Personal Compensation For Activities Research Articles

Upregulation of Inflammatory Cytokines in Painful Diabetic Neuropathy (P05.154)

Objective: To quantify cutaneous cytokines in patients with painful diabetic neuropathy. We hypothesized that cutaneous interstitial fluid, obtained through vacuum blisters, would allow measurement of local cytokines within specific areas of interest. We also hypothesized that pro-inflammatory cytokines would be upregulated in patients with painful diabetic neuropathy compared to healthy control subjects. Background Inflammatory cytokines have been implicated in the pathogenesis of painful neuropathy. However, studies typically procure cytokines from circulating plasma, not from local tissues where neuropathic pain is generated. Design/Methods: Five patients with painful diabetic neuropathy (but only mild neuropathy impairment scores in the lower limb) and 5 healthy volunteers were recruited. Blisters (8mm diameter) were induced on the dorsum of the foot via 20 mmHg vacuum pressure, and blister fluid was collected after 90 minutes. Cytokine levels were measured using an Elisa bead-based multiplex assay. Results: Cytokine levels of IL-4, IL-13, IL-10, IL-8 and TNF-alpha were significantly higher in patients with painful diabetic neuropathy (p Conclusions: Analysis of blister fluid showed an increase of IL-8 and TNF-alpha in painful diabetic neuropathy compared to control subjects suggesting an involvement of macrophages and neutrophils, increase in IL-10 was evidence for a pro-inflammatory response and IL-4 and IL-13 recruitment of type 2 helper T cells. Results suggest an environment shifted towards pro-inflammatory cytokines in patients with painful diabetic neuropathy. Further study in larger numbers of patients with diabetes with and without painful neuropathy are necessary to further validate these findings and confirm the utility of this technique. Supported by: NIH NINDS K23NS050209 (CHG). Disclosure: Dr. Illigens has nothing to disclose. Dr. Freeman has received personal compensation for activities with Pfizer Inc, Eli Lilly & Company, GlaxoSmithKline, Inc., Solvay S.A., and Chelsea Pharmaceuticals. Dr. Freeman has received personal compensation in an editorial capacity for Clinical Journal of Pain. Dr. Gibbons has nothing to disclose.

Quantitative Susceptibility Mapping: Initial Experience for Multiple Sclerosis Lesion Characterization (P03.058)

Objective: To assess whether quantitative susceptibility mapping (QSM) can function as a biomarker in patients with multiple sclerosis (MS) and provide an independent characterization of lesions commonly seen on T2-weighted images (T2WI). Background Although T2WI are used to support and confirm the clinical diagnosis of MS, T2 hyperintensity may indicate demyelination and/or edema. Previous studies have shown that iron deposition is associated with demyelination, but usually not appreciated on T2WI. Because QSM is sensitive to iron deposition, we hypothesize that QSM may provide a novel and independent biomarker in MS lesion characterization. Design/Methods: We retrospectively reviewed 181 white matter lesions in 16 consecutive confirmed MS patients (age=41±7, M/F=4/12) acquired with a protocol including T2W and QSM sequences. Lesions were identified on both T2W and QSM images with their sizes and signal intensities assessed. Differences were evaluated with a t-test. Results: A total of 181 lesions were detected on T2WI, 130(72%) of which presented on QSM. Lesion size on QSM was significantly smaller than that on T2WI(p 0.05ppm) compared to cortical gray matter. The size discrepancy was expected, since edema is hyperintense on T2WI but not on QSM. The increased signal on QSM lesions may be explained by the loss of myelin, whose susceptibility is usually negative. However, demyelination alone is unable to explain the strong paramagnetism seen in type (b) lesions, whose susceptibility is higher than cortical gray matter. In these lesions, iron may be responsible for the signal change. Further investigation may include correlation with clinical symptoms, spatial distribution of lesions, and global alternation in susceptibility value. Conclusions: MS lesions are smaller in size and demonstrate two distinct patterns on QSM when compared to routine T2WI. Disclosure: Dr. Chen has nothing to disclose. Dr. Comunale has nothing to disclose. Dr. Gauthier has received personal compensation for activities with Teva Neuroscience, Biogen Idec, Pfizer Inc, and Serono, Inc. as consultant. Dr. Gauthier has received research support from Biogen Idec, Pfizer Inc, and Serono, Inc. Dr. Heier has nothing to disclose. Dr. Liu has received personal compensation for activities with MedImageMetric LL as an employee. Dr. Tsiