Incomplete Third Nerve Palsy Due to a Carotid-Cavernous Fistula.

INTRODUCTION: The approach to oculomotor nerve palsies involves the exclusion of compressive, infective, inflammatory, or ischemic lesions. Dural arteriovenous fistulae, including carotid-cavernous fistulae (CCF), are known causes of third nerve palsy. However, diagnosis can sometimes be delayed or missed due to the various clinical presentations. CCF remains a rare but treatable cause of third nerve palsy. CASE REPORT: A 63-year-old Chinese female presented to our unit with gradual onset horizontal diplopia. Clinical examination revealed a partial left oculomotor nerve palsy without congestive eye symptoms. A cerebral angiogram revealed a left indirect CCF supplied by the inferolateral trunk of the left internal carotid artery. She underwent successful transvenous embolization. She improved postprocedure and was discharged well on day 10 of her admission. She was reviewed at 2 months follow-up and had recovered completely. CONCLUSION: Our case is a classic description of a CCF with posterior drainage into the inferior petrosal sinus. We hope this case and a review of the literature can serve as a reminder to clinicians of the varied presentations of CCF. We believe this case adds value to the clinicians in contributing to their diagnostic process and to our interventional colleagues in highlighting a case with a successful postembolization outcome.

Post-stroke patients with moderate function have the greatest risk of falls: a National Cohort Study.

BACKGROUND: Stroke patients have increased risks of falls. We examined national registry data to evaluate the association between post-stroke functional level and the risk of low falls among post-stroke patients. METHODS: This retrospective cohort study analyzed data from national registries to examine the risk factors for post-stroke falls. Data for patients who suffered ischemic strokes and survived the index hospital admission was obtained from the Singapore National Stroke Registry and matched to the National Trauma Registry, from 2011 to 2015. The primary outcome measure was a low fall (fall height ≤ 0.5 m). Competing risk analysis was performed to examine the association between functional level (by modified Rankin score [mRS] at discharge) and the risk of subsequent low falls. RESULTS: In all, 2255 patients who suffered ischemic strokes had recorded mRS. The mean age was 66.6 years and 58.5% were men. By the end of 2015, 54 (2.39%) had a low fall while 93 (4.12%) died. After adjusting for potential confounders, mRS was associated with fall risk with an inverted U-shaped relationship. Compared to patients with a score of zero, the sub-distribution hazard ratio (SHR) increased to a maximum of 3.42 (95%CI:1.21-9.65, p = 0.020) for patients with a score of 2. The SHR then declined to 2.45 (95%CI:0.85-7.12, p = 0.098), 2.86 (95%CI:0.95-8.61, p = 0.062) and 1.93 (95%CI:0.44-8.52, p = 0.38) for patients with scores of 3, 4 and 5 respectively. CONCLUSIONS: An inverted U-shaped relationship between functional status and fall risk was observed. This is consistent with the complex interplay between decreasing mobility (hence decreased opportunity to fall) and increasing susceptibility to falls. Fall prevention intervention could be targeted accordingly. (263 words).

Revisiting the public awareness, attitudes, and understanding towards epilepsy among Singapore residents.

A survey to assess the familiarity, attitudes, and knowledge about epilepsy was done using a questionnaire identical to the one used in 1999. Two hundred forty-six people participated in our survey in 2017 as compared with 214 in the 1999 survey. In terms of familiarity about epilepsy, 76% had heard or read about epilepsy, 55.7% had witnessed a seizure, and 35.8% knew someone with epilepsy (85%, 56%, and 36% respectively in 1999). Forty point five percent were not familiar with or did not know what to do if they witnessed a seizure (44% in 1999); 25.6% would put something in the mouth of a person having a seizure (32% in 1999). In terms of attitudes towards epilepsy, 14.6% would object to their children associating with one with epilepsy while 19.9% would object to their children marrying a person with epilepsy (13% and 36% respectively in 1999). Only 43.1% would employ a person with epilepsy while 68.3% would employ if seizures do not interfere with the job (42 and 66% respectively in 1999). In terms of knowledge of seizures and epilepsy, 66.3% associated epileptic attack with convulsion (68% in 1999). Only 37.5% were aware of nonconvulsive forms of epilepsy (25% in 1999). Twenty-six point eight percent did not know what treatment to recommend to relatives/friends with epilepsy while 60.6% recommend western medicine (22% and 60% respectively in 1999). CONCLUSION: The awareness, attitudes, and understanding towards epilepsy does not seem to show any significant difference when compared with that in 1999. Reluctance to marry and employ a person with epilepsy persists. The awareness about first aid of a patient having a seizure, attitudes towards marrying a person with epilepsy, and the understanding of cause of epilepsy have shown some positive changes over 17 years.

Ictal and interictal EEG patterns in patients with nonconvulsive and subtle convulsive status epilepticus.

BACKGROUND: Electroencephalography findings in nonconvulsive or subtle convulsive status epilepticus (NCSE and SCSE, respectively) can be heterogenous. We aimed to study the different patterns on EEG in our cohort of patients. OBJECTIVE: Our objective was to study ictal and interictal EEG patterns in patients with NCSE and SCSE. METHODS: From January 2012 to December 2013, EEGs recorded from patients admitted for altered mental status suspected of having NCSE or SCSE were reviewed retrospectively. Electroencephalography status was defined as having (a) continuous ictal discharges lasting >5 min or (b) >2 discrete bursts of ictal discharges, each lasting <5 min, without returning to previous background rhythm in between these bursts. RESULTS: Among 1698 EEGs recorded for at least 30 min from hospitalized patients, 55 (3.23%) satisfied the criteria of EEG SE. The ictal onset was regional in 37 (67.2%) EEGs, multiregional independent in 8 (14.5%), and generalized in 10 (18.4%). The EEG seizure duration was >5 min in 24 (43.6%) EEGs, between 1 and 5 min in 14 (25.4%), and less than 1 min in 17 (30.8%). Twenty (36.3%) EEGs showed one continuous prolonged seizure episode of >5-minute duration, 15 (27.2%) had 10 or less discrete episodes, 20 (36.3%) had more than 10 episodes, and 11 (20%) had 2 or more ictal patterns. Thirty (54.5%) EEGs had onset ictal frequency of >8 Hz whereas the rest had <8-Hz ictal frequency. In the interictal segment, 29 patients had continuous generalized slow waves, while 12 had intermittent generalized slow waves. Eleven patients had continuous slow waves lateralized to one hemisphere, and these were ipsilateral to the ictal focus in 10 but contralateral in 1. Other interictal waves seen were PLEDS (6), sharp waves (3), suppression (5), and triphasic waves (1). The background alpha rhythm was absent in 36 patients and slow in 14, and normal background alpha was seen in the interictal period in 5 patients. CONCLUSION: The ictal and interictal EEG patterns in NCSE and SCSE can be varied. Further study to look for etiologic and clinical correlates of each pattern could add to its clinical value. This article is part of a Special Issue entitled "Status Epilepticus".

Central pontine myelinolysis presenting as isolated sixth nerve palsy in third trimester of pregnancy.

A 30-year-old primigravida presented with isolated left sixth nerve palsy at 38 weeks gestation. Her MRI showed a lesion consistent with central pontine myelinolysis (CPM). Extensive investigations did not reveal any secondary cause for the CPM. She recovered spontaneously in 2 weeks with complete resolution of her MRI changes. To our knowledge, this is the first report of CPM occurring in third trimester in the absence of identifiable secondary causes and of CPM presenting as an isolated sixth nerve palsy. We discuss the reported causes of CPM in pregnancy, possible pathophysiologic mechanisms involved and the anatomic basis of the unique clinical presentation of sixth nerve palsy in our case.

Surgical outcomes in patients with extratemporal epilepsy and subtle or normal magnetic resonance imaging findings.

BACKGROUND: Surgery is an important therapeutic option in patients with medically refractory epilepsy. The combination of an extratemporal epileptic focus and nonlesional magnetic resonance imaging (MRI) was often believed to portend a poor outcome. OBJECTIVE: To investigate the outcome and analyze potential prognostic predictors in patients without lesions on MRI who underwent extratemporal resections. METHODS: Clinical, presurgical evaluation, invasive monitoring, and postoperative data of patients with high-resolution MRI that was initially reported as nonlesional were reviewed. Patients were reclassified as MRI-positive if an MRI abnormality related to the epilepsy was revealed at the multidisciplinary presurgical patient management conference, or as MRI-negative if imaging remained normal or revealed incidental findings. RESULTS: Sixty patients were identified; 72% were MRI-negative. In the original cohort, the median seizure-free duration was 1.32 years (95% confidence interval [CI], 0.16-2.0); probability of seizure freedom at 2 years was 36% (95% CI, 30%-43%). In the MRI-negative group, the median seizure-free duration was 1.52 years (95% CI, 0.12-5.17); probability of seizure freedom at 2 years was 42% (95% CI, 33%-50%). Complete resection of ictal onset areas and absence of acute postoperative seizures were significantly associated with longer seizure freedom (risk ratio 4.9, P = .004; 95% CI, 1.6-16.7 and 22.1, P < .001; 95% CI, 5.9-94.7, respectively). CONCLUSION: Among patients with medically refractory MRI nonlesional extratemporal epilepsy, detailed evaluation and subsequent resection leads to seizure freedom in 42% of patients at 2 years.

Combined temozolomide and radiation as an initial treatment for anaplastic glioma.

AIM: Combined temozolomide (TMZ) and radiation therapy (RT) is often used as initial treatment for anaplastic glioma. However, there is no prospective randomized data available that proves the efficacy of the combination for anaplastic glioma. In this retrospective study we aimed to compare the outcome of patients who had combined TMZ and RT with those who had RT alone for the initial treatment of anaplastic glioma in our centers. METHODS: Patients with anaplastic astrocytoma or oligoastrocytoma treated at our centers between 2000 and 2010 were reviewed. Only patients who received initial RT or concurrent TMZ and RT (TMZ-RT) were included. RESULTS: Of 62 patients, 55 were less than 66-years old; 36 (58.1%) had a tumor resection and 26 had a biopsy only. An oligodendroglial component in their tumor histology was present in 21 patients (33.9%). At a median follow up of 20.7 months for all patients, median progression-free survival was similar for the two treatment groups (RT alone: 16.7 months (95% CI 9.4, 34.8 months) versus TMZ-RT: 14.8 months (95% CI 8.6, 28.6 months, P = NS). Median overall survival was 27.4 months (95% CI 10.6, not estimable [NE] months) for patients who had RT alone and 34.1 months (95% CI 19.8, 42.1 months) for those who had TMZ-RT. CONCLUSION: No significant benefit of combined TMZ with RT compared to RT alone was observed as the initial treatment of anaplastic glioma. Prospective randomized trials are needed to evaluate the optimal treatment for this disease.

Promising role of [18F] fluorocholine PET/CT vs [18F] fluorodeoxyglucose PET/CT in primary brain tumors-early experience.

Primary brain tumors (PBT), in particular gliomas, are among the most difficult neoplasms to treat, necessitating good quality imaging to guide clinicians at many junctures. Current imaging modalities, including [18F] fluorodeoxyglucose (FDG) PET/CT, MRI and MR spectroscopy (MRS), have various limitations, particularly with regard to differentiating tumor from radiation induced necrosis (RIN) and from normal cerebral metabolic uptake. [18F] fluorocholine (FCH) is an analog of choline with potentially optimal imaging characteristics, as pharmacokinetic studies with FCH conducted in patients showed minimal FCH uptake by normal brain parenchyma, whereas high-grade tumors are known to have increased choline uptake. We present two cases of our early experience with FCH PET/CT for patients with PBT and discuss the potential use and comparative limitations of this imaging modality.

Vanishing glioblastoma after corticosteroid therapy.

