Platypnea Orthodeoxia Due to a Patent Foramen Ovale and Intrapulmonary Shunting After Severe COVID-19 Pneumonia.

BACKGROUND Platypnea orthodeoxia syndrome (POS) presents with positional dyspnea and hypoxemia defined as arterial desaturation of at least 5% or a drop in PaO2 of at least 4 mmHg. Causes of POS include a variety of cardiopulmonary etiologies and has been reported in patients recovering from severe COVID-19 pneumonia. However, clinical presentation and outcomes in a patient with multiple interrelated mechanisms of shunting has not been documented. CASE REPORT An 85-year-old man hospitalized for hypertensive emergency and severe COVID-19 pneumonia was diagnosed with platypnea orthodeoxia on day 28 of illness. During his disease course, the patient required supplemental oxygen by high-flow nasal cannula but never required invasive mechanical ventilation. Chest imaging revealed evolving mixed consolidation and ground-glass opacities with a patchy and diffuse distribution, involving most of the left lung. Echocardiography was ordered to evaluate for intracardiac shunt, which revealed a patent foramen ovale. Closure of the patent foramen ovale was not pursued. Management included graded progression to standing and supplemental oxygen increases when upright. The patient was discharged to a skilled nursing facility and his positional oxygen requirement resolved on approximately day 78. CONCLUSIONS The present case highlights the multiple interrelated mechanisms of shunting in patients with COVID-related lung disease and a patent foramen ovale. Eight prior cases of POS after COVID-19 pneumonia have been reported to date but none with a known patent foramen ovale. In patients with persistent positional oxygen requirements at follow-up, quantifying shunt fraction over time through multiple modalities can guide treatment decisions.

Time-delayed contrast-enhanced MRI improves detection of brain metastases: a prospective validation of diagnostic yield.

The radiological detection of brain metastases (BMs) is essential for optimizing a patient's treatment. This statement is even more valid when stereotactic radiosurgery, a noninvasive image guided treatment that can target BM as small as 1-2 mm, is delivered as part of that care. The timing of image acquisition after contrast administration can influence the diagnostic sensitivity of contrast enhanced magnetic resonance imaging (MRI) for BM. Investigate the effect of time delayed acquisition after administration of intravenous Gadavist® (Gadobutrol 1 mmol/ml) on the detection of BM. This is a prospective IRB approved study of 50 patients with BM who underwent post-contrast MRI sequences after injection of 0.1 mmol/kg Gadavist® as part of clinical care (time-t0), followed by axial T1 sequences after a 10 min (time-t1) and 20 min delay (time-t2). MRI studies were blindly compared by three neuroradiologists. Single measure intraclass correlation coefficients were very high (0.914, 0.904 and 0.905 for time-t0, time-t1 and time-t2 respectively), corresponding to a reliable inter-observer correlation. The delayed MRI at time-t2 delayed sequences showed a significant and consistently higher diagnostic sensitivity for BM by every participating neuroradiologist and for the entire cohort (p = 0.016, 0.035 and 0.034 respectively). A disproportionately high representation of BM detected on the delayed studies was located within posterior circulation territories (compared to predictions based on tissue volume and blood-flow volumes). Considering the safe and potentially high yield nature of delayed MRI sequences, it should supplement the standard MRI sequences in all patients in need of precise delineation of their intracranial disease.

Increased Lung Expression of Anti-Angiogenic Factors in Down Syndrome: Potential Role in Abnormal Lung Vascular Growth and the Risk for Pulmonary Hypertension.

