Frameless stereotactic neuronavigation provides tracking of surgical instruments on radiographic images and orients the surgeon to tumor margins at surgery. Bipolar electrical stimulation mapping (ESM) delineates safe limits for resection of brain tumors adjacent to eloquent cortex. These standard techniques could complement the capability of intraoperative MR (iMR) imaging to evaluate for occult residual disease during surgery and promote more complete tumor removal. The use of frameless neuronavigation in the high-field iMR imaging suite requires that a few pieces of standard equipment be replaced by nonferromagnetic instruments. Specific use of ESM in a high-field iMR imaging suite has not been reported in the literature. To study whether frameless neuronavigation and electrical stimulation mapping could be successfully integrated in the high-field iMR imaging suite, the authors employed these modalities in 10 consecutive cases involving patients undergoing conscious craniotomy for primary brain tumors located in or adjacent to eloquent cortices. Equipment included a custom high-field MR imaging–compatible head holder and dynamic reference frame attachment, a standard MR imaging–compatible dynamic reference frame, a standard MR imaging machine with a table top that could be translated to a pedestal outside the 5-gauss line for the operative intervention, and standard neuronavigational and cortical stimulation equipment. Both ESM and frameless stereotactic guidance were performed outside the 5-gauss line. The presence of residual neoplasm was evaluated using iMR imaging; resection was continued until eloquent areas were encountered or iMR imaging confirmed complete removal of any residual tumor. Mapping identified essential language (5 patients), sensory (6), and motor (7) areas. The combined use of frameless stereotactic navigation, ESM, and iMR imaging resulted in complete radiographic resection in 7 cases and resection to an eloquent margin in 3 cases. Postoperative MR imaging confirmed final iMR imaging findings. No patient experienced a permanent new neurological deficit. Familiar techniques such as frameless navigation and ESM can be rapidly, inexpensively, safely, and effectively integrated into the high-field iMR imaging suite.
brain mapping; intraoperative magnetic resonance imaging; brain tumor surgery; stereotactic techniques
The pathogenesis of syringomyelia in patients with an associated spinal lesion is incompletely understood. The authors hypothesized that in primary spinal syringomyelia, a subarachnoid block effectively shortens the length of the spinal subarachnoid space (SAS), reducing compliance and the ability of the spinal theca to dampen the subarachnoid CSF pressure waves produced by brain expansion during cardiac systole. This creates exaggerated spinal subarachnoid pressure waves during every heartbeat that act on the spinal cord above the block to drive CSF into the spinal cord and create a syrinx. After a syrinx is formed, enlarged subarachnoid pressure waves compress the external surface of the spinal cord, propel the syrinx fluid, and promote syrinx progression.
To elucidate the pathophysiology, the authors prospectively studied 36 adult patients with spinal lesions obstructing the spinal SAS. Testing before surgery included clinical examination; evaluation of anatomy on T1-weighted MRI; measurement of lumbar and cervical subarachnoid mean and pulse pressures at rest, during Valsalva maneuver, during jugular compression, and after removal of CSF (CSF compliance measurement); and evaluation with CT myelography. During surgery, pressure measurements from the SAS above the level of the lesion and the lumbar intrathecal space below the lesion were obtained, and cardiac-gated ultrasonography was performed. One week after surgery, CT myelography was repeated. Three months after surgery, clinical examination, T1-weighted MRI, and CSF pressure recordings (cervical and lumbar) were repeated. Clinical examination and MRI studies were repeated annually thereafter. Findings in patients were compared with those obtained in a group of 18 healthy individuals who had already undergone T1-weighted MRI, cine MRI, and cervical and lumbar subarachnoid pressure testing.
In syringomyelia patients compared with healthy volunteers, cervical subarachnoid pulse pressure was increased (2.7 ± 1.2 vs 1.6 ± 0.6 mm Hg, respectively; p = 0.004), pressure transmission to the thecal sac below the block was reduced, and spinal CSF compliance was decreased. Intraoperative ultrasonography confirmed that pulse pressure waves compressed the outer surface of the spinal cord superior to regions of obstruction of the subarachnoid space.
These findings are consistent with the theory that a spinal subarachnoid block increases spinal subarachnoid pulse pressure above the block, producing a pressure differential across the obstructed segment of the SAS, which results in syrinx formation and progression. These findings are similar to the results of the authors' previous studies that examined the pathophysiology of syringomyelia associated with obstruction of the SAS at the foramen magnum in the Chiari Type I malformation and indicate that a common mechanism, rather than different, separate mechanisms, underlies syrinx formation in these two entities. Clinical trial registration no.: NCT00011245. (http://thejns.org/doi/abs/10.3171/2012.8.SPINE111059)
syringomyelia; physiology; ultrasonography; surgery; cerebrospinal fluid; magnetic resonance imaging; myelography
Blocking interleukin-1 with anakinra in patients with the autoinflammatory syndrome neonatal-onset multisystem inflammatory disease (NOMID) reduces systemic and organ-specific inflammation. However, the impact of long-term treatment has not been established. This study was undertaken to evaluate the long-term effect of anakinra on clinical and laboratory outcomes and safety in patients with NOMID.
