Ruth Geraldes

Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis.

BACKGROUND There is increasing recognition of antibody-mediated immunotherapy-responsive neurologic diseases and a need for appropriate immunoassays. OBJECTIVES To develop a clinically applicable quantitative assay to detect the presence of aquaporin-4 (AQP4) antibodies in patients with neuromyelitis optica and to characterize the anti-AQP4 antibodies. DESIGN We compared a simple new quantitative fluorescence immunoprecipitation assay (FIPA) with both indirect immunofluorescence and an AQP4-transfected cell-based assay, both previously described. We used the cell-based assay to characterize the antibodies for their immunoglobulin class, IgG subclass, and ability to induce complement C3b deposition in vitro. SETTING United Kingdom and Germany. PARTICIPANTS Serum samples from patients with neuromyelitis optica (n = 25) or longitudinally extensive transverse myelitis (n = 11) and from relevant controls (n = 78) were studied. MAIN OUTCOME MEASURES Comparison of different assays for AQP4 antibodies and characterization of anti-AQP4 antibodies in patients with neuromyelitis optica. RESULTS We found antibodies to AQP4 in 19 of 25 patients with neuromyelitis optica (76%) using FIPA, in 20 of 25 patients with neuromyelitis optica (80%) using the cell-based assay, and in 6 of 11 patients with longitudinally extensive transverse myelitis (55%) with both assays; these assays were more sensitive than indirect immunofluorescence and 100% specific. The antibodies bound to extracellular epitope(s) of AQP4, were predominantly IgG1, and strongly induced C3b deposition. CONCLUSIONS Aquaporin-4 is a major antigen in neuromyelitis optica, and antibodies can be detected in more than 75% of patients. Further studies on larger samples will show whether this novel FIPA is suitable for clinical use. The IgG1 antibodies bind to AQP4 on the cell surface and can initiate complement deposition. These approaches will be useful for investigation of other antibody-mediated diseases.

Distinct brain imaging characteristics of autoantibody-mediated CNS conditions and multiple sclerosis.

Brain imaging characteristics of MOG antibody disease are largely unknown and it is unclear whether they differ from those of multiple sclerosis and AQP4 antibody disease. The aim of this study was to identify brain imaging discriminators between those three inflammatory central nervous system diseases in adults and children to support diagnostic decisions, drive antibody testing and generate disease mechanism hypotheses. Clinical brain scans of 83 patients with brain lesions (67 in the training and 16 in the validation cohort, 65 adults and 18 children) with MOG antibody (n = 26), AQP4 antibody disease (n = 26) and multiple sclerosis (n = 31) recruited from Oxford neuromyelitis optica and multiple sclerosis clinical services were retrospectively and anonymously scored on a set of 29 predefined magnetic resonance imaging features by two independent raters. Principal component analysis was used to perform an overview of patients without a priori knowledge of the diagnosis. Orthogonal partial least squares discriminant analysis was used to build models separating diagnostic groups and identify best classifiers, which were then tested on an independent cohort set. Adults and children with MOG antibody disease frequently had fluffy brainstem lesions, often located in pons and/or adjacent to fourth ventricle. Children across all conditions showed more frequent bilateral, large, brainstem and deep grey matter lesions. MOG antibody disease spontaneously separated from multiple sclerosis but overlapped with AQP4 antibody disease. Multiple sclerosis was discriminated from MOG antibody disease and from AQP4 antibody disease with high predictive values, while MOG antibody disease could not be accurately discriminated from AQP4 antibody disease. Best classifiers between MOG antibody disease and multiple sclerosis were similar in adults and children, and included ovoid lesions adjacent to the body of lateral ventricles, Dawsons fingers, T1 hypointense lesions (multiple sclerosis), fluffy lesions and three lesions or less (MOG antibody). In the validation cohort patients with antibody-mediated conditions were differentiated from multiple sclerosis with high accuracy. Both antibody-mediated conditions can be clearly separated from multiple sclerosis on conventional brain imaging, both in adults and children. The overlap between MOG antibody oligodendrocytopathy and AQP4 antibody astrocytopathy suggests that the primary immune target is not the main substrate for brain lesion characteristics. This is also supported by the clear distinction between multiple sclerosis and MOG antibody disease both considered primary demyelinating conditions. We identify discriminatory features, which may be useful in classifying atypical multiple sclerosis, seronegative neuromyelitis optica spectrum disorders and relapsing acute disseminated encephalomyelitis, and characterizing cohorts for antibody discovery.

