Visual Evoked Potential Latency Prolongation in MS: Correlation with Cognitive Performance on a Computerized Testing Battery (P07.260)

Objective: To report results of BG-12 on tertiary magnetic resonance imaging (MRI)-related outcomes from the Phase 3 DEFINE study. Background BG-12 is an experimental oral treatment for relapsing-remitting multiple sclerosis (RRMS) that may have anti-inflammatory and neuroprotective effects via the Nrf2 pathway. DEFINE, a randomized, double-blind, placebo-controlled study evaluating BG-12 over 2 years in RRMS patients, showed significant reductions in clinical relapses, accumulation of disability progression, and number of lesions on brain MRI images. Design/Methods: Patients aged 18-55 years with RRMS (McDonald criteria) and EDSS score of 0.0-5.0 were enrolled. Patients were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). A subset of patients from 76 sites had MRI scans at baseline, 24 weeks, 1 year, and 2 years. Tertiary endpoints included brain atrophy from 6 months to 2 years measured using the SIENA method and the volume of T2, gadolinium-enhancing (Gd+), and T1 hypointense lesions at 1 and 2 years. Results: The MRI intent-to-treat cohort comprised 540 patients. The median percent whole brain volume change from 6 months to 2 years was -0.660% in placebo compared with -0.460% and -0.550% in the BG-12 BID and TID groups, respectively, representing reductions of 30% (P=0.0214) and 17% (P=0.2478) versus placebo. Over 2 years, the median percent change of T2 hyperintense lesion volume from baseline was 20.1% with placebo versus -6.2% (P Conclusions: Results of the MRI analysis of the DEFINE study demonstrate reduced brain atrophy and lesion volume compared with placebo and supports BG-129s potential as an effective oral treatment for RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Zhang has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received personal compensation for activities with Biogen Idec as an employee. Dr. Stephan has received research support from Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Objective: To report the impact of BG-12 on patient quality of life (QoL) after 2 years9 treatment in the Phase 3 DEFINE study. Background In DEFINE, a randomized, double-blind, placebo-controlled, multicenter study that evaluated the efficacy and safety of BG-12 over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), BG-12 significantly reduced clinical relapses, disability progression, and magnetic resonance imaging measures of disease activity. Design/Methods: Patients aged 18-55 years with RRMS (McDonald criteria) and Expanded Disability Status Scale score of 0.0-5.0 were eligible for enrollment. Patients were randomized 1:1:1 to placebo or BG-12 240 mg twice (BID) or three times daily (TID). A Short Form (SF)-36 questionnaire measured patients9 health status and health-related QoL on 8 multi-item 100-point scales at baseline and 6, 12, and 24 months; higher scores indicated higher QoL. These scores were used to calculate the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Results: Overall, 1234 patients enrolled and received study treatment. At 2 years, patients reported higher mean SF-36 PCS scores with BG-12 BID (43.4) and TID (44.2) versus placebo (41.9; P Conclusions: Together with the significant effects on clinical measures (reduced relapse risk, annualized relapse rate, and disability progression), the demonstrated benefits on patient-reported health-related QoL further supports a potential role for BG-12 as a valuable oral treatment option in RRMS patients. Supported by: Biogen Idec Inc. Disclosure: Dr. Agarwal has received personal compensation for activities with Biogen Idec Inc as an employee. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Gold has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received (royalty or license fee or contractual rights) payments from Biogen Idec. Dr. Gold has received research support from Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis and Teva Neuroscience. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Bar-Or has received personal compensation for activities with Aventis Pharmaceuticals, Bayhill Therapeutics, Biogen Idec, Berlex Laboratories, Eli Lilly & Company, Genentech, Inc., GlaxoSmithKline, Ono Pharmaceutical, Diogenix, Roche Diagnostics Corporation, Merck Serono, Novartis, Teva Neuroscience. Dr. Giovannoni has received personal compensation for activities with Bayer-Pharmaceuticals Corporation, Biogen Idec, Five Prime Therapeutics, Inc, Genzyme Corporation, Ironwood Pharmaceuticals, Merck Serono, Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals and Vertex Pharmaceuticals as a speaker, consultant and/or serving on data monitoring boards. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Kong has received personal compensation for activities with Biogen Idec as an employee. Dr. Sheikh has received personal compensation for activities with Biogen Idec as an employee. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.

