber were quantified according to a standardized protocol, normalized to internal standards, and compared between cases and controls. Inter-rater reliability was assessed and clinical features were analyzed according to MRI features. RESULTS: Compared with control patients, the 15 genetic optic atrophy patients demonstrated significantly increased T2 STIR signal (fold-change 1.6, P = 0.0016) and decreased optic nerve caliber (fold-change 0.72, P = 0.00012) after internal normalization. These metrics were reliable (inter-reader reliability correlation coefficients of 0.98 [P = 0.00036] and 0.74 [P = 0.0025] for normalized STIR and nerve caliber, respectively) and significantly correlated with visual acuity, cup-to-disc ratio, and visual field testing. CONCLUSION: Normalized optic nerve STIR signal and optic nerve caliber significantly correlate with visual acuity, cup-to-disc ratio, and perimetric performance in patients with genetic optic atrophy. A formalized protocol to characterize these differences on MRI may help to guide accurate and expedient diagnostic evaluation.

Monogenic Causes of Cerebrovascular Disease in Childhood: A Case Series.

BACKGROUND: Despite an increase in the number of genes associated with pediatric stroke, imaging phenotypes in children have not been well reported. Guidelines are needed to facilitate the identification and treatment of patients with monogenic causes of cerebrovascular disorders. METHODS: We performed a retrospective review of imaging and medical records of patients aged zero to 21 years with monogenic causes of vascular malformations, small or large vessel disease, transient ischemic attacks, and/or ischemic or hemorrhagic stroke. We classified patients according to their imaging phenotype and reviewed neurological and systemic features and management strategies. We reviewed the literature to identify genes associated with cerebrovascular disorders presenting in childhood. RESULTS: We identified 18 patients with monogenic causes of cerebrovascular disorders and classified each patient as belonging to one or more of three cerebrovascular phenotypes according to predominant imaging characteristics: small vessel disease, large vessel disease, and/or vascular malformations. Preventative treatments included aspirin, N-acetylcysteine, tocilizumab, therapeutic low-molecular-weight heparin, and resection of vascular malformations. CONCLUSIONS: Classifying pediatric patients with cerebrovascular disorders by imaging phenotype can aid in determining the next steps in genetic testing and treatment.

Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy.

Blood-brain barrier disruption marks the onset of cerebral adrenoleukodystrophy (CALD), a devastating cerebral demyelinating disease caused by loss of ABCD1 gene function. The underlying mechanism are not well understood, but evidence suggests that microvascular dysfunction is involved. We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation. We found widespread and sustained normalization of white matter permeability and microvascular flow. We demonstrate that ABCD1 functional bone marrow-derived cells can engraft in the cerebral vascular and perivascular space. Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects.

A description of novel variants and review of phenotypic spectrum in UBA5-related early epileptic encephalopathy.

Early infantile epileptic encephalopathy-44 (EIEE44, MIM: 617132) is a previously described condition resulting from biallelic variants in UBA5, a gene involved in a ubiquitin-like post-translational modification system called UFMylation. Here we report five children from four families with biallelic pathogenic variants in UBA5 All five children presented with global developmental delay, epilepsy, axial hypotonia, appendicular hypertonia, and a movement disorder, including dystonia in four. Affected individuals in all four families have compound heterozygous pathogenic variants in UBA5 All have the recurrent mild c.1111G > A (p.Ala371Thr) variant in trans with a second UBA5 variant. One patient has the previously described c.562C > T (p. Arg188*) variant, two other unrelated patients have a novel missense variant, c.907T > C (p.Cys303Arg), and the two siblings have a novel missense variant, c.761T > C (p.Leu254Pro). Functional analyses demonstrate that both the p.Cys303Arg variant and the p.Leu254Pro variants result in a significant decrease in protein function. We also review the phenotypes and genotypes of all 15 previously reported families with biallelic UBA5 variants, of which two families have presented with distinct phenotypes, and we describe evidence for some limited genotype-phenotype correlation. The overlap of motor and developmental phenotypes noted in our cohort and literature review adds to the increasing understanding of genetic syndromes with movement disorders-epilepsy.

Predictors of Anesthetic Exposure in Pediatric MRI.

