Multidisciplinary Ophthalmic Imaging Progressive Loss of Retinal Ganglion Cells and Axons in Nonoptic Neuritis Eyes in Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study

Citation: Graham EC, You Y, Yiannikas C, et al. Progressive loss of retinal ganglion cells and axons in non-optic neuritis eyes in multiple sclerosis: a longitudinal optical coherence tomography study. Invest Ophthalmol Vis Sci. 2016;57:231157: -231757: . DOI:10.1167 PURPOSE. To examine the rate of retinal ganglion cell (RGC) layer and retinal nerve fiber layer (RNFL) changes in nonoptic neuritis (NON) eyes of relapsing remitting multiple sclerosis (RRMS) patients, and to find a specific imaging parameter useful for identifying disease progression. METHODS. Forty-five consecutive RRMS patients and 20 age-and sex-matched healthy subjects were enrolled. All patients were followed up for 3 years with annual optical coherence tomography (OCT) scans, which included a peripapillary ring scan protocol for RNFL analysis and a macular radial star-like scan to obtain RGC/inner plexiform layer (IPL) thickness measures. Healthy controls were scanned twice, 3 years apart. RESULTS. Retinal ganglion cell/inner plexiform layer and temporal RNFL (tRNFL) demonstrated highly significant thinning (P < 0.01), but all nasal segments and global RNFL (gRNFL) were not significantly different from normal controls. While receiver operating characteristics (ROC) analysis showed no advantage of RGC/IPL over tRNFL in cross-sectional detection of thinning, cut-off point based of fifth percentile in healthy controls demonstrated higher rate of abnormality for RGC/IPL. There was a significant progressive loss of RGC/IPL and tRNFL during the follow-up period. The largest thickness reduction was observed in tRNFL. ROC analysis demonstrated that tRNFL provided better sensitivity/specificity for detecting change over time than RGC/IPL (area under the curve [AUC] 0.78 vs. 0.52), which was confirmed by higher detection rate when 95 th percentile of progression in healthy controls was used as a cut-off. CONCLUSIONS. This study confirmed significant thinning of RGC/IPL and tRNFL in NON eyes of RRMS patients. Progressive losses were more apparent on tRNFL, while RGC/IPL showed less change over the follow-up period

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Introduction: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. Methods: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. Results: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). Conclusion: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases. © 2019 The Author

Corticomotoneuronal function and hyperexcitability in acquired neuromyotonia

Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 ± 1.9%; amyotrophic lateral sclerosis 2.6 ± 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 ± 3.1%; amyotrophic lateral sclerosis 38.1 ± 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia −0.9 ± 1.3%; amyotrophic lateral sclerosis −2.3 ± 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 ± 1.6%; amyotrophic lateral sclerosis 57.2 ± 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 ± 6.9 ms; amyotrophic lateral sclerosis 181.1 ± 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity in acquired neuromyotonia, arguing against a contribution of central processes to the development of nerve hyperexcitability in acquired neuromyotonia

Multifocal visual evoked potential (mfVEP) and pattern-reversal visual evoked potential changes in patients with visual pathway disorders : a case series

The purpose of this study was to evaluate multifocal visual evoked potential (mfVEP) and pattern-reversal visual evoked potential (PVEP) changes in patients with pathology at various levels of the visual pathway determined by other methods. Six patients with different visual pathway disorders, including vascular ischaemic events and compressive optic neuropathy, were reviewed. All patients were tested with both mfVEP and full-field and half-field PVEPs. Results were assessed in relation to other diagnostic tests such as magnetic resonance imaging, Humphrey visual field test, and optical coherence topography. The cases in this study demonstrate a potential higher sensitivity of mfVEP compared with conventional PVEPs in detecting lesions affecting the peripheral field, horizontal hemifields, and lesions of the post-chiasmal pathway. The limitation of the PVEP in this setting is probably due to phase cancellation and overrepresentation of the macular region. mfVEP provides a more accurate assessment of visual defects when compared with conventional PVEP. The independent assessment of different areas of the visual field improves the detection and localization of lesions and provides an objective topographical map that can be used in clinical practice as an adjunct to other diagnostic tests and to assess disease progression.14 page(s