N-terminal pro-brain natriuretic peptide shows diagnostic accuracy for detecting atrial fibrillation in cryptogenic stroke patients.

Background Diagnosing paroxysmal atrial fibrillation in patients with stroke can be difficult. We aimed to determine if N-terminal pro-brain natriuretic peptide can help identify paroxysmal atrial fibrillation in cryptogenic stroke. Methods and results Among 264 ischemic stroke patients, serum levels of N-terminal pro-brain natriuretic peptide were measured within 72 h of stroke onset. In cryptogenic stroke patients, 24-h Holter monitoring was used to look for paroxysmal atrial fibrillation within the first week and also three-and six-months after admission. First, patients with a defined etiology were used to construct a receiver operating characteristic curve for the diagnosis of atrial fibrillation. From this curve, the sensitivity and specificity of preestablished cutoff points for the diagnosis of atrial fibrillation were calculated. A logistic regression was performed to assess the independent relationship of the logarithm of N-terminal pro-brain natriuretic peptide levels with atrial fibrillation. The cutoff points were then evaluated in patients with cryptogenic stroke. Results One hundred eighty-four patients had a specific stroke etiology. Fifty-five patients had atrial fibrillation. Using multivariate analysis, the logarithm of N-terminal pro-brain natriuretic peptide levels was independently associated with atrial fibrillation. The area under the receiver operating characteristic curve of N-terminal pro-brain natriuretic peptide for the diagnosis of atrial fibrillation was 0·91 (95% confidence interval 0·87–0·95). The cutoff point of 265·5 pg/ml had a sensitivity of 100% and specificity of 70·5% for the diagnosis of atrial fibrillation. The cutoff point of 912 pg/ml had a sensitivity of 81·8% and a specificity of 87·5%. Eighty patients had a cryptogenic stroke. In 17, paroxysmal atrial fibrillation was found during follow-up. In these patients, the area under the curve for the diagnosis of paroxysmal atrial fibrillation was 0·83. The cutoff point of 265·5 had a sensitivity of 88·2% and a specificity of 61·9%. The cutoff point of 912 pg/ml had a sensitivity of 47·1% and a specificity of 88·9%. Conclusion N-terminal pro-brain natriuretic peptide has good accuracy in predicting the presence of paroxysmal atrial fibrillation in patients with cryptogenic stroke and can help to identify these patients.

Age‐related small vessel disease: A potential contributor to neurodegeneration in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system wherein, after an initial phase of transient neurological defects, slow neurological deterioration due to progressive neuronal loss ensues. Age is a major determinant of MS progression onset and disability. Over the past years, several mechanisms have been proposed to explain the key drivers of neurodegeneration and disability accumulation in MS. However, the effect of commonly encountered age‐related cerebral vessel disease, namely small vessel disease (SVD), has been largely neglected and constitutes the aim of this review. SVD shares some features with MS, that is, white matter demyelination and brain atrophy, and has been shown to contribute to the neuronal damage seen in vascular cognitive impairment. Several lines of evidence suggest that an interaction between MS and SVD may influence MS‐related neurodegeneration. SVD may contribute to hypoperfusion, reduced vascular reactivity and tissue hypoxia, features seen in MS. Venule and endothelium abnormalities have been documented in MS but the role of arterioles and of other neurovascular unit structures, such as the pericyte, has not been explored. Vascular risk factors (VRF) have recently been associated with faster progression in MS, though the mechanisms are unclear since very few studies have addressed the impact of VRF and SVD on MS imaging and pathology outcomes. Therapeutic agents targeting the microvasculature and the neurovascular unit may impact both SVD and MS and may benefit patients with dual pathology.