Objective: To report long-term outcomes and safety of fingolimod in relapsing multiple sclerosis (RMS) patients participating in a phase 2 study. Background After the 6-month (M) placebo controlled study in which fingolimod (1.25mg and 5mg dose groups) significantly reduced MRI and relapse activity compared to placebo all patients were invited to continue on fingolimod. The final analysis after 7 years is presented. Design/Methods: In the extension, placebo patients were re-randomized to fingolimod 1.25mg or 5mg (placebo/fingolimod group); fingolimod patients (1.25 or 5mg) continued with their core phase dose (fingolimod group). After the M24 visit, all patients received open-label, 1.25mg fingolimod and between M24-M60 were converted to 0.5mg. Results: Of 281 initially randomized patients 122 (43.4%) completed up to 7 years on study (core and extension). The overall ARR for the fingolimod group was 0.16 and for placebo/fingolimod 0.21. By study completion, 55-66% of fingolimod and 44% of placebo/fingolimod patients were relapse-free. The KM estimate of the proportion of patients who were free from 6-month confirmed disability progression ranged from 53-70% for both groups. At the end of study, 83% of all remaining patients were free of gadolinium-enhanced lesions. No increase in T2 lesion volume was observed. No chronic effects of fingolimod treatment were observed on heart rate or atrioventricular conduction. No cases of confirmed macular edema were observed. Twelve cases of skin malignancies have been reported (majority within the first 3 years): 5, basal cell carcinoma; 4, squamous cell carcinoma; 3, malignant melanoma. Conclusions: Long-term (>7 years) fingolimod treatment was associated with sustained low MRI and clinical disease activity in those remaining on therapy and was well tolerated with no new safety concerns arising with long-term dosing. Supported by: Novartis Pharma AG, Basel, Switzerland. Disclosure: Dr. Antel has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals, Inc., Biogen Idec, Novartis, Serono, Inc., Genzyme Corporation, Teva Neuroscience, and GlaxoSmithKline. Dr. Antel has received personal compensation in an editorial capacity for Multiple Sclerosis. Dr. Antel has received research support from Novartis. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. O9Connor has received personal compensation for activities with Abbott Labratories, Inc., Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceuticals Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals as a consultant. Dr. O9Connor has received research support from Abbott Labratories, Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Cognosci, Daiichi Pharmaceutical Corporation, Serono, Inc., Genentech, Inc., Genmab, Novartis, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Teva Neuroscience, Warburg Pincus and Wyeth Pharmaceuticals. Dr. De Vera has received personal compensation for activities with Novartis Pharma AG as an employee. Dr. Cremer has received personal compensation for activities with Novartis. Dr. Sfikas has received personal compensation for activities with Novartis as an employee. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations.

Influence of Cataract Surgery on Optical Coherence Tomography and Neurophysiology Measurements in Patients With Retinitis Pigmentosa

Objective: To report MRI features of 3 cases with confirmed progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients treated with natalizumab that presented with subtle new lesions on MRI several months prior to diagnosis. Background Clinical vigilance and early recognition of specific MRI changes are considered caveats for early diagnoses of PML in natalizumab treated patients. Design/Methods: Retrospective clinical and MRI evaluation of 3 patients with confirmed PML (by detection of JC virus in cerebrospinal fluid), who had several serial scans prior to the PML diagnosis. Results: Case 1: 41 year old man who received 29 monthly natalizumab infusions. A small new T2 hyperintense/T1 enhancing lesion in the subcortical white matter of the left frontal lobe was detected. No clinical symptoms were associated and he tested negative for prior JC virus exposure 6 months previous. Seven months later, a large T2 hyperintense/T1 enhancing lesion, indicative of PML was detected in the same location. He tested positive for JC virus exposure on repeat analysis, one month prior to diagnosis. Case 2: 47 year old woman on natalizumab for 31 months complained of new onset double vision. A small T2 hyperintense, T1 non-enhancing lesion was detected in pons. Two months later, a large T2 hyperintense lesion consistent with PML was detected in the same location, in addition to multiple other lesions. Case 3: 54 year old woman on natalizumab for 61 months presented with mild vertigo. A small new T2 hyperintense lesion in pons was seen retrospectively. Four months later a large T2 hyperintense lesion consistent with PML was detected in the same location, in addition to multiple other lesions. Conclusions: The appearance of subtle new T2 hyperintense lesions may suggest PML in patients treated with natalizumab for more than two years. Disclosure: Dr. Hojnacki has received personal compensation for activities with Biogen Idec, Serono, Inc., Pfizer Inc, and Teva Neuroscience as a speaker and/or participant on scientific advisory boards. Dr. Zivadinov has received personal compensation for activities with Teva Neuroscience, Biogen Idec, EMD Serono, and Questcor Pharmaceuticals as a speaker and/or consultant. Dr. Zivadinov has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corporation, Bracco, Questcor Pharmaceuticals and EMD Serono. Dr. Weinstock-Guttman has received personal compensation for activities with Acorda Therapeutics, Biogen Idec, Serono, Inc., Novartis, Pfizer Inc, Teva Neuroscience as a speaker and/or participant on an advisory board. Dr. Weinstock-Guttman has received research support from Acorda Therapeutics, Biogen Idec, Serono Inc., Novartis, Pfizer Inc, Teva Neuroscience, National Multiple Sclerosis Society, the National Institutes of Health, ITN, Teva Neuroscience, Aspreva-Roche, Acorda Therapeutics and Shire Pharmaceuticals.

