Evaluation of 209At as a theranostic isotope for 209At-radiopharmaceutical development using high-energy SPECT.

The development of alpha-emitting radiopharmaceuticals using 211At requires quantitative determination of the time-dependent nature of the 211At biodistribution. However, imaging-based methods for acquiring this information with 211At have not found wide-spread use because of its low abundance of decay emissions suitable for external detection. In this publication we demonstrate the theranostic abilities of the 211At/209At isotope pair and present the first-ever 209At SPECT images. The VECTor microSPECT/PET/CT scanner was used to image 209At with a collimator suitable for the 511 keV annihilation photons of PET isotopes. Data from distinct photopeaks of the 209At energy spectrum (195 keV (22.6%), 239 keV (12.4 %), 545 keV (91.0 %), a combined 782/790 keV peak (147 %), and 209Po x-rays (139.0 %)) were independently evaluated for use in image reconstructions using Monte Carlo (GATE) simulations and phantom studies. 209At-imaging in vivo was demonstrated in a healthy mouse injected with 10 MBq of free [209At]astatide. Image-based measurements of 209At uptake in organs of interest-acquired in 5 min intervals-were compared to ex vivo gamma counter measurements of the same organs. Simulated and measured data indicated that-due to the large amount of scatter from high energy (>750 keV) gammas-reconstructed images using the x-ray peak outperformed those obtained from other peaks in terms of image uniformity and spatial resolution, determined to be <0.85 mm. 209At imaging using the x-ray peak revealed a biodistribution that matched the known distribution of free astatide, and in vivo image-based measurements of 209At uptake in organs of interest matched ex vivo measurements within 10%. We have acquired the first 209At SPECT images and demonstrated the ability of quantitative SPECT imaging with 209At to accurately determine astatine biodistributions with high spatial and temporal resolution.

Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.

Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease.

Atypical presentation of atypical teratoid rhabdoid tumor in a child.

Atypical Teratoid Rhabdoid Tumor (ATRT) is a rare malignant intracranial neoplasm more commonly diagnosed in young children. The authors report the case of an 11-year-old boy with a long standing history of slowly progressive weight loss, fatigue, and weakness over 1.5 years whose magnetic resonance imaging revealed a large heterogeneous enhancing dorsally exophytic lower brainstem mass. Examination revealed extreme cachexia, gaze-evoked nystagmus, dysphagia, dysarthria, bilateral dysmetria, and global weakness without ambulation. The protracted history and neuroimaging features were most suggestive of a low grade glioma. However, pathology revealed a hypercellular tumor with large hyperchromatic nucleoli and loss of INI-1 staining on immunohistochemistry consistent with a diagnosis of an ATRT. The child died shortly after surgery due to complications from his brainstem infiltrative disease. This case illustrates the diverse presentation of ATRT in childhood that can clinically and radiographically mimic that of low grade glioma.

An unusual case of recurrent guillain-barre syndrome of a different subtype five years after initial diagnosis.

We present a case of a previously healthy 17-year-old girl with history of Guillain-Barre Syndrome 5 years after initial presentation who presented with bilateral lower extremity pain, worsening dysphagia, subsequent weakness, and decreased reflexes. Cerebrospinal fluid analysis had a prominent lymphocytic pleocytosis. MRI of spine showed significant anterior nerve root enhancement. Electromyogram demonstrated a mild axonal greater than demyelinating motor polyneuropathy and intact sensory responses, with no evidence of conduction block or temporal dispersion, unlike her first presentation that revealed a demyelinating polyneuropathy. The patient recovered with mild subjective weakness following 5 days of intravenous immunoglobulin treatment. This case represents a recurrence of a predominantly motor variant polyradiculoneuropathy distinct from the initial presentation with a lymphocytic predominant CSF pleocytosis, nerve root enhancement on MRI spine, and rapid recovery following treatment with intravenous immunoglobulin.

Acute hemiparesis in a child as a presenting symptom of hemispheric cerebral proliferative angiopathy.

A 9-year-old girl with a several-month history of unilateral intermittent headaches presented to the hospital with worsening headaches and unsteadiness. Neurologic exam was positive for a mild right hemiparesis and right homonymous hemianopsia. Noncontrast computed tomography revealed an engorged sagittal and straight sinus with prominent cortical veins concerning an arteriovenous malformation and the patient was admitted to the pediatric intensive care unit. Computed tomography angiogram demonstrated a left hemispheric vascular malformation, without evidence of dural arteriovenous fistula on conventional angiogram consistent with a diagnosis of cerebral proliferative angiopathy. There was no evidence of infarct on magnetic resonance imaging, and the patient's symptoms were completely resolved within 24 hours. Cerebral proliferative angiopathy is a rare but important vascular malformation distinct from classic arteriovenous malformations that may present with stroke-like symptoms in childhood.