Hereditary sensory neuropathy type 1 in a Portuguese family—electrodiagnostic and autonomic nervous system studies

Hereditary sensory and autonomic neuropathy type 1 (HSAN 1) is a dominantly inherited disorder; its gene locus is mapped on chromosome 9q22. Three different missense mutations (C133Y, C133W and V144D) have been described in 11 families from Australia, England and Austria. Common clinical features have been found in these families. We report the clinical and electrophysiological features of three members of a large Portuguese family with HSAN 1 and the C133Y missense mutation. The affected members showed typical clinical features. Electrophysiological findings were consistent with a distal axonal predominantly sensory neuropathy with motor involvement, in three different severity stages. No autonomic involvement was detected in sudomotor and cardiovascular tests. This report documents the lesion of the motor nerve fibers in this disease, as well as the preservation of the autonomic nervous system function, therefore suggesting that HSNA is an inappropriate name for this disorder.

Epileptic manifestations in stroke patients treated with intravenous alteplase

Intravenous alteplase (rtPA) may be associated with seizures and epileptic activity in the electroencephalogram (EEG). The aim of this work was to compare the frequency of seizures and EEG abnormalities between stroke patients treated and not treated with rtPA.

Improvement of sleep architecture in the follow up of a patient with bilateral paramedian thalamic stroke

Normal sleep architecture and arousal require an intact thalamus. Thalamic vascular lesions, particularly in the paramedian region may cause arousal disturbances and hypersomnolence. Although hypersomnolence is one of the main characteristics of acute bilateral paramedian thalamic infarcts, there are only scarce reports in literature concerning polysomnographic follow-up of these patients. The few reported cases in literature show that sleep stages do not significantly change from the acute to chronic phase. We present a case report of a patient with a bilateral paramedian thalamic infarct in which a polysomnographic evaluation of sleep was performed four days and five months after stroke. In the acute phase, polysomnography showed an impairment of phase 2 NREM and absence of phase 3 and 4 NREM with absent sleep spindles. After the acute stroke phase, hypersomnolence improved and sleep spindles reappeared as well as phase 3 and 4 of NREM sleep. Our patient clear clinical and polysomnographic improvement makes us suppose that in this case the initial impairment could have been essentially due to a functional transitory impairment of the thalamocortical and corticothalamic connections. This case report is peculiar because it discloses a marked improvement of sleep architecture which to the best of our knowledge has not been clearly described before.

Takayasu Arteritis Presenting with Internal Carotid Artery Dissection

Discussion Our patient fulfills all the American College of Rheumatology criteria for TA [5] , and vessel vasculitis was histologically proven. Arterial dissection in TA is rare [2, 6] , with few reports of aortic dissection [7] and only one report of ICA dissection [8] . In our patient, at the moment of ICA dissection, all the other aortic archs and their branches were angiographically normal and the laboratory tests unremarkable. Extension of arteritis in TA seems to occur in a symmetric way to the paired vascular beds and contiguously in the aortic arch, brachiocephalic trunk and the aorta [1] . Iliac occlusion is an uncommon complication of TA [2, 3] . Our case, with initial ICA and external iliac artery involvement, is atypical but clearly evolved to a typical TA. Large-vessel vasculitis is not in the differentials of ICA dissection [9] ; however, ICA dissection can be the first manifestation of TA and is another possible mechanism of cerebrovascular ischemia in TA. Background In Takayasu arteritis (TA), vessel wall thickening and stenosis are the most common findings, whereas aneurysmal dilatations occur less frequently [1, 2] and arterial dissection is rare. Cerebral ischemia may occur in up to 16% of the patients with TA [3] and can be due to several mechanisms such as subclavian steal in the arm, vessel stenosis/occlusion and embolism from the aorta or the heart [4] .

Biopsy-negative, varicella zoster virus (VZV)-positive giant cell arteritis, zoster, VZV encephalitis and ischemic optic neuropathy, all in one

A 72-year-old man developed clinical features of giant cell arteritis (GCA) and ipsilateral ophthalmic-distribution zoster, followed within 2 weeks by VZV encephalitis and 2 months later by ischemic optic neuropathy. Temporal artery biopsy was histopathologically negative for GCA, but contained VZV antigen and VZV DNA in multiple non-contiguous (skip) areas. The collective clinical and laboratory findings revealed a remarkably close temporal association of zoster, multifocal VZV vasculopathy with temporal artery infection, biopsy-negative VZV-positive GCA and VZV encephalitis.

Symptomatic internal carotid artery thrombosis in acute carbon monoxide intoxication.

Stroke has been rarely associated with carbon monoxide (CO) intoxication. We report a symptomatic internal carotid artery (ICA) thrombosis in a patient with acute CO intoxication.