Management of brain tumour related epilepsy (BTRE): a narrative review and therapy recommendations.

Brain Tumour Related Epilepsy (BTRE) has a significant impact on Quality of Life with implications for driving, employment, and social activities. Management of BTRE is complex due to the higher incidence of drug resistance and the potential for interaction between anti-cancer therapy and anti-seizure medications (ASMs). Neurologists, neurosurgeons, oncologists, palliative care physicians and clinical nurse specialists treating these patients would benefit from up-to-date clinical guidelines. We aim to review the current literature and to outline specific recommendations for the optimal treatment of BTRE, encompassing both Primary Brain Tumours (PBT) and Brain Metastases (BM). A comprehensive search of the literature since 1995 on BTRE was carried out in PubMed, MEDLINE and EMCARE. A broad search strategy was used, and the evidence evaluated and graded based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Seizure frequency varies between 10 and 40% in patients with Brain Metastases (BM) and from 30% (high-grade gliomas) to 90% (low-grade gliomas) in patients with PBT. In patients with BM, risk factors include number of BM and melanoma histology. In patients with PBT, BTRE is more common in patients with lower grade histology, frontal and temporal tumours, presence of an IDH mutation and cortical infiltration. All patients with BTRE should be treated with ASMs. Non-enzyme inducing ASMs are recommended as first line treatment for BTRE, but up to 50% of patients with BTRE due to PBT remain resistant. There is no proven benefit for the use of prophylactic ASMs, although there are no randomised trials testing newer agents. Surgical and oncological treatments i.e. radiotherapy and chemotherapy improve BTRE. Vagus Nerve Stimulation has been used with partial success. The review highlights the relative dearth of high-quality evidence for the management of BTRE and provides a framework for further studies aiming to improve seizure control, quality of life, and indications for ASMs.KEY POINTSOffer levetiracetam or lamotrigine to all patients with primary or metastatic brain tumours who have seizure(s), irrespective of whether these are partial or generalised.ASM withdrawal for patients in remission is not recommended due to high rates of seizure recurrence.ASM prophylaxis is not generally recommended in the management of seizure-naïve patients.Both levetiracetam and lamotrigine are safe in pregnancy and breastfeeding.

Peripheral nerve neurolymphomatosis: Clinical features, treatment, and outcomes.

This series characterises nine patients with neurohistopathologically proven peripheral nerve neurolymphomatosis. A search of the hospital neuropathology database from 2002 to 2019 identified biopsy proven cases. Clinical data, investigation modalities, treatments, and outcomes were collated. Median age at neuropathy onset was 47 y, the neuropathy commonly as the initial lymphoma disease manifestation. Most (8/9) presented with painful asymmetrical sensory disturbance, with additional cranial nerve involvement in three. Neurophysiology typically demonstrated multiple axonal mononeuropathies. Cerebrospinal fluid protein was often raised (6/8). Magnetic resonance imaging suggested peripheral nerve infiltration in 6/9 and positron emission tomography CT in 4/9. Bone marrow biopsy was abnormal in 6/8. Treatment involved systemic or intrathecal chemotherapy and radiotherapy. Median survival was 23 mo. Neurolymphomatosis is a rare but important cause of neuropathy, particularly in those lacking systemic evidence of lymphoma as correct aggressive treatment can prolong survival. Nerve biopsy is essential to classify lymphoma type and rule out alternatives.

Acute demyelination following radiotherapy for glioma: a cautionary tale.

Radiotherapy is the mainstay of treatment after surgery for high-grade gliomas and is usually well tolerated. Radiation toxicity in the brain is usually classified according to the timing of side effects in relation to treatment, as either acute (during radiotherapy), early delayed (within 12 weeks of radiotherapy) or late delayed (months to years after radiotherapy). We report two cases of young women who developed severe acute demyelination within 4 months of radiotherapy for glioma, one of whom had a previous history of transverse myelitis. Both improved with corticosteroids and remain in tumour remission. These cases emphasise the importance of careful discussion with patients before starting radiotherapy if there is a previous history of central nervous system demyelination or multiple white matter lesions on MRI.

White matter integrity assessed by diffusion tensor tractography in a patient with a large tumor mass but minimal clinical and neuropsychological deficits.

Diffusion tensor imaging (DTI) tractography and image registration were used to investigate a patient with a massive left-sided brain tumor, whose size was largely disproportionate to his subtle neurological deficits. MRI was obtained from the patient and his healthy identical twin, who acted as anatomical reference for DTI and as a control for quantitative measures. To compensate for the patient's altered anatomy, seed and way points for probabilistic tractography were drawn on the color-coded direction maps of the healthy twin. Registration, based on the combination of b0-images, T2-weighted and T1-weighted images, was used to identify the corresponding regions in the patient. The corticospinal tract (CST), the superior longitudinal fasciculus (SLF), and the cingulum bundle (CB) showed displaced anatomy. A significant difference was found between fractional anisotropy distribution along the left SLF and CB, but not along the CST. These findings fit well with the patient's substantial preservation of his motor abilities, while abnormalities of the SLF and CB could explain the subtle but detectable cognitive deficits.

Quantitative magnetisation transfer imaging in glioma: preliminary results.

Quantitative magnetisation transfer imaging (qMTI) is an extension of conventional MT techniques and allows the measurement of parameters that reflect tissue ultrastructure through the properties of macromolecule-bound protons; these include the bound proton fraction and the relaxation times of free and bound proton pools. It has been used in multiple sclerosis and Alzheimer's disease, and has shown changes in some of the parameters, particularly the bound proton fraction. The purpose of this pilot study was to assess whether qMTI could distinguish between gliomas and normal brain tissue, and provide proof of principle for its use in tumour characterisation. Eight subjects [three men, five women; mean age, 44 years; range, 27-66 years; seven World Health Organization (WHO) Grade II, one Grade III] with biopsy-proven glioma were imaged with a structural MRI protocol that included three-dimensional qMTI. qMTI parameters were extracted from regions of interest selected from different tumour components visible on conventional MR sequences, normal-appearing peritumoral tissue and distant normal-appearing white matter. All patients gave informed consent and the study was approved by the Local Research Ethics Committee. Almost all of the qMTI parameters detected abnormalities in both glioma and the peritumoral region relative to the distant white matter. In particular, the bound proton fraction was reduced significantly from 6.0 percentage units (pu) [standard deviation (SD), 0.5 pu] in normal-appearing white matter to 1.7 pu (SD = 0.5 pu) in solid tumour and 2.2 pu (SD = 0.5 pu) in peritumoral areas. This work shows that qMTI reveals abnormalities, not only in glioma, but also in the apparently normal tissue surrounding the conventionally defined tumour. Thus, qMTI shows promise for tumour characterisation and for studying tumour boundaries. These preliminary data justify larger studies in a range of different tumour types and grades.

A case study investigating the role of the anterior temporal lobes in general semantics and semantics specific to persons, emotions and social conceptual knowledge.

The role of the anterior temporal lobes (ATLs) in semantic representation remains still much debated. Long thought to support domain-general semantic processing, recent accounts have alternatively suggested that they may be preferentially involved in the processing of person-related semantic knowledge. Several studies have supported such a distinction, but few have either examined both types of semantic processing together, or considered the role of potentially important confounding variables. Here, we address these issues by investigating both domain-general and person-specific semantic processing in a patient with focal ATL damage. The patient presents with dense anterograde and retrograde amnesia. Performance was impaired on tests of general semantic knowledge, but most striking deficits were for person-related semantics, including recognition and identification, knowledge of emotions and social conceptual knowledge. This unique case provides compelling evidence that, in addition to the role in general semantic knowledge, the ATLs are critical for person-related semantics.

Seizure outcomes and survival in adult low-grade glioma over 11 years: living longer and better.

