Linda Heier

Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA

Late infantile neuronal ceroid lipofuscinosis (LINCL) is an autosomal recessive, neurodegenerative lysosomal storage disease affecting the CNS and is fatal by age 8 to 12 years. A total average dose of 2.5 10(12) particle units of an adeno-associated virus (AAV) serotype 2 vector expressing the human CLN2 cDNA (AAV2 CU h-CLN2) was administered to 12 locations in the CNS of 10 children with LINCL. In addition to safety parameters, a neurological rating scale (primary variable) and three quantitative magnetic resonance imaging (MRI) parameters (secondary variables) were used to compare the rate of neurological decline for 18 months in treated subjects compared with untreated subjects. Although there were no unexpected serious adverse events that were unequivocally attributable to the AAV2 CU hCLN2 vector, there were serious adverse effects, the etiology of which could not be determined under the conditions of the experiment. One subject died 49 days postsurgery after developing status epilepticus on day 14, but with no evidence of CNS inflammation. Four of the 10 subjects developed a mild, mostly transient, humoral response to the vector. Compared with control subjects, the measured rates of decline of all MRI parameters were slower, albeit the numbers were too small for statistical significance. Importantly, assessment of the neurologic rating scale, which was the primary outcome variable, demonstrated a significantly reduced rate of decline compared with control subjects. Although the trial is not matched, randomized, or blinded and lacked a contemporaneous placebo/sham control group, assessment of the primary outcome variable suggests a slowing of progression of LINCL in the treated children. On this basis, we propose that additional studies to assess the safety and efficacy of AAV-mediated gene therapy for LINCL are warranted.

Possible axonal regrowth in late recovery from the minimally conscious state

We used diffusion tensor imaging (DTI) to study 2 patients with traumatic brain injury. The first patient recovered reliable expressive language after 19 years in a minimally conscious state (MCS); the second had remained in MCS for 6 years. Comparison of white matter integrity in the patients and 20 normal subjects using histograms of apparent diffusion constants and diffusion anisotropy identified widespread altered diffusivity and decreased anisotropy in the damaged white matter. These findings remained unchanged over an 18-month interval between 2 studies in the first patient. In addition, in this patient, we identified large, bilateral regions of posterior white matter with significantly increased anisotropy that reduced over 18 months. In contrast, notable increases in anisotropy within the midline cerebellar white matter in the second study correlated with marked clinical improvements in motor functions. This finding was further correlated with an increase in resting metabolism measured by PET in this subregion. Aberrant white matter structures were evident in the second patients DTI images but were not clinically correlated. We propose that axonal regrowth may underlie these findings and provide a biological mechanism for late recovery. Our results are discussed in the context of recent experimental studies that support this inference.

Multiagent Chemotherapy and Deferred Radiotherapy in Infants With Malignant Brain Tumors: A Report From the Children’s Cancer Group

PURPOSE To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Dissociations between behavioural and functional magnetic resonance imaging-based evaluations of cognitive function after brain injury

Functional neuroimaging methods hold promise for the identification of cognitive function and communication capacity in some severely brain-injured patients who may not retain sufficient motor function to demonstrate their abilities. We studied seven severely brain-injured patients and a control group of 14 subjects using a novel hierarchical functional magnetic resonance imaging assessment utilizing mental imagery responses. Whereas the control group showed consistent and accurate (for communication) blood-oxygen-level-dependent responses without exception, the brain-injured subjects showed a wide variation in the correlation of blood-oxygen-level-dependent responses and overt behavioural responses. Specifically, the brain-injured subjects dissociated bedside and functional magnetic resonance imaging-based command following and communication capabilities. These observations reveal significant challenges in developing validated functional magnetic resonance imaging-based methods for clinical use and raise interesting questions about underlying brain function assayed using these methods in brain-injured subjects.