BACKGROUND AND AIMS: Infants with Down syndrome (DS) or Trisomy 21, are at high risk for developing pulmonary arterial hypertension (PAH), but mechanisms that increase susceptibility are poorly understood. Laboratory studies have shown that early disruption of angiogenesis during development impairs vascular and alveolar growth and causes PAH. Human chromosome 21 encodes known anti-angiogenic factors, including collagen18a1 (endostatin, ES), ß-amyloid peptide (BAP) and Down Syndrome Critical Region 1 (DSCR-1). Therefore, we hypothesized that fetal lungs from subjects with DS are characterized by early over-expression of anti-angiogenic factors and have abnormal lung vascular growth in utero. METHODS: Human fetal lung tissue from DS and non-DS subjects were obtained from a biorepository. Quantitative reverse transcriptase PCR (qRT-PCR) was performed to assay 84 angiogenesis-associated genes and individual qRT-PCR was performed for ES, amyloid protein precursor (APP) and DSCR1. Western blot analysis (WBA) was used to assay lung ES, APP and DSCR-1 protein contents. Lung vessel density and wall thickness were determined by morphometric analysis. RESULTS: The angiogenesis array identified up-regulation of three anti-angiogenic genes: COL18A1 (ES), COL4A3 (tumstatin) and TIMP3 (tissue inhibitor of metallopeptidase 3) in DS lungs. Single qRT-PCR and WBA showed striking elevations of ES and APP mRNA (p = 0.022 and p = 0.001) and protein (p = 0.040 and p = 0.002; respectively). Vessel density was reduced (p = 0.041) and vessel wall thickness was increased in DS lung tissue (p = 0.033) when compared to non-DS subjects. CONCLUSIONS: We conclude that lung anti-angiogenic factors, including COL18A1 (ES), COL4A3, TIMP3 and APP are over-expressed and fetal lung vessel growth is decreased in subjects with DS. We speculate that increased fetal lung anti-angiogenic factor expression due to trisomy 21 impairs lung vascular growth and signaling, which impairs alveolarization and contributes to high risk for PAH during infancy.

Cerebral Arteriovenous Malformations and Epilepsy, Part 2: Predictors of Seizure Outcomes Following Radiosurgery.

OBJECTIVE: Seizure outcomes after arteriovenous malformation (AVM) management with radiosurgery are incompletely understood. In this case-control study, we aim to determine the incidences and define the predictors of seizure improvement and de novo seizures in patients with AVM with and without seizures at presentation, respectively. METHODS: We evaluated our institutional AVM radiosurgery database to determine the factors that were associated with favorable seizure outcome (seizure improvement or lack of de novo seizures). In patients with seizures at presentation, seizure improvement was defined as decreased seizure frequency or complete seizure remission. In patients without seizures at presentation, de novo seizures were defined as new-onset seizures after radiosurgery. Logistic regression analyses were performed to identify predictors of favorable seizure outcome. RESULTS: In 229 patients with seizures at presentation, the rates of seizure improvement and seizure remission were 57% and 20%, respectively. Prior AVM hemorrhage (P = 0.015), longer follow-up (P < 0.0001), and lack of hemorrhage after radiosurgery (P = 0.048) were independent predictors of seizure improvement in the multivariate analysis. In 778 patients without seizures at presentation, the overall rate of de novo seizures was 1.7%. Prior AVM hemorrhage (P = 0.001) and higher Spetzler-Martin grade (P = 0.018) were independent predictors of the absence of de novo seizures in the multivariate analysis. AVM obliteration was not significantly associated with seizure outcomes after radiosurgery. CONCLUSIONS: Radiosurgery provides reasonable rates of seizure improvement for patients with AVM who present with seizures. For patients with AVM without seizures at presentation, the risk of de novo seizures after radiosurgery is very low, obviating the need for prophylactic antiepileptic drug therapy. Further investigation of epilepsy in patients with AVM undergoing stereotactic radiosurgery should be considered with validated outcome measures and prospective study design.

Radiosurgery for temporal lobe arteriovenous malformations: effect of temporal location on seizure outcomes.

