Late Ebola virus relapse causing meningoencephalitis: a case report.

BACKGROUND: There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13.2). METHODS: A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. FINDINGS: On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23.7) than plasma (31.3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. INTERPRETATION: Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. FUNDING: Royal Free London NHS Foundation Trust.

Fully automatic segmentation of the hippocampus and the amygdala from MRI using hybrid prior knowledge.

The segmentation of macroscopically ill-defined and highly variable structures, such as the hippocampus Hc and the amygdala Am, from MRI requires specific constraints. Here, we describe and evaluate a hybrid segmentation method that uses knowledge derived from a probabilistic atlas and from anatomical landmarks based on stable anatomical characteristics of the structures. Combined in a previously published semi-automatic segmentation method, they lead to a fast, robust and accurate fully automatic segmentation of Hc and Am. The probabilistic atlas was built from 16 young controls and registered with the "unified segmentation" of SPM5. The algorithm was quantitatively evaluated with respect to manual segmentation on two MRI datasets: the 16 young controls, with a leave-one-out strategy, and a mixed cohort of 8 controls and 15 subjects with epilepsy with variable hippocampal sclerosis. The segmentation driven by hybrid knowledge leads to greatly improved results compared to that obtained by registration of the thresholded atlas alone: mean overlap for Hc on the 16 young controls increased from 78% to 87% (p < 0.001) and on the mixed cohort from 73% to 82% (p < 0.001) while the error on volumes decreased from 10% to 7% (p < 0.005) and from 18% to 8% (p < 0.001), respectively. Automatic results were better than the semi-automatic results: for the 16 young controls, average overlap increased from 84% to 87% (p < 0.001) for Hc and from 81% to 84% (p < 0.002) for Am, with equivalent improvements in volume error.

Cerebral damage in epilepsy: a population-based longitudinal quantitative MRI study.

PURPOSE: Whether cerebral damage results from epileptic seizures remains a contentious issue. We report on the first longitudinal community-based quantitative magnetic resonance imaging (MRI) study to investigate the effect of seizures on the hippocampus, cerebellum, and neocortex. METHODS: One hundred seventy-nine patients with epilepsy (66 temporal lobe epilepsy, 51 extratemporal partial epilepsy, and 62 generalized epilepsy) and 90 control subjects underwent two MRI brain scans 3.5 years apart. Automated and manual measurement techniques identified changes in global and regional brain volumes and hippocampal T2 relaxation times. RESULTS: Baseline hippocampal volumes were significantly reduced in patients with temporal lobe epilepsy and could be attributed to an antecedent neurologic insult. Rates of hippocampal, cerebral, and cerebellar atrophy were not syndrome specific and were similar in control and patient groups. Global and regional brain atrophy was determined primarily by age. A prior neurologic insult was associated with reduced hippocampal and cerebellar volumes and an increased rate of cerebellar atrophy. Significant atrophy of the hippocampus, neocortex, or cerebellum occurred in 17% of patients compared with 6.7% of control subjects. Patients with and without significant volume reduction were comparable in terms of seizure frequency, antiepileptic drug (AED) use, and epilepsy duration, with no identifiable risk factors for the development of atrophy. CONCLUSIONS: Overt structural cerebral damage is not an inevitable consequence of epileptic seizures. In general, brain volume reduction in epilepsy is the cumulative effect of an initial precipitating injury and age-related cerebral atrophy. Significant atrophy developed in individual patients, particularly those with temporal lobe and generalized epilepsy. Longer periods of observation may detect more subtle effects of seizures.

Serial imaging of the brain.

Epilepsy is a heterogeneous condition and it is likely that susceptibility factors and genetic predisposition interact with acquired influences such as seizures, AEDs, cerebral insults, subclinical seizures,and ongoing neurodegenerative processes to render certain individuals selectively vulnerable to cerebral damage. There is currently in substantial evidence to suggest that neuroprotective treatments that rely entirely on their anticonvulsant properties are sufficient to prevent the development of cerebral atrophy. The development of postprocessing techniques in serial imaging studies have allowed the detection of subtle changes, and it is likely that development of more sensitive imaging techniques with higher-strength MR magnets and novel MR contrasts will expand our understanding of the factors that render an individual susceptible to hippocampal and extratemporal atrophy. This will allow a more informed assessment of the role required of neuroprotective agents in arresting the progression of cerebral damage and dysfunction.