A recurrent right temporal glioblastoma that vanished on MRI after a short course of intense corticosteroid therapy is reported. This was associated with development of new multicentric lesions in the right frontal lobe and right splenium of the corpus callosum. Rapid disappearance of tumor with steroid therapy is frequently associated with lymphoma and is rarely described in high-grade gliomas. Literature review showed that multicentricity and involvement of the corpus callosum are common features of glioblastoma that vanish after corticosteroid therapy.

Cryopreservation of neurospheres derived from human glioblastoma multiforme.

Cancer stem cells have been shown to initiate and sustain tumor growth. In many instances, clinical material is limited, compounded by a lack of methods to preserve such cells at convenient time points. Although brain tumor-initiating cells grown in a spheroid manner have been shown to maintain their integrity through serial transplantation in immune-compromised animals, practically, it is not always possible to have access to animals of suitable ages to continuously maintain these cells. We therefore explored vitrification as a cryopreservation technique for brain tumor-initiating cells. Tumor neurospheres were derived from five patients with glioblastoma multiforme (GBM). Cryopreservation in 90% serum and 10% dimethyl sulfoxide yielded greatest viability and could be explored in future studies. Vitrification yielded cells that maintained self-renewal and multipotentiality properties. Karyotypic analyses confirmed the presence of GBM hallmarks. Upon implantation into NOD/SCID mice, our vitrified cells reformed glioma masses that could be serially transplanted. Transcriptome analysis showed that the vitrified and nonvitrified samples in either the stem-like or differentiated states clustered together, providing evidence that vitrification does not change the genotype of frozen cells. Upon induction of differentiation, the transcriptomes of vitrified cells associated with the original primary tumors, indicating that tumor stem-like cells are a genetically distinct population from the differentiated mass, underscoring the importance of working with the relevant tumor-initiating population. Our results demonstrate that vitrification of brain tumor-initiating cells preserves the biological phenotype and genetic profiles of the cells. This should facilitate the establishment of a repository of tumor-initiating cells for subsequent experimental designs.

Characterization of a side population of astrocytoma cells in response to temozolomide.

OBJECT: Cancer progenitor-like cells isolated by Hoechst 33342 dye efflux (termed the "side population" [SP]) have been studied in a variety of cancers, including malignant brain tumors. In this study, the authors investigate the nature of the SP phenotype in 2 glioma cell lines, U87MG and T98G, and their response to temozolomide. The roles of several adenosine triphosphate-binding cassette (ABC) multidrug transporters expressed by SP cells, in particular ABCG2, are also examined. METHODS: Using fluorescence-activated cell sorting, the cells were separated into SP and non-SP fractions and analyzed for progenitor cell-like properties with immunofluorescence staining, quantitative real-time polymerase chain reaction, and their ability to reform glioma mass in an immune-compromised mouse. The response of the SP cells to temozolomide was investigated at the cellular and molecular levels. Small interfering RNA knockdown was used to examine the specific role of the ABCG2 transporter, and the cells' tumorigenic potential was measured using the soft agar clonogenic assay. RESULTS: Side population cells are characterized by the presence of progenitor cell-like properties: increased expression of nestin, musashi-1, and ABCG2 were observed. In addition, only SP cells were able to reconstitute cellular heterogeneity; these cells were also more invasive than the non-SP cells, and possessed tumorigenic capacity. Temozolomide treatment increased the number of SP cells, and this corresponded to more progenitor-like cells, concurrent with elevated expression of several ABC transporters. CONCLUSIONS: Knockdown of ABCG2 transporters did not abrogate the SP cell response to temozolomide. Upregulation of several other ABC drug transporter genes is proposed to account for this chemoresistance.

A rare cause of reversible unilateral third nerve palsy.

