Brain biopsy in neurological disease of unknown etiology: A single-center 12-year retrospective analysis.

There are no international guidelines for brain biopsy in neurological disease of unknown etiology, yet most practicing neurologists will encounter difficult cases in which biopsy is considered. This patient cohort is heterogenous, and it is unclear in which circumstances biopsy is most useful. We performed an audit of brain biopsies reviewed in our neuropathology department from 2010 to 2021. Of 9,488 biopsies, 331 biopsies undertaken for an undiagnosed neurological disease were identified. Where documented, the commonest symptoms were hemorrhage, encephalopathy, and dementia. 29% of biopsies were non-diagnostic. The most common clinically relevant findings on biopsy were infection, cerebral amyloid angiopathy with or without angiitis, and demyelination. Rarer conditions included CNS vasculitis, non-infectious encephalitis, and Creutzfeldt Jakob Disease. We highlight the value of brain biopsy in the workup of cryptogenic neurological disease despite recent advances in less invasive diagnostics.

Establishing a committee for antemortem reviews of suspect Creutzfeldt-Jakob disease cases in Ireland.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, neurodegenerative disease. In Ireland, clinical diagnostics and laboratory testing remain the responsibility of the managing clinician and the Neuropathology Department at the Beaumont Hospital, respectively. Centralized review of individual cases is not undertaken. AIMS: To determine how diagnostic processes for CJD could be improved in Ireland and to outline the structure and referral process for a new CJD review panel at the Beaumont Hospital. METHODS: We surveyed Irish neurologists' experiences on the management of CJD in Ireland. We measured turnaround times (TAT) for CSF samples referred for diagnostic CJD testing. Finally, we retrospectively reviewed imaging of autopsy-proven CJD cases to compare with initial reports. RESULTS: Ninety-three percent of neurologists supported a national central review of suspect CJD cases. A second clinical opinion was considered to be of likely benefit by 79%. Additionally, 93% reported that a centralized review of neuroradiology would be useful. All respondents felt that expediting turnaround of CSF analysis would be of benefit. The average TAT for CSF testing was 35.4 days. In retrospective review of imaging, all patients demonstrated MRI findings consistent with CJD. However, in only one of these cases were the initial pre-autopsy radiological findings reported as being consistent with CJD. CONCLUSIONS: These findings support the need for improvements to the Irish National CJD Surveillance Unit to maximize antemortem diagnostic accuracy. On foot of this, a clinical CJD Multidisciplinary Team (CJD MDT) has been established to provide a second opinion on (i) the patient's clinical history, (ii) neuroradiology and (iii) and neurophysiology reports (where available).

Intracranial haemorrhage and falls: cause or effect?

INTRODUCTION: A difficult question in autopsy practice is whether intracranial haemorrhage has resulted from or brought about a fall. MATERIAL AND METHODS: To address this we undertook a retrospective study of all autopsy reports (N = 2126) complied over a 10 year period (2009-2018). Of 720 patients who underwent a comprehensive post mortem neuropathologic examination we found 226 patients who had a history of a fall. RESULTS: Of the 226 with a history of fall, 175 (79%) had an intracranial haemorrhage which was classified as truamatic (n = 134, 77%) or spontaneous (n = 41, 23%. Within the traumatic group, falls from a standing height (51%) were more common than falls involving stairs (31%) or falls from a height (12%). Cerebral contusional injury (51%) and subdural haemorrhage (45%) were the most common type of haemorrhage in the traumatic group. In the spontaneous haemorrhage group cerebral amyloid angiopathy (49%) was the commonest detected cause and was typically lobar in distribution). CONCLUSION: We are of the view that a comprehensive analysis of fatal falls with intracranial haemorrhage warrants a detailed neuropathologic examination as part of the overall death analysis.

CJD surveillance in the Republic of Ireland from 2005 to 2015: a suggested algorithm for referrals.

Definitive diagnosis of Creutzfeldt Jakob disease (CJD) remains tissue-based. Possible and probable CJD are useful clinical terms but may be used indiscriminately. The aim of this study was to assess the effectiveness of the Irish surveillance system and to ascertain how diagnostic accuracy in identifying clinically "definite" cases might be improved. We reviewed the clinical information, relevant investigations, and samples n = 100; (autopsy n = 87; biopsy n = 13) in 96 patients between January 1, 2005 and December 31, 2015. In 4 cases both a biopsy and autopsy were performed. CJD was confirmed in 50 patients (45 at autopsy and 5 at biopsy). Sporadic CJD (sCJD) accounted for 90% of cases (n = 45); variant CJD (vCJD) for 6% (n = 3) with 1 case each of familial CJD and iatrogenic CJD. CSF 14-3-3, EEG, and MRI investigations were helpful but not available on all patients. CJD mimics (n = 46) fell into the following categories: neurodegenerative (n = 22), immune mediated (n = 3), cerebrovascular disease (n = 5), tumor (n = 5), dual pathology (n = 3), and miscellaneous (n = 8). The Irish surveillance system fulfils its main objective as all clinically suspicious cases are being referred. CJD was confirmed in 52% (n = 50/96) of referrals. Based on this, we propose an algorithm for CJD referrals to reduce both infection control and diagnostic difficulties encountered in CJD surveillance.
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Ten years on: genetic screening for mitochondrial disease in Ireland.

