Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

Hypermutated phenotype in gliosarcoma of the spinal cord.

Gliosarcoma is a variant of glioblastoma with equally poor prognosis and characterized by mixed glial and mesenchymal pathology. Metastasis is not uncommon but the involvement of the spinal cord is rare, and comprehensive genetic characterization of spinal gliosarcoma is lacking. We describe a patient initially diagnosed with a low-grade brain glioma via biopsy, followed by adjuvant radiation and temozolomide treatment. Nearly 2 years after diagnosis, she developed neurological deficits from an intradural, extramedullary tumor anterior to the spinal cord at T4, which was resected and diagnosed as gliosarcoma. Whole-exome sequencing (WES) of this tumor revealed a hypermutated phenotype, characterized by somatic mutations in key DNA mismatch repair (MMR) pathway genes, an abundance of C>T transitions within the identified somatic single nucleotide variations, and microsatellite stability, together consistent with temozolomide-mediated hypermutagenesis. This is the first report of a hypermutator phenotype in gliosarcoma, which may represent a novel genomic mechanism of progression from lower grade glioma.

Clinical and genomic factors associated with seizures in meningiomas.

OBJECTIVE: The association of seizures with meningiomas is poorly understood. Moreover, any relationship between seizures and the underlying meningioma genomic subgroup has not been studied. Herein, the authors report on their experience with identifying clinical and genomic factors associated with preoperative and postoperative seizure presentation in meningioma patients. METHODS: Clinical and genomic sequencing data on 394 patients surgically treated for meningioma at Yale New Haven Hospital were reviewed. Correlations between clinical, histological, or genomic variables and the occurrence of preoperative and postoperative seizures were analyzed. Logistic regression models were developed for assessing multiple risk factors for pre- and postoperative seizures. Mediation analyses were also conducted to investigate the causal pathways between genomic subgroups and seizures. RESULTS: Seventeen percent of the cohort had presented with preoperative seizures. In a univariate analysis, patients with preoperative seizures were more likely to have tumors with a somatic NF2 mutation (p = 0.020), WHO grade II or III tumor (p = 0.029), atypical histology (p = 0.004), edema (p < 0.001), brain invasion (p = 0.009), and worse progression-free survival (HR 2.68, 95% CI 1.30-5.50). In a multivariate analysis, edema (OR 3.11, 95% CI 1.46-6.65, p = 0.003) and atypical histology (OR 2.00, 95% CI 1.03-3.90, p = 0.041) were positive predictors of preoperative seizures, while genomic subgroup was not, such that the effect of an NF2 mutation was indirectly mediated through atypical histology and edema (p = 0.012). Seizure freedom was achieved in 83.3% of the cohort, and only 20.8% of the seizure-free patients, who were more likely to have undergone gross-total resection (p = 0.031), were able to discontinue antiepileptic drug use postoperatively. Preoperative seizures (OR 3.54, 95% CI 1.37-9.12, p = 0.009), recurrent tumors (OR 2.89, 95% CI 1.08-7.74, p = 0.035), and tumors requiring postoperative radiation (OR 2.82, 95% CI 1.09-7.33, p = 0.033) were significant predictors of postoperative seizures in a multivariate analysis. CONCLUSIONS: Seizures are relatively common at meningioma presentation. While NF2-mutated tumors are significantly associated with preoperative seizures, the association appears to be mediated through edema and atypical histology. Patients who undergo radiation and/or have a recurrence are at risk for postoperative seizures, regardless of the extent of resection. Preoperative seizures may indeed portend a more potentially aggressive molecular entity and challenging clinical course with a higher risk of recurrence.

Diagnosis and management of periodic hypothermia.

Hypothermia, defined as a core temperature below 35°C, can occur in a variety of clinical settings, including environmental exposure, shock, infection, metabolic disorders (such as hypothyroidism, adrenal insufficiency, and Wernicke encephalopathy), malnutrition, and alcohol or drug toxicity. Typically, hypothermia should resolve with treatment of the underlying disorder. However, in rare cases patients experience recurrent episodes of hypothermia in the context of a stereotyped syndrome due to a hypothalamic lesion, which can be either congenital or acquired. The episodes are characterized by progressive confusion and a decreased level of arousal, hypothermia, and eventual resolution with a return to baseline. Additional clinical findings during episodes may include diaphoresis, asterixis, bradycardia, and thrombocytopenia. These recurrent episodes represent periodic hypothermia.

Anaplastic gliomas: radiation, chemotherapy, or both?

The optimal treatment of anaplastic gliomas is controversial. Options for treatment include radiation, chemotherapy or a combination of modalities. This article describes how treatment algorithms for anaplastic gliomas have evolved and interprets the results of recent studies. The available evidence indicates that patients can be treated with either chemotherapy or radiation as initial therapy, with use of the other treatment modality at relapse. Whether subpopulations exist for whom one treatment modality is superior to the other at initial diagnosis must be studied prospectively.