An unusual cause of pediatric stroke secondary to congenital basilar artery fenestration.

Basilar artery fenestration is an uncommon congenital variant that has been associated with aneurysms and posterior circulation infarcts in the adult literature. Little is known about the functional consequences of basilar artery fenestration, if any, in childhood. We present a case of a previously healthy 12-year-old boy who presented with diplopia, tinnitus, and ataxia who had subtle findings on diffusion-weighted magnetic resonance imaging consistent with posterior circulation territory infarction. Computed tomography angiography and magnetic resonance angiography revealed an area of signal abnormality in the basilar artery, which was confirmed on conventional angiography to be a type 2 basilar artery fenestration, without thrombus or aneurysm. The patient recovered from his neurologic deficits over two days and was placed on prophylactic aspirin therapy without recurrence of symptoms. This rare anatomic variant of the posterior circulation is important for physicians to recognize and may have associated neurologic consequences during childhood worthy of further investigation.

Secondary glioblastoma multiforme in a child with disseminated juvenile pilocytic astrocytoma.

Secondary glioblastoma multiforme (sGBM) can occur after a long latency period following radiation treatment of various diseases including brain tumors, leukemia, and more benign disorders like tinea capitis. Outcomes of radiation-induced sGBM remain poor in both children and adults. We report a case of a 16-year-old girl with a history of disseminated juvenile pilocytic astrocytoma treated with chemotherapy and craniospinal radiation 9 years prior who developed sGBM in the absence of a tumor predisposition syndrome. She presented with a several-week history of headaches and no acute findings on computed tomography compared to baseline neuroimaging 3 months prior. Repeat computed tomography performed just 3 weeks later for worsening headaches revealed a new large posterior fossa tumor where pathology confirmed the diagnosis of sGBM. In spite of maximal surgical resection, reirradiation, and adjuvant chemotherapy, she died 1 year postdiagnosis. Our case highlights the potential late effects of high-dose cranial radiation, how symptomatology may precede neuroimaging findings, and the rapid formation of sGBM that mirrors that of de novo Glioblastoma Multiforme.

Medulloblastoma with excessive nodularity: radiographic features and pathologic correlate.

Medulloblastoma with extensive nodularity is a rare subtype of the most common malignant childhood brain tumor and has been associated with more favorable prognosis. The authors report the case of a 10-month-old girl with a posterior fossa tumor of excessive nodularity with decreased diffusivity on diffusion-weighted magnetic resonance imaging sequences and robust grape-like postgadolinium contrast enhancing features. The unique neuroradiographic features were confirmed by histopathology and a diagnosis of medulloblastoma with extensive nodularity was made. This case highlights the importance of recognizing this unique medulloblastoma subtype preoperatively, as the more favorable outcome may preclude less aggressive medical management.

Incidental MRI findings of acute gadolinium hypersensitivity.

A 13-year-old girl with a remote history of juvenile pilocytic astrocytoma developed acute onset flushing, tachycardia and shortness of breath immediately following administration of gadopentetate dimeglumine during routine brain MRI that subsided following intravenous diphenhydramine. A retrospective review of the MRI results revealed multiple areas of contrast enhancement of the face, consistent with observed urticaria. The patient received pretreatment medications prior to subsequent gadolinium injections without incident. Gadolinium allergy is extremely rare and has been reported in less than 0.1% of injections. However, in patients who undergo anesthesia for MRI studies, similar subtle extracranial MRI findings should alert the neuroradiologist to possible gadolinium allergy that may warrant premedication prior to future injections.

Unrecognized visual field deficits in children with primary central nervous system brain tumors.