Mitochondrial DNA (mtDNA) analysis is centralized in the Department of Neuropathology, Beaumont Hospital. Services offered include analysis of common mtDNA point mutations, large scale mtDNA deletions/rearrangements, and sequencing of the nuclear gene POLG. The aims of this study were to audit the mtDNA diagnostic service over a 10-year period, to determine appropriate use of the service, and to improve efficient use of the service by devising a requisition form that includes diagnostic algorithms. Between July 2002 and October 2013, 716 samples were received for analysis. Overall, the number of confirmed mutations was low. Lack of diagnostic algorithms may result in expansive, unrefined requests, leading to costly investigations. We introduced a requisition form that extracts clinical, biochemical, and pathological data prior to analysis. With this information, diagnostic algorithms can be applied to select the most relevant mutations for initial analysis and also to increase the incidence of mutation detection.

Intensity of human prion disease surveillance predicts observed disease incidence.

BACKGROUND: Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt-Jakob disease (CJD) and whether such measures correlate with disease incidence. METHOD: From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17,610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28,780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. RESULTS: Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. CONCLUSIONS: Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries.

Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib.

High-grade gliomas (HGG), are the most common aggressive brain tumours in adults. Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate. To accurately evaluate response to targeted therapies further in vitro studies are necessary. Growth factor pathway expression using epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), platelet derived growth factor receptor (PDGFR), C-Kit and C-Abl together with phosphatase and tensin homolog (PTEN) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 (P70S6K) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and imatinib. Response to TKIs was assessed using 50% inhibitory concentrations (IC(50)). Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis (HCA) and principal component analysis (PCA). Erlotinib response was not strongly associated with high expression of the growth factor pathway components. PTEN expression did not correlate with response to any of the three TKIs. Increased EGFR expression was associated with gefitinib response; increased PDGFR-α expression was associated with imatinib response. The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile.

Partial status epilepticus - rapid genetic diagnosis of Alpers' disease.

We describe four children with a devastating encephalopathy characterised by refractory focal seizures and variable liver dysfunction. We describe their electroencephalographic, radiologic, genetic and pathologic findings. The correct diagnosis was established by rapid gene sequencing. POLG1 based Alpers' disease should be considered in any child presenting with partial status epilepticus.

Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) in a sibling pair with a homozygous p.A467T POLG mutation.

Two siblings who developed fifth-decade-onset, concurrent progressive sensory ataxia, dysarthria, and ophthalmoparesis were found to be homozygous for the p.A467T mutation of the polymerase gamma (POLG) gene. The clinical course in both subjects was progression to severe disability. The enlarging spectrum of sensory ataxic neuropathies associated with mitochondrial DNA (mtDNA) instability and POLG mutations should be recognized and considered in the differential diagnosis of this unusual presentation.

Phenotypic diversity associated with the mitochondrial m.8313G>A point mutation.

We report the clinical, histochemical, and molecular genetic findings in a patient with progressive mitochondrial cytopathy due to the m.8313G>A point mutation in the mitochondrial tRNA(Lys) (MTTK) gene. The clinical features in this case are severe, including short stature, myopathy, peripheral neuropathy, and osteoporosis, while extensive analysis of maternal relatives indicate that the mutation has arisen de novo and was not maternally inherited. This report of a second case, together with single muscle fiber mutation analysis that shows clear segregation of mutation load with cytochrome c oxidase deficiency, confirms that the mutation is pathologic.

Creutzfeldt-Jakob disease in Ireland: epidemiological aspects 1980-2002.

Surveillance for Creutzfeldt-Jakob disease (CJD) has been carried out in the Republic of Ireland since 1980. Initial surveillance was passive and based on consented autopsy confirmation of CJD in patients in whom there was a high index of clinical suspicion. Since 1999, an active surveillance programme involving formal notification of all suspect CJD cases has been in place. The annual mortality rate has increased from 0.34 cases/million in 1980 to 1.27 cases/million in 2001. In all, 29 cases have been pathologically confirmed: 1 had variant CJD (vCJD), 1 had iatrogenic human growth hormone-induced CJD and 1 had fatal insomnia. Sporadic CJD (sCJD) accounted for the remainder. This paper details the change in incidence over 22 years as the surveillance programme in Ireland got under way; the increased incidence is attributed to better case ascertainment, as has occurred in other countries where active surveillance programmes have been established.

vCJD risk in the Republic of Ireland.

BACKGROUND: The Republic of Ireland has the second highest incidence of BSE worldwide. Only a single case of vCJD has been identified to date. METHODS: We estimate the total future number of clinical cases of vCJD using an established mathematical model, and based on infectivity of bovine tissue calculated from UK data and on the relative exposure to BSE contaminated meat. RESULTS: We estimate 1 future clinical case (95% CI 0-15) of vCJD in the Republic of Ireland. Irish exposure is from BSE infected indigenous beef products and from imported UK beef products. Additionally, 2.5% of the Irish population was exposed to UK beef through residing in the UK during the 'at-risk' period. The relative proportion of risk attributable to each of these three exposures individually is 2:2:1 respectively. CONCLUSIONS: The low numbers of future vCJD cases estimated in this study is reassuring for the Irish population and for other countries with a similar level of BSE exposure.