We conducted a cohort study of 26 NOMID patients ages 0.80–42.17 years who were followed up at the NIH and treated with anakinra 1–5 mg/kg/day for at least 36 months. Disease activity was assessed using daily diaries, questionnaires, and C-reactive protein level. Central nervous system (CNS) inflammation, hearing, vision, and safety were evaluated.
Sustained improvements in diary scores, parent’s/patient’s and physician’s global scores of disease activity, parent’s/patient’s pain scores, and inflammatory markers were observed (all P < 0.001 at 36 and 60 months). At 36 and 60 months, CNS inflammation was suppressed, with decreased cerebrospinal fluid white blood cell counts (P = 0.0026 and P = 0.0076, respectively), albumin levels, and opening pressures (P = 0.0012 and P < 0.001, respectively). Most patients showed stable or improved hearing. Cochlear enhancement on magnetic resonance imaging correlated with continued hearing loss. Visual acuity and peripheral vision were stable. Low optic nerve size correlated with poor visual field. Bony lesions progressed. Adverse events other than viral infections were rare, and all patients continued to receive the medication.
These findings indicate that anakinra provides sustained efficacy in the treatment of NOMID for up to 5 years, with the requirement of dose escalation. Damage progression in the CNS, ear, and eye, but not bone, is preventable. Anakinra is well tolerated overall.
To evaluate a fast T1 mapping technique using incomplete inversion recovery 3D balanced steady-state free precession acquisition along with a two parameter model fit.
Materials and Methods
Using Bloch simulations, we explore the two parameter model fit for data acquired using such an acquisition scheme. The parameter space over which the fit holds good is determined through simulations. A linear correction is derived for the R1* (1/T1*) values so determined. Two phantoms and six volunteers were scanned using the described technique. Comparison scans using full recovery as well as gold standard inversion recovery spin echo were also performed.
The two parameter fit works exceedingly well over a large parameter space. T1 values in the phantoms showed an error of 4.9% and 39% before correction and 0.9% and 1.6% after correction. For the six volunteers, error in T1 value was 5.3% for white matter (WM) and 2.4% for gray matter (GM) after correction, while it was 11.2% and 18.2% before correction.
The work presented here allows for T1 map determination with higher resolution and shorter acquisition time than previously possible. The technique is especially well suited for GM/WM T1 mapping.
T1 map; two parameter model; incomplete inversion recovery
von Hippel-Lindau disease (VHL) is an autosomal dominant neoplasia syndrome that is the result of a germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. VHL patients are predisposed to develop lesions of the central nervous system (CNS) and viscera. CNS lesions include hemangioblastomas (the most common tumor in VHL) and endolymphatic sac tumors (ELSTs). Visceral manifestations include renal carcinomas and cysts, pancreatic neuroendocrine tumors and cysts, pheochromocytomas and cystadenomas of the reproductive adnexal organs. Despite their benign pathology, hemangioblastomas and ELSTs are a frequent cause of morbidity and mortality in VHL patients. Recent molecular biologic investigations into these VHL-associated CNS lesions provide new insight into their origin and development. Emerging data from serial imaging and clinical surveillance protocols provide insight into the natural history of these lesions. Because of the dissimilar pathobiology and clinical course between hemangioblastomas and ELSTs, the optimal management strategies for these neurologic manifestations of VHL are very different.
Enlargement of the vestibular aqueduct (EVA) is the most common inner ear anomaly detected in ears of children with sensorineural hearing loss. Pendred syndrome (PS) is an autosomal recessive disorder characterized by bilateral sensorineural hearing loss with EVA and an iodine organification defect that can lead to thyroid goiter. Pendred syndrome is caused by mutations of the SLC26A4 gene. SLC26A4 mutations may also be identified in some patients with nonsyndromic EVA (NSEVA). The presence of two mutant alleles of SLC26A4 is correlated with bilateral EVA and Pendred syndrome, whereas unilateral EVA and NSEVA are correlated with one (M1) or zero (M0) mutant alleles of SLC26A4. Thyroid gland enlargement (goiter) appears to be primarily dependent on the presence of two mutant alleles of SLC26A4 in pediatric patients, but not in older patients. In M1 families, EVA may be associated with a second, undetected SLC26A4 mutation or epigenetic modifications. In M0 families, there is probably etiologic heterogeneity that includes causes other than, or in addition to, monogenic inheritance.