OBJECT: The temporal lobe is particularly susceptible to epileptogenesis. However, the routine use of anticonvulsant therapy is not implemented in temporal lobe AVM patients without seizures at presentation. The goals of this case-control study were to determine the radiosurgical outcomes for temporal lobe AVMs and to define the effect of temporal lobe location on postradiosurgery AVM seizure outcomes. METHODS: From a database of approximately 1400 patients, the authors generated a case cohort from patients with temporal lobe AVMs with at least 2 years follow-up or obliteration. A control cohort with similar baseline AVM characteristics was generated, blinded to outcome, from patients with non-temporal, cortical AVMs. They evaluated the rates and predictors of seizure freedom or decreased seizure frequency in patients with seizures or de novo seizures in those without seizures. RESULTS: A total of 175 temporal lobe AVMs were identified based on the inclusion criteria. Seizure was the presenting symptom in 38% of patients. The median AVM volume was 3.3 cm3, and the Spetzler-Martin grade was III or higher in 39% of cases. The median radiosurgical prescription dose was 22 Gy. At a median clinical follow-up of 73 months, the rates of seizure control and de novo seizures were 62% and 2%, respectively. Prior embolization (p = 0.023) and lower radiosurgical dose (p = 0.027) were significant predictors of seizure control. Neither temporal lobe location (p = 0.187) nor obliteration (p = 0.522) affected seizure outcomes. The cumulative obliteration rate was 63%, which was significantly higher in patients without seizures at presentation (p = 0.046). The rates of symptomatic and permanent radiation-induced changes were 3% and 1%, respectively. The annual risk of postradiosurgery hemorrhage was 1.3%. CONCLUSIONS: Radiosurgery is an effective treatment for temporal lobe AVMs. Furthermore, radiosurgery is protective against seizure progression in patients with temporal lobe AVM-associated seizures. Temporal lobe location does not affect radiosurgery-induced seizure control. The low risk of new-onset seizures in patients with temporal or extratemporal AVMs does not seem to warrant prophylactic use of anticonvulsants.

Cerebral Arteriovenous Malformations and Epilepsy, Part 1: Predictors of Seizure Presentation.

OBJECTIVE: Seizures are relatively common in patients harboring cerebral arteriovenous malformations (AVMs). Because the pathogenesis of AVM-associated epilepsy is not well-defined, we aim to determine the factors associated with seizure presentation in AVM patients. METHODS: We evaluated our institutional AVM radiosurgery database, from 1989-2013, to select patients in whom pertinent clinical information at presentation and adequate clinical and radiologic follow-up was available. Baseline patient demographics and AVM angioarchitectural features were compared between patients with and without seizure presentation. In addition to standard descriptive statistics, logistic regression analyses were performed to identify predictors of seizure presentation. RESULTS: Of the 1007 AVM patients included for analysis, 229 patients presented with seizures (22.7%). The incidence of seizure presentation was significantly higher in cortical than noncortical AVMs (33.1% vs. 6.6%, P < 0.0001). Among the cortical locations, occipital AVMs had the lowest rate of seizure presentation (21.5%, P = 0.0012), whereas the rates of seizure presentation in frontal (37.3%), temporal (37.7%), and parietal (34.0%) AVMs were similar. The lack of prior AVM hemorrhage (P < 0.0001), larger nidus diameter (P < 0.0001), and cortical location (P < 0.0001) were independent predictors of seizure presentation in the multivariate analysis. The strongest independent predictors of seizure presentation were lack of prior AVM hemorrhage (OR 16.8) and cortical location (OR 4.2). CONCLUSIONS: Large, unruptured, cortical nidi are most prone to seizure presentation in patients referred for radiosurgery. Further investigations of the molecular biology, neuronal and glial physiology, and natural history of AVM-associated epilepsy appear warranted.

Seizure and anticonvulsant outcomes following stereotactic radiosurgery for intracranial arteriovenous malformations.

OBJECT: Epilepsy associated with arteriovenous malformations (AVMs) has an unclear course after stereotactic radiosurgery (SRS). Neither the risks of persistent seizures nor the requirement for postoperative antiepileptic drugs (AEDs) are well defined. METHODS: The authors performed a retrospective review of all patients with AVMs who underwent SRS at the University of Virginia Health System from 1989 to 2012. Seizure status was categorized according to a modified Engel classification. The effects of demographic, AVM-related, and SRS treatment factors on seizure outcomes were evaluated with logistic regression analysis. Changes in AED status were evaluated using McNemar's test. RESULTS: Of the AVM patients with pre- or post-SRS seizures, 73 with pre-SRS epilepsy had evaluable data for subsequent analysis. The median patient age was 37 years (range 5-69 years), and the median follow-up period was 65.6 months (range 12-221 months). Sixty-five patients (89%) achieved seizure remission (Engel Class IA or IB outcome). Patients presenting with simple partial or secondarily generalized seizures were more likely to achieve Engel Class I outcome (p = 0.045). Twenty-one (33%) of 63 patients tapered off of pre-SRS AEDs. The incidence of freedom from AED therapy increased significantly after SRS (p < 0.001, McNemar's test). Of the Engel Class IA patients who continued AED therapy, 54% had patent AVM nidi, whereas only 19% continued AED therapy with complete AVM obliteration (p = 0.05). CONCLUSIONS: Stereotactic radiosurgery is an effective treatment for long-term AVM-related epilepsy. Seizure-free patients on continued AED therapy were more likely to have residual AVM nidi. Simple partial or secondarily generalized seizure type were associated with better seizure outcomes following SRS.

