Diagnosing Optic Disc Drusen in the Modern Imaging Era: A Practical Approach.

Optic disc drusen (ODD) are a well-recognised cause of an elevated optic disc appearance. When visible with ophthalmoscopy and fundus photography, ODD are readily identified. Yet, in more subtle cases of ODD, ancillary testing may be needed to render the diagnosis. Facilitating the diagnosis of ODD has clinical relevance, because affected individuals may otherwise undergo unnecessary costly and invasive investigations to rule out raised intracranial pressure and other causes of optic disc oedema. In this review, the role of established and emerging optical coherence tomography (OCT) techniques in the diagnosis and management of ODD cases is reviewed. A practical approach is taken to explain how to optimise use of commercially available OCT technology in the clinical setting. Optical coherence tomography provides many advantages over other imaging modalities in the diagnosis of ODD, including the ability to correlate retinal measures of neuroaxonal structure with drusen characteristics. Earlier spectral domain OCT techniques, however, were hindered by poor penetrance. In the modern imaging era, enhanced depth imaging OCT and swept source OCT enable higher resolution of ODD and other optic nerve head structures that might otherwise be mistaken for drusen. Ongoing studies featuring OCT angiography indicate that this technique may provide complementary information about microvascular supply that correlate with structural measures of optic nerve injury. Advances in OCT will continue to improve diagnostic accuracy and inform clinical understanding regarding structure-function correlations germane to the longitudinal follow up of ODD patients.

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.

The prevalence of incidental findings in multiple sclerosis patients.

BACKGROUND: Incidental findings arising from imaging research have important implications for patient safety. Magnetic resonance imaging is widespread in multiple sclerosis (MS) studies and care, yet the prevalence rate of incidental findings in MS is poorly defined. The absence of such reports in the MS literature suggests that such findings may be deemed inappropriate for documentation in research publications, or possibly, not fully reported at all. OBJECTIVE: We sought to document incidental findings from a study designed to detect features of chronic cerebrospinal venous insufficiency (CCSVI) in MS patients and control subjects. METHODS: Magnetic resonance images were obtained as part of a prospective study conducted between October 2010 and September 2012. Patients with MS (relapsing-remitting, primary progressive, secondary progressive), clinically isolated syndromes, and neuromyelitis optica and age/sex-matched healthy controls were included. All images were reviewed by neuro-radiologists for quality-control purposes. RESULTS: Magnetic resonance imaging was successfully obtained in 166 participants (110 patients, 56 controls). Incidental abnormalities (n = 33) were detected in 15% of patients (n = 17) and 27% of controls (n = 15), comprising 19% overall (n = 32). CONCLUSIONS: The prevalence of incidental findings from the MS population was not significantly different from the control population. However, the overall prevalence was high and warrants a careful management strategy for future imaging studies.Prévalence des découvertes fortuites chez les patients atteints de sclérose en plaques.

Tracking retinal nerve fiber layer loss after optic neuritis: a prospective study using optical coherence tomography.

INTRODUCTION: Optic neuritis causes retinal nerve fiber layer damage, which can be quantified with optical coherence tomography. Optical coherence tomography may be used to track nerve fiber layer changes and to establish a time-dependent relationship between retinal nerve fiber layer thickness and visual function after optic neuritis. METHODS: This prospective case series included 78 patients with optic neuritis, who underwent optical coherence tomography and visual testing over a mean period of 28 months. The main outcome measures included comparing inter-eye differences in retinal nerve fiber layer thickness between clinically affected and non-affected eyes over time; establishing when RNFL thinning stabilized after optic neuritis; and correlating retinal nerve fiber layer thickness and visual function. RESULTS: The earliest significant inter-eye differences manifested 2-months after optic neuritis, in the temporal retinal nerve fiber layer. Inter-eye comparisons revealed significant retinal nerve fiber layer thinning in clinically affected eyes, which persisted for greater than 24 months. Retinal nerve fiber thinning manifested within 6 months and then stabilized from 7 to 12 months after optic neuritis. Regression analyses demonstrated a threshold of nerve fiber layer thickness (75 microm), which predicted visual recovery after optic neuritis. CONCLUSIONS: Retinal nerve fiber layer changes may be tracked and correlated with visual function within 12 months of an optic neuritis event.