SLC26A4; Pendred syndrome; Hearing; Deafness; Inner ear; Genotype-phenotype correlation
The purpose of this study was to evaluate the activity of single-agent bevacizumab in patients with recurrent anaplastic glioma and assess correlative advanced imaging parameters. Patients with recurrent anaplastic glioma were treated with bevacizumab 10 mg/kg every 2 weeks. Complete patient evaluations were repeated every 4 weeks. Correlative dynamic contrast-enhanced MR and 18fluorodeoxyglucose PET imaging studies were obtained to evaluate physiologic changes in tumor and tumor vasculature at time points including baseline, 96 h after the first dose, and after the first 4 weeks of therapy. Median overall survival was 12 months (95% confidence interval [CI]: 6.08–22.8). Median progression-free survival was 2.93 months (95% CI: 2.01–4.93), and 6-month progression-free survival was 20.9% (95% CI: 10.3%–42.5%). Thirteen (43%) patients achieved a partial response. The most common grade ≥3 treatment-related toxicities were hypertension, hypophosphatemia, and thromboembolism. Single-agent bevacizumab produces significant radiographic response in patients with recurrent anaplastic glioma but did not meet the 6-month progression-free survival endpoint. Early change in enhancing tumor volume at 4 days after start of therapy was the most significant prognostic factor for overall and progression-free survival.
anaplastic glioma; bevacizumab; FDG; perfusion MRI
Patients with neurofibromatosis type 2 (NF2) develop bilateral cochleovestibular schwannomas (CVSs) that cause binaural deafness in most individuals. Hearing loss occurs in an unpredictable manner and the underlying mechanisms are not known. To gain insight into the pathophysiologic basis for hearing loss in NF2, we performed a prospective cross-sectional study of untreated ears in NF2 patients.
One hundred consecutive NF2 patients in a prospective natural history study were included. Clinical and audiometric data were analyzed for treatment naïve ears. In addition to standard MR-imaging sequences, alterations in intralabyrinthine protein content were determined utilizing high resolution FLAIR, the presence of cochlear aperture obstruction was determined by examining 3D T2 sequences, and endolymphatic hydrops was identified on delayed post-contrast FLAIR sequences.
Eighty-nine ears harboring 84 untreated CVSs in 56 consecutive NF2 patients (age 30±16 years) were analyzed. Thirty-four (38%) ears had varying degrees of hearing loss. Elevated intralabyrinthine protein was identified in 70 (75%) ears by FLAIR MR-imaging and was strongly associated with the presence of hearing loss (32/34 hearing loss ears; 94%)(Fisher's exact test; P = .005). Elevated intralabyrinthine protein was associated with the presence of CVS-associated cochlear aperture obstruction (64 of 67 ears with elevated protein; 96%)(Fisher's exact test; P<0.0001) in both normal and hearing loss ears. Elevated intralabyrinthine protein was not identified in ears without CVS (5 ears). While larger tumor size was associated with hearing loss (P = 0.006), 16 hearing loss ears (47%) harbored CVSs less than 0.5 cm3, including 14 ears (88%) with block of the cochlear aperture and elevated protein.
These findings are consistent with a model in which hearing loss develops as a result of cochlear aperture obstruction and accumulation of intralabyrinthine protein. MRI based identification of elevated intralabyrinthine protein may help identify the ear at-risk for developing hearing loss.
Primary lateral sclerosis is a sporadic disorder characterized by slowly progressive corticospinal dysfunction. Primary lateral sclerosis differs from amyotrophic lateral sclerosis by its lack of lower motor neuron signs and long survival. Few pathological studies have been carried out on patients with primary lateral sclerosis, and the relationship between primary lateral sclerosis and amyotrophic lateral sclerosis remains uncertain. To detect in vivo structural differences between the two disorders, diffusion tensor imaging of white matter tracts was carried out in 19 patients with primary lateral sclerosis, 18 patients with amyotrophic lateral sclerosis and 19 age-matched controls. Fibre tracking was used to reconstruct the intracranial portion of the corticospinal tract and three regions of the corpus callosum: the genu, splenium and callosal fibres connecting the motor cortices. Both patient groups had reduced fractional anisotropy, a measure associated with axonal organization, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibres compared with controls, without changes in the genu or splenium. Voxelwise comparison of the whole brain white matter using tract-based spatial statistics confirmed the differences between patients and controls in the diffusion properties of the corticospinal tracts and motor fibres of the callosum. This analysis further revealed differences in the regional distribution of white matter alterations between the patient groups. In patients with amyotrophic lateral sclerosis, the greatest reduction in fractional anisotropy occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In patients with primary lateral sclerosis, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in fractional anisotropy in the corticospinal tract in patients with amyotrophic lateral sclerosis and increased mean diffusivity and volume loss of the corticospinal tract in patients with primary lateral sclerosis. Changes in the diffusion properties of the motor fibres of the corpus callosum were strongly correlated with changes in corticospinal fibres in patients, but not in controls. These findings indicate that degeneration is not selective for corticospinal neurons, but affects callosal neurons within the motor cortex in motor neuron disorders.