CASE REPORT: A 59-year-old Chinese male presented in January 2007 with acute left retro-orbital headache, diplopia and left partial ptosis. Isolated left third nerve palsy was diagnosed. Imaging studies and cerebral angiography excluded a posterior communicating artery aneurysm. Anti-nuclear (titre 1/800, speckled pattern), anti-PR3, anti-Ro and anti-La antibodies were present. Sjogren's syndrome (SS) was considered in view of positive anti-Ro and La antibodies, and was confirmed with focal lymphocytic infiltrates on labial salivary gland biopsy and a positive Schirmer's test (6 mm of tear flow over 5 min). Immunosuppressive therapy was started 2 months after his initial presentation and within 2 weeks, the patient experienced an almost complete recovery of both ptosis and diplopia. He has been on tapering doses of prednisolone since and his condition remains stable. CONCLUSION: This patient has cranial neuropathy secondary to Sjogren's syndrome. The rapid reversibility of the oculomotor nerve palsy with immunosuppression suggests lymphocytic infiltration or autoantibodies as the cause rather than a vasculitic process, which would have led to irreversible or slowly, partially reversible ischaemic damage.

Application of the McDonald MRI criteria in multiple sclerosis.

INTRODUCTION: The aim of this study was to assess the sensitivity of McDonald's magnetic resonance imaging (MRI) criteria for the diagnosis of multiple sclerosis (MS) in a group of Asian patients diagnosed with clinically definite MS, based on lesion characterisation on MRI scans. MATERIALS AND METHODS: Forty-nine patients from 3 major neurological institutions were classified as having Asian- or Western-type MS based on clinical assessment. Each MRI scan was reviewed by 2 neuroradiologists for the presence and characteristics of brain and spinal lesions. The McDonald's MRI criteria were then applied and its sensitivity evaluated. RESULTS: Nine patients were excluded, leaving 34 females and 6 males who were dominantly Chinese (90%), with a mean age of 36.2 years. The MRI brain and spinal findings were detailed and tabulated. Statistically significant differences (P <0.01) in MRI brain findings and sensitivity of McDonald's MRI criteria were found between our Asian- and Western-type MS patients. The diagnostic yield of McDonald's MRI criteria increased by 20% when we substituted a cord for a brain lesion, and applied the substitution for enhancing cord lesions as well. CONCLUSION: The diagnosis is more likely to be made when using McDonald MRI criteria based on brain findings, in a patient who presents clinically with Western-type MS. The provision for substitution of "one brain for a spinal lesion" is helpful in Asian-type MS, where there is preponderance of spinal lesion load. Our findings suggest that minor modifications in the interpretation of McDonald's MRI criteria have significant impact on the diagnosis in patients clinically presenting as Asian-type MS, with potential bearing on their subsequent management.

Improved median survival for glioblastoma multiforme following introduction of adjuvant temozolomide chemotherapy.

INTRODUCTION: The use of adjuvant temozolomide (TMZ) in patients managed with surgery and adjuvant radiation therapy (RT) for glioblastoma multiforme (GBM) has been demonstrated to improve median and 2-year survival in a recent large international multicentre study. To confirm this result in routine clinical practice, an audit of the management and outcome of patients with GBM at The Cancer Institute Radiation Oncology was performed. MATERIALS AND METHODS: All patients with GBM managed radically at The Cancer Institute Radiation Oncology from May 2002 to 2006 were entered into a prospective database. Patient, tumour and treatment factors were analysed for association with the outcome of median survival (MS). Survival was calculated using the Kaplan-Meier technique and correlation was assessed using Cox proportional hazards regression. RESULTS: Forty-one patients with GBM were managed with radical intent over the 4- year period. The median age was 54 years and 66% were Eastern Cooperative Oncology Group (ECOG) 0-1 performance status. Macroscopic, subtotal and biopsy alone procedures were performed in 61%, 29% and 10% of patients, respectively. The median time from surgery to RT was 26 days. Adjuvant TMZ was used in 44% of patients (n = 18). The MS of the total group was 13.6 months, with a 24% 2-year overall survival. The use of TMZ was associated with improved MS (19.6 versus 12.8 months; P = 0.035) and improved 2-year survival (43% versus 0%). A requirement of dexamethasone dose greater than 4 mg at the end of RT (P = 0.012) was associated with worse survival, but there was no association of MS with age, ECOG, tumour size or extent of surgery. CONCLUSION: The median and 2-year survival outcomes are comparable to the results of the European Multicentre Study and justify the continued use of TMZ in routine clinical practice.

