Cardiovascular Risk Factors and Disparities in Management of Embolic Stroke: A Western Sydney Perspective.

BACKGROUND: Ischaemic stroke remains one of the leading causes of death and disability worldwide. The population of Western Sydney has a unique demographic with lower socioeconomic status and a culturally and linguistically diverse population. This study aims to investigate the demographics and cardiovascular risk factors of patients in Western Sydney, focusing on the prevalence and profile of cardioembolic (CE) strokes and embolic strokes of undetermined source (ESUS). METHOD: Prospective data were collected in 463 patients with ischaemic stroke presenting to a tertiary centre in Western Sydney, who underwent predischarge transthoracic echocardiography. Patients with haemorrhagic strokes or unclear stroke diagnosis were excluded. Analysis of stroke subtype (CE, ESUS, or non-embolic) and clinical characteristics was performed based on age, gender, and prior atrial fibrillation (AF) prevalence. RESULTS: Of the 463 patients, 147 (32%) had CE strokes, and 147 (32%) had ESUS. Cardioembolic (CE) strokes were associated with older age (≥65 years) and a history of congestive cardiac failure. Older patients had higher rates of hypertension, ischaemic heart disease, AF, and congestive heart failure. History of AF was present in 67 patients (14.5%); however, only 51% received anticoagulation before admission despite a low bleeding risk. The transthoracic echocardiography characteristics of ESUS/non-embolic strokes differed from those of CE strokes; 20% of patients with ESUS had an enlarged left atrium, suggesting a subset of patients with ESUS with a left atrial myopathy. CONCLUSIONS: Patients with ischaemic stroke in Western Sydney have a high prevalence of cardiovascular risk factors which were often undertreated. Half of the patients with prior AF did not receive anticoagulation despite low bleeding risk, indicating a gap in optimal stroke prevention. There were distinct echocardiographic characteristics among stroke subtypes. Further analysis of left atrium parameters may provide greater insights into the pathogenesis and prevention of embolic strokes.

Demographic and clinical profile of cardioembolic stroke patients in Western Sydney.

BACKGROUND: Cardioembolism (CE) contributes to a large proportion of ischaemic stroke. AIMS: To evaluate the demographic and clinical profile of CE stroke in Western Sydney. METHODS: A retrospective analysis of ischaemic stroke patients presenting to Westmead Hospital (January-October 2016) was performed. Strokes were classified by TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria into different categories. Clinical and demographic data were collected on all stroke patients, and differences between CE and other stroke causes were identified. RESULTS: Two hundred and twenty-eight consecutive patients (70.9 years; 53% male) were identified. By TOAST criteria, 21 (9%) had large-artery atherosclerosis, 94 (41%) CE, 10 (5%) small-vessel disease, 2 (1%) other aetiology and 101 (44%) undetermined aetiology. A significant proportion of CE stroke patients had cardiovascular risk factors including hypertension (66%), hypercholesterolaemia (50%), diabetes (26%) and ischaemic heart disease (28%). The majority (81%) of patients with CE had atrial flutter/flutter. CE stroke, compared with other types of stroke, was more common in females (56 vs 41%, P = 0.022) and patients with CE stroke were more likely to have previous cerebral ischaemia (34 vs 21%, P = 0.026), suggesting increased recurrence in this group. Of the patients with atrial flutter/flutter (n = 56), the majority (87%) had a high CHA2 DS2 -VASC score (≥2); however, a significant proportion (55.4%) were not on anticoagulation. CONCLUSIONS: Cardioembolic stroke remains a significant burden in Western Sydney, and it is likely that a significant proportion may be preventable, as evidenced by the substantial presence of modifiable cardiovascular risk factors, and inadequate anticoagulation of patients with atrial arrhythmias.

A novel cause of chronic viral meningoencephalitis: Cache Valley virus.

OBJECTIVE: Immunodeficient patients are particularly vulnerable to neuroinvasive infections that can be challenging to diagnose. Metagenomic next generation sequencing can identify unusual or novel microbes and is therefore well suited for investigating the etiology of chronic meningoencephalitis in immunodeficient patients. METHODS: We present the case of a 34-year-old man with X-linked agammaglobulinemia from Australia suffering from 3 years of meningoencephalitis that defied an etiologic diagnosis despite extensive conventional testing, including a brain biopsy. Metagenomic next generation sequencing of his cerebrospinal fluid and brain biopsy tissue was performed to identify a causative pathogen. RESULTS: Sequences aligning to multiple Cache Valley virus genes were identified via metagenomic next generation sequencing. Reverse transcription polymerase chain reaction and immunohistochemistry subsequently confirmed the presence of Cache Valley virus in the brain biopsy tissue. INTERPRETATION: Cache Valley virus, a mosquito-borne orthobunyavirus, has only been identified in 3 immunocompetent North American patients with acute neuroinvasive disease. The reported severity ranges from a self-limiting meningitis to a rapidly fatal meningoencephalitis with multiorgan failure. The virus has never been known to cause a chronic systemic or neurologic infection in humans. Cache Valley virus has also never previously been detected on the Australian continent. Our research subject traveled to North and South Carolina and Michigan in the weeks prior to the onset of his illness. This report demonstrates that metagenomic next generation sequencing allows for unbiased pathogen identification, the early detection of emerging viruses as they spread to new locales, and the discovery of novel disease phenotypes. Ann Neurol 2017;82:105-114.