BACKGROUND. Anesthetic exposure in children may impact long-term neurocognitive outcomes. Therefore, minimizing pediatric MRI scan time in children under anesthesia and the associated anesthetic exposure is necessary. OBJECTIVE. The purpose of this study was to evaluate pediatric MRI scan time as a predictor of total propofol dose, considering imaging and clinical characteristics as covariates. METHODS. Electronic health records were retrospectively searched to identify MRI examinations performed from 2016 to 2019 in patients 0-18 years old who received propofol anesthetic. Brain; brain and spine; brain and abdomen; and brain, head, and neck MRI examinations were included. Demographic, clinical, and imaging data were extracted for each examination, including anesthesia maintenance phase time, MRI scan time, and normalized propofol dose. MRI scan time and propofol dose were compared between groups using a t test. A multiple linear regression with backward selection (threshold, p < .05) was used to evaluate MRI scan time as a predictor of total propofol dose, adjusting for sex, age, time between scan and study end, body part, American Society of Anesthesiologists (ASA) classification, diagnosis, magnet strength, and IV contrast medium administration as covariates. RESULTS. A total of 501 examinations performed in 426 patients (172 girls, 254 boys; mean age, 6.55 ± 4.59 [SD] years) were included. Single body part examinations were shorter than multiple body part examinations (mean, 52.7 ± 18.4 vs 89.3 ± 26.4 minutes) and required less propofol (mean, 17.7 ± 5.7 vs 26.1 ± 7.7 mg/kg; all p < .001). Among single body part examinations, a higher ASA classification, oncologic diagnosis, 1.5-T magnet, and IV contrast medium administration were associated with longer MRI scan times (all p ≤ .009) and higher propofol exposure (all p ≤ .005). In multivariable analysis, greater propofol exposure was predicted by MRI scan time (mean dose per minute of examination, 0.178 mg/kg; 95% CI, 0.155-0.200; p < .001), multiple body part examination (p = .04), and IV contrast medium administration (p = .048); lower exposure was predicted by 3-T magnet (p = .04). CONCLUSION. Anesthetic exposure during pediatric MRI can be quantified and predicted based on imaging and clinical variables. CLINICAL IMPACT. This study serves as a valuable baseline for future efforts to reduce anesthetic doses and scan times in pediatric MRI.

Clinical and radiographic course of arrested cerebral adrenoleukodystrophy.

OBJECTIVE: To gain insight into the natural history of arrested cerebral adrenoleukodystrophy (CALD) by quantifying the change in Neurologic Function Score (NFS) and Loes Score (LS) over time in patients whose cerebral lesions spontaneously stopped progressing. METHODS: We retrospectively reviewed a series of 22 patients with arrested CALD followed longitudinally over a median time of 2.4 years (0.7-17.0 years). Primary outcomes were change in radiographic disease burden (measured by LS) and clinical symptoms (measured by NFS) between patients who never developed a contrast-enhancing lesion (gadolinium enhancement (GdE)- subgroup) and those who did (GdE+ subgroup). Secondary analyses comparing patterns of neuroanatomic involvement and lesion number, and prevalence estimates, were performed. RESULTS: Cerebral lesions were first detected at a median age of 23.3 years (8.0-67.6 years) with an initial LS of 4 (0.5-9). NFS was 0.5 (0-6). Overall change in NFS or LS per year did not differ between subgroups. No patients who remained GdE- converted to a progressive CALD phenotype. The presence of contrast enhancement was associated with disease progression (r s = 0.559, p < 0.001). Four patients (18.2%) underwent step-wise progression, followed by spontaneous resolution of contrast enhancement and rearrest of disease. Three patients (13.6%) converted to progressive CALD. Nineteen patients (86.4%) had arrested CALD at the most recent follow-up. The prevalence of arrested CALD is 12.4%. CONCLUSION: Arrested CALD lesions can begin in childhood, and patients are often asymptomatic early in disease. The majority of patients remain stable. However, clinical and MRI surveillance is recommended because a minority of patients undergo step-wise progression or conversion to progressive CALD.

Congenital nasal piriform aperture atresia: A case report and novel finding.

Congenital nasal piriform aperture stenosis and choanal atresia are types of nasal obstructions that can be life threatening to infants if left untreated. While there has been numerous reports on both of them there has not been a single reported case of congenital nasal piriform aperture atresia. Here, we present the first case of piriform aperture atresia that includes the diagnostic and clinical approach.