Objective: To describe the outcomes of early detected progressive multifocal leukoencephalopathy (PML) in natalizumab-treated multiple sclerosis (NTMS) patients utilizing novel interventions. PML is an opportunistic brain infection caused by the JC virus (JCV) in NTMS patients. Background To address the need for effective approach to ameliorating PML. Design/Methods: Our empirical protocol for early diagnosis of PML in NTMS patients uses cranial MRIs at 4-6 month intervals or with new symptoms. Diagnosis was based on PML suspected MRI findings and positive JCV PCR in the CSF. Management consisted of plasma exchange, subcutaneous filgrastim 5 mg/kg/day (to restore lymphocyte adhesion capacity and immuno surveillance), oral maraviroc 150 mg twice daily (to modulate T cell recruitment), and oral mefloquin 300 mg/day and mirtazapine 50 mg/day (for their putative anti JCV effects). Patients were concurrently monitored using weekly contrast-MRIs and received intravenous corticosteroids upon emergence of immune reconstitution inflammatory syndrome (IRIS). Results: Six patients with NTMS were diagnosed with PML after 29-54 months of treatment. MRI discovered PML in two asymptomatic and two mildly symptomatic ones. Medications were well tolerated. Except for transient worsenings and seizures during IRIS, these patients did not significantly progress, remaining independent. Two of them already resumed employment, and the third one is soon expected to, as well. The two patients who were more severely symptomatic at diagnosis suffered intensified deficits, precluding independence. MS activity reoccurred in two patients after 6 and 8 months. Duration of post PML follow up 6-28 months. Conclusions: Our novel approach to PML in NTMS patients included monitoring that allowed very early diagnosis and administration of filgrastim and maraviroc, which likely contributed to the favorable clinical outcome in four patients. The two symptomatic at diagnosis patients remain incapacitated, though this regimen may have prevented fatal outcomes. The present interventions are of clinical significance and warrant further exploration. Disclosure: Dr. Stefoski has received personal compensation for activities with Biogen Idec, Acorda, Serono, Elan, and Teva Neuroscience. Dr. Stefoski has received royalty payments from Acorda Therapeutics. Dr. Stefoski has received research support from Biogen Idec, Novartis, Serono, and Pfizer. Dr. Ko has received personal compensation for activities with Biogen Idec, Serono, Inc., and Teva Neuroscience for consulting services. Dr. Javed has received personal compensation for activities with Teva Neuroscience, Bayer Pharmaceuticals, Serono, Inc., Novartis, Questcor and Biogen Idec as a consultant and/or speaker. Dr. Balabanov has received personal compensation for activities with Biogen Idec, Teva Neuroscience and Genzyme as a consultant, and speaker bureau honoraria from Biogen Idec and Teva Neuroscience.Dr. Balabanov has received research support from Biogen Idec.