Salvage chemotherapy in progressive high-grade astrocytoma.

INTRODUCTION: Despite aggressive multidisciplinary interventions, patients with high-grade astrocytomas experience tumour progression or recurrence. Treatment for this group of patients remains a formidable challenge. We describe our experience of salvage chemotherapy for these patients. MATERIALS AND METHODS: A retrospective review of relevant clinical and radiographic information of patients who received at least one cycle of salvage chemotherapy for progressive high-grade astrocytoma at the National Cancer Center, Singapore, from March 2004 to September 2006, was conducted. Patients underwent regular assessment with clinical examination and magnetic resonance brain imaging to gauge response to salvage chemotherapy. Survival and progression free interval data were analysed via Kaplan-Meier method. RESULTS: Twenty-four patients (13 glioblastomas, 11 anaplastic astrocytomas) had received chemotherapy as salvage treatment following progression of their high-grade astrocytoma. Among 20 patients assessable for tumour response, there were 4 patients with partial responses and 9 with stable responses. The 12-month survival rate for the entire group from time of onset of tumour progression was 49.6%. Eight patients had survived more than 12 months at the time of writing. Among patients with glioblastoma, the 12-month survival rate was 30% and the median survival was 11.2 months. For patients with anaplastic astrocytoma, the 12-month survival rate was 73%. CONCLUSION: Durable disease control and prolonged survival were seen in a significant portion of selected patients with progressive high-grade astrocytoma who received salvage chemotherapy.

Improvements in quality of care resulting from a formal multidisciplinary tumour clinic in the management of high-grade glioma.

INTRODUCTION: There is increasing belief that a formal protocol-based multidisciplinary care model should be adopted as an optimal care model in oncology. However, there is minimal outcome evidence to demonstrate an improvement in patient care. The aim of this study was to compare clinical quality outcomes between patients with high-grade glioma managed at one hospital using a formal neuro-oncology multidisciplinary tumour clinic (MTC) and a second hospital with a traditional on-call referral pattern (non-MTC). MATERIALS AND METHODS: Patients with high-grade glioma managed radically with radiation therapy at 2 Singapore hospitals from May 2002 to May 2006 were entered into a prospective database. Patients were grouped into management via MTC or non-MTC. Four clinical quality indicators were chosen retrospectively to assess the variation in practice: a) Use of computed tomography (CT) or magnetic resonance (MR) imaging post-resection (POI) for assessment of residual disease; b) Commencement of radiation therapy (RT) within 28 days of surgery; c) Adjuvant chemotherapy use for glioblastoma multiforme (CTGBM) and d) Median survival. RESULTS: Sixty-seven patients were managed radically, with 47 by MTC and by 20 by non-MTC. MTC patients were more likely to have POI (P = 0.042), and CTGBM (P = 0.025). Although the RT start time was similar for the whole cohort (60% versus 45%: P = 0.296); for GBM patients, the RT start was earlier (63% vs 33% P = 0.024). The median survival for the MTC group was 18.7 months versus 11.9 months for the non-MTC group (P = 0.11). CONCLUSION: Clinical quality outcomes were significantly improved in patients with high-grade glioma managed in this neuro-oncology MTC.

Chemotherapy in adults with gliomas.

Treating patients with gliomas requires a multidisciplinary approach, which often includes surgery, radiation and chemotherapy. Recent developments have demonstrated the efficacy of chemotherapeutic agents in patients with newly diagnosed or recurrent gliomas. Large clinical studies have provided important information on the impact of chemotherapy for anaplastic oligodendrogliomas in the upfront setting. Randomised trials have demonstrated the benefit of chemoradiation for patients with glioblastoma. Investigations are also under way to clarify the role of chemotherapy for low-grade gliomas. This review article summarises the recent developments and approaches in the use of chemotherapy to treat adult patients with astrocytomas and oligodendrogliomas.