Mechanism of delayed conduction of fellow eyes in patients with optic neuritis

To test the hypothesis that latency delay in the fellow eyes of optic neuritis (ON) patients and to compensate for delayed transmission of visual information, latency change of multi-focal visual evoked potential (mfVEP) traces in fellow eyes of 15 ON patients were analyzed. Patients with low risk (LR) for developing multiple sclerosis (MS) were examined separately from MS patients to isolate effect of cortical plasticity from potential pathological changes in disseminated disease. The small increase in latency in fellow eyes of LR group was statistically not significant. In MS patients, the latency was significantly delayed (P<0.02). The magnitude of the latency change in the fellow eyes did not correlate with the severity of latency delay in the affected eyes (R2<0.02, P=0.3). The differences between ON patients with and without MS, reported here, suggest that the presence of disseminated disease plays critical role in latency delay of the fellow eye

Predicting a positive response to intravenous immunoglobulin in isolated lower motor neuron syndromes.

OBJECTIVE: To determine clinically related characteristics in patients with pure lower motor neuron (LMN) syndromes, not fulfilling accepted diagnostic criteria, who were likely to respond to intravenous immunoglobulin (IVIg) treatment. METHODS: Demographic, clinical, laboratory and neurophysiological characteristics were prospectively collected from patients with undifferentiated isolated LMN syndromes who were then treated with IVIg. Patients were classified as either responders or non-responders to therapy with IVIg based on clinical data and the two groups were compared. RESULTS: From a total cohort of 42 patients (30 males, 12 females, aged 18-83 years), 31 patients responded to IVIg and 11 did not. Compared to patients that developed progressive neurological decline, responders were typically younger (45.8 compared to 56.0 years, P<0.05) and had upper limb (83.9% compared to 63.6%, NS), unilateral (80.6% compared to 45.5%, P<0.05), and isolated distal (54.1% compared to 9.1%, P<0.05) weakness. Patients with predominantly upper limb, asymmetrical, and distal weakness were more likely to respond to IVIg therapy. Of the patients who responded to treatment, only 12.9% had detectable GM(1) antibodies and conduction block (not fulfilling diagnostic criteria) was only identified in 22.6%. CONCLUSIONS: More than 70% of patients with pure LMN syndromes from the present series responded to treatment with IVIg therapy, despite a low prevalence of detectable GM(1) antibodies and conduction block. Patients with isolated LMN presentations, not fulfilling accepted diagnostic criteria, may respond to IVIg therapy, irrespective of the presence of conduction block or GM(1) antibodies, and should be given an empirical trial of IVIg to determine treatment responsiveness

Hereditary sensory and autonomic neuropathy type IC accompanied by upper motor neuron abnormalities and type II juxtafoveal retinal telangiectasias

Hereditary sensory and autonomic neuropathy type I (HSAN-1) is an autosomal dominant sensory neuropathy occurring secondary to mutations in the SPTLC1 and SPTLC2 genes. We present two generations of a single family with Ser384Phe mutation in the SPTLC2 gene located on chromosome 14q24 characterized by a typical HSAN-1c presentation, with additional findings upper motor neuron signs, early demyelinating features on nerve conduction studies, and type II juxtafoveal retinal telangiectasias also known as macular telangiectasias (MacTel II). Although HSAN1 is characterized as an axonal neuropathy, demyelinating features were identified in two subjects on serial nerve conduction studies comprising motor conduction block, temporal dispersion, and prolongation of F-waves. MacTell II is a rare syndrome characterized by bilateral macular depigmentation and Müller cell loss. It has a presumed genetic basis, and these cases suggest that the accumulation of toxic sphingoplipids may lead to Müller cell degeneration, subsequent neuronal loss, depigmentation, and progressive central macular thinning

