Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases.

INTRODUCTION: Brain metastases are common in metastatic melanoma and radiosurgery is often utilized for local control. Immune checkpoint inhibitors (CPIs) play a central role in contemporary melanoma management; however, there is limited data exploring outcomes and potential toxicities for patients treated with CPIs and radiosurgery. METHODS: We retrospectively identified all consecutive cases of newly diagnosed melanoma brain metastases (MBM) treated with Gamma Knife radiosurgery at a single institution between 2012 and 2017, and included only patients that initiated CPIs within 8 weeks before or after radiosurgery. RESULTS: Thirty-eight patients were included with a median follow-up of 31.6 months. Two-year local control was 92%. Median time to out-of-field CNS and extra-CNS progression were 8.4 and 7.9 months, respectively. Median progression-free survival (PFS) was 3.4 months and median overall survival (OS) was not reached (NR). Twenty-five patients (66%) received anti-CTLA4 and 13 patients (34%) received anti-PD-1+/-anti-CTLA4. Compared with anti-CTLA4, patients that received anti-PD-1+/-anti-CTLA4 had significant improvements in time to out-of-field CNS progression (p = 0.049), extra-CNS progression (p = 0.015), and PFS (p = 0.043), with median time to out-of-field CNS progression of NR vs. 3.1 months, median time to extra-CNS progression of NR vs. 4.4 months, and median PFS of 20.3 vs. 2.4 months. Six patients (16%) developed grade ≥ 2 CNS toxicities (grade 2: 3, grade 3: 3, grade 4/5: 0). CONCLUSIONS: Excellent outcomes were observed in patients that initiated CPIs within 8 weeks of undergoing radiosurgery for newly diagnosed MBM. There appears to be an advantage to anti-PD-1 or combination therapy compared to anti-CTLA4.

Persistent dyskinesias in patients with fetal tissue transplantation for Parkinson disease.

Cell transplants are being developed for patients with Parkinson disease (PD) who have insufficient benefit with standard medical treatment. We describe the clinical features of five patients who developed persistent dyskinesias after fetal dopaminergic tissue transplantation. All had levodopa-induced dyskinesias preoperatively. We implanted fetal mesencephalic dopaminergic tissue into the putamina bilaterally in 34 patients with advanced PD. They were not immunosuppressed. Five of 34 patients (15%) developed troublesome choreic or dystonic dyskinesias that persisted despite lowering or discontinuing medications. Attempts to treat the involuntary movements with amantadine, clozapine, anticholinergics, dopamine depletors and other medicines had limited success. Metyrosine eliminated dyskinesias but led to the parkinsonian "off" state. Increasing the dose of levodopa worsened the dyskinesias. Three patients required placement of pallidal stimulators, bilaterally in two and unilaterally in one patient who had only contralateral dyskinesias. The two with the bilateral stimulators had improvement in dyskinesias. The patient with the unilateral pallidal stimulator had a substantial reduction of the dyskinesias, but attempts to treat residual "off" symptoms with levodopa were limited by worsening dyskinesias. Although the number of patients developing these persistent dyskinesias was small, these five patients had dramatic improvement after transplant. As a group, they had milder Parkinson signs at baseline and improved to the point of having minimal parkinsonism, with reduction or elimination of levodopa therapy prior to developing persistent dyskinesias. These involuntary movements establish the principle that fetal dopaminergic tissue transplants can mimic the effects of levodopa, not only in reducing bradykinesia, but also in provoking dyskinesias.

Microvascular Decompression for Trigeminal Neuralgia: A Durable, Noncompressive Technique Using Teflon Secured With Mini Clip.