Role of thrombocytosis in diagnosis of giant cell arteritis and differentiation of arteritic from non-arteritic anterior ischemic optic neuropathy.

PURPOSE: To investigate the role of thrombocytosis in the diagnosis of giant cell arteritis (GCA), and differentiation of arteritic (A-AION) from non-arteritic (NA-AION) anterior ischemic optic neuropathy; and comparison of the sensitivity and specificity of platelet count to that of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and some other hematologic variables in the diagnosis of GCA. METHODS: This retrospective study is based on 121 temporal artery biopsy confirmed GCA patients and 287 patients with NA-AION seen in our clinic. For inclusion in this study, all GCA patients, at their initial visit, prior to the initiation of corticosteroid therapy, must have had ESR (Westergren), platelet count and complete blood count, and temporal artery biopsy. From 1985 onwards CRP estimation was done. For inclusion in this study, all NA-AION patients at the initial visit must have undergone evaluation similar to that described above for GCA, except for temporal artery biopsy. Wilcoxon rank-sum test and the two-sample t-test were used to compare hematologic variables between GCA patients with and without visual loss, between those with and without systemic symptoms, and also between GCA and NA-AION patients. Pearson correlation coefficient was computed to measure the association of platelet counts and the other hematologic variables with ESR. Receiver operating characteristic (ROC) curves were constructed for ESR, CRP, platelet count, combinations of ESR and platelet count, and CRP and platelet count, hemoglobin, hematocrit, and white blood cell (WBC) count and the area under the curve (AUC) were compared. RESULTS: Comparison of ESR, CRP, and hematologic variables of GCA patients and of A-AION with the NA-AION group, showed significantly (p <0.0001) higher median levels of ESR, CRP, platelet count, and WBC count and lower levels of hemoglobin and hematocrit in the GCA patients and A-AION than in NA-AION. Comparing AUC of the ROC curve between ESR and platelet count, ESR was a better predictor of GCA compared to platelet count (AUC of 0.946 vs. 0.834). There was a slight improvement in prediction of GCA using the combination of ESR and platelet count (AUC=0.953). The other hematologic variables had an AUC that was smaller than platelet count (0.854 for hemoglobin; 0.841 for hematocrit), with WBC being the least predictive of GCA (AUC=0.666). The AUC of the ROC curve for CRP was 0.978. There was no improvement in prediction of GCA using platelet count in combination with CRP (AUC=0.976). CONCLUSIONS: Patients with GCA had significantly (p <0.0001) higher values of platelet count, ESR, CRP and WBC but lower values for hemoglobin and hematocrit compared to the NA-AION group. Predictive ability of an elevated platelet count did not surpass elevated ESR or CRP as a diagnostic marker for GCA. Thrombocytosis may complement ESR. Hemoglobin, hematocrit and WBC were much less predictive of GCA. Elevated CRP had a greater predictive ability for GCA compared to ESR or the other hematologic parameters; thrombocytosis in combination with CRP did not yield an improvement in prediction of GCA.

MRI findings in Susac's syndrome.

BACKGROUND: Susac syndrome (SS) is a self-limited syndrome, presumably autoimmune, consisting of a clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss. All three elements of the triad may not be present or recognized, and MR imaging is often necessary to establish the diagnosis. OBJECTIVE: To determine the spectrum of abnormalities on MRI in SS. METHODS: The authors reviewed the MR images of 27 previously unreported patients with the clinical SS triad, and 51 patients from published articles in which the MR images were depicted or reported. RESULTS: All 27 patients had multifocal supratentorial white matter lesions including the corpus callosum. The deep gray nuclei (basal ganglia and thalamus) were involved in 19 (70%). Nineteen (70%) also had parenchymal enhancement and 9 (33%) had leptomeningeal enhancement. Of the 51 cases from the literature, at least 32 had callosal lesions. The authors could not determine the presence of callosal lesions in 18 of these patients, and only one was reported to have a normal MRI at the onset of encephalopathy. CONCLUSIONS: The MR scans in SS show a rather distinctive pattern of supratentorial white matter lesions that always involve the corpus callosum. There is often deep gray matter, posterior fossa involvement, and frequent parenchymal with occasional leptomeningeal enhancement. The central callosal lesions differ from those in demyelinating disease, and should support the diagnosis of SS in patients with at least two of the three features of the clinical triad.

