Pattern ERGs suggest a possible retinal contribution to the visual acuity loss in acute optic neuritis.

PURPOSE: Macular involvement in optic neuritis (ON) is well-recognised but poorly understood and may be of clinical relevance. This study explores macular structure-function correlates in acute ON. METHODS: This cross-sectional cohort study recruited ON patients within 14 days of symptom onset. Subjects underwent pattern electroretinography (PERG), pattern visual evoked potentials (PVEP) and optical coherence tomography (OCT) imaging. PERG P50 and N95 components were correlated with OCT data. RESULTS: Twenty-six individuals with ON were recruited, comprising eleven multiple sclerosis (MS-ON), six myelin oligodendrocyte glycoprotein associated (MOG-ON) and nine with isolated ON. These were compared with 28 healthy controls. PVEPs were undetectable in 11 (42%) of individuals with ON. When detectable, PVEP P100 was delayed (median 136 ms range 110-173 ms) and amplitude reduced (median 6 µV, range 3-14 µV) in ON compared with controls (both p < 0.001). PERG P50 component amplitudes, largely reflecting macular function, were reduced in affected eyes (median 2.3 µV; range 0.8-5.0 µV) compared with controls (3.3 µV; range 2.8-5.7 µV) and compared with fellow eyes (p < 0.001). The N95:P50 ratio was below the reference range in the affected eyes of five patients. Eight cases (32%) had subnormal P50 amplitudes (< 2.0 µV), and these patients had poorer visual acuity (p = 0.020). P50 amplitudes were positively correlated with an increase in inner nuclear layer thickness (rs = 0.36; p = 0.009) and macular ganglion cell and inner plexiform layer (mGCIPL) thickness (rs = 0.44, p = 0.022). CONCLUSION: PERG P50 component reduction reveals dysfunction of inner macular layers in acute ON and correlates with structural alterations on OCT. These early macular pathologic processes are likely to contribute to the visual loss.

Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria.

BACKGROUND: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. OBJECTIVE: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. METHODS: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. RESULTS: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. CONCLUSION: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.

A 'web app' for diagnosing hemianopia.

BACKGROUND: Hemianopia commonly complicates stroke and, less frequently, head injury and brain tumours. Patients' activities of daily living are often affected although these can be ameliorated by appropriate behavioural therapy. Identifying a field defect is the first step in the rehabilitation process. An online visual field test (an 'app') was developed as part of a free to use web based therapy site for patients with hemianopic alexia, called Read-Right (http://www.readright.ucl.ac.uk). This study is an attempt to validate this test by comparing with a clinical 'gold standard'-the Humphrey automated visual field analyser. METHODS: 22 patients had their visual fields assessed with both techniques on the same day. The criterion validity of the Read-Right was examined by comparing it with Humphrey 10-2 and 24-2 perimetry using the following measures: (1) sensitivity and specificity; (2) κ statistics; and (3) intraclass correlation. RESULTS: Read-Right demonstrated high sensitivity and specificity, particularly for the undamaged field. In the damaged field, κ values were highly significant, especially for points along the horizontal meridian. The intraclass correlation score for the damaged field indicated excellent correlation between the two tests. Read-Right perimetry performed well on all measures. It had a tendency to under call damaged points offset from the horizontal meridian, and this and other aspects of the test will be revamped. CONCLUSION: Read-Right is not designed to replace standardised visual perimetry; it does, however, offer a quick and easy assessment that can be used to screen patients. The test is available as part of two free to use web based therapy applications.

MRI only conversion to multiple sclerosis following a clinically isolated syndrome.

OBJECTIVES: Using current diagnostic criteria, patients who present with a clinically isolated syndrome (CIS) may develop multiple sclerosis (MS) by subsequently exhibiting dissemination in space and time on clinical (clinically definite (CD) MS) or radiological (MRI) grounds. This study investigated the frequency of radiological without clinical conversion to MS after long term follow-up as this has not previously been defined. METHODS: Two cohorts who underwent serial clinical and MRI studies from presentation with a CIS and who were followed-up over a mean of 6 and 20 years were investigated. The distribution and formation of lesions visible on brain MRI were assessed using the revised McDonald criteria (2005). Radiologically defined (RD) MS was determined by fulfilment of the MRI but not the CDMS criteria. RESULTS: 105 people were followed-up for 6 years after a CIS, of whom 51% developed CDMS, 15% RDMS and the remainder were classified as still having had a CIS. 70 people were followed-up at 20 years, of whom 61% and 11% had developed CDMS and RDMS, respectively. CONCLUSION: About 10-15% of CIS patients may develop MS on MRI criteria only, without further clinical events for up to two decades.

Neuromyelitis optica-IgG (aquaporin-4) autoantibodies in immune mediated optic neuritis.

The clinical course of immune mediated optic neuritis (ON) will depend on the specific underlying inflammatory disease. These disorders have traditionally been classified according to clinical and MRI findings. Aquaporin-4 (AQP4) autoantibodies (neuromyelitis optica-IgG (NMO-IgG)) may have diagnostic and prognostic value in patients who present with isolated ON. In this prospective study, NMO-IgG was evaluated in 114 patients with ON in the following contexts: neuromyelitis optica (NMO), multiple sclerosis (MSON), chronic relapsing inflammatory ON (CRION), relapsing isolated ON (RION) and single isolated ON (SION). The proportion seropositive was 56% for NMO (n = 9), 0% for MSON (n = 28) and 5% for the remaining diagnostic categories (CRION (n = 19), RION (n = 17) and SION (n = 41)). Testing for NMO-IgG in patients with recurrent or severe ON who lack convincing evidence of MS may identify patients who would benefit from immunosuppression rather than MS directed immunomodulatory therapies.

Recurrent ptosis due to myopathy of the levator palpebrae superioris.

The authors report the 10-year follow-up of a case with a recurrent ptosis affecting both eyelids independently. The histology of the levator palpebrae superioris and Müller's muscle was consistent with a localised myopathic process. A therapeutic response to acetazolamide suggests that ion-channel dysfunction may be the underlying cause for this new myopathy.

Brain atrophy and lesion load measures over 1 year relate to clinical status after 6 years in patients with clinically isolated syndromes.

BACKGROUND: Conventional MRI lesion measures modestly predict long term disability in some clinically isolated syndrome (CIS) studies. Brain atrophy suggests neuroaxonal loss in multiple sclerosis (MS) with the potential to reflect disease progression to a greater extent than lesion measures. OBJECTIVE: To investigate whether brain atrophy and lesion load, during the first year in patients presenting with CIS, independently predict clinical outcome (development of MS and disability at 6 years). METHODS: 99 patients presenting with CIS were included in the study. T1 gadolinium enhanced and T2 weighted brain MRI was acquired at baseline and approximately 1 year later. Percentage brain atrophy rate between baseline and follow-up scans was analysed using SIENA. RESULTS: Mean annual brain atrophy rates were -0.38% for all patients, -0.50% in patients who had developed MS at 6 years and -0.26% in those who had not. Brain atrophy rate (p = 0.005) and baseline T2 lesion load (p<0.001) were independent predictors of clinically definite MS. While brain atrophy rate was a predictor of Expanded Disability Status Scale (EDSS) score in a univariate analysis, only 1 year T2 lesion load change (p = 0.007) and baseline gadolinium enhancing lesion number (p = 0.03) were independent predictors of EDSS score at the 6 year follow-up. T1 lesion load was the only MRI parameter which predicted Multiple Sclerosis Functional Composite score at the 6 year follow-up. CONCLUSIONS: The findings confirm that brain atrophy occurs during the earliest phases of MS and suggest that 1 year longitudinal measures of MRI change, if considered together with baseline MRI variables, might help to predict clinical status 6 years after the first demyelinating event in CIS patients, better than measurements such as lesion or brain volumes on baseline MRI alone.

Early MRI in optic neuritis: the risk for clinically definite multiple sclerosis.

MRI brain lesions at presentation with optic neuritis (ON) increase the risk for developing clinically definite (CD) multiple sclerosis (MS). More detailed early MRI findings may improve prediction of conversion. The objectives of this study were to investigate the influence of number, location and activity of lesions at presentation, new lesions at early follow-up and non-lesion MRI measures on conversion from optic neuritis (ON) to CDMS. 142/143 ON patients, prospectively recruited into a serial MRI and clinical follow-up study, were followed-up at least once. Cox regression analysis determined independent early MRI predictors of time to CDMS from: (i) baseline lesion number, location and activity measures, (ii) three-month lesion activity measures and (iii) brain atrophy, magnetization transfer ratio and spectroscopy measures. 114/142 (80%) had abnormal baseline brain or cord MRI. 57 (40%) developed CDMS (median of 16 months from clinically isolated syndrome onset). Median follow-up of the non-converters was 62 months. Multivariate analysis of baseline parameters revealed gender, periventricular and gadolinium-enhancing lesions as independent predictors of CDMS. Considering both scans together, gender, baseline periventricular and new T2 lesions at follow-up remained significant (hazard ratios 2.1, 2.4 and 4.9, respectively). No non-conventional measure predicted CDMS. It was concluded that new T2 lesions on an early follow-up scan were the strongest independent predictor of CDMS.

Neural correlates of hemianopic completion across the vertical meridian.

Hemianopic completion refers to the perceptual completion of figures located across the vertical meridian in the context of hemianopia, such that one half of the figure falls within the blind hemifield. It can occur whether the figure is itself complete (veridical completion) or incomplete (paracompletion). Psychophysical evidence suggests that this phenomenon may be a constructive one, and may share features with completion phenomena in normal vision. The neural structures mediating hemianopic completion are unknown. Here we studied the neural activity evoked by hemianopic completion using event-related fMRI in an individual (POV) with a large right visual field homonymous hemianopic scotoma due to left occipital damage. Either a large achromatic circular contour straddling the vertical meridian or a semicircular contour within the left hemifield just crossing the vertical meridian was presented to POV on each trial. POV indicated by button press whether he perceived a semicircular contour, a patchy circular contour or a complete circular contour. On trials where he reported perceiving a complete circular contour despite being presented with a semicircular contour (paracompletion), activity was increased in a region of ipsilateral extrastriate cortex (contralateral to the lesion, ipsilateral to the illusory edge of the circle). These results are discussed in the context of illusory contour completion in healthy subjects and more generally in the recovery of function after brain damage.

Structural anatomy of pure and hemianopic alexia.

BACKGROUND: The two most common types of acquired reading disorder resulting from damage to the territory of the dominant posterior cerebral artery are hemianopic and pure alexia. Patients with pronounced hemianopic alexia have a right homonymous hemianopia that encroaches into central or parafoveal vision; they read individual words well, but generate inefficient reading saccades when reading along a line of text. Patients with pure alexia also often have a hemianopia but are more disabled, making frequent errors on individual words; they have sustained damage to a brain region that supports efficient word identification. OBJECTIVE: To investigate the differences in lesion site between hemianopic alexia and pure alexia groups, as rehabilitative techniques differ between the two conditions. METHODS: High-resolution magnetic resonance images were obtained from seven patients with hemianopic alexia and from six patients with pure alexia caused by a left occipital stroke. The boundary of each lesion was defined and lesion volumes were then transformed into a standard stereotactic space so that regional comparisons could be made. RESULTS: The two patient groups did not differ in terms of damage to the medial left occipital lobe, but those with pure alexia had additional lateral damage to the posterior fusiform gyrus and adjacent tissue. CONCLUSIONS: Clinicians will be able to predict the type of reading disorder patients with left occipital lesions have from simple tests of reading speed and the distribution of damage to the left occipital lobe on brain imaging. This information will aid management decisions, including recommendations for reading rehabilitation.

Is the frequency of abnormalities on magnetic resonance imaging in isolated optic neuritis related to the prevalence of multiple sclerosis? A global comparison.

The link between optic neuritis and multiple sclerosis is well established, as is the increased risk of conversion to multiple sclerosis, with lesions seen at presentation on the magnetic resonance imaging (MRI) scan of the brain. One or more asymptomatic lesions were present in 77% of the optic neuritis cohort from London, UK, a higher proportion than that reported in other large cohorts studied elsewhere, where generally lower prevalence rates for multiple sclerosis are also reported. These observations may support the hypothesis that optic neuritis is more likely to be associated with abnormalities on MRI and to be due to multiple sclerosis in geographical regions where multiple sclerosis is more common.

Modification of MRI criteria for multiple sclerosis in patients with clinically isolated syndromes.

BACKGROUND: The McDonald criteria include MRI evidence for dissemination in space and dissemination in time for the diagnosis of multiple sclerosis in young adult patients who present with clinically isolated syndromes (CIS) typical of the disease. Although a major advance, the criteria have limited sensitivity for making an early diagnosis. OBJECTIVE: To compare the performance of McDonald criteria and modified McDonald criteria for dissemination in space and time for assessing the development of clinically definite multiple sclerosis. METHODS: McDonald criteria were modified using the combination of a less stringent definition for dissemination in space and allowing a new T2 lesion per se after three months as evidence for dissemination in time. Modified and McDonald criteria were applied in 90 CIS patients at baseline and at three month follow up scans. RESULTS: Both criteria were highly specific (>90%) but the modified criteria were more sensitive (77% v 46%) and more accurate (86% v 73%). CONCLUSIONS: These modified criteria should be evaluated in other CIS cohorts.

