Nelarabine-induced peripheral and central neurotoxicity: can sequential MRI brain imaging help to define its natural history?

A 14-year-old boy with relapsed T cell acute lymphoblastic leukaemia received reinduction chemotherapy that included nelarabine, a purine nucleoside analogue known to cause dose-dependent neurotoxicity. Although he achieved aminimal residual disease negative remission after two cycles of chemotherapy he also developed severe, progressive peripheral and central neurotoxicities. Loss of grey-white differentiation was seen on a T2-weighted magnetic resonance imaging brain scan. This unusual clinical picture and previously unreported radiological findings are thought to be due to nelarabine toxicity. He was bridged with 6-mercaptopurine while transplant was deferred pending sustainable neurological improvement. This case posed clinical and ethical dilemmas while demonstrating previously unreported radiological features.

Electroclinical biomarkers of early peripheral neurotoxicity from oxaliplatin.

Peripheral neuropathy is the principal dose-limiting side effect of chemotherapy with oxaliplatin. Early biomarkers of oxaliplatin-related neuropathy (ON) are important for guiding management and as outcomes for neuroprotective trials. We compared a number of clinical and neurophysiological techniques to identify early features of ON. Median nerve motor excitability testing, nerve conduction studies, vibration perception threshold (VPT) and clinical assessments were carried out on 17 patients and 105 controls. Neuropathy was graded using the total neuropathy score and National Cancer Institute Common Toxicity Criteria scales. Oxaliplatin causes a length-dependent sensory neuropathy. The most sensitive early marker of neuropathy was abnormal VPT in the foot followed by diminished sensory nerve action potential amplitudes. Median nerve excitability studies revealed no biologically significant effects of treatment on motor axons. VPT is an easily applicable and effective marker of neuropathy at low cumulative doses of oxaliplatin. Nerve excitability measures may be useful in predicting ON but motor studies do not reveal early cumulative changes following treatment with the drug.

Analysis of routine EEG usage in a general adult ICU.

BACKGROUND: Non-convulsive seizures and status epilepticus are common in brain-injured patients in intensive care units. Continuous electroencephalography (cEEG) monitoring is the most sensitive means of their detection. In centres where cEEG is unavailable, routine EEG is often utilized for diagnosis although its sensitivity is lower. AIMS: To establish the rate of electrographic seizure detection in ICU using routine EEG. METHODS: We identified all routine EEGs performed within a general adult ICU in Ireland over 3 years, and analyzed the clinical and EEG data. RESULTS: Fifty-two patients underwent single or repeated EEG evaluation during the time period. Epileptiform abnormalities were evident in 15%, periodic abnormalities in 14%, and electrographic seizures in just one patient (2%) in their first or only routine EEG recording. CONCLUSION: The rate of electrographic seizure detection by routine EEG in a general ICU is lower than anticipated. Earlier and more prolonged recordings are needed in this setting.

Retrospective comparison of the original and revised McDonald criteria in a general neurology practice in Ireland.

BACKGROUND: The McDonald criteria were introduced in 2001 as guidelines to facilitate early and accurate diagnosis of multiple sclerosis (MS). They were revised in 2005. Although validated in a number of research-focused clinical centres, their adequacy and utility in the general neurology setting is less certain. OBJECTIVE: In this study, we assessed new diagnoses of MS in our practice for compliance with both the original and the revised criteria. METHODS: We retrospectively identified new diagnoses of MS from 2001. Clinical notes and imaging were evaluated for compliance with McDonald criteria. RESULTS: Sixty-two patients were included: 53 with ;practice-definite' and nine with ;practice-possible' diagnoses of MS. At the time of diagnosis, 47% of the ;practice-definite' group fulfilled the 2001 criteria and 49% the revised criteria. Among patients not satisfying the criteria at time of diagnosis, 21% went on to fulfil the McDonald criteria over the 23-month follow-up. CONCLUSIONS: There is a considerable gap between the clinical diagnosis of MS in a general neurology setting and compliance with the McDonald criteria. Failure to perform follow-up MRI on patients with clinically isolated syndromes is a sizeable factor in this diagnostic-gap and needs to be improved. In this setting, practical differences between the original and revised criteria appear to be small.

Cost of disorders of the brain in Ireland.

The "Cost of Disorders of the Brain in Europe" (CBDE) study was conducted by the European Brain Council (EBC) to estimate prevalence and cost of the twelve leading disorders encountered in Neurology, Neurosurgery, and Psychiatry. The data for Ireland are presented here. Prevalence and costing information was obtained by structured review of published literature for each country. Where such information was lacking, figures were estimated from European data. Costs included direct medical, direct non-medical, and indirect costs. None of the costs presented here are directly from Irish data and the prevalence figures are mostly estimated from known European rates. In 2004, 1.1 million people in Ireland were affected by a disorder of the brain. Total cost of included disorders in Ireland was 3.0 billion Euro, representing 3% of gross national product, and costing each Irish citizen Euro 775 per year. Brain disorders are prevalent and pose significant economic burden in Ireland.

Variant Creutzfeldt-Jakob disease: first two indigenous cases in Republic of Ireland. Case report and perspective.

The first two cases of indigenous variant Creutzfeldt-Jakob disease (vCJD) in the Republic of Ireland are reported in two men, neither of whom had lived outside Ireland. Both diagnoses were made ante-mortem based on clinical presentation, brain imaging, positive 14-3-3 protein in one case, and tonsillar biopsy. We discuss some of the clinical aspects of vCJD and the significance of these cases in the Irish context.

Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes.

The triggering of T- or B-cell antigen-specific receptors is accompanied by rapid tyrosine phosphorylation of distinct cellular substrates, one of which is the gamma 1 isoform of inositol phospholipid-specific phospholipase C (PLC-gamma 1). This phosphorylation event, mediated by a putative protein tyrosine kinase coupled to the antigen receptor, probably stimulates the enzymatic activity of PLC-gamma 1, thereby promoting inositol phospholipid hydrolysis and other downstream signal transduction events. Recently, another ubiquitously expressed PLC isoform, PLC-gamma 2 (which shares 50.2% amino acid homology with PLC-gamma 1), has been identified. PLC-gamma 2-specific antibodies were used to evaluate the distribution and potential signaling role of this isoform in lymphocytes. Here, we report that, in contrast to T lymphocytes that express predominantly PLC-gamma 1, the major isoform expressed in murine and human resting B cells is PLC-gamma 2. Among B-cell tumor lines, all five murine B-lymphoma lines tested and one of six human B-lymphoblastoid cell lines also expressed predominantly PLC-gamma 2. However, three other human lines preferentially expressed PLC-gamma 1, and two others displayed similar levels of the two PLC-gamma isoforms. Furthermore, the triggering of B-cell surface immunoglobulin by anti-receptor antibodies was accompanied by a rapid tyrosine phosphorylation of PLC-gamma 2, which peaked after 5 min of stimulation. Conversely, and in agreement with recent reports, triggering of the T-cell antigen receptor complex led to the predominant phosphorylation of PLC-gamma 1 on tyrosine. These findings identify PLC-gamma 2 as a substrate for a B-cell putative protein tyrosine kinase coupled to the antigen receptor and suggest that its tyrosine phosphorylation constitutes a critical and early event in B-cell activation and, furthermore, that PLC-gamma 1 and PLC-gamma 2 may participate in similar but distinct signal transduction pathways in lymphocytes.