Personality and outcome in depression: an 18-month prospective follow-up study.

BACKGROUND: The relationship between personality and depressive illness is complex. The aim of this study was to assess whether the presence of a personality disorder or high neuroticism (N) scores predicted longer times to discharge or remission onset or higher risks of relapse for a cohort of depressed subjects admitted for the first time. METHODS: 100 consecutive subjects with ICD-10-defined depression were recruited on admission and followed up prospectively over an 18-month period. Personality function was rated using the informant-rated Standard Assessment of Personality in addition to the self-rated Maudsley Personality Inventory. Remission onset and relapse were defined operationally by scores on the Hamilton Rating Scale using recommended criteria. RESULTS: The presence of a personality disorder predicted longer times to remission onset. Personality trait accentuation did not. Higher end N-scores correlated with longer times to remission onset. Neither personality disorder nor high N-scores predicted relapse or discharge risk. Subjects with a personality disorder were treated as aggressively as those without but those with higher N-scores were not. LIMITATIONS: It is an in-patient sample. Fifteen subjects dropped out of follow-up and those who did so were more likely to have met criteria for two or more personality disorder categories or four or more traits from one personality disorder category. The analysis assumes that state and scar effects on N-scores were minimised. Treatment decisions were not controlled. CONCLUSIONS: These findings support the view that the presence of a personality disorder and high N-scores modify the short-term course to remission onset in depression.

Testing two theories of conceptual combination: alignment versus diagnosticity in the comprehension and production of combined concepts.

People often interpret novel noun-noun combinations by transferring a property from one constituent concept of the combination to the other. Two theories make different predictions about these "property" interpretations. Dual-process theory predicts that properties transferred will be alignable differences of the concepts being combined. Constraint theory predicts that properties transferred will be diagnostic properties of the concepts in which they originate. An experimental study tested these contrasting predictions in interpretation comprehension and interpretation production tasks. The results showed that participants reliably preferred diagnostic property interpretations, whether alignable or nonalignable, in both tasks. There was no reliable preference for alignable interpretations in either task. This confirms constraint theory's predictions about property interpretations and goes against the predictions of dual-process theory.

Remission onset and relapse in depression. An 18-month prospective study of course for 100 first admission patients.

BACKGROUND: Few prospective studies of course for first admission depressives are reported. METHODS: One hundred consecutive depressed inpatients were followed prospectively over 18 months. Course was defined operationally using the Hamilton Depression scale and ICD-10 criteria. Results were analysed using life-tables. RESULTS: The cumulative probabilities of remission onset by 3 and 18 months were 0.67 (95% C.I.=0.57-0.77) and 0.82 (95% C.I.=0.74-0.90). The cumulative probability of relapse was 0.25 (95% C.I.=0.15-0.35); 53% of those relapsing did so in the first 2 months. Younger age at onset, longer illness length, higher depression and anxiety ratings, predicted delayed remission onset. ICD-10 episode severity predicted relapse. CONCLUSIONS: The chances of remission onset at 3 months and relapse were increased relative to other studies; risk of chronicity was similar. Predictors of outcome to emerge were similar to other studies. CLINICAL IMPLICATIONS: Adoption of these remission onset criteria may identify earlier (at 3 months), subjects at high risk of chronicity. After remission onset, subjects with severe illnesses warrant careful follow-up to detect relapse, particularly during the first 2 months. LIMITATIONS: The operational criteria used were different to other prospective studies. Relatively few psychosocial variables were included in the analysis.

First admissions for depression: is the 'no-treatment interval' a critical predictor of time to remission?

BACKGROUND: This study aimed to replicate findings that length of episode prior to adequate antidepressant treatment (the 'no-treatment interval') and premorbid neuroticism predict time to remission from the institution of adequate treatment for depression. METHODS: Eighty-three inpatients meeting ICD-10 criteria for a depressive illness were entered into an 18-month prospective follow-up study of illness course. Subjects were assessed using the Schedules for Clinical Assessment in Neuropsychiatry, Maudsley Personality Inventory (MPI) and the Hamilton Rating Scale for Depression (HRSD). Remission was defined as an HRSD score of < 8 for 2 consecutive weeks. RESULTS: Twenty-two patients (27%) remained depressed 12 months after the onset of adequate treatment. Significantly longer times to remission were predicted by a longer no-treatment interval and higher premorbid neuroticism scores. LIMITATIONS: Adequate antidepressant treatment was commenced prior to admission in half the cases, requiring a retrospective assessment of illness course prior to study entry. Twenty-four patients (29%) had not remitted at the time of completion of the MPI. CONCLUSIONS: These results replicate previous findings identifying a longer time to treatment and higher neuroticism scores as predictors of chronicity in depression.