Objective: To evaluate characteristics related to 2-year relapse rate for the TOP MS study completer cohort. Background The Therapy Optimization in MS Study (TOP MS) is a prospective, open-label parallel group study of patients who are being treated with disease-modifying therapies (DMT). All of the DMT have been shown to effectively reduce relapse rates. Design/Methods: Potential participants for TOP MS were identified at specialty pharmacies with medication therapy management programs. Signed informed consent forms were returned to the pharmacies, and study enrollment produced log-on instructions for the study website. At baseline and monthly intervals over 24 months, enrolled participants receive reminders to respond to surveys. Self-reported responses are entered directly into the study database. Results: The TOP MS completer cohort consists of 531 subjects with a mean duration of disease of 11.1+9.2 years. Nearly 90% of participants met the criteria for relapsing forms of MS. The 2-year relapse rate for this cohort was 35.3%. Glatiramer acetate was being used by 50.8%, and 49.2% were using interferon-beta at study enrollment. Over two years therapy change occurred for 50 patients (9.4%) and was significantly associated with the number of confirmed relapses (chi 2 = 13.9, df = 2, p = .001). While mean duration of current DMT treatment was 4.3+4.1 years, shorter duration was correlated with more confirmed relapses (p = .004). One-third of the completer cohort had used other DMT prior to starting their current therapy (mean number of previous therapies: 1.3) and number of previous DMT was positively correlated with number of confirmed relapses (p = .001). Disease duration and enrollment DMT were not associated with relapses. Conclusions: The two-year relapse rate in the completer cohort of the TOP MS Study was influenced by change in DMT therapy, time on DMT treatment, and number of previous DMT treatments. Supported by: Teva Pharmaceuticals. Disclosure: Dr. Coyle has received personal compensation for activities with Acorda Therapeutics, Avanir Pharmaceuticals, Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, Novartis, Questcor, Roche Diagnostics Corporation, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Coyle has received personal compensation in an editorial capacity for NEURA. Dr. Coyle has received research support from Serono, Inc., Novartis, and Sanofi-Aventis Pharmaceuticals, Inc. Dr. Zwibel has received personal compensation for activities with Serono, Inc., and Teva Neuroscience. Dr. Zwibel has received research support from Teva Neuroscience. Dr. Cohen has received research support from Biogen Idec. Dr. Leist has received personal compensation for activities with EMD Serono, Teva Neuroscience and Bayer.Dr. Leist has received research support from Bayer, EMD Serono and Teva Neuroscience. Dr. Tullman has received personal compensation for activities with Acorda Therapeutics, Biogen Idec, Serono Inc., Novartis, Pfizer Inc., Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Abbott Labortories, Inc. and Vaccinex as a consultant and/or speaker. Dr. Tullman has received research support from Acorda Therapeutics, BioMS, Novartis, and Genentech, Inc. Dr. Markowitz has received personal compensation for activities with Bayer, Teva, EMD-Serono, Biogen Idec, and Eli Lilly. Dr. Hughes has received research support from Teva Neuroscience, Berlex Labratories and Genentech, Inc..

Prior studies have reported an association between visual evoked potentials (VEPs) and cognitive performance in people with multiple sclerosis (PwMS), but the specific mechanisms that account for this relationship remain unclear. We examined the relationship between VEP latency and cognitive performance in a large sample of PwMS, hypothesizing that VEP latency indexes not only visual system functioning but also general neural efficiency. Standardized performance index scores were obtained for the domains of memory, executive function, visual-spatial processing, verbal function, attention, information processing speed, and motor skills, as well as global cognitive performance (NeuroTrax battery). VEP P100 component latency was obtained using a standard checkerboard pattern-reversal paradigm. Prolonged VEP latency was significantly associated with poorer performance in multiple cognitive domains, and with the number of cognitive domains in which performance was ≥ 1 SD below the normative mean. Relationships between VEP latency and cognitive performance were significant for information processing speed, executive function, attention, motor skills, and global cognitive performance after controlling for disease duration, visual acuity, and inter-ocular latency differences. This study provides evidence that VEP latency delays index general neural inefficiency that is associated with cognitive disturbances in PwMS.

During detailed visual function testing, pattern-reversal visual evoked potentials (VEP), generated by different spatial frequencies (3 c/d, 1 c/d and 0.6 c/d) and visual contrasts (100% and 10%) were recorded in 21 adolescent and young adult phenylketonuric (PKU) patients (11 females and 10 males; mean age 14.8 years, range 9-22.8) on and off diet. In 14 of the 21 patients, disease had been detected at neonatal screening and in 7 later. Ten age-matched healthy subjects acted as controls. Recordings in more than 40% of eyes in the whole group and 30% of eyes in the screening subgroup showed a prolonged P100 latency. All visual pattern stimuli elicited a significantly longer P100 latency in PKU patients than in controls. VEP latencies to 3 c/d, 1 c/d and 1 c/d with 10% contrast--but not to 0.6 c/d--were longer in patients off diet than in patients on diet. No differences were found between VEP latencies in early- and later-detected subjects. To study the link between biochemical variables and VEP latencies, we envisaged either a linear relationship between recent exposure to phenylalanine (Phe) and VEP abnormalities or a threshold model considering phenylalanine (Phe) concentrations among the factors influencing VEP latencies. The correlation analysis detected an association between plasma Phe concentrations and abnormal VEP latencies, predicting that plasma Phe concentrations > 901 mumol/L would prolong VEP latencies to 1 c/d; concentrations > 879 mumol/L would prolong latencies to 3 c/d; and concentrations > 898 mumol/L would prolong latencies to 1 c/d with 10% contrast.