diffusion tensor imaging; diffusion tensor tractography; motor neuron disorders; primary lateral sclerosis; corpus callosum
Cryopyrin-associated periodic syndromes (CAPS) represent a spectrum of CIAS1 gene-mediated autoinflammatory diseases characterized by recurrent systemic inflammation. The clinical spectrum of CAPS varies from mild to severe and includes the syndromes historically described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). This article presents the largest cohort of patients with CAPS. The objective is to describe the pathogenesis, otolaryngologic, and audiologic manifestations of CAPS.
National Institutes of Health.
Subjects and Methods
Fifty-seven patients with a diagnosis of CAPS were identified (31 NOMID, 11 NOMID/MWS, 9 MWS, and 6 FCAS). Comprehensive data regarding clinical manifestations, audiologic phenotype, and fluid attenuation inversion recovery MRI (FLAIR-MRI) of the brain and inner ear were obtained.
Complete audiologic data obtained on 70% of ears revealed conductive hearing loss in 4 (11%) NOMID ears and mixed hearing loss in 5 (13%) NOMID and 2 (14%) NOMID/MWS ears. Sensorineural hearing loss (SNHL), worse in higher frequencies, was the most common type of hearing loss and was present in 23 (61%) NOMID, 10 (71%) NOMID/MWS, and 4 (33%) MWS ears. All of the patients with FCAS had normal hearing except 2, who had SNHL from 4 to 8 kHz. On FLAIR-MRI sequence, cochlear enhancement was noted in 26 of 29 (90%) NOMID, 6 of 11 (55%) NOMID/MWS, 3 of 9 (33%) MWS, and 1 of 6 (17%) FCAS patients and was significantly associated with the presence of hearing loss. Maxillary sinus hypoplasia and mucosal thickening were found in 39% and 86% of the cohort, respectively.
CIAS1 pathway–mediated CAPS is associated with unregulated autoinflammation mediated by interleukin-1 in the cochlea and hearing loss. Timely diagnosis is crucial to initiate early treatment with interleukin-1 receptor antagonists.
cryopyrin-associated periodic syndromes; familial cold autoinflammatory syndrome; Muckle-Wells syndrome; neonatal-onset multisystem inflammatory disease; chronic infantile neurological cutaneous and articular syndrome
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by cortical and spinal motor neuron dysfunction. Routine magnetic resonance imaging (MRI) studies have previously shown hypointense signal in the motor cortex on T2-weighted images in some ALS patients, however, the cause of this finding is unknown. To investigate the utility of this MR signal change as a marker of cortical motor neuron degeneration, signal abnormalities on 3T and 7T MR images of the brain were compared, and pathology was obtained in two ALS patients to determine the origin of the motor cortex hypointensity. Nineteen patients with clinically probable or definite ALS by El Escorial criteria and 19 healthy controls underwent 3T MRI. A 7T MRI scan was carried out on five ALS patients who had motor cortex hypointensity on the 3T FLAIR sequence and on three healthy controls. Postmortem 7T MRI of the brain was performed in one ALS patient and histological studies of the brains and spinal cords were obtained post-mortem in two patients. The motor cortex hypointensity on 3T FLAIR images was present in greater frequency in ALS patients. Increased hypointensity correlated with greater severity of upper motor neuron impairment. Analysis of 7T T2*-weighted gradient echo imaging localized the signal alteration to the deeper layers of the motor cortex in both ALS patients. Pathological studies showed increased iron accumulation in microglial cells in areas corresponding to the location of the signal changes on the 3T and 7T MRI of the motor cortex. These findings indicate that the motor cortex hypointensity on 3T MRI FLAIR images in ALS is due to increased iron accumulation by microglia.
To quantitate cerebral blood flow (CBF) in the entire brain using 3D EPI PULSAR (Pulsed STAR labeling) technique.