Automatic segmentation of the brain and intracranial cerebrospinal fluid in T1-weighted volume MRI scans of the head, and its application to serial cerebral and intracranial volumetry.

A new fully automatic algorithm for the segmentation of the brain and total intracranial cerebrospinal fluid (CSF) from T(1)-weighted volume MRI scans of the head, called Exbrain v.2, is described. The algorithm was developed in the context of serial intracranial volumetry. A brain mask obtained using a previous version of the algorithm forms the basis of the CSF segmentation. Improved brain segmentation is then obtained by iterative tracking of the brain-CSF interface. Gray matter (GM), white matter (WM), and intracranial CSF volumes and probability maps are calculated based on a model of intensity probability distribution (IPD) that includes two partial volume classes: GM-CSF and GM-WM. Accuracy was assessed using the Montreal Neurological Institute's (MNI) digital phantom scan. Reproducibility was assessed using scan pairs from 24 controls and 10 patients with epilepsy. Segmentation overlap with the gold standard was 98% for the brain and 95%, 96%, and 97% for the GM, WM, and total intracranial contents, respectively; CSF overlap was 86%. In the controls, the Bland and Altman coefficient of reliability (CR) was 35.2 cm(3) for the total brain volume (TBV) and 29.0 cm(3) for the intracranial volume (ICV). Scan-matching reduced CR to 25.2 cm(3) and 17.1 cm(3) for the TBV and ICV, respectively. For the patients, similar CR values were obtained for the ICV.

Progressive neocortical damage in epilepsy.

Our objective was to determine the pattern and extent of generalized and focal neocortical atrophy that develops in patients with epilepsy and the factors associated with such changes. As part of a prospective, longitudinal follow-up study of 122 patients with chronic epilepsy, 68 newly diagnosed patients, and 90 controls, serial magnetic resonance imaging scans were obtained 3.5 years apart. Image subtraction was used to identify diffuse and focal neocortical change that was quantified with a regional brain atlas and a fully automated segmentation algorithm. New focal or generalized neocortical volume losses were identified in 54% of patients with chronic epilepsy, 39% of newly diagnosed patients and 24% of controls. Patients with chronic epilepsy were significantly more likely to develop neocortical atrophy than control subjects. The increased risk of cerebral atrophy in epilepsy was not related to a history of documented seizures. Risk factors for neocortical atrophy were age and multiple antiepileptic drug exposure. Focal and generalized neocortical atrophy commonly develops in chronic epilepsy. Neocortical changes seen in a quarter of our control group over 3.5 years were likely to reflect physiological changes. Our results show that ongoing cerebral atrophy may be widespread and remote from the putative epileptic focus, possibly reflecting extensive networks and interconnections between cortical regions.

The structural consequences of newly diagnosed seizures.

Intractable epilepsy may be associated with widespread structural cerebral damage. We determined whether structural damage occurs to the hippocampus, cerebellum and neocortex in the first few years following a diagnosis of seizures. Sixty-eight patients over the age of 14 years with newly diagnosed seizures and 90 matched controls underwent serial magnetic resonance imaging (MRI) brain scans 3.5 years apart. Using quantitative analysis of serial scans, we determined changes in hippocampal volume, hippocampal T2 relaxometry and total and regional brain volumes. Thirty-four (50%) patients had recurrent unprovoked seizures between baseline and follow-up scans. One patient with pre-existing hippocampal sclerosis (HS) did not develop progressive hippocampal damage. Group analyses found no difference in change in cerebral measures between patients and controls or between patients with and without recurrent seizures. Significant quantitative changes in individuals were largely attributable to pre-existing cerebral lesions or alcohol abuse. Subtle changes detected in individuals over 3.5 years but were not related to a history of overt seizures. Our results show patients with newly diagnosed seizures are not generally at increased risk of seizure-induced structural cerebral damage as detected with MRI. Cerebral damage may occur before the onset of seizures or develop insidiously over a more prolonged period.