Plantar flexion with noxious dorsal foot stimulation in brain death.

BACKGROUND: Plantar flexion with plantar stimulation has been well described in brain death, and is compatible with brain death. However, plantar flexion with stimulation to the dorsal surface of the foot has not been reported previously in brain dead patients. METHODS: Case report with Technetium-99 m hexamethylpropyleneamine oxime brain scan and video. RESULTS: A 46-year-old woman suffered severe anoxic brain injury following massive pulmonary embolism 5 days after arthroscopic knee surgery. Neurologic examination was consistent with brain death, with the exception of plantar flexion when noxious stimulation was applied to the dorsal surface of the great toe on each side. Ancillary testing with a technetium-99 m nuclear scan demonstrated absence of cerebral perfusion, supporting the diagnosis of brain death. CONCLUSIONS: Noxious stimulation to the dorsal surface of the foot may trigger spinally mediated plantar flexion in patients with brain death.

Paraneoplastic syndrome of inappropriate antidiuretic hormone mimicking limbic encephalitis.

OBJECTIVE: To compare the features of paraneoplastic syndrome of inappropriate antidiuretic hormone with those of limbic encephalitis. DESIGN: Case study. SETTING: Academic medical center. PATIENT: A 46-year-old woman with progressive memory impairment, hyponatremia, and seizures. INTERVENTIONS: Magnetic resonance imaging of the brain, fluoro-2-deoxyglucose positron emission tomography of the body, and immunohistochemical analysis of a resected tumor. RESULTS: Though the patient presented with clinical features of classic limbic encephalitis, magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid analysis findings were unremarkable. Her chronic hyponatremia was ultimately found to be due to ectopic secretion of antidiuretic hormone by a neuroendocrine tumor with Merkel cell carcinoma phenotype. CONCLUSIONS: Patients presenting with memory impairment, seizures, and hyponatremia should undergo a thorough workup for occult malignancy. In addition to considering classic immune-mediated paraneoplastic limbic encephalitis, the ectopic secretion of antidiuretic hormone should be included in the differential diagnosis.

Neurologic prognosis in cardiac arrest patients treated with therapeutic hypothermia.

BACKGROUND: Therapeutic hypothermia is now commonly used to improve neurologic outcomes in eligible patients after cardiac arrest. The physiologic effects of cooling and pharmacologic effects of sedatives and neuromuscular blocking agents can affect the clinical exam and neurophysiologic findings. This can lead to uncertainty in neurologic prognostication. In this article, we review data on assessing prognosis in patients treated with therapeutic hypothermia. REVIEW SUMMARY: Features of the clinical examination, neurophysiologic testing (including somatosensory-evoked potentials and electroencephalography), serum/cerebrospinal fluid biomarkers and neuroimaging can be used to help predict prognosis. However, no single test can predict poor prognosis with absolute certainty. Given the features that help to predict poor, indeterminate, or good outcome, we provide practical advice in assessing neurologic prognosis after cardiac arrest in patients treated with therapeutic hypothermia. CONCLUSIONS: The American Academy of Neurology practice parameters for assessing prognosis after cardiac arrest may not be accurate for patients treated with therapeutic hypothermia. Application of these guidelines may lead to overly pessimistic prognostication and premature withdrawal of care. If uncertainty exists regarding the prognosis in a given patient after cardiac arrest, additional time should be allowed to pass, as patients may ultimately recover with good neurologic outcome.

Thrombolysis in right versus left hemispheric stroke.

BACKGROUND: Recent evidence has suggested that patients with right hemispheric stroke (RHS) present later to an emergency department, have a lower chance to receive intravenous (IV) recombinant tissue plasminogen activator (t-PA), and have poorer clinical outcomes than do patients with left hemispheric stroke (LHS). METHODS: We analyzed the rate of IV t-PA administration with respect to the side of the affected hemisphere in a large community population, to determine whether a difference exists. The study population was a large prospective cohort of patients with acute stroke treated with IV t-PA at our hospital's stroke center (October 2000 to October 2006). RESULTS: Of 2,932 patients presenting with ischemic stroke, 953 met criteria for study inclusion. In all, 151 patients received IV t-PA. Between groups, there was no significant difference in presentation within 3 hours after acute stroke (P=.180). There was no difference in the use of IV t-PA between patients with RHS and LHS (P=.237). CONCLUSIONS: There was no difference with respect to affected hemisphere in time to presentation to the emergency department. Furthermore, there was no difference in the rate of IV t-PA administration for patients with RHS versus LHS. This finding is in contrast to previous research on IV t-PA use in hemispheric stroke and may reflect improved recognition of right hemispheric syndromes.