Materials and Methods
The PULSAR technique was modified to (a) incorporate a non-selective inversion pulse to suppress background signal (b) to use 3D echo planar (EPI) acquisition and (c) to modulate flip angle in such a manner as to minimize the blurring resulting from T1 modulation along the slice encoding direction. Computation of CBF was performed using the general kinetic model (GKM). In a series of healthy volunteers (n = 12), we first investigated the effects of introducing an inversion pulse on the measured value of CBF and on the temporal stability of the perfusion signal. Next, we investigated the effect of flip angle modulation on the spatial blurring of the perfusion signal. Finally, we evaluated the repeatability of the CBF measurements, including the influence of the measurement of arterial blood magnetization (a calibration factor for the GKM).
The sequence provides sufficient perfusion signal to achieve whole brain coverage in about five minutes. Introduction of the inversion pulse for background suppression did not significantly affect computed CBF values, but did reduce the fluctuation in the perfusion signal. Flip angle modulation reduced blurring, resulting in higher estimates of GM CBF and lower estimates of WM CBF. The repeatability study showed that measurement of arterial blood signal did not result in significantly higher error in the perfusion measurement.
Improvements in acquisition and sequence preparation presented here allow for better quantification and localization of perfusion signal allowing for accurate whole brain CBF measurements in five minutes.
Arterial spin labeling; 3D PULSAR; blurring reduction; whole brain perfusion imaging
Fibrous dysplasia (FD) is a benign bone tumor which most commonly involves the craniofacial skeleton. The most devastating consequence of craniofacial FD (CFD) is loss of vision due to optic nerve compression (ONC). Radiological evidence of ONC is common, however the management of this condition is not well established. Our objective was to compare the long-term outcome of patients with optic nerve compression (ONC) due to craniofacial fibrous dysplasia (CFD) who either underwent surgery or were managed expectantly.
We performed a meta-analysis of 27 studies along with analysis of the records of a cohort of patients enrolled in National Institutes of Health (NIH) protocol 98-D-0145, entitled Screening and Natural History of Fibrous Dysplasia, with a diagnosis of CFD. The study group consisted of 241 patients; 122 were enrolled in the NIH study and 119 were extracted from cases published in the literature. The median follow-up period was 54 months (range, 6–228 months). A total of 368 optic nerves were investigated. All clinically impaired optic nerves (n = 86, 23.3%) underwent therapeutic decompression. Of the 282 clinically intact nerves, 41 (15%) were surgically decompressed and 241 (85%) were followed expectantly. Improvement in visual function was reported in fifty-eight (67.4%) of the clinically impaired nerves after surgery. In the intact nerves group, long-term stable vision was achieved in 31/45 (75.6%) of the operated nerves, compared to 229/241 (95.1%) of the non-operated ones (p = 0.0003). Surgery in asymptomatic patients was associated with visual deterioration (RR 4.89; 95% CI 2.26–10.59).
Most patients with CFD will remain asymptomatic during long-term follow-up. Expectant management is recommended in asymptomatic patients even in the presence of radiological evidence of ONC.
Glioma cells secrete glutamate and also express AMPA glutamate receptors, which contribute to proliferation, migration and neurotoxicity of malignant gliomas. Talampanel is an oral AMPA receptor inhibitor with excellent CNS penetration and good tolerability in clinical trials for epilepsy and other neurological disorders.
We conducted a phase II trial to evaluate the efficacy of talampanel in patients with recurrent malignant glioma as measured by 6-month progression free survival (PFS6).
Thirty patients (22 glioblastomas [GBM], 8 anaplastic gliomas [AG]; 63% men) with median age of 51 years (range, 20 to 67) and median KPS of 80 were included. Patients tolerated treatment well and most adverse events were mild and reversible; the most common toxicities were fatigue (27%), dizziness (23%) and ataxia (17%). There was only one partial response (5%) in the GBM stratum and none among AG patients. With a median follow-up of 13 months, 28 patients (93%) had died. The PFS6 was 4.6% for the initial 22 GBM patients and the study was terminated early due to treatment futility; PFS6 was 0% for 8 AG patients. Median PFS was 5.9 weeks for GBM and 8.9 weeks for AG patients. Median overall survival was 13 weeks for GBM and 14 months for AG patients.
Talampanel was well tolerated but had no significant activity as a single agent in unselected recurrent malignant gliomas.
glioma; glioblastoma; talampanel; glutamate receptors
Recessive mutations of fibroblast growth factor 3 (FGF3) can cause LAMM syndrome (OMIM 610706), characterized by fully penetrant complete labyrinthine aplasia, microtia and microdontia.
We performed a prospective molecular genetic and clinical study of families segregating hearing loss linked to FGF3 mutations. Ten affected individuals from three large Pakistani families segregating FGF3 mutations were imaged with CT, MRI, or both to detect inner ear abnormalities. We also modeled the three dimensional structure of FGF3 to better understand the structural consequences of the three missense mutations.