The efficacy of cannabidiol on renal angiomyolipoma and subependymal giant cell tumor volume in tuberous sclerosis complex.

In patients with tuberous sclerosis complex (TSC) the upregulation of the mechanistic target of rapamycin (mTOR) pathway leads to the development and growth of subependymal giant cell tumors (SGCTs) and renal angiomyolipomas (AMLs). Drugs that inhibit the mTOR pathway, such as sirolimus, can reduce the size of both SGCTs and AMLs. Recent preclinical studies have suggested cannabidiol (CBD) may mediate the mTOR pathway, however, its exact effects are unclear. This study examines the volumes of SGCTs and renal AMLs in patients with TSC during treatment with purified CBD for refractory epilepsy. We retrospectively reviewed the medical records of patients with TSC with radiological evidence of AMLs and SGCTs who were being treated with plant-derived highly purified CBD in oral solution (Epidiolex®, GW Research Ltd) for refractory epilepsy at Massachusetts General Hospital. Patients who had surgical intervention for AMLs or SGCTS, and patients who had been treated with mTOR inhibitors were excluded. The volumes of SGCTs and dominant renal AML were measured before and after CBD initiation using abdominal and brain scans and compared. Patient demographics and CBD doses were collected from medical records. Six out of the seven dominant renal AMLs and three out of the three SGCTs increased in volume during CBD treatment. One AML had a decrease in volume after CBD initiation which was not considered significant. The results suggest that unlike mTOR inhibitors, CBD treatment does not decrease the volume of SGCTs or AMLs in TSC patients.

Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy.

Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.

MRI brain lesions in asymptomatic boys with X-linked adrenoleukodystrophy.

OBJECTIVE: To describe the brain MRI findings in asymptomatic patients with childhood cerebral adrenoleukodystrophy (CCALD). METHODS: We retrospectively reviewed a series of biochemically or genetically confirmed cases of adrenoleukodystrophy followed at our institution between 2001 and 2015. We identified and analyzed 219 brain MRIs from 47 asymptomatic boys (median age 6.0 years). Patient age, MRI scan, and brain lesion characteristics (e.g., contrast enhancement, volume, and Loes score) were recorded. The rate of lesion growth was estimated using a linear mixed effect model. RESULTS: Sixty percent of patients (28/47) showed brain lesions (median Loes score of 3.0 points; range 0.5-11). Seventy-nine percent of patients with CCALD (22/28) had contrast enhancement on first lesional or subsequent MRI. Lesion progression (Loes increase of ≥0.5 point) was seen in 50% of patients (14/28). The rate of lesion growth (mL/mo) was faster in younger patients (r = -0.745; p < 0.0001). Older patients (median age 14.4 y/o) tended to undergo spontaneous arrest of disease. Early lesions grew 46× faster when still limited to the splenium, genu of the corpus callosum, or the brainstem (p = 0.001). CONCLUSION: We provide a description of CCALD lesion development in a cohort of asymptomatic boys. Understanding the early stages of CCALD is crucial to optimize treatments for children diagnosed by newborn screening.

Chiari malformations: An important cause of pediatric aspiration.

Chronic aspiration poses a major health risk to the pediatric population. We describe four cases in which work up for chronic aspiration with a brain MRI revealed a Chiari I malformation, a poorly described etiology of pediatric aspiration. All patients had at least one non-specific neurologic symptom but had swallow studies more characteristic of an anatomic than a neurologic etiology. Patients were referred to neurosurgery and underwent posterior fossa decompression with symptom improvement. A high index of suspicion for Chiari malformation should be maintained when the standard work up for aspiration is non-diagnostic, particularly when non-specific neurologic symptoms are present.

CSF1R mosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids.

Mutations in the colony stimulating factor 1 receptor (CSF1R) have recently been discovered as causal for hereditary diffuse leukoencephalopathy with axonal spheroids. We identified a novel, heterozygous missense mutation in CSF1R [c.1990G > A p.(E664K)] by exome sequencing in five members of a family with hereditary diffuse leukoencephalopathy with axonal spheroids. Three affected siblings had characteristic white matter abnormalities and presented with progressive neurological decline. In the fourth affected sibling, early progression halted after allogeneic haematopoietic stem cell transplantation from a related donor. Blood spot DNA from this subject displayed chimerism in CSF1R acquired after haematopoietic stem cell transplantation. Interestingly, both parents were unaffected but the mother's blood and saliva were mosaic for the CSF1R mutation. Our findings suggest that expression of wild-type CSF1R in some cells, whether achieved by mosaicism or chimerism, may confer benefit in hereditary diffuse leukoencephalopathy with axonal spheroids and suggest that haematopoietic stem cell transplantation might have a therapeutic role for this disorder.