Left atrial shape as a marker of atrial myopathy in embolic stroke of undetermined source.

AIMS: Embolic Stroke of Undetermined Source (ESUS) results in significant morbidity. A left atrial (LA) myopathy is implicated in a proportion of these patients. We hypothesized that LA shape varies by cause of stroke (cardioembolic versus ESUS). METHODS AND RESULTS: 236 ischemic stroke, atrial fibrillation (AF) patients and controls were recruited prospectively. AF was classified as paroxysmal (PAF) or persistent AF (PersAF). Stroke patients comprised cardioembolic stroke (CE) secondary to AF and ESUS. There were 81 AF (47 PAF, 34 PersAF), 50 ESUS, 57 CE patients (subdivided into CE with PAF (CEpaf) and CE with PersAF (CEpers) and 48 controls. Echocardiographic parameters including LA volume, function, and shape/sphericity (3D LA-sphericity and 2D-derived LA-circularity, ellipticity, sphericity and eccentricity indices) were evaluated. Increased LA volume and sphericity with LA dysfunction was present in CE, AF and ESUS groups compared to controls. K-means cluster analysis demonstrated a spectrum of LA myopathy with controls at the lowest and CEpers and PersAF at the upper extremes, with ESUS, PAF and CEpaf being similar and falling between these extremes. After adjusting for age, sex and left ventricular (LV) and LA parameters, LA sphericity markers differentiated ESUS from controls (p < 0.01). CONCLUSIONS: Alterations in LA shape are present in ESUS, AF and CE patients, particularly increased spherical remodelling. The novel markers of LA sphericity proposed may identify LA myopathy in ESUS patients and potentially guide management for secondary prevention.

Case series: Immune checkpoint inhibitor-induced transverse myelitis.

Introduction: Increasing implementation of the highly efficacious immune checkpoint inhibitors (ICIs) has raised awareness of their various complications in the form of immune-related adverse events (irAEs). Transverse myelitis following ICIs is thought to be a rare but serious neurologic irAE and knowledge is limited about this distinct clinical entity. Cases: We describe four patients across three tertiary centers in Australia with ICI-induced transverse myelitis. Three patients had a diagnosis of stage III-IV melanoma treated with nivolumab and one patient had stage IV non-small cell lung cancer treated with pembrolizumab. All patients had longitudinally extensive transverse myelitis on magnetic resonance imaging (MRI) spine and clinical presentation was accompanied by inflammatory cerebrospinal fluid (CSF) findings. Half of our cohort had received spinal radiotherapy, with the areas of transverse myelitis extending beyond the level of previous radiation field. Inflammatory changes on neuroimaging did not extend to the brain parenchyma or caudal nerve roots, except for one case involving the conus medullaris. All patients received high dose glucocorticoids as first-line therapy, however the majority relapsed or had a refractory state (3/4) despite this, requiring escalation of their immunomodulation, with either induction intravenous immunoglobulin (IVIg) or plasmapheresis. Patients in our cohort who relapsed had a poorer outcome with more severe disability and reduced functional independence following resolution of their myelitis. Two patients had no progression of their malignancy and two patients had malignancy progression. Of the three patients who survived, two had resolution of their neurological symptoms and one remained symptomatic. Conclusion: We propose that prompt intensive immunomodulation is favored for patients with ICI-transverse myelitis in an attempt to reduce associated significant morbidity and mortality. Furthermore, there is a significant risk of relapse following cessation of immunomodulatory therapy. We suggest one treatment approach of IVMP and induction IVIg for all patients presenting with ICI-induced transverse myelitis based on such findings. With the increasing use of ICIs across oncology, further studies are required to explore this neurological phenomenon in greater detail to help establish management consensus guidelines.

Varicella zoster-associated progressive lower cranial and upper cervical polyneuropathy: a case report.

BACKGROUND: Multiple cranial neuropathies carry a wide range of differential diagnoses, and when combined with cerebrospinal fluid monocytosis they often suggest an infective etiology. Reactivation of varicella zoster virus has been associated with a wide range of neurological complications. Among the cranial nerves, the upper cranial nerves (trigeminal and facial nerves) are more commonly affected; there have been some reports of lower cranial polyneuropathies resulting from varicella zoster virus reactivation. However, polyneuropathy involving both the cranial and cervical nerves is rarely reported. CASE PRESENTATION: This report highlights the case of a 64-year-old Chinese man presenting with an acute, severe dysphagia and dysphonia secondary to herpes zoster-associated progressive polyneuropathy involving the lower cranial and upper cervical nerves, without any mucocutaneous manifestations. CONCLUSIONS: To our knowledge, this is the first case of varicella zoster virus-associated cranial and cervical polyneuropathy in the literature. The report also highlights the poor sensitivity of varicella zoster virus DNA detection by polymerase chain reaction in the cerebrospinal fluid, and proposes that serology be routinely performed in such polymerase chain reaction-negative cases without a clear diagnosis.