Two families segregated reported mutations (p.R104X and p.R95W) and one family segregated a novel mutation (p.R132GfsX26) of FGF3. All individuals homozygous for p.R104X or p.R132GfsX26 had fully penetrant features of LAMM syndrome. However, recessive p.R95W mutations were associated with nearly normal looking auricles and variable inner ear structural phenotypes, similar to that reported for a Somali family also segregating p.R95W. This suggests that the mild phenotype is not entirely due to genetic background. Molecular modeling result suggests a less drastic effect of p.R95W on FGF3 function compared with known missense mutations detected in fully penetrant LAMM syndrome. Since we detected significant intrafamilial variability of the inner ear structural phenotype in the family segregating p.R95W, we also sequenced FGF10 as a likely candidate for a modifier. However, we did not find any sequence variation, pointing out that a larger sample size will be needed to map and identify a modifier. We also observed a mild to moderate bilateral conductive hearing loss in three carriers of p.R95W, suggesting either a semi-dominant effect of this mutant allele of FGF3, otitis media, or a consequence of genetic background in these three family members.
We noted a less prominent dental and external ear phenotype in association with the homozygous p.R95W. Therefore, we conclude that the manifestations of recessive FGF3 mutations range from fully penetrant LAMM syndrome to deafness with residual inner ear structures and, by extension, with minimal syndromic features, an observation with implications for cochlear implantation candidacy.
Identify correlations among SLC26A4 genotype, cochlear structural anomalies, and hearing loss associated with enlargement of the vestibular aqueduct (EVA).
Prospective cohort survey, National Institutes of Health, Clinical Center, a federal biomedical research facility.
83 individuals, 11 months to 59 years of age, with EVA in at least one ear. Correlations among pure-tone hearing thresholds, number of mutant SLC26A4 alleles, and the presence of cochlear anomalies detected by computed tomography or magnetic resonance imaging.
Linear mixed-effect model indicates significantly poorer hearing in ears with EVA from individuals with two mutant alleles of SLC26A4 than in those with EVA and a single mutant allele (p = .012) or no mutant alleles (p = .007) in this gene. There was no detectable relationship between degree of hearing loss and the presence of structural cochlear anomalies.
The number of mutant alleles of SLC26A4, but not the presence of cochlear anomalies, has a significant association with severity of hearing loss in ears with EVA. This information will be useful for prognostic counseling of patients and families with EVA.
enlarged vestibular aqueduct; SLC26A4; hearing
Enzastaurin, a potent inhibitor of protein kinase C-beta, inhibits angiogenesis and has direct cytotoxic activity against glioma cells in preclinical studies. Patients with recurrent high-grade gliomas were stratified by histology and use of enzyme-inducing antiepileptic drugs (EIAEDs). Patients on EIAED were treated on the phase I dose-escalation portion of the trial with evaluation of serum pharmacokinetics as the primary endpoint. Patients not on EIAED were treated on the phase II portion of the trial with radiographic response and progression-free survival (PFS) as primary objectives. Patients in phase I received enzastaurin 525–900 mg/d. Phase II patients received 500 or 525 mg/d. One hundred and eighteen patients were accrued to this trial. Therapy was well tolerated with thrombosis, thrombocytopenia, hemorrhage, and elevated alanine aminotransferase as the most commonly observed drug-associated grade 3 or higher toxicities. Patients on EIAED had serum enzastaurin exposure levels approximately 80% lower than those not on EIAED. Dose escalations up to 900 mg/d did not substantially increase serum exposure levels and a maximally tolerated dose was never reached. Twenty-one of 84 evaluable patients (25%) experienced an objective radiographic response. The 6-month PFS was 7% for patients with glioblastoma and 16% for patients with anaplastic glioma. Phosphorylation of glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential biomarker of drug activity. Enzastaurin has anti-glioma activity in patients with recurrent high-grade glioma, but does not appear to have enough single-agent activity to be useful as monotherapy.
angiogenesis; biomarker; glioblastoma; malignant glioma; targeted therapy
To determine the effectiveness of stereotactic radiosurgery (SRS) treatment to central nervous system (CNS) hemangioblastomas in von Hippel–Lindau disease (VHL), we analyzed long-term results in VHL patients treated with SRS. Patients were enrolled in a prospective VHL natural history study, undergoing SRS treatment of CNS hemangioblastomas. Treatment regimens, serial clinical evaluations, and longitudinal imaging data were analyzed. Twenty VHL patients (10 males and 10 females) underwent SRS treatment of 44 CNS hemangioblastomas (39 cerebellar and 5 brainstem). Mean (±SD) age at treatment was 37.5 ± 12.0 years (range: 13–67). Mean follow-up was 8.5 ± 3.2 years (range: 3.0–17.6 years). All patients were alive at last follow-up. Mean treated tumor volume was 0.5 ± 0.7 cm3 (range: 0.01–3.6 cm3). Mean prescription dose was 18.9 Gy (range: 12–24 Gy) at the tumor margin. Local control rate at 2, 5, 10, and 15 years after SRS treatment was 91%, 83%, 61%, and 51%, respectively. Univariate analysis did not identify variables associated (P > .05) with worse tumor control at last follow-up. Thirty-three percent of SRS-treated small (<1.0 cm diameter), asymptomatic tumors progressed over a long-term follow-up. There were no long-term adverse radiation effects. Although SRS treatment of hemangioblastomas in VHL has a low risk for adverse radiation effects, it is associated with diminishing control over a long-term follow-up. These results indicate that SRS should not be used to prophylactically treat asymptomatic tumors and should be reserved for the treatment of tumors that are not surgically resectable.