Quantification of optic nerve head topography in optic neuritis: a pilot study.

AIMS: To investigate optic nerve head topography in patients with optic neuritis compared to controls using the Heidelberg retina tomograph-II (HRT-II) and to determine if detected changes are related to visual function and electrophysiology. METHODS: 25 patients with a previous single episode of unilateral optic neuritis and 15 controls were studied with HRT-II, visual evoked potentials, and pattern electroretinogram. Patients also had testing of visual acuity, visual field, and colour vision. RESULTS: In affected eyes compared to fellow eyes, there was reduction of both the mean retinal nerve fibre layer (RNFL) thickness at the disc edge (p = 0.009) and the neuroretinal rim volume (p = 0.04). In affected eyes compared to control eyes, the three dimensional optic cup shape measure was increased (p = 0.01), indicative of an abnormal cup shape. There were no other significant differences in HRT-II measures. Within patient interocular difference correlation was used to investigate the functional relevance of these changes and demonstrated associations between RNFL thickness change and changes in visual acuity, visual field, and colour vision. Colour vision change was also associated with change in neuroretinal rim volume. CONCLUSIONS: HRT detects functionally relevant changes in RNFL thickness and neuroretinal rim volume between eyes affected by optic neuritis and unaffected fellow eyes.

Brain biopsy in dementia.

Brain biopsy has an uncertain role in the diagnosis of dementia. Here we report a retrospective analysis of 90 consecutive cerebral biopsies undertaken for the investigation of dementia in adults at a tertiary referral centre between 1989 and 2003. In most cases (90%), biopsy consisted of a right frontal full thickness resection of cortex, white matter and overlying leptomeninges. Fifty-seven per cent of biopsies were diagnostic: the most frequent diagnoses were Alzheimer's disease (18%), Creutzfeldt-Jakob disease (12%) and inflammatory disorders (9%). Other diagnoses in individual patients included Pick's disease, corticobasal degeneration and other tauopathies, Lewy body dementia, multiple sclerosis, Whipple's disease, progressive multifocal leucoencephalopathy, cerebral autosomal dominant arteriopathy with subcortical ischaemic leucoencephalopathy, vasculopathies and paraneoplastic encephalopathy. The most frequent biopsy finding in the non-diagnostic group and for the series as a whole (37%) was non-specific gliosis variably affecting both cortex and white matter. Complications (11%) included seizures, intracranial and wound infections, and intracranial haemorrhage; there were no deaths or lasting neurological sequelae attributable to the procedure. No trends in diagnostic yield or complication rate over the course of the series were identified. Information obtained at biopsy determined treatment in 11%. A raised cerebrospinal fluid cell count was the only robust predictor of a potentially treatable (inflammatory) process at biopsy. The constellation of behavioural change, raised CSF protein and matched oligoclonal bands in CSF and serum was associated with non-specific gliosis at biopsy. This series underlines the value of cerebral biopsy in the diagnosis of dementia, and suggests that certain clinical and laboratory features may be useful in guiding the decision to proceed to brain biopsy where a treatable disease cannot be excluded by other means.

Magnetization transfer histograms in clinically isolated syndromes suggestive of multiple sclerosis.

In established multiple sclerosis, magnetization transfer ratio (MTR) histograms reveal abnormalities of normal-appearing white matter (NAWM) and grey matter (NAGM). The aim of this study was to investigate for such abnormalities in a large cohort of patients presenting with clinically isolated syndromes suggestive of multiple sclerosis. Magnetization transfer imaging was performed on 100 patients (67 women, 33 men, median age 32 years) a mean of 19 weeks (SD 3.8, range 12-33 weeks) after symptom onset with a clinically isolated syndrome and in 50 healthy controls (34 women, 16 men, median age 32.5 years). SPM99 software was used to generate segmented NAWM and NAGM MTR maps. The volumes of T2 lesions, white matter and grey matter were calculated. Eighty-one patients were followed up clinically and with conventional MRI after 3 years (n = 61) or until they developed multiple sclerosis if this occurred sooner (n = 20). Multiple regression analysis was used to investigate differences between patients and controls with age, gender and volume measures as covariates to control for potential confounding effects. The MTR histograms for both NAWM and NAGM showed a reduction in the mean (NAWM, 38.14 versus 38.33, P = 0.001; NAGM 32.29 versus 32.50, P = 0.009; units in pu) and peak location, with a left shift in the histogram. Mean NAWM and NAGM MTR were also reduced in the patients who developed clinically definite multiple sclerosis and multiple sclerosis according to the McDonald criteria but not in the 24 patients with normal T2-weighted brain magnetic resonance imaging (MRI). MTR abnormalities occur in the NAWM and NAGM at the earliest clinical stages of multiple sclerosis.

