Brain biopsies requiring Creutzfeldt-Jakob disease precautions in the Republic of Ireland 2005-2016.

AIMS: Creutzfeldt-Jakob disease (CJD) risk precautions are required when performing brain biopsies on patients with a dementing illness and in 'risk' groups. The impact on a diagnostic neuropathology service is considerable. We sought to determine if better case selection might reduce the necessity for application of CJD risk precautions. METHODS: We reviewed the clinical information, contributory investigations and final neuropathologic diagnosis in a cohort of patients (n = 21), referred to the National CJD Surveillance Centre between January 1, 2005, and December 31, 2016. RESULTS: Of this 21-patient cohort, five were positive for CJD, four belonged to the 'at risk of CJD' category requiring brain surgery, while the remaining 12 were referred to the National CJD Surveillance Unit with CJD as part of their differential diagnosis. CJD was confirmed in 5/21 (three sporadic [s]CJD, one variant [v]CJD and one iatrogenic [i] CJD). CJD was clinically probable in 4/5 proven CJD patients (80%). The patients (n = 4) in the 'at risk of CJD' group were diagnosed with tumour (n = 2), inflammation (n = 1) and non-specific changes (n = 1). Of the remaining 12 patients (in whom CJD was included in the differential diagnosis), the final neuropathologic diagnoses included tumour (n = 2), neurodegenerative (n = 2), inflammatory (n = 1), metabolic (n = 2), vascular (n = 2) and non-specific gliosis (n = 3). CONCLUSIONS: More often than not, the clinical suspicion of CJD was not borne out by the final neuropathological diagnosis. Failure by clinicians to adhere to the recommended CJD investigation algorithm impacts adversely on the neuropathology workload and causes unnecessary concern among operating theatre, laboratory and nursing personnel.

Temporal stability of MGMT promoter methylation in glioblastoma patients undergoing STUPP protocol.

Epigenetic silencing of O-6-methylguanine-DNA methyltransferase (MGMT) promoter via methylation in a glioblastoma (GBM), has been correlated with a more favourable response to alkylating chemotherapeutic agents such as temozolomide. The use of global methylation surrogates such as Long Interspersed Nucleotide Element 1 (LINE1) may also be valuable in order to fully understand these highly heterogeneous tumours. In this study, we analysed both original and recurrent GBMs in 22 patients (i.e. 44 tumours), for both MGMT and LINE1 methylation status. In the 22 patients: 14 (63.6%) displayed MGMT methylation stability in the recurrent GBM versus 8 (36.4%), with instability of methylation status. No significant differences in overall and progression free survival was evident between these two groups. LINE1 methylation status remained stable for 12 (54.5%) of recurrent GBM patients versus 9 (41%) of the patients with instability in LINE1 methylation status (p = 0.02), resulting in an increase in overall survival of the stable LINE1 group (p = 0.04). The results obtained demonstrated major epigenetic instability of GBMs treated with temozolomide as part of the STUPP protocol. GBMs appear to undergo selective evolution post-treatment, and have the ability to recur with a newly reprogrammed epigenetic status. Selective targeting of the altered epigenomes in recurrent GBMs may facilitate the future development of both prognostic biomarkers and enhanced therapeutic strategies.

Neurosarcoidosis-related intracranial haemorrhage: three new cases and a systematic review of the literature.

BACKGROUND AND PURPOSE: Intracranial haemorrhage in neurosarcoidosis (NS-ICH) is rare, poorly understood and the diagnosis of NS may not be immediately apparent. METHODS: The clinical features of three new NS-ICH cases are described including new neuropathological findings and collated with cases from a systematic literature review. CASES: (i) A 41-year-old man with headaches, hypoandrogenism and encephalopathy developed a cerebellar haemorrhage. He had neuropathological confirmation of NS with biopsy-proven angiocentric granulomata and venous disruption. He responded to immunosuppressive therapy. (ii) A 41-year-old man with no history of hypertension was found unconscious. A subsequently fatal pontine haemorrhage was diagnosed. Liver biopsy revealed sarcoid granulomas. (iii) A 36-year-old man with raised intracranial pressure headaches presented with a seizure and a frontal haemorrhage. Hilar lymph node biopsy confirmed sarcoidosis, and he was treated successfully. Systematic review: Twelve other published cases were identified and collated with our cases. Average age was 36 years and M:F = 2.3:1; 46% presented with neurological symptoms and 31% had CNS-isolated disease. Immediate symptoms of ICH were acute/worsening headache or seizures (60%). ICH was supratentorial (62%), infratentorial (31%) or subarachnoid (7%). Forty percent had definite NS, 53% probable NS and 7% possible NS (Zajicek criteria). Antigranulomatous/immunosuppressive therapy regimens varied and 31% died. CONCLUSIONS: This series expands our knowledge of the pathology of NS-ICH, which may be of arterial or venous origin. One-third have isolated NS. Clinicians should consider NS in young-onset ICH because early aggressive antigranulomatous therapy may improve outcome.

Comparative genomic and proteomic analysis of high grade glioma primary cultures and matched tumor in situ.

Developing targeted therapies for high grade gliomas (HGG), the most common primary brain tumor in adults, relies largely on glioma cultures. However, it is unclear if HGG tumorigenic signaling pathways are retained under in-vitro conditions. Using array comparative genomic hybridization and immunohistochemical profiling, we contrasted the epidermal and platelet-derived growth factor receptor (EGFR/PDGFR) in-vitro pathway status of twenty-six primary HGG cultures with the pathway status of their original HGG biopsies. Genomic gains or amplifications were lost during culturing while genomic losses were more likely to be retained. Loss of EGFR amplification was further verified immunohistochemically when EGFR over expression was decreased in the majority of cultures. Conversely, PDGFRα and PDGFRß were more abundantly expressed in primary cultures than in the original tumor (p<0.05). Despite these genomic and proteomic differences, primary HGG cultures retained key aspects of dysregulated tumorigenic signaling. Both in-vivo and in-vitro the presence of EGFR resulted in downstream activation of P70s6K while reduced downstream activation was associated with the presence of PDGFR and the tumor suppressor, PTEN. The preserved pathway dysregulation make this glioma model suitable for further studies of glioma tumorigenesis, however individual culture related differences must be taken into consideration when testing responsiveness to chemotherapeutic agents.

Case report. Glioblastoma multiforme presenting as a haemorrhagic minimally enhancing mass of the trigone.

Tumours of the trigone are rare, representing less than 2.5% of all intracranial tumours. The most common cause in adults is a meningioma. Glioblastoma multiforme of the trigone is extremely rare, with only six cases reported in the literature. We present a case of a glioblastoma multiforme of the trigone presenting in a 57-year-old man with temporal lobe seizures. Imaging revealed a haemorrhagic minimally enhancing mass of the trigone. Histology showed a high-grade malignant glial-derived neoplasm of World Health Organization Grade IV.

Vacuolar leucoencephalopathy and pulvinar sign in association with coeliac disease.

Several neurological disorders have been associated with coeliac disease, including epilepsy, ataxia and neuropathy. Here we report a rare case of white matter disease in a 55-year-old man with coeliac disease. He presented with anxiety, headache and left upper limb jerking. He subsequently developed epilepsy and brain MRI revealed diffuse white matter abnormality. He died 6 months after presentation due to status epilepticus and sepsis. Brain biopsy demonstrated vacuolar leucoencephalopathy with no evidence of vCJD. An extensive clinical screen excluded infectious, inflammatory and para-neoplastic causes for this condition. Coeliac disease may be causally associated with vacuolar leucoencephalopathy in this case.

Relapsing granulomatous angiitis of the central nervous system in a patient while in remission from Hodgkin lymphoma.

We present a patient with granulomatous angiitis of the central nervous system (GANS) and Hodgkin lymphoma. His GANS resolved with treatment for the lymphoma, but then reactivated six months later in the absence of activate lymphoma. He made a full neurological recovery after treatment with reducing oral prednisolone over one year. This case indicates that prolonged use of steroids may be necessary to treat GANS in this setting and that it can run a course independent of the Hodgkin lymphoma.

Treatment of neuroendocrine cancer metastatic to the liver: the role of ablative techniques.

Carcinoid tumors and islet cell neoplasms are neuroendocrine neoplasms with indolent patterns of growth and association with bizarre hormone syndromes. These tumors behave in a relatively protracted and predictable manner, which allows for multiple therapeutic options. Even in the presence of hepatic metastases, the standard of treatment for neuroendocrine malignancy is surgery, either with curative intent or for tumor cytoreduction, i.e., resection of 90% or more of the tumor volume. Image-guided ablation, as either an adjunct to surgery or a primary treatment modality, can be used to treat neuroendocrine cancer metastatic to the liver. Image-guided ablative techniques, including radiofrequency ablation, alcohol injection, and cryoablation, can be used in selected patients to debulk hepatic tumors and improve patient symptoms. Although long-term follow-up data are not available, the surgical literature indicates that significant ablative debulking may improve patient survival. In this review, we discuss metastatic neuroendocrine disease and its treatment options, especially image-guided ablative techniques.

Fatal toxic leukoencephalopathy: clinical, radiological, and necropsy findings in two patients.

BACKGROUND: Toxic leukoencephalopathy has been described with inhalation and intravenous consumption of heroin and cocaine. The clinical picture varies widely but the imaging and histological features are characteristic. Magnetic resonance imaging (MRI) typically reveals diffuse bihemispheric white matter lesions. Histologically there is extensive spongiform degeneration of the cerebral white matter. OBJECTIVE: To report two cases of fatal toxin associated leukoencephalopathy, along with detailed imaging and neuropathological studies. RESULTS: MRI revealed diffuse white matter changes. Histologically there was widespread confluent vacuolar degeneration of the deep white matter. In both cases, there was sparing of the brain stem and cerebellar white matter. There was evidence of severe and extensive axonal injury. CONCLUSIONS: This pattern of radiological involvement and histological findings has not previously been reported and may reflect the presence of a yet unidentified impurity.

Imaging-guided radiofrequency ablation of solid renal tumors.

OBJECTIVE: We performed a retrospective review of imaging-guided radiofrequency ablation of solid renal tumors. MATERIALS AND METHODS: Since May 2000, 35 tumors in 20 patients have been treated with radiofrequency ablation. The size range of treated tumors was 0.9-3.6 cm (mean, 1.7 cm). Reasons for patient referrals were a prior partial or total nephrectomy (nine patients), a comorbidity excluding nephrectomy or partial nephrectomy (10 patients), or a treatment alterative to nephron-sparing surgery (one patient who refused surgery). Tumors were classified as exophytic, intraparenchymal, or central. Sixteen patients had 31 lesions that showed serial growth on CT or MR imaging. Of these 16 patients, four patients with 10 lesions had a history of renal cell carcinoma, and two patients with 11 lesions had a history of von Hippel-Lindau disease. Four patients had incidental solid masses, two of which were biopsied and shown to represent renal cell carcinoma, and the remaining two masses were presumed malignant on the basis of imaging features. Successful ablation was regarded as any lesion showing less than 10 H of contrast enhancement on CT or no qualitative evidence of enhancement after IV gadolinium contrast-enhanced MR imaging. RESULTS: Of the 35 tumors, 22 were exophytic and 13 were intraparenchymal. Twenty-seven of the 35 were treated percutaneously using either sonography (n = 22) or CT (n = 5). Two patients had eight tumors treated intraoperatively using sonography. Patients were followed up with contrast-enhanced CT (n = 18), MR imaging (n = 5), or both (n = 5) with a follow-up range of 1-23 months (mean, 9 months). No residual or recurrent tumor and no major side effects were seen. CONCLUSION: Preliminary results with radiofrequency ablation of exophytic and intraparenchymal renal tumors are promising. Radiofrequency ablation is not associated with significant side effects. Further follow-up is necessary to determine the long-term efficacy of radiofrequency ablation.

Familial childhood onset neuropathy and cirrhosis with the 4977bp mitochondrial DNA deletion.

The common 4977 base pair mitochondrial deletion has been identified in association with a number of distinct clinical phenotypes. These include the Kearns-Sayre syndrome, the Pearson marrow-pancreas syndrome, and chronic progressive external ophthalmoplegia. We report the clinical and pathological findings in two siblings in whom the 4977 base pair mitochondrial DNA deletion was identified in muscle-derived mitochondrial DNA. One sibling manifested early onset liver and renal failure, and both developed prominent peripheral sensorimotor neuropathy. These clinical findings have not been previously described in association with the 4977bp mtDNA deletion and thus represent a further expansion of the spectrum of mitochondrial disease.