BACKGROUND: In cases of trigeminal neuralgia, the importance of durable separation of involved vessels from the trigeminal nerve as well as avoiding ongoing or recurrent compression by implanted material has been affirmed in recent literature. OBJECTIVE: To demonstrate a novel and straightforward technique for trigeminal nerve decompression using a construct of Teflon felt patty (Bard Peripheral Vascular, Tempe, Arizona) secured with an aneurysm mini clip to achieve lasting results with no residual contact between implant or vessels and the nerve. METHODS: Description of our technique and accompanying surgical video. RESULTS: As demonstrated in the video, this technique achieves an ideal, durable separation of the trigeminal nerve from the offending vasculature. CONCLUSION: The authors present a description of a technique for decompression with the goal of leaving no contact between implanted material and the nerve. This is accomplished by securing the Teflon felt (Bard Peripheral Vascular) to the tentorium with an aneurysm clip.

Four-year Survival (and Counting) after Stereotactic Radiosurgery to Nearly 100 Brain Metastases: A Case Report.

Brain metastases are a relatively common consequence of Stage IV melanoma. Historically, patients with brain metastases fare poorly, with median survival of only weeks to months. Patients with multiple metastases in the brain have often been overlooked in the literature, with the focus being placed more on patients with only a small number of metastases. The authors present a case of a 42-year-old man with a total of 98 brain metastases treated over several Gamma Knife sessions. He is nearly five years out from his initial treatment. This case highlights the fact that there is a large amount of variability in survival after diagnosis with brain metastases. Selection for treatment should be based on the clinical picture and clinicians should take care to avoid selection bias in this population.

Clip ligation for ruptured intracranial aneurysm in a child with Loeys-Dietz syndrome: case report.

The authors present the case of a pediatric patient with Loeys-Dietz syndrome (LDS) who underwent craniotomy for clip ligation of a ruptured intracranial aneurysm. To the authors' knowledge, this is the youngest reported patient with LDS who has been treated for a ruptured intracranial aneurysm. The patient presented with aneurysmal subarachnoid hemorrhage even though the results of surveillance screening were negative, and the aneurysm arose from the wall of the parent artery away from an arterial branch point. She was treated with open clip ligation and recovered well. The authors review the other reported cases of treated intracranial aneurysms in patients with LDS.

Excellent Outcomes with Radiosurgery for Multiple Brain Metastases in ALK and EGFR Driven Non-Small Cell Lung Cancer.

INTRODUCTION: Patients with brain metastases (BMs) arising from EGFR-mutated and anaplastic lymphoma kinase gene (ALK)-rearranged NSCLC have a favorable prognosis compared with patients with non-oncogene-addicted NSCLC, emphasizing the importance of minimizing toxicities such as the cognitive sequelae of whole brain radiation therapy (WBRT). Although radiosurgery without WBRT is the preferred strategy for one to three BMs, this paradigm remains controversial for patients with multiple BMs. METHODS: We reviewed the cases of patients with EGFR-mutated and ALK-rearranged NSCLC presenting to our cancer center between 2008 and 2017 and included only patients receiving treatment to four or more BMs in a single radiosurgery session. RESULTS: We identified 35 patients with a median follow-up of 4.1 years. The maximum number of BMs treated in a single radiosurgery session ranged from four to 26 (median number of BM treated per radiosurgery course: 6), and in total over all courses the number ranged from four to 47 (median: 10). The median survival was 3.0 years (4.2 for ALK-rearranged NSCLC; 2.4 for EGFR-mutated NSCLC) from the diagnosis of BM, and survival was comparable regardless of number of radiosurgery courses, number of BMs treated in total, or number of BMs treated in a single radiosurgery session. The mean hippocampal and whole-brain doses were exceedingly low even for patients receiving treatment to more than 10 BMs (1.2 and 0.8 Gy, respectively). Radiosurgery was well tolerated overall and the 5-year rate of freedom from neurologic death was 84%. The 5-year rate of freedom from WBRT was 97%. CONCLUSIONS: Radiosurgery for multiple BMs is controversial, yet patients with EGFR-mutated and ALK-rearranged NSCLC may be uniquely suited to benefit from this approach. These results support single and multiple courses of radiosurgery without WBRT for patients with oncogene-addicted NSCLC with four or more BMs.

Reaction time and movement time after embryonic cell implantation in Parkinson disease.