Epitope mapping of Aleutian mink disease parvovirus virion protein VP1 and 2.

Six overlapping fragments of the Aleutian Mink Disease parvoVirus (AMDV) virion protein VP1 and 2 (VP1/2) gene were inserted into the expression vector pMAL-c2. Four of the clones carried large overlapping fragments covering the entire VP1/2 gene. The remaining two clones covered specifically chosen regions within the VP1/2 gene. Using a Western blotting detection system, sera from AMDV-infected mink were tested against the recombinant polypeptides. These studies showed reactions primarily directed against the two AMDV polypeptides ranging from amino acids 297 to 518. Weaker reactions against other regions of the VP1/2 were also observed. The small fusion protein designed to cover the presumed AMDV VP1/2 loop 4 was purified by affinity chromatography and used to develop solid-phase immunoassays. Twelve small synthetic peptides were constructed and used as inhibitors. A peptide covering amino acids S428 to T448 was shown to block the reactivity of a pool of positive mink sera, indicating the presence of one dominant linear epitope.

Expression of Aleutian mink disease parvovirus capsid proteins in defined segments: localization of immunoreactive sites and neutralizing epitopes to specific regions.

The capsid proteins of the ADV-G isolate of Aleutian mink disease parvovirus (ADV) were expressed in 10 nonoverlapping segments as fusions with maltose-binding protein in pMAL-C2 (pVP1, pVP2a through pVP2i). The constructs were designed to capture the VP1 unique sequence and the portions analogous to the four variable surface loops of canine parvovirus (CPV) in individual fragments (pVP2b, pVP2d, pVP2e, and pVP2g, respectively). The panel of fusion proteins was immunoblotted with sera from mink infected with ADV. Seropositive mink infected with either ADV-TR, ADV-Utah, or ADV-Pullman reacted preferentially against certain segments, regardless of mink genotype or virus inoculum. The most consistently immunoreactive regions were pVP2g, pVP2e, and pVP2f, the segments that encompassed the analogs of CPV surface loops 3 and 4. The VP1 unique region was also consistently immunoreactive. These findings indicated that infected mink recognize linear epitopes that localized to certain regions of the capsid protein sequence. The segment containing the hypervariable region (pVP2d), corresponding to CPV loop 2, was also expressed from ADV-Utah. An anti-ADV-G monoclonal antibody and a rabbit anti-ADV-G capsid antibody reacted exclusively with the ADV-G pVP2d segment but not with the corresponding segment from ADV-Utah. Mink infected with ADV-TR or ADV-Utah also preferentially reacted with the pVP2d sequence characteristic of that virus. These results suggested that the loop 2 region may contain a type-specific linear epitope and that the epitope may also be specifically recognized by infected mink. Heterologous antisera were prepared against the VP1 unique region and the four segments capturing the variable surface loops of CPV. The antisera against the proteins containing loop 3 or loop 4, as well as the anticapsid antibody, neutralized ADV-G infectivity in vitro and bound to capsids in immune electron microscopy. These results suggested that regions of the ADV capsid proteins corresponding to surface loops 3 and 4 of CPV contain linear epitopes that are located on the external surface of the ADV capsid. Furthermore, these linear epitopes contain neutralizing determinants. Computer comparisons with the CPV crystal structure suggest that these sequences may be adjacent to the threefold axis of symmetry of the viral particle.

The effects of porcine somatotropin on muscle fibre morphology and meat quality of pigs of known stress susceptibility.