The distinctive movement disorder of ovarian teratoma-associated encephalitis.

The movement disorder observed in four cases of ovarian teratoma associated encephalitis is described. The illness began with neuropsychiatric symptoms and was followed by prolonged unresponsiveness, respiratory failure, and autonomic instability. The movement disorder consisted of semirhythmic repetitive bulbar and limb movements and persisted during prolonged periods of unresponsiveness, diminishing as awareness returned. The characteristics of the movement disorder differed from recognized dyskinesias. It is suggested that interruption of forebrain corticostriatal inputs by anti-N-methyl-D-aspartate (NMDA) receptor antibodies removes tonic inhibition of brainstem pattern generators releasing primitive patterns of bulbar and limb movement. Recognition of the distinctive movements should prompt a search for an ovarian teratoma since the condition is responsive to tumor resection and immunomodulation.

Gamma-aminobutyric acid-B limbic encephalitis and asystolic cardiac arrest: a case report.

BACKGROUND: Gamma-aminobutyric acid-B receptor autoantibodies are becoming an increasingly recognized contributor to the spectrum of autoimmune limbic encephalitis. They are classically associated with seizures and behavioral disturbance, and may coexist with other autoantibodies. Many are paraneoplastic, most commonly associated with small cell lung cancer. Until now there have been no reports of cardiac dysrhythmias in these patients. CASE PRESENTATION: A 65-year-old Caucasian man presented with multiple seizures, dysarthria and behavioral disturbance of unclear etiology, with associated asystolic cardiac arrest. Antibody testing showed anti-Gamma-aminobutyric acid-B receptor and anti-Hu antibodies in serum and Gamma-aminobutyric acid-B receptor autoantibodies in cerebrospinal fluid. The diagnosis of small cell lung cancer was subsequently made after lung biopsy, and the patient showed improvement with chemotherapy and intravenous immunoglobulin. CONCLUSIONS: We present the case of a patient with Gamma-aminobutyric acid-B receptor limbic encephalitis associated with asystolic cardiac arrest, an association not previously described. This case illustrates how difficult it is to make the diagnosis on clinical grounds alone. We therefore propose more routine antibody testing in patients with similar symptomatology who remain undifferentiated after initial workup. We also recommend that in the acute setting, patients with Gamma-aminobutyric acid-B receptor encephalitis should receive cardiac monitoring, as further research is required to clarify its possible link with cardiac dysrhythmias.

Information theory, novelty and hippocampal responses: unpredicted or unpredictable?

Shannon's information theory provides a principled framework for the quantitative analysis of brain responses during the encoding and representation of event streams. In particular, entropy measures the expected uncertainty of events in a given context. This contextual uncertainty or unpredictability may, itself, be important for balancing [bottom-up] sensory information and [top-down] prior expectations during perceptual synthesis. Using event-related functional magnetic resonance imaging (fMRI), we found that the anterior hippocampus is sensitive to the entropy of a visual stimulus stream. In contrast, activity in an extensive bilateral cortico-thalamic network was dictated by the surprise or information associated with each particular stimulus. In short, we show that the probabilistic structure or context in which events occur is an important predictor of hippocampal activity.

A complex vector space model of single neuronal coding and experience.

A model of consciousness is proposed, in which the experience attributable to a single sensory neuron is related to its instantaneous firing rate. In that this can only be quantified within statistical limits from the incidence of spikes across multiple presentations of a stimulus, consciousness remains inaccessible to direct measurement on a single trial. In this way, the model disambiguates subjective experience from objective neural properties. The model adopts a quantum mechanical formalism, in which the state of the neuron is represented as a vector in a complex vector space.

Dissociating intentional learning from relative novelty responses in the medial temporal lobe.

The establishment of a role for medial temporal lobe (MTL) structures in episodic memory has led to an investigative focus on the specific contributions and interactions between constituent MTL regions, including the hippocampus and surrounding medial temporal cortices. By dissociating an intentional stimulus-category learning condition from a passive viewing condition, we demonstrate, using fMRI, that novelty- and familiarity-driven responses in human anterior and posterior hippocampus, respectively, only occur during intentional learning. With increasing familiarity of stimulus-category associations, there is a shift in neuronal responses from anterior to posterior hippocampal regions. This anterior/posterior response gradient may reflect a weighting of functional hippocampal architecture related to encoding of novel and retrieval of familiar information. By contrast, perirhinal cortex is engaged by novel stimuli irrespective of task, highlighting this region as a component of a generic familiarity discrimination system. By introducing distinct stimulus types, we further demonstrate that these MTL responses are independent of stimulus complexity. Different patterns of activity for intentional learning vs. passive viewing indicate that intentional encoding/retrieval of stimulus-category associations and automatic novelty/familiarity assessment of stimuli are processed in anatomically dissociable neuronal ensembles within the MTL memory system.