Visual field deficits can be a consequence of brain tumor location or treatment. The prevalence of unrecognized visual field deficits in children diagnosed with brain tumors is not known. All children at a single tertiary care pediatric children's hospital diagnosed with a primary brain tumor were tested for visual field deficits by a child neurologist and neuro-ophthalmologist over 16 months. Children with reproducible visual field deficits on two separate occasions were included in the analysis. Patients with optic glioma, craniopharyngioma, or previously known visual field deficits were excluded. Fourteen of 92 (15.2%) children (average 8.9 years, 8 girls) had undiagnosed visual field deficits. Average time between diagnosis of tumor and unrecognized visual field deficit was 3.7 years (range 0-13 years). Unrecognized visual field deficits were not associated with age (P = 0.27) or gender (P = 0.38). Visual field deficits were attributed to direct tumor infiltration (n = 8), postoperative complications (n = 5) and post-radiation edema (n = 1). Deficits included bitemporal hemianopsia (n = 2), homonymous hemianopsia (n = 9), quadrantanopsia (n = 2), and concentric visual field loss (n = 1.) Tumor location included temporal lobe (n = 9), parietal lobe (n = 2), posterior fossa (n = 2), hypothalamic-chiasmatic (n = 2) and multifocal areas (n = 4). Children with temporal lobe tumors were more likely to have unrecognized visual field deficits (P = 0.004). In all 14 patients, visual field deficits were determined by examination only and were not reported by either the patient or caregiver regardless of age. The prevalence of unrecognized visual field deficits in children with brain tumors can be surprisingly high. Serial neuro-ophthalmologic evaluation of children with brain tumors is often required to diagnose a visual field deficit since patient or caregiver reporting may be limited.

CNS germ cell tumor (CNSGCT) of childhood: presentation and delayed diagnosis.

OBJECTIVE: To describe the relationship between symptomatology and time to diagnosis of an institutional series of patients with CNS germ cell tumor (CNSGCT) over a 16-year period. METHODS: Thirty consecutive patients newly diagnosed with CNSGCT (mean age 10.9 years; range 6 to 17 years; 70% boys) were evaluated at our institution between 1990 and 2006. RESULTS: Duration of symptoms prior to diagnosis ranged from 5 days to 3 years (mean 8.4 months). Tumor location included pineal (14), suprasellar (8), pineal/suprasellar (3), pineal/thalamic (4), and basal ganglionic/thalamic (3). Five patients had disseminated disease at the time of diagnosis. Features including headache, nausea, vomiting, and visual changes led to earlier diagnosis. Symptoms including movement disorders, enuresis, anorexia, and psychiatric complaints delayed diagnosis in 9 of 30 patients, diagnosed 7 months to 3 years (mean 22.3 months) from symptom onset. In 7 of 9 patients with delayed diagnosis, enuresis was present. Seventeen of 30 patients had signs of endocrine dysfunction at presentation that included diabetes insipidus (4), hypothyroidism (8), and growth hormone deficiency (4). Ophthalmologic findings of decreased visual acuity, visual field deficits, or ocular abnormalities were present in 13 patients. Duration of symptoms did not correlate with tumor subtype or event-free survival. In three patients with basal ganglionic/temporal lobe, thalamic, or pineal/suprasellar signal abnormalities on MRI, neuroradiographic diagnosis was difficult. CONCLUSIONS: Diagnosis of CNS germ cell tumor is often delayed, and presentation may include movement disorders or mimic psychiatric disease. MRI interpretation can be challenging and may require serum/CSF markers and biopsy for diagnosis.

A model of personality change after traumatic brain injury and the development of the Brain Injury Personality Scales.

OBJECTIVE: The aims of this study were to develop models of personality change after traumatic brain injury (TBI) based on information provided by the TBI survivor and a significant other (SO), and to compare the models generated from the two different sources of information. METHODS: Individuals with and without TBI and an SO were interviewed separately about their current personality. The SOs were also interviewed about the personality of the TBI survivor before the injury. A subset of TBI survivors and their SOs were interviewed twice to assess test-retest reliability. Items which were not associated with personality change after TBI, which could not be measured reliably or which did not contribute to the model, were excluded. RESULTS: Of the 123 original items, 29 items from the interview with the survivor and 31 items from the interview with the SO were retained to form the Brain Injury Personality Scales. Separate factor analyses of ratings from each interview (survivor and SO) resulted in seven first order factors. The second order factor analyses for each interview resulted in four factors. Concordance between the information obtained from the two interviews was low. CONCLUSIONS: The information obtained from the interviews with the TBI survivors and the SOs produced two models with a similar structure: three superordinate factors of personality items (affective regulation, behavioural regulation and engagement) and one superordinate factor of items relevant to mental state (restlessness and range of thought). Despite the similarity in structure, the content of the information obtained from the two interviews was different.

Psychometric properties of the BASIS-24© (Behaviour and Symptom Identification Scale-Revised) Mental Health Outcome Measure.