central nervous system hemangioblastoma; radiosurgery; treatment; von Hippel–Lindau disease
To identify and characterize otolaryngologic markers for the early diagnosis of Turner Syndrome (TS).
Prospective cohort survey.
Clinical Center of the National Institutes of Health (NIH).
Ninety-one females, 7 - 61 years old (average = 28.7 y), enrolled in a multidisciplinary study of karyotype-phenotype correlations in TS.
Main Outcome Measures
Age at diagnosis, X chromosome karyotype, history of chronic or recurrent otitis media (OM), sensorineural hearing loss (SNHL), palate dysmorphism, pinna deformity, pterygium colli, low posterior hairline, low-set ears, and micrognathia.
Sixty-nine (76%) patients had a history of chronic or recurrent OM, 62 (68%) had a dysmorphic palate, 57 (63%) had SNHL, and 90 (99%) had one or more of these findings. 83 (91%; average age at diagnosis = 9.4 y) had one or more external craniofacial signs: pinna abnormalities, pterygium colli, low-set ears, micrognathia or a low posterior hairline. Eight patients (average age at diagnosis = 13.2 y) had no external craniofacial signs, although seven (88%) of these eight patients had a history of chronic or recurrent OM, dysmorphic palate or SNHL. The age at diagnosis was not significantly different between groups with or without external craniofacial signs (P = 0.126).
Patients with mild or incompletely penetrant TS phenotypes often present with otitis media, hearing loss, or both before the diagnosis of TS is established. Palatal dysmorphism, including ogival morphology, is another otolaryngologic marker for TS. Prompt recognition of these manifestations of TS could hasten its diagnosis and appropriate medical care.
To demonstrate a modification of the Look-Locker (LL) technique that enables rapid high resolution T1 mapping over the physiologic range of intracranial T1 values, ranging from white matter to cerebrospinal fluid (CSF). This is achieved by use of a three-dimensional (3D) balanced steady-state free precession (b-SSFP) acquisition (for high signal-to-noise and resolution) along with variable repetition time to allow effective full recovery of longitudinal magnetization.
Materials and Methods
Two modifications to the Look-Locker technique were made to realize high resolution imaging in a clinically reasonable scan time. 3D balanced SSFP acquisition after an initial inversion pulse was followed by a variable repetition time. This technique makes it possible to image a volume of thin contiguous slices with high resolution and accuracy using a simple fitting procedure and is particularly useful for imaging long T1 species such as CSF. The total scan time is directly proportional to the number of slices to be acquired. The scan time was reduced by almost half when the repetition time was modified using a pre-designed smooth function. Phantoms and volunteers were imaged at different resolutions on a 3T scanner. Results were compared with other accepted techniques.
T1 values in the brain corresponded well with full repetition time imaging as well as inversion recovery spin echo imaging. T1 values for white matter, gray matter and CSF were measured to be 755±10ms, 1202±9ms and 4482±71ms, respectively. Scan times were reduced by about half over full repetition time measurements.
High resolution T1 maps can be obtained rapidly and with a relatively simple post-processing method. The technique is particularly well suited for long T1 species. For example, changes in the composition of proteins in CSF are linked to various pathologies. The T1 values showed excellent agreement with values obtained from inversion recovery spin-echo imaging.
T1 Map; Look-Locker; 3D; variable repetition time
Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1–receptor antagonist, with prominent involvement of skin and bone.
We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1–receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1–pathway genes including IL1RN.
We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1–family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1β stimulation. Patients treated with anakinra responded rapidly.