BACKGROUND: Embryonic nigral cell implants are a novel treatment for Parkinson disease (PD). Reaction time (RT) and movement time (MT) analysis, validated quantitative measures of premovement neural processing and motor execution, can be used as objective physiological markers of motor performance in PD. OBJECTIVES: To gauge the change in motor performance in patients with PD who received implants, and to determine whether the physiological findings correlate with clinical outcome measures after transplantation. DESIGN: Double-blind, placebo-controlled trial. Patients Forty patients with levodopa-responsive, Hoehn and Yahr stage III or greater PD. INTERVENTIONS: Random assignment to embryonic tissue implants or placebo (sham) operation. MAIN OUTCOME MEASURES: Combined RT + MT scores measured preoperatively and at 4 and 12 months postoperatively in the "off" state. RESULTS: The difference in mean RT + MT scores between the sham and implant groups was statistically significant (P =.005) and was greatest in those 60 years or older (P =.003). Changes correlated with Unified Parkinson's Disease Rating Scale off scores at 4 (r = 0.87, P =.001) and 12 (r = 0.75, P =.01) months in those younger than 60 years. There was a significant deterioration in the sham surgery group at 12 months (P =.03) that was thought to be due to worsening in subjects 60 years and older (P<.001). CONCLUSIONS: The physiological measures detected significant changes in patients undergoing embryonic nigral cell implants and correlated directly with clinical outcome measures. Comprehensive analyses of RT paradigms can document subtle changes in motor performance over time, making them useful outcome measures in therapeutic trials of PD. These findings support further research into nigral cell implantation for PD.

Do patients with Parkinson's disease benefit from embryonic dopamine cell transplantation?

Embryonic dopamine cell transplants survive in nearly all patients regardless of age and without immunosuppression. Transplants can improve Parkinson "off" symptoms up to the best effects of L-dopa observed preoperatively. They cannot improve the "best on" state. Transplants appear to survive indefinitely. In 10 to 15% of patients, transplants can reproduce the dyskinetic effects of L-dopa even after discontinuing all L-dopa. Neurotransplantation should be tried earlier in the clinical course of Parkinson's to see if earlier intervention can prevent progression of the disease, particularly the dyskinetic responses seen after longterm L-dopa treatment.

Differential gene expression in human cerebrovascular malformations.

OBJECTIVE: We sought to identify genes with differential expression in cerebral cavernous malformations (CCMs), arteriovenous malformations (AVMs), and control superficial temporal arteries (STAs) and to confirm differential expression of genes previously implicated in the pathobiology of these lesions. METHODS: Total ribonucleic acid was isolated from four CCM, four AVM, and three STA surgical specimens and used to quantify lesion-specific messenger ribonucleic acid expression levels on human gene arrays. Data were analyzed with the use of two separate methodologies: gene discovery and confirmation analysis. RESULTS: The gene discovery method identified 42 genes that were significantly up-regulated and 36 genes that were significantly down-regulated in CCMs as compared with AVMs and STAs (P = 0.006). Similarly, 48 genes were significantly up-regulated and 59 genes were significantly down-regulated in AVMs as compared with CCMs and STAs (P = 0.006). The confirmation analysis showed significant differential expression (P < 0.05) in 11 of 15 genes (angiogenesis factors, receptors, and structural proteins) that previously had been reported to be expressed differentially in CCMs and AVMs in immunohistochemical analysis. CONCLUSION: We identify numerous genes that are differentially expressed in CCMs and AVMs and correlate expression with the immunohistochemistry of genes implicated in cerebrovascular malformations. In future efforts, we will aim to confirm candidate genes specifically related to the pathobiology of cerebrovascular malformations and determine their biological systems and mechanistic relevance.

Cerebellar mutism associated with a midbrain cavernous malformation. Case report and review of the literature.