Multifocal Motor Neuropathy Presenting as Pseudodystonia

Multifocal motor neuropathy (MMN) is an immune-mediated neuropathy. Wasting and weakness typically dominate the clinical presentation. We describe four cases presenting with prominent cramping resembling a primary movement disorder. All cases had features of focal motor conduction block on neurophysiological studies. The involuntary movements resolved in all four patients following treatment with intravenous immunoglobulin. The presented cases highlight an unusual presentation of MMN and emphasize that peripheral nerve pathology can present with movement disorders mimicking central nervous system disease. Furthermore, the movement disorder appears particularly sensitive to standard therapy

Interrelationship of optical coherence tomography and multifocal visual-evoked potentials after optic neuritis

Purpose. Acute optic neuritis (ON) is often followed by recovery of visual function. Although this recovery is mainly attributable to resolution of the acute inflammation, the redistribution of ion channels along the demyelinated membrane, and subsequent remyelination, part of it may be the result of neural plasticity. In the present study, the interrelationship was examined between structural (retinal nerve fiber layer [RNFL] thickness) and functional (amplitude of multifocal visual evoked potentials [mfVEPs]) measures of the integrity of the visual pathway in the postacute stage of ON, to determine whether there was any evidence of ongoing neural reorganization. Methods. Twenty-five subjects with acute unilateral ON underwent serial RNFL thickness measurement and mfVEP recording. The inter-eye asymmetry of both measures was analyzed. In the period between 6 and 12 months, the subjects were considered free of optic disc edema, and that period was used to analyze the structure–function relationship. Twenty control subjects were also examined. Results. There were significant but opposite changes in RNFL thickness and mfVEP amplitude. The average asymmetry of RNFL thickness between affected and fellow eyes increased from 17.5 ± 11.5 to 21.1 ± 12.8 µm (P = 0.0003), indicating progressive axonal loss, whereas mfVEP amplitude asymmetry decreased from 46.6 ± 32.4 to 38.3 ± 31.1 nV (P = 0.0015), indicating continuous functional recovery. In comparison to the 6-month results, the mfVEP amplitude in the ON eye improved by 17.8%, whereas RNFL thickness decreased by 20.8%. The result remained unchanged regardless of the degree of optic nerve remyelination. Conclusions. The finding of structural–functional discrepancy at the postinflammatory stage may support the concept that neural plasticity contributes to functional recovery after acute ON.8 page(s

Progressive injury in chronic multiple sclerosis lesions is gender-specific : a DTI study

Objective: To evaluate the longitudinal integrity of white matter tracts in patients with relapsing remitting multiple sclerosis (RRMS) as determined by changes in diffusivity indices of lesional and non-lesional white matter in the optic radiation over 12 months. Methods: The optic radiation (OR) was identified in sixty RRMS patients using probabilistic tractography. MS lesions were segmented on FLAIR T2 images and a lesion mask was intersected with the co-registered OR. Lesions within the OR were identified in 39 patients. Voxel-based analysis of axial diffusivity (AD) and radial diffusivity (RD) within OR lesions and non-lesional normal appearing white matter (NAWM) was performed at baseline and 12 months in 34 patients (five patients excluded due to new OR lesions). Results: Both RD and AD demonstrated much higher values within the lesions compared with non-lesional NAWM. There was a significant (p<0.001) increase of lesional AD and RD during the follow-up period. This increase, however, was driven almost entirely by the male cohort, in which a significantly greater change in both AD (M-2.7%, F-0.9%) and RD (M-4.6%, F-0.7%) was observed during the follow-up period. Non-lesional NAWM also demonstrated an increase in both AD and RD, albeit on a much lesser scale (1.0% and 0.6% respectively). In contradistinction to lesions, the diffusivity change in non-lesional NAWM was similar between sexes. Conclusions: The evolution of AD and RD in chronic MS lesions over 12 months suggests ongoing inflammatory demyelinating activity accompanied by axonal loss. In addition, our findings are consistent with the recently observed trend of more rapid clinical progression in males and establish a potential in vivo biomarker of gender dichotomy by demonstrating a significantly faster rate of microstructural change in the chronic lesions of male patients with MS.11 page(s