To identify immune-response signatures in the blood of multiple sclerosis (MS) patients predictive for clinical disease trajectories and supporting personalized treatment decisions based on pathobiological principles.

Objective: To describe the MRI characteristics of HDLS patients with a known gene mutation on chromosome 5. Background Adult-onset leukoencephalopathies are a heterogeneous group of rare disorders, with natural histories ranging from being asymptomatic to inexorably progressive and fatal. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first described in 1984, and is an autosomal dominant disorder. Currently, 23 HDLS reports have been published. The pathological hallmark of HDLS is cerebral white matter lesions (WML) with axonal spheroids.Recently, a chromosome 5 mutation, CSF1R , was identified. Design/Methods: Twenty brain MRIs of 15 patients with autopsy/biopsy verified HDLS and chromosome 5 mutations were reviewed. Sagittal T1-, axial T1-, T2- weighted, and FLAIR images were assessed for distribution of WML, grey matter involvement, and atrophy. Results: In this study, the mean age of onset was 44 years (range, 19-71); mean disease duration was 5 years (range, 3-11); and the mean age at death was 50 years (30-75). 80 % (12/15) demonstrated focal WML, whereas in two the lesions were patchy. One patient had generalized WMLs. All patients had bilateral, though slightly asymmetric lesions. WMLs with frontal predominance, involving deep and subcortical regions, were found in all cases. 93 % (14/15) had periventricular involvement, while 73% (11/15) had involvement of the corpus callosum. Of the latter, seven had more than one callosal segment affected and five had involvement of the entire corpus callosum. Typically, brain atrophy was present in the same region as the WMLs; however, in three cases isolated atrophy of the parietal, occipital and temporal cortices were found, respectively. Central atrophy was invariably present. Corticospinal tract involvement occurred late in the disease course. The grey matter, brain stem and cerebellum were spared, and enhancement was absent. Conclusions: MRI is valuable in helping to define the natural history of HDLS and will be useful in assessing future treatment responses. The MRI patterns of HDLS are sufficiently typical to aid in diagnosis. Supported by: ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). SF is partially supported by MCF Research Committee CR program ( MCF #90052030). CS was partially supported by Anna-Lisa och Bror Bjornssons-, Sven and Dagmar Salens-, Signe och Olof Wallenius- and Gamla Tjanarinnor Foundations, Sweden. The Swedish Society of Medicine Gothenburg (GLS), Sweden, The Swedish Society of Medicine Sweden, The Swedish and Gothenburg Societies for the Neurologically Disabled and The Gothenburg Foundation for Neurological Research. Disclosure: Dr. Sundal has nothing to disclose. Dr. Fujioka has nothing to disclose. Dr. Van Gerpen has nothing to disclose. Dr. Wider has nothing to disclose. Dr. Aasly has nothing to disclose. Dr. Shuster has nothing to disclose. Dr. Ghetti has received personal compensation for activities with Bayer Pharmaceuticals Corporation. Dr. Ghetti has received research support from the National Institute of Health. Dr. Garbern has received personal compensation for activities with Genzyme Corporation, Lundbeck Research USA, Inc., StemCells, Inc, and Serono, Inc. as a consultant and/or speaker. Dr. Garbern has received personal compensation in an editorial capacity for Medlink Neurology. Dr. Garbern has received research support from Genzyme Corporation. Dr. Tselis has received research support from Teva Neuroscience and Biogen Idec. Dr. Swerdlow has received personal compensation for activities with Eisai, Inc. as a consultant. Dr. Miller has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Broderick has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Roeber has nothing to disclose.