The authors report a case of cerebellar mutism arising from a hemorrhagic midbrain cavernous malformation in a 14-year-old boy. No cerebellar lesion was identified; however, edema of the dorsal midbrain was noted on postoperative magnetic resonance images. Dysarthric speech spontaneously returned and then completely resolved to normal speech. This case provides further evidence for the theory that involvement of the dentatothalamic tracts, and not a cerebellar lesion per se, is the underlying cause of "cerebellar" mutism.

Prevalence of intracranial aneurysms in first-degree relatives of patients with aneurysms.

OBJECT: A familial predisposition toward cerebral aneurysms has been previously described in patients with two or more affected family members. In the present study the familial incidence of unruptured intracranial aneurysms was studied in 96 patients with at least one first-degree relative (parent, sibling, or child) in whom a cerebral aneurysm was diagnosed. METHODS: All patients were between 20 and 70 years of age and underwent three-dimensional fast-spin echo magnetic resonance imaging. Sixty-one patients (63.5%) were women. The majority of patients (84%) were caucasian and the remainder were Hispanic (13%) or African-American (3%). No patient suffered a medical condition (excluding hypertension and smoking) known to be associated with cerebral aneurysm formation. In four patients at least one aneurysm was found (two harbored multiple aneurysms). Three of the four patients were women. Two of the patients were siblings. The estimated prevalence in first-degree relatives was 4.2% (95% confidence interval 1.2-10.1). Of note, the mean age in the current study population was 39 years. The authors of recent metaanalyses have suggested that the prevalence of nonfamilial aneurysms is approximately 2%, despite earlier reports in which higher figures were cited. CONCLUSIONS: The authors conclude that first-degree relatives of patients with aneurysms are at higher risk for harboring an intracranial aneurysm.

Endolymphatic hydrops in Ménière's disease: cause, consequence, or epiphenomenon?

OBJECTIVE: To determine the relationship of endolymphatic hydrops to Ménière's disease. DATA SOURCES: Comprehensive review of articles from 1938 through 2012 via Medline and Index Medicus. STUDY SELECTION: Articles discussing Ménière's disease and/or endolymphatic hydrops that include temporal bone autopsy data. DATA EXTRACTION: Fifty-three case reports and series were studied containing examination of 541 hydropic temporal bones and including 276 patients with Ménière's disease. These were divided into those meeting the 1995 American Academy of Otolaryngology-Head and Neck Surgery criteria for Ménière's disease and those that failed to meet these criteria. CONCLUSION: An individual meeting the 1995 criteria for Ménière's disease has a near certain probability of having endolymphatic hydrops in at least 1 ear. Autopsy data do not support the view that the association of MD and EH is an epiphenomenon or that MD causes EH; this leaves us with the probability that EH causes MD. If it is causative, hydrops alone is insufficient to cause Ménière's disease, indicating that there must be one or more additional cofactors that cause asymptomatic hydrops to become symptomatic Ménière's disease. Vascular risk factors should be studied as possible cofactors.

Dopamine cell transplantation for Parkinson's disease: the importance of controlled clinical trials.

Transplantation of human fetal dopamine neurons into the brain of Parkinson's disease patients started in the late 1980s, less than 10 years after experiments in rats showed that embryonic dopamine neurons from a narrow window of development are suitable for transplantation. For human transplantation, the critical stage of development is 6 to 8 weeks after conception. Because putamen is the basal ganglia structure most depleted of dopamine in Parkinson's disease and because it is the structure most closely mapped to the motor cortex, it has been the primary target for neurotransplantation. The double blind trial conducted at the University of Colorado, Columbia University, and North Shore University is the first controlled surgical trial performed in the field of neurosurgery. Results have shown that transplants of fetal dopamine neurons can survive transplantation without immunosuppression and without regard to the age of the patients. Transplants improved objective signs of Parkinson's disease to the best effects of L-DOPA seen preoperatively. Placebo surgery produced no clinical changes. In subjects in whom transplants replaced the need for L-DOPA, the implants replicated the preoperative effects of L-DOPA, including dyskinesias in susceptible patients. Our trial has provided the first controlled evidence that dopamine cell transplants can improve the clinical state of patients with Parkinson's disease.