Primary neurosurgery for pediatric low-grade gliomas: A prospective multi-institutional study from the children's oncology group

BACKGROUND:Central nervous system neoplasms are the most common solid tumors in children, and more than 40% are low-grade gliomas. Variable locations, extent of resection, postoperative neurodiagnostic evaluation, and histology have confounded therapy and outcome. OBJECTIVES:To investigate disease control and survival after surgery. METHODS:A prospective natural history trial from 1991 to 1996 produced a subset of patients with low-grade gliomas managed by primary surgery and subsequent observation. Patients were evaluable if eligibility, tumor location, and extent of resection were confirmed by pathological diagnosis, preoperative and postoperative imaging, and the surgeons report. Primary end points were overall survival (OS), progression-free survival (PFS), and postprogression survival. RESULTS:Of 726 patients enrolled, 518 were fully evaluable for analysis. The 5- and 8-year OS rates were 97% ± 0.8% and 96% ± 0.9%, respectively, and PFS rates were 80% ± 1.8% and 78% ± 2.0%. In univariate analyses, histological type, extent of residual tumor, and disease site were significantly associated with PFS and OS. In multivariate analysis, gross total resection (GTR) without residual disease was the predominant predictor of PFS. In patients with limited residual disease, 56% were free of progression at 5 years. CONCLUSION:GTR should be the goal when it can be achieved with an acceptable functional outcome. The variable rate of progression after incomplete resection highlights the need for new predictors of tumor behavior.

Posterior distribution of infarcts in strokes related to cardiac operations.

BACKGROUND Stroke complicates cardiac surgical procedures in a substantial number of patients. The mechanism of stroke is predominantly embolic, although hypoperfusion may play a role. The aim of this study was to determine whether radiologic appearances in this population were consistent with an embolic cause. METHODS We reviewed computed tomographic scans and medical records in 24 patients who suffered stroke after cardiac operation. Stroke was evident at 24 hours in 19 patients (79%). Infarcts were multiple in 16 and single in 3 patients (group 1). The remaining 5 patients suffered stroke beyond 24 hours and had single infarcts on computed tomographic scan (group 2). RESULTS In group 1, 15 patients (79%) had bilateral cerebellar infarcts, 4 (74%) had posterior cerebral artery infarcts, 10 (53%) had posterior watershed infarcts, and 11 patients (58%) had middle cerebral artery branch infarcts. The mean number of vascular territories involved was 5.1 (range, 1 to 10). Mobile atheromatous plaque was present in the ascending aorta or arch in 5 of 9 patients (56%) in group 1. In group 2, stroke occurred in close association with atrial or ventricular fibrillation in 3 of 5 patients (60%). CONCLUSIONS In patients with radiologic evidence of infarction, perioperative strokes after cardiac operation are typically multiple, and involve the posterior parts of the brain, consistent with atheroembolization. Delayed strokes may be attributable to cardiogenic embolism.

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study†

Chronic fatigue syndrome (CFS) is a controversial diagnosis because of the lack of biomarkers for the illness and its symptom overlap with neuropsychiatric, infectious, and rheumatological disorders. We compared lateral ventricular volumes derived from tissue‐segmented T1‐weighted volumetric MRI data and cerebrospinal fluid (CSF) lactate concentrations measured by proton MRS imaging (1H MRSI) in 16 subjects with CFS (modified US Centers for Disease Control and Prevention criteria) with those in 14 patients with generalized anxiety disorder (GAD) and in 15 healthy volunteers, matched group‐wise for age, sex, body mass index, handedness, and IQ. Mean lateral ventricular lactate concentrations measured by 1H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate. CFS is associated with significantly raised concentrations of ventricular lactate, potentially consistent with recent evidence of decreased cortical blood flow, secondary mitochondrial dysfunction, and/or oxidative stress abnormalities in the disorder. Copyright

Using Quantitative CT Perfusion for Evaluation of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage

BACKGROUND AND PURPOSE: DCI is a serious complication following aneurysmal SAH leading to permanent neurologic deficits, infarction, and death. Our aim was to prospectively evaluate the diagnostic accuracy of CTP and to determine a quantitative threshold for DCI in aneurysmal SAH. MATERIALS AND METHODS: Patients with SAH were prospectively enrolled in a protocol approved by the institutional review board. CTP was performed during the typical time period for DCI, between days 6 and 8 following SAH. Quantitative CBF, CBV, and MTT values were obtained by using standard region-of-interest placement sampling of gray matter. The reference standard for DCI is controversial and consisted of clinical and imaging criteria in this study. In a subanalysis of vasospasm, DSA was used as the reference standard. ROC curves determined the diagnostic accuracy by using AUC. Optimal threshold values were calculated by using the patient population utility method. RESULTS: Ninety-seven patients were included; 41% (40/97) had DCI. Overall diagnostic accuracy was 93% for CBF, 88% for MTT, and 72% for CBV. Optimal threshold values were 35 mL/100 g/min (90% sensitivity, 68% specificity) for CBF and 5.5 seconds (73% sensitivity, 79% specificity) for MTT. In the subanalysis (n = 57), 63% (36/57) had vasospasm. Overall diagnostic accuracy was 94% for CBF, 85% for MTT, and 72% for CBV. Optimal threshold values were 36.5 mL/100 g/min (95% sensitivity, 70% specificity) for CBF and 5.4 seconds (78% sensitivity, 70% specificity) for MTT. CONCLUSIONS: CBF and MTT have the highest overall diagnostic accuracy. Threshold values of 35 mL/100 g/min for CBF and 5.5-second MTT are suggested for DCI on the basis of the patient population utility method. Absolute threshold values may not be generalizable due to differences in scanner equipment and postprocessing methods.

Magnetic Resonance Imaging in the Congenital Adrenal Hyperplasia Population: Increased Frequency of White-Matter Abnormalities and Temporal Lobe Atrophy

Congenital adrenal hyperplasia results from an adrenal enzyme deficiency, that causes an underproduction of glucocorticoids and sometimes mineralocorticoids and a resultant overproduction of androgens, until treatment with replacement glucocorticoids is instituted. The goal of this study was to determine the frequency and etiology of white-matter changes and temporal lobe atrophy demonstrable on magnetic resonance imaging (MRI) in a group of children and young adults with congenital adrenal hyperplasia. About one third of the patients evidenced white-matter abnormalities or temporal lobe atrophy. All patients, except one with a known stroke, had normal neurologic examinations. Exposure to excess exogenous glucocorticoids in the process of being treated for congenital adrenal hyperplasia is the most theoretically appealing explanation for these MRI findings. However, the relationship of MRI findings to treatment status (over- versus under-suppressed) does not run in clear parallel. (J Child Neurol 1997;12:181-186).

Neurological deterioration in late infantile neuronal ceroid lipofuscinosis

Background: Late infantile neuronal ceroid lipofuscinosis (LINCL) is associated with progressive degeneration of the brain and retina starting in early childhood. Methods: Thirty-two individual neurologic, ophthalmologic, and CNS imaging (MRI and MRS) assessments of 18 children with LINCL were analyzed. Disease severity was followed by two rating scales, one previously established but modified to solely assess the brain and exclude the retinal disease (modified Hamburg LINCL scale), and a newly developed scale, with expanded evaluation of the CNS impairment (Weill Cornell LINCL scale). Results: For the 18 children, the Weill Cornell scale yielded a closer correlation with both age and time since initial clinical manifestation of the disease than did the modified Hamburg scale. There were no significant differences as a function of age or time since initial manifestation of the disease in the rating scales among the most frequent CLN2 mutations (G3556C, 56% of all alleles or C3670T, 22% of all alleles). Measurements of cortical MRS N-acetyl-aspartate content, MRI ventricular, gray matter and white matter volume, and cortical apparent diffusion coefficient correlated to a variable degree with the age of the children and the time since initial clinical manifestation of the disease. All imaging measurements correlated better with the Weill Cornell CNS scale compared to the modified Hamburg LINCL scale. Conclusion: The data suggest that the Weill Cornell late infantile neuronal ceroid lipofuscinosis (LINCL) scale, together with several of the MRI measurements, may be useful in the assessment of severity and progression of LINCL and for the evaluation of novel therapeutic strategies.