Visual evoked potentials in children prenatally exposed to methylmercury

Objective: Identify relapsing multiple sclerosis (RMS) patients with aggressive disease characterized by rapid disability progression. Background Criteria for identifying RMS patients with aggressive disease, which would be useful for clinical decision making and trial design, are currently unavailable. Design/Methods: The Multiple Sclerosis Collaborative Research Group (MSCRG) study was a phase 3, double-blind, placebo-controlled trial of intramuscular interferon beta-1a (IM IFNβ-1a) in patients with RMS. Patients received IM IFNβ-1a 30 μg or placebo once weekly for up to 2 years. Patients were required to have a baseline Expanded Disability Status Scale (EDSS) score of 1.0–3.5. Patients with a ≥2.0-point increase in EDSS score resulting in a score ≥4.0 by study end were considered to have aggressive RMS. The risk of a poor long-term outcome, defined as an EDSS score ≥8.0 at 8 years of follow-up, was calculated as an odds ratio from a logistic regression model comparing patients with and without aggressive RMS. Results: Few patients (n=39) had EDSS ≥4.0 over 2 years. Only 25 patients met the criteria for aggressive RMS. Among these patients, mean disease duration was 5.1±3.85 years, mean baseline age was 37.2±6.35 years, and mean baseline EDSS was 2.8±0.74. More patients in the placebo group (22%) than in the IM IFNβ-1a group (7%) met the criteria for aggressive RMS at 2 years ( P =0.0072). Thirteen patients reached the EDSS milestone of 8.0 (severe disability) by the end of the 8-year follow-up. The odds ratio for attaining severe disability was 31.4 (95% confidence interval, 7.7–127.8; P Conclusions: The proposed definition for aggressive RMS characterized by rapid EDSS progression appeared to be useful in identifying patients at high risk for a more severe long-term disease course with greater accumulation of physical disability. Supported by: Biogen Idec Inc. Disclosure: Dr. Scott has received personal compensation for activities with Novartis, Biogen Idec, Teva Neuroscience, and Genzyme as a consultant or speaker. Dr. Scott has received research support from the Pittsburgh Foundation. Dr. Laforet has received personal compensation for activities with Biogen Idec Inc. as an employee.Dr. Laforet holds stock and/or stock options in Biogen Idec Inc., which sponsored research in which Dr. Laforet was involved as an investigator. Dr. You has received personal compensation for activities with Biogen Idec as an employee.

Purpose:Visual evoked potentials (VEP) are used to determine the function of visual pathway from the optic nerve to visual cortex. Various factors may affect VEP response, viz., technical and environmental. The aim of this study is to obtain the normative value of VEP latency and amplitude parameters in adulthood in Indonesia, as well as the relationship of height, weight, body mass index (BMI), head circumference, and visual acuity with the variety of latency and amplitude values of VEP parameters.Methods:It is a cross-sectional study on 120 healthy subjects consisting of 60 males and 60 females between 18 and 65 years old. Height, weight, BMI, head circumference, and visual acuity were measured and continued with VEP examination using a 26′ checkerboard pattern on the left and right eyes alternately. All data were collected and analyzed with the Shapiro–Wilk test using statistical software R version 3.5.2.Results:Mean value of P100 latency (interocular latency) of left and right eye were 104.6 ± 3.4 ms and 104.1 ± 3.4 ms, respectively, as well as 9.8 ± 4.7 μV and 10.3 ± 5.4 μV for the amplitude. There was no significant difference between the male and female group, as well as on the age group. Female significantly exhibited a higher P100 amplitude than male. The greater the age, the lower amplitude of P100 significantly.Conclusion:Gender and age do not affect the P100 latency value but only affect P100 amplitude. Height, weight, BMI, head circumference, and visual acuity also do not affect the P100 latency and amplitude.

Normalisation of the visual evoked potential (VEP) in patients with optic neuritis (ON) appears to be a rare phenomenon. However, although several workers have indicated that it can happen, they have not followed up with subsequent VEP tests to confirm how long the VEP latency of the affected eye remains in the normal range. To resolve this, 18 patients with a clinical diagnosis of acute unilateral ON were followed for 5 years with repeated VEP tests to determine if the latency of the P2 wave from affected eye could return to the normal range. Furthermore, in cases where the latency returned to normal, the length of time that it remained so was also assessed. The normal range for the latency of the P2 wave was determined by measuring VEPs from a group of 18 healthy control subjects with a similar age distribution to the patients. This established an upper limit of 115.9 ms. At presentation the mean P2 latency of the affected eyes of the patients was 140 ms with a standard deviation of 16 ms. In general, the VEP latencies remained constant over the period of the investigation. However two patients demonstrated a return to normal latencies but this was only temporary. Their latencies become prolonged again within 2 years. These results provide evidence that the delayed P2 latency observed in patients with ON can return to the normal range in a small percentage of cases. However, this improvement may spontaneously deteriorateonce more as a result of further episodes of subacute demyelination.