We propose the term deficiency of the interleukin-1–receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1–receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
Hearing loss with enlargement of the vestibular aqueduct (EVA) can be associated with mutations of the SLC26A4 gene encoding pendrin, a transmembrane Cl−/I−/HCO3− exchanger. Pendrin’s critical transport substrates are thought to be I− in the thyroid gland and HCO3− in the inner ear. We previously reported that bi-allelic SLC26A4 mutations are associated with Pendred syndromic EVA whereas one or zero mutant alleles are associated with nonsyndromic EVA. One study proposed a correlation of nonsyndromic EVA with SLC26A4 alleles encoding pendrin with residual transport activity. Here we describe the phenotypes and SLC26A4 genotypes of 47 EVA patients ascertained since our first report of 39 patients. We sought to determine the pathogenic potential of each variant in our full cohort of 86 patients. We evaluated the trafficking of 11 missense pendrin products expressed in COS-7 cells. Products that targeted to the plasma membrane were expressed in Xenopus oocytes for measurement of anion exchange activity. p.F335L, p.C565Y, p.L597S, p.M775T, and p.R776C had Cl−/I− and Cl−/HCO3− exchange rate constants that ranged from 13 to 93% of wild type values. p.F335L, p.L597S, p.M775T and p.R776C are typically found as mono-allelic variants in nonsyndromic EVA. The high normal control carrier rate for p.L597S indicates it is a coincidentally detected nonpathogenic variant in this context. We observed moderate differential effects of hypo-functional variants upon exchange of HCO3− versus I− but their magnitude does not support a causal association with nonsyndromic EVA. However, these alleles could be pathogenic in trans configuration with a mutant allele in Pendred syndrome.
enlargement of the vestibular aqueduct; EVA; deafness; DFNB4; hearing; genotype-phenotype correlation; PDS; pendrin; SLC26A4
To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma.
Patients and Methods
Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m2 or 125 mg/m2 every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks.
Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% CI, 12 to 26 weeks). The 6-month PFS was 29% (95% CI, 18% to 48%). The 6-month overall survival was 57% (95% CI, 44% to 75%). Median overall survival was 31 weeks (95% CI, 21 to 54 weeks). Early magnetic resonance imaging response (first 96 hours and 4 weeks) was predictive of long-term PFS, with the Levin criteria being more predictive than Macdonald criteria. Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses. Eighteen patients (95%) experienced disease progression by the second cycle, and the median PFS was 30 days.
We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma.
Although endolymphatic sac tumors (ELSTs) frequently destroy the posterior petrous bone and cause hearing loss, the anatomical origin of these neoplasms is unknown. To determine the precise topographic origin of ELSTs, the authors analyzed the imaging, operative, and pathological findings in patients with von Hippel–Lindau disease (VHL) and ELSTs.
Consecutive VHL patients with small (≤ 1.5 cm) ELSTs who underwent resection at the National Institutes of Health were included. Clinical, imaging, operative, and pathological findings were analyzed.
Ten consecutive VHL patients (6 male and 4 female) with 10 small ELSTs (≤ 1.5 cm; 9 left, 1 right) were included. Serial imaging captured the development of 6 ELSTs and revealed that they originated within the intraosseous (vestibular aqueduct) portion of the endolymphatic duct/sac system. Imaging just before surgery demonstrated that the epicenters of 9 ELSTs (1 ELST was not visible on preoperative imaging) were in the vestibular aqueduct. Inspection during surgery established that all 10 ELSTs were limited to the intraosseous endolymphatic duct/sac and the immediately surrounding region. Histological analysis confirmed tumor within the intraosseous portion (vestibular aqueduct) of the endolymphatic duct/sac in all 10 patients.
ELSTs originate from endolymphatic epithelium within the vestibular aqueduct. High-resolution imaging through the region of the vestibular aqueduct is essential for diagnosis. Surgical exploration of the endolymphatic duct and sac is required for complete resection.
anatomy; endolymphatic sac tumor; origin; pathology; vestibular aqueduct
Hemangioblastomas are frequently associated with peritumoral edema caused by extravasation of plasma ultra-filtrate through permeable neoplastic vessels. The authors report the clinical and imaging findings in a 62-year-old man with von Hippel–Lindau disease who presented with rapid (within 24 hours) loss of color vision and near-complete loss of left eye vision (acuity too poor to test). Serial MR imaging demonstrated a stable vascular tumor in the medioinferior aspect of the left optic nerve, associated with progressive edema extending from the nerve through to the bilateral optic radiations. Complete resection of the lesion was performed via an extended transsphenoidal approach, and histological examination confirmed the lesion was a hemangioblastoma. Postoperatively, the patient recovered color vision and had improvement in visual acuity (20/320). Serial imaging in this unique case captured the progressive extravasation of peritumoral edema that tracked and defined the parallel white matter tracts of first- and second-order neurons of the optic system, causing vision loss. Tumor resection led to resolution of the edema and improvement in visual function.
edema; hemangioblastoma; optic nerve; tumor; von Hippel‒Lindau disease