Stereotactic radiosurgery for facial nerve schwannomas: A preliminary assessment and review of the literature.

OBJECTIVE: Facial nerve schwannomas (FNS) are rare tumors, and their appropriate management remains the subject of considerable debate. This report details the results of a series of patients with FNS treated with stereotactic radiosurgery (SRS) at the University of Virginia. METHODS: We performed a retrospective review of the clinical and imaging outcomes of 5 patients who underwent Gamma Knife RS (GKRS) for small-to-medium-sized (<5 mL) FNS at our institution. The study population consisted of 3 males and 2 females with a median age of 35 years. All patients presented with varying degrees of facial palsy and/or hearing dysfunction. Tumor volumes at GKRS ranged from 0.1 to 5 (median=0.8) mL. The median maximum radiosurgical dose and tumor margin dose were 24 Gy and 12 Gy, respectively. RESULTS: After a median follow-up period of 12 (range, 6-36) months, three tumors were radiographically smaller and two remained stable. Facial function improved in three patients, remained stable in one patient, and slightly declined from House-Brackmann grade I to II in one patient. Hearing function was preserved in three patients and deteriorated in two patients, one from Gardner-Robertson grade I to II and the other from serviceable hearing grade II to III. CONCLUSION: SRS appears to offer a reasonable rate of facial nerve preservation and tumor control for patients with small-to-medium-sized FNS. Considering the published outcomes achieved with resection, RS may be the preferred first-line treatment for these tumors.

Stereotactic radiosurgery for acromegaly.

CONTEXT: The role of stereotactic radiosurgery (SRS) in acromegaly is being assessed. OBJECTIVE: We evaluated the efficacy and safety of SRS for patients with acromegaly. Prognostic factors related to outcomes were also analyzed. DESIGN: This was a retrospective study of patients treated with SRS at the University of Virginia; the data were collected from 1989 to 2012, with a median follow-up of 61.5 months. PATIENTS: A total of 136 patients underwent SRS for acromegaly. Diagnosis of acromegaly was based on the combination of clinical features and biochemical assessment, including the serum GH level and age- and gender-matched serum IGF-1 level. All patients underwent a complete endocrine evaluation, neuroimaging study, and ophthalmic examinations before SRS. MAIN OUTCOME MEASURES: After withdrawal of GH- or IGF-1-altering medications, patients who had an oral glucose tolerance test GH of < 1.0 ng/mL or normal IGF-1 were considered in remission. Post-radiosurgical hypopituitarism was defined as a decrease in one or more hormones below normal. RESULTS: With a median follow-up of 61.5 months, 65.4% of the patients achieved remission. The mean time to remission was 27.5 months. The actuarial remission rates at 2, 4, 6, and 8 years after radiosurgery were 31.7, 64.5, 73.4, and 82.6%, respectively. Favorable prognostic factors for remission included a higher margin radiation dose, higher maximum dose, and lower initial IGF-1 level. New pituitary hormone deficiency occurred in 43 patients (31.6%); two patients (1.5%) developed panhypopituitarism. Corresponding risk factors for new pituitary hormone deficiency were a margin dose > 25 Gy and tumor volume > 2.5 mL. Other complications included an adverse radiation effect in one patient, visual deterioration in four, and new oculomotor nerve palsy in one. CONCLUSION: SRS affords a reasonable rate of endocrine remission in patients with acromegaly and generally does so with a low rate of adverse effects.