BACKGROUND: There has been a trend toward earlier and more aggressive resection for low-grade gliomas (LGGs). This study set out to compare seizure control and survival of adults with LGG seen in the same neuro-oncology clinic over 11 years and to determine whether a change in surgical philosophy has led to a corresponding improvement in outcomes. METHODS: We conducted a retrospective analysis using case-note review of 153 adults with histologically verified or radiologically suspected LGG, collecting data on patient, tumor, and seizure characteristics between 2006 and 2017. RESULTS: We studied 79 patients in 2006 and 74 patients in 2017. There was no significant difference between the 2 groups in age at presentation, tumor location, or integrated pathological diagnosis. The numbers of complete or partial resections increased from 21.5% in 2006 to 60.8% in 2017 (P < .05). Five- and 10-year overall survival increased from 81.8% and 51.7% in 2006 to 100% and 95.8% in 2017 (P < .001); similarly, 5- and 10-year progression-free survival increased from 47.0% and 30.7% in 2006 to 93.1% and 68.7% in 2017. The proportion of patients with intractable epilepsy declined from 72.2% in 2006 to 43.2% in 2017 (P < .05). The neurosurgical morbidity rate was identical in both groups (11.8% in 2006 vs 11.1% in 2017). CONCLUSION: Management of LGG over the last 11 years has led to substantial improvements in survival and seizure control. This is most likely thanks to a change in surgical philosophy, with early resection now favored over watchful waiting where possible.

Effect of frontal lobe lesions on the recollection and familiarity components of recognition memory.

Single-process theories assume that familiarity is the sole influence on recognition memory with decisions being made as a continuous process. Dual-process theories claim that recognition involves both recollection and familiarity processes with recollection as a threshold process. Although, the frontal lobes of the brain play an important role in recognition memory, few studies have examined the effect of frontal lobe lesions on recollection and familiarity. In the current study, the nonverbal recognition memory of 24 patients with focal frontal lesions due to tumour or stroke was examined. Recollection and familiarity were estimated using the receiver operating characteristic (ROC) method. A secondary analysis was also conducted using standard signal detection theory methodology. Both analyses led to similar conclusions where only the familiarity component of recognition memory was impaired in frontal patients compared to healthy controls whilst the recollection-type (or variance ratio) processes remained intact.

Low-grade gliomas: do changes in rCBV measurements at longitudinal perfusion-weighted MR imaging predict malignant transformation?

PURPOSE: To prospectively perform longitudinal magnetic resonance (MR) perfusion imaging of conservatively treated low-grade gliomas to determine whether relative cerebral blood volume (rCBV) changes precede malignant transformation as defined by conventional MR imaging and clinical criteria. MATERIALS AND METHODS: All patients gave written informed consent for this institutional ethics committee-approved study. Thirteen patients (seven men, six women; age range, 29-69 years) with biopsy-proved low-grade glioma treated only with antiepileptic drugs were examined longitudinally with susceptibility-weighted perfusion, T2-weighted, fluid-attenuated inversion recovery, and high-dose contrast material-enhanced T1-weighted MR imaging at 6-month intervals to date or until malignant transformation was diagnosed. Student t tests were used to determine differences in rCBV values between "transformers" and "nontransformers" at defined time points throughout study follow-up. RESULTS: Seven patients showed progression to high-grade tumors between 6 and 36 months (mean, 22.3 months), and disease in six patients remained stable over a period of 12-36 months (mean, 23 months). Transformers had a slightly (but not statistically significantly) higher group mean rCBV than nontransformers at the point of study entry (1.93 vs 1.31). In nontransformers, the rCBV remained relatively stable and increased to only 1.52 over a mean follow-up of 23 months. In contrast, transformers showed a continuous increase in rCBV up to the point of transformation, when contrast enhancement became apparent on T1-weighted images. The group mean rCBV was 5.36 at transformation but also showed a significant increase from the initial study at 12 months (3.14, P = .022) and at 6 months (3.65, P = .049) before transformation. Rates of rCBV change between two successive time points were also significantly higher in transformers than in nontransformers. CONCLUSION: In transforming low-grade glioma, susceptibility-weighted MR perfusion imaging can demonstrate significant increases in rCBV up to 12 months before contrast enhancement is apparent on T1-weighted MR images.

Seizures and epilepsy in oncological practice: causes, course, mechanisms and treatment.