To study the effects of porcine somatotropin (pST) administration on muscle fibre characteristics and meat quality, 48 pigs of the Lacombe breed (equal numbers of barrows and gilts) of known halothane genotype (NN, Nn or nn) were randomly assigned to either a control (excipient buffer) or pST (3.0 mg d(-1)) treatment. At a pen average animal weight of 106 kg, pigs were slaughtered and muscle samples were collected post mortem for determination of fibre type, glucidic metabolites and meat quality. There was a 16% increase in muscle weight of the semimembranosus (SM) and psoas major (PM) in pST-treated animals (p ≤ 0.01). However, there was no significant change in fibre type associated with the pST treatment in either the SM or PM (p > 0.05). In the PM muscle there was a 65-70% increase in fast, oxidative, glycolytic (FOG) and fast, glycolytic (FG) fibre areas in pST-treated gilts (p ≤ 0.05). These cellular changes were manifest in meat colour that was lighter and spectrally shifted towards yellow (significantly higher L (∗) and hue angle values), higher drip loss, lower moisture content and a tendency towards higher Kramer-Press shears (p = 0.06) in the PM of pST-treated gilts. Although these changes were in the same direction as pale, soft, exudative meat, the average values fell within the normal range. Based on the observed gender by pST treatment interactions, administration of pST (timing, dosage and protein requirements in the feed) may need to be tailored to suit different genders and breeds to achieve the maximal response.

Subcellular localization of Aleutian mink disease parvovirus proteins and DNA during permissive infection of Crandell feline kidney cells.

Confocal microscopy allowed us to localize viral nonstructural (NS) and capsid (VP) proteins and DNA simultaneously in cells permissively infected with Aleutian mink disease parvovirus (ADV). Early after infection, NS proteins colocalized with viral DNA to form intranuclear inclusions, whereas VP proteins formed hollow intranuclear shells around the inclusions. Later, nuclei had irregular outlines and were virtually free of ADV products. In these cells, inclusions of viral DNA with or without associated NS protein were embedded in cytoplasmic VP protein. These findings implied that ADV replication within an infected cell is regulated spatially as well as temporally.

The relationship between capsid protein (VP2) sequence and pathogenicity of Aleutian mink disease parvovirus (ADV): a possible role for raccoons in the transmission of ADV infections.

Aleutian mink disease parvovirus (ADV) DNA was identified by PCR in samples from mink and raccoons on commercial ranches during an outbreak of Aleutian disease (AD). Comparison of DNA sequences of the hypervariable portion of VP2, the major capsid protein of ADV, indicated that both mink and raccoons were infected by a new isolate of ADV, designated ADV-TR. Because the capsid proteins of other parvoviruses play a prominent role in the determination of viral pathogenicity and host range, we decided to examine the relationship between the capsid protein sequences and pathogenicity of ADV. Comparison of the ADV-TR hypervariable region sequence with sequences of other isolates of ADV revealed that ADV-TR was 94 to 100% related to the nonpathogenic type 1 ADV-G at both the DNA and amino acid levels but less than 90% related to other pathogenic ADVs like the type 2 ADV-Utah, the type 3 ADV-ZK8, or ADV-Pullman. This finding indicated that a virus with a type 1 hypervariable region could be pathogenic. To perform a more comprehensive analysis, the complete VP2 sequence of ADV-TR was obtained and compared with that of the 647-amino-acid VP2 of ADV-G and the corresponding VP2 sequences of the pathogenic ADV-Utah, ADV-Pullman, and ADV-ZK8. Although the hypervariable region amino acid sequence of ADV-TR was identical to that of ADV-G, there were 12 amino acid differences between ADV-G and ADV-TR. Each of these differences was at a position where other pathogenic isolates also differed from ADV-G. Thus, although ADV-TR had the hypervariable sequence of the nonpathogenic type 1 ADV-G, the remainder of the VP2 sequence resembled sequences of other pathogenic ADVs. Under experimental conditions, ADV-TR and ADV-Utah were highly pathogenic and induced typical AD in trios of both Aleutian and non-Aleutian mink, whereas ADV-Pullman was pathogenic only for Aleutian mink and ADV-G was noninfectious. Trios of raccoons experimentally inoculated with ADV-TR and ADV-Utah all became infected with ADV, but only a single ADV-Pullman-inoculated raccoon showed evidence of infection. Furthermore, none of the ADV isolates induced pathological findings of AD in raccoons. Finally, when a preparation of ADV-TR prepared from infected raccoon lymph nodes was inoculated into mink and raccoons, typical AD was induced in Aleutian and non-Aleutian mink, but raccoons failed to show serological or pathological evidence of infection. These results indicated that raccoons can become infected with ADV and may have a role in the transmission of virus to mink but that raccoon-to-raccoon transmission of ADV is unlikely.