The Use of Magnetic Resonance Spectroscopy in the Evaluation of Pediatric Patients With Seizures.

BACKGROUND: The objective was to determine if it is useful to routinely add magnetic resonance spectroscopy (MRS) to magnetic resonance imaging (MRI) in the evaluation of seizure in the pediatric patient. Specifically, how often does MRS contribute information to conventional MRI? METHODS: A retrospective search, over a period of 3 years, of patients <18 years of age who underwent both MRI and MRS as part of the evaluation of seizures yielded a total of 233 cases in 216 patients. The medical records were reviewed to determine how many patients carried a diagnosis relevant to seizures. The MRIs and MRSs were reviewed by two neuroradiologists and an MR physicist/spectroscopist who determined by consensus in how many cases MRS contributed information regarding management, diagnosis, or prognosis, in addition to the findings on MRI alone. RESULTS: In 100 of 233 cases (43%), MRS contributed information additional to MRI. In 40 cases, MRS contributed information relevant to patient management by prompting an evaluation for an underlying inborn error of metabolism. MRS contributed information relevant to diagnosis in 24 of 100 cases (e.g., neoplasm versus dysplasia). MRS contributed information relevant to prognosis in 36 cases (e.g., hypoxic-ischemic injury). MRS added more information in cases where the patients had a diagnosis relevant to seizure before imaging. Interestingly, in 25 cases where the MRI was normal, MRS was found to be abnormal, which prompted evaluation for an inborn error of metabolism. CONCLUSIONS: These results suggest that MRS is a useful evaluation tool in addition to MRI for children undergoing imaging for the evaluation of seizures.

Incidence of CNS Injury for a Cohort of 111 Patients Treated With Proton Therapy for Medulloblastoma: LET and RBE Associations for Areas of Injury.

BACKGROUND: Central nervous system (CNS) injury is a rare complication of radiation therapy for pediatric brain tumors, but its incidence with proton radiation therapy (PRT) is less well defined. Increased linear energy transfer (LET) and relative biological effectiveness (RBE) at the distal end of proton beams may influence this risk. We report the incidence of CNS injury in medulloblastoma patients treated with PRT and investigate correlations with LET and RBE values. METHODS AND MATERIALS: We reviewed 111 consecutive patients treated with PRT for medulloblastoma between 2002 and 2011 and selected patients with clinical symptoms of CNS injury. Magnetic resonance imaging (MRI) findings for all patients were contoured on original planning scans (treatment change areas [TCA]). Dose and LET distributions were calculated for the treated plans using Monte Carlo system. RBE values were estimated based on LET-based published models. RESULTS: At a median follow-up of 4.2 years, the 5-year cumulative incidence of CNS injury was 3.6% for any grade and 2.7% for grade 3+. Three of 4 symptomatic patients were treated with a whole posterior fossa boost. Eight of 10 defined TCAs had higher LET values than the target but statistically nonsignificant differences in RBE values (P=.12). CONCLUSIONS: Central nervous system and brainstem injury incidence for PRT in this series is similar to that reported for photon radiation therapy. The risk of CNS injury was higher for whole posterior fossa boost than for involved field. Although no clear correlation with RBE values was found, numbers were small and additional investigation is warranted to better determine the relationship between injury and LET.

The use of magnetic resonance spectroscopy in the evaluation of epilepsy.

Magnetic resonance spectroscopy (MRS) is indicated in the imaging protocol of the patient with epilepsy to screen for metabolic derangements such as inborn errors of metabolism and to characterize masses that may be equivocal on conventional magnetic resonance imaging for dysplasia versus neoplasia. Single-voxel MRS with echo time of 35 milliseconds may be used for this purpose as a quick screening tool in the epilepsy imaging protocol. MRS is useful in the evaluation of both focal and generalized epilepsy.