There are few data available on the causes and mechanistic basis, outcome and treatment of seizures and epilepsy in people with systemic cancer. Seizures and epilepsy in people with cancers other than primary brain tumours are reviewed here. Articles published in English, which discussed the neurological manifestations and complications of cancer and its treatment, were searched and information on the frequency, aetiology, and course of seizures and epilepsy was extracted. The frequency, aetiology and outcome of seizure disorders in patients with cancer differ from those in the general population. Intracranial metastasis, cancer drugs and metabolic disturbances are the most common causes. Infections, cerebrovascular complications of systemic cancer and paraneoplastic disorders are among the rarer causes of seizures in patients with neoplasms. Several drugs used in the treatment of cancer, or complications arising from their use, can trigger seizures through varied mechanisms. Most drug-induced seizures are provoked and do not require long-term treatment with antiepileptic drugs.

Severity of Guillain-Barré syndrome is associated with Fc gamma Receptor III polymorphisms.

Macrophages and ganglioside-specific IgG are involved in the pathogenesis of Guillain-Barre syndrome (GBS). Leukocyte IgG receptors (Fc gammaR) confer potent cellular effector functions to the specificity of IgG. The efficacy of IgG-mediated cellular inflammatory responses is determined by functional polymorphisms of three Fc gammaR subclasses (Fc gammaRIIa: H131/R131; Fc gammaRIIIa: V158/F158; Fc gammaRIIIb: NA1/NA2). Fc gammaR genotype distributions were determined in a Dutch, and British cohort of GBS patients and controls. In addition, a meta-analysis incorporating all previously published data, encompassing a total of 345 GBS patients and 714 healthy controls, was performed. Results suggest that Fc gammaRIII genotypes may represent mild disease-modifying factors in GBS.

Relative cerebral blood volume measurements of low-grade gliomas predict patient outcome in a multi-institution setting.

BACKGROUND/PURPOSE: The prognostic value of defining subcategories of gliomas is still controversial. This study aims to determine the utility of relative cerebral blood volume (rCBV) in predicting clinical response in patients with low-grade glioma at multiple institutions. MATERIALS AND METHODS: Sixty-nine patients were studied with dynamic susceptibility contrast-enhanced perfusion MRI at two institutions. The pathologic diagnoses of the low-grade gliomas were 34 astrocytomas, 20 oligodendroglioma, 9 oligoastrocytomas, 1 ganglioglioma and 5 with indeterminate histology. Wilcoxon tests were used to compare patients in different response categories with respect to baseline rCBV. Kaplan-Meier curve and log-rank tests were used to predict the association of rCBV with time to progression. RESULTS: At both institutions, patients with an adverse event (progressive disease or death) had a significantly higher baseline rCBV than those without (complete response or stable disease) (p value=0.0138). The odds ratio for detecting an adverse event when using rCBV was 1.87 (95% confidence interval: 1.14-3.08). rCBV was significantly negatively associated with time to progression (p=0.005). The median time to progression among subjects with rCBV>1.75 was 365 days, while there was 95% confidence that the median time to progression was at least 889 days among subjects with rCBV<1.75. CONCLUSION: Our study suggests not only that rCBV measurements correlate well with time to progression or death, but also that the findings can be replicated across institutions, which supports the application of rCBV as an adjunct to pathology in predicting glioma biology.

Quantitative imaging biomarkers in neuro-oncology.

Conventional structural imaging provides limited information on tumor characterization and prognosis. Advances in neurosurgical techniques, radiotherapy planning and novel drug treatments for brain tumors have generated increasing need for reproducible, noninvasive, quantitative imaging biomarkers. This Review considers the role of physiological MRI and PET molecular imaging in understanding metabolic processes associated with tumor growth, blood flow and ultrastructure. We address the utility of various techniques in distinguishing between tumors and non-neoplastic processes, in tumor grading, in defining anatomical relationships between tumor and eloquent brain regions and in determining the biological substrates of treatment response. Much of the evidence is derived from limited case series in individual centers. Despite their 'added value', the effect of these techniques as an adjunct to structural imaging in clinical research and practice remains limited.

Apparent diffusion coefficient histograms may predict low-grade glioma subtype.

The subtypes of glioma are known to have different prognosis and response to treatment. The purpose of this work was to investigate whether apparent diffusion coefficient (ADC) histograms of untreated low-grade astrocytomas and oligodendrogliomas exhibit different characteristics due to their biological differences, and whether a diagnosis of tumour subtype can be made at presentation using the histogram alone, which, if possible, would have an impact on clinical practise. Fifteen patients with astrocytoma (AC) [11 male (mean age +/- standard deviation) 40 +/- 11 years], nine with oligodendroglioma (OD) (four male, 45 +/- 13 years) and three with oligoastrocytoma (OA) (two male, 60 +/- 11 years) were recruited and diffusion-weighted images (b = 0 and 1000 s mm(-2)) were acquired every 6 months to date or until malignant transformation. Whole tumour ADC histograms were calculated, a multiple discriminant analysis was performed and quantitative morphological parameters extracted, the AC and OD subtypes were then compared using Student's unpaired t-test. Classification of the histograms was also performed. ODs had significantly lower group ADC values than ACs and up to 83% of the subjects could be correctly classified into the OD and AC groups by reference to the histogram. The group differences were most significant for the multiple discriminant analysis (p = 1 x 10(-5)) and at the 10th centile point [AC = 1170 +/- 170, OD = (1030 +/- 80) x 10(-6) mm(2) s(-1)] (p = 0.01). ODs have a lower ADC than ACs with differences throughout the histogram. Both tumour types show similar intra-tumour heterogeneity, as seen from the equal group peak heights, but ACs shows more intra-group heterogeneity. ADC histogram analysis may aid non-invasive sub-classification of low-grade glioma histological subtypes.

Quantitative analysis of whole-tumor Gd enhancement histograms predicts malignant transformation in low-grade gliomas.

PURPOSE: To quantify subtle gadolinium (Gd) enhancement (signal increase) in whole-tumor histograms and optimize their ability to predict subsequent malignant transformation in low-grade gliomas (LGGs). MATERIALS AND METHODS: We analyzed histograms from 21 adult subjects with LGGs (eight nontransformers and 13 transformers) who had been imaged every six months for periods of two to five years. Before transformation these tumors were reported as radiologically non-enhancing. Imaging included a T(1)-weighted volume sequence before and after a double dose of Gd-DTPA contrast agent. Image data sets were spatially registered and subtracted to obtain maps of percent enhancement (%E). Tumor outlines were defined on fluid-attenuated inversion recovery (FLAIR) images, and the volumes were calculated. Histogram tails were analyzed to obtain the volume (mL) of subtly enhancing tissue (%E > 10%). RESULTS: Baseline enhancing volumes were higher for Ts than for NTs (P < 0.005). Kaplan-Meier survival curves for a threshold of 4 mL showed clear differences at five years (P < 0.04). Pretransformation examinations predicted transformation (corrected threshold = 3.0 mL, P = 0.011). CONCLUSION: Clear histogram differences at presentation suggest that the process of transformation starts very early. It is now possible to identify individuals at high risk for transformation at baseline by quantifying the volume of subtly enhancing tumor tissue, and such findings could have an impact on patient management.

Low-grade gliomas in adults.

PURPOSE OF REVIEW: This paper aims to summarize the current thinking about the management of adult supratentorial low-grade gliomas. These are well differentiated primary brain tumours that typically develop in young adults. Their biological behaviour is poorly understood but the majority of these tumours grow slowly, infiltrate surrounding normal brain, and show an intrinsic tendency to undergo malignant transformation to high-grade gliomas. Surgery and radiotherapy are the main treatment options, but their precise role and timing are controversial. RECENT FINDINGS: Resective surgery is at best regarded as a practice option because there is a paucity of good quality evidence to show that extent of resection correlates with survival. Radiotherapy prolongs progression-free survival but not overall survival and may lead to long-term cognitive deficits, although not as widespread as had previously been thought. A minority of tumours with oligodendroglial differentiation are chemosensitive and this correlates with allelic loss of chromosomes 1p and 19q. New imaging and molecular techniques, in particular gene microarray studies, are providing more information about these tumours, although they have yet to have a significant impact on clinical management. SUMMARY: The best management of low-grade gliomas is still unknown but advances in molecular genetics and imaging are improving our ability to prognosticate and follow the natural history of these tumours.