Genetic evaluation of lipoprotein(a) in intracranial aneurysm disease.

OBJECTIVE: Elevations in serum lipoprotein(a) [Lp(a)] levels have been reported in intracranial aneurysm (IA) disease. Our aim was to investigate a genetic basis for this observation. METHODS: We performed a comparative analysis of size polymorphisms at two loci (kringle 4 [K4] and TTTTA pentanucleotide [PN] repeats) within the apolipoprotein(a) gene on Chromosome 6q26-27 among patients with sporadic IAs (n = 50), members of three IA families (n = 50), and control subjects (n = 50). RESULTS: There was no significant difference in mean Lp(a) levels between patients with sporadic IAs and control subjects, but IA family members exhibited a more than twofold elevation in mean Lp(a) levels, compared with control subjects (29.2 versus 12.9 mg %). Inverse relationships between K4/PN numbers and serum Lp(a) levels were demonstrated; genotype frequencies did not differ significantly from a Hardy-Weinberg equilibrium or from published frequencies for other Caucasian populations. We detected no difference in mean K4 and PN genotypic indices between patients with IAs and control subjects (9.3 and 16.92 versus 9.0 and 16.92, respectively), but IA families did exhibit a lower mean K4 genotypic index (7.7), compared with control subjects. Superficial analysis of family pedigrees revealed no suggestion of linkage between K4/PN genotypes and IA disease. CONCLUSION: The previously described elevation in Lp(a) levels among patients with sporadic IAs might be explained by an acute-phase response. Crude Lp(a) measurements might provide a useful predictive test for familial IA disease, but with the disadvantage of low specificity. The possibility of linkage of familial IA disease to a particular apolipoprotein(a) isoform size range has not been eliminated.

Assessment of Crohn's disease activity by Doppler sonography of the superior mesenteric artery, clinical evaluation and the Crohn's disease activity index: a prospective study.

AIM: Recent data have shown that superior mesenteric artery (SMA) flow rates are significantly increased in active Crohn's disease, suggesting that SMA flow may be a useful, non-invasive index of disease activity. The aim of this prospective study was to evaluate the use of SMA Doppler sonography as an indicator of Crohn's disease activity and to compare with clinical evaluation and the Crohn's disease activity index (CDAI). MATERIALS AND METHODS: Patients with active Crohn's (n = 19), inactive Crohn's (n = 17) and control subjects (n = 17) were evaluated. Categorization of disease activity was based on a reference standard. CDAI scores were also calculated independently. The SMA flow parameters evaluated were resistive index, pulsatility index, end diastolic velocity, peak systolic velocity, time averaged maximum velocity, cross-sectional area and maximum flow volume. RESULTS: Using a three-group ANOVA for each of peak systolic velocity (PSV) (P = 0.01), end-diastolic velocity (EDV) (P = 0.04), pulsatility index (PI) (P = 0.003), time-averaged maximum velocity (TAMV) (P = 0.05), and maximum flow volume (TAMV.CSA) (P = 0.01), there was a significant effect of group. Using post-hoc tests, only EDV (P = 0.01), TAMV (P = 0.02) and TAMV.CSA (P = 0.003) were significantly different between active and inactive Crohn's disease, though with considerable overlap of values for EDV and TAMV. The mean CDAI scores were significantly different between patients with active Crohn's (287) and inactive Crohn's (71) (P = 0.0001) and correlated well with the reference standard. CONCLUSION: Only three of several parameters previously described as allowing Crohn's disease activity assessment actually did so in our study. However, for two of these parameters (EDV, TAMV), there was overlap between the measurements in the active and inactive groups, thus limiting the ability to discriminate disease activity in practice. The degree of overlap for maximum flow volume (TAMV.CSA) between active and inactive disease was considerably less and this parameter may be more discriminatory of disease activity. On the other hand, we found CDAI scores to be accurate in disease categorization. We agree that there appear to be hyperdynamic changes in active Crohn's disease but suggest that Doppler ultrasound assessment does not reliably assess disease activity in routine clinical practice.