ALK positive inflammatory myofibroblastic tumour of the pineal region.

Inflammatory myofibroblastic tumours (IMTs) are an uncommon spindle cell neoplasm with a dense inflammatory infiltrate, usually encountered in children. IMTs of the central nervous system are extremely rare. This report describes the case of an IMT in a 61 year old man, in the pineal region. The tumour was completely excised, and immunohistochemistry demonstrated anaplastic lymphoma kinase 1 expression. There was no tumour recurrence during 18 months of follow-up. Our case extends both the age range and sites of occurrence of this rare tumour.

Paroxysmal raised intracranial pressure associated with spinal meningeal cysts.

Raised intracranial pressure in association with spinal meningeal cysts has rarely been reported. We describe four patients in whom evidence of paroxysmal raised intracranial pressure was found in association with spinal meningeal cysts. Cerebrospinal fluid diversion procedures have previously been shown to relieve local symptoms due to spinal cysts. In our patients symptoms of paroxysmal headache were alleviated by this method, suggesting a causal relationship with the raised pressure. This association may be an under diagnosed cause of paroxysmal headaches. We review the medical literature on the classification of spinal meningeal cysts, evaluate the theories of their origin and offer suggestions on the pathogenesis of the abnormal CSF dynamics that may allow an interplay between raised intracranial pressure and spinal meningeal cysts to produce paroxysmal symptoms.

Optic disc duplication or coloboma?

AIM: To describe lesions resembling optic disc duplication and highlight their unusual visual fields. The authors also report the first case of pseudo-duplication of the optic disc with overlying retinal nerve fibre layer. METHODS: Retrospective, non-comparative review of case notes. Humphrey visual fields and OCT-3 imaging were performed. RESULTS: All 11 cases represented peripapillary chorioretinal coloboma, some of which lie superior to the optic disc. A double blind spot or superior hemifield defects can be demonstrated by automated visual field testing. CONCLUSION: Clinical examination and identification of bridging retinal vessels from the true optic disc to the second pseudo disc can usually avoid unnecessary invasive and non-invasive investigations.

A hypothetical scheme for the brainstem control of vertical gaze.

OBJECTIVES: To develop a hypothetical scheme to account for clinical disorders of vertical gaze based on recent insights gained from experimental studies. METHODS: The authors critically reviewed reports of anatomy, physiology, and effects of pharmacologic inactivation of midbrain nuclei. RESULTS: Vertical saccades are generated by burst neurons lying in the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF). Each burst neuron projects to motoneurons in a manner such that the eyes are tightly coordinated (yoked) during vertical saccades. Saccadic innervation from riMLF is unilateral to depressor muscles but bilateral to elevator muscles, with axons crossing within the oculomotor nucleus. Thus, riMLF lesions cause conjugate saccadic palsies that are usually either complete or selectively downward. Each riMLF contains burst neurons for both up and down saccades, but only for ipsilateral torsional saccades. Therefore, unilateral riMLF lesions can be detected at the bedside if torsional quick phases are absent during ipsidirectional head rotations in roll. The interstitial nucleus of Cajal (INC) is important for holding the eye in eccentric gaze after a vertical saccade and coordinating eye-head movements in roll. Bilateral INC lesions limit the range of vertical gaze. The posterior commissure (PC) is the route by which INC projects to ocular motoneurons. Inactivation of PC causes vertical gaze-evoked nystagmus, but destructive lesions cause a more profound defect of vertical gaze, probably due to involvement of the nucleus of the PC. Vestibular signals originating from each of the vertical labyrinthine canals ascend to the midbrain through several distinct pathways; normal vestibular function is best tested by rotating the patient's head in the planes of these canals. CONCLUSIONS: Predictions of a current scheme to account for vertical gaze palsy can be tested at the bedside with systematic examination of each functional class of eye movements.