Objective. Outcome measurement in mental health services is an area of considerable clinical interest and policy priority. This study sought to assess the Behaviour and Symptom Identification Scale-24 (BASIS-24©), a brief, patient self-reported measure of psychopathology and functioning, in a UK sample, including establishing population norms for comparative purposes. Methods. Participants were 588 adults recruited from psychiatric inpatient, outpatient and primary care settings; and 630 adults randomly sampled from primary care lists who completed the BASIS-24©, and the Brief Symptom Inventory (BSI) at two time points. Results. BASIS-24© demonstrated adequate reliability (coefficient α values for combined clinical sample across subscales ranged from 0.75 to 0.91), validity and responsiveness to change (effect size for change of the BASIS-24© was 0.56 compared with 0.48 for BSI Global Severity Index). Population norms were established for the general population and adult in-patients (at in-take). The scale proved straightforward to complete across clinical settings. Variable rates of questionnaire distribution across clinical settings highlighted the ongoing challenge of incorporating outcome measures in clinical settings. Conclusion. BASIS-24© is a brief, easily administered, self-complete measure of mental well-being and functioning that adequately meets the requirements of reliability, validity and responsiveness to change required of an outcome measure.

Personal disturbance scale: factor structure confirmed in a large nonclinical sample.

The two-component structure of anxiety and depression items of the short form Personal Disturbance Scale, reported in an earlier clinical study of 480 adult psychiatric patients, was substantially replicated in a large nonclinical sample of 758 adults.

Bone loss at hip resurfacing: A comparison with total hip arthroplasty.

Resurfacing arthroplasty of the hip has been advocated as a bone-conserving procedure although concerns have been raised as to whether this is truly the case. We therefore compared bone loss during hip resurfacing with bone loss at total hip arthroplasty under controlled conditions using dry pelvic and femoral Sawbones (DePuy, Leeds, UK). Ten sets of femoral and pelvic Sawbones were included in the study. Five sets were prepared for implantation of a hybrid total hip arthroplasty and five sets were prepared for insertion of hip resurfacing components. The Sawbones were weighed before and after preparation and the amount of dry bone loss was determined. During preparation of the femur for a resurfacing arthroplasty we resected 51.4% less Sawbone than for a total hip arthroplasty (mean 12.3g vs 25.3g, p<0.001). More bone (311.1%) was removed, however, during acetabular preparation for a resurfacing arthroplasty than for a total hip arthroplasty (mean 5.6g vs 1.8g, p<0.001). The total amount of Sawbone removed was 33.9% less for a resurfacing arthroplasty compared with a total hip arthroplasty (mean 17.9g vs 27.1g, p=0.001). We conclude that although reduced resection of femoral bone may be an advantage of hip resurfacing arthroplasty, the increased amount of bone that is removed from the acetabulum may prove problematic should patients require future revision surgery. (Hip International 2005; 15: 195-8).

Compression of the sciatic nerve by wear debris following total hip replacement: a report of three cases.

Pain in the distribution of the sciatic nerve is common in the elderly. In the presence of a long-standing joint replacement, consideration should be given as to whether compression might be due to an extraspinal cause. We present three women, in whom a mass of wear debris from a previous total hip replacement caused compression of the sciatic nerve posterior to the hip. The symptoms were relieved immediately following operation.

Differential deficits in expression recognition in gene-carriers and patients with Huntington's disease.

Previous studies in symptomatic patients and asymptomatic gene-carriers of Huntington's disease (HD) reported a differential deficit in the recognition of facial expressions of disgust. This impairment may point to involvement of the basal ganglia in the recognition of disgust. In this study, we compared the performance of 20 patients with symptoms of HD, 20 gene-carriers of HD and 20 healthy controls on two tests of facial expressions in order to further investigate the role of the basal ganglia in disgust recognition. Recognition of fear, rather than disgust, was most severely impaired in the patients, who were also impaired at recognising expressions of anger, disgust and sadness. Direct testing for a differential deficit in disgust at the group level (and at the level of individual HD cases) revealed that the patients were in fact significantly more impaired on the other negative expressions than on disgust. The gene-carriers were not impaired on any expression, although there was a trend for the gene-carriers to be poorer at recognising fearful faces than the controls. We argue that the expression recognition performance of the patients and gene-carriers simply reflects differences in task difficulty, rather than dysfunction of any mechanisms dedicated to specific emotions. In contrast to previous studies in patients or gene-carriers of HD, our findings provide no evidence for a role of the basal ganglia in the recognition of disgust and cast doubt on whether results from HD patients and gene-carriers can be used in support of a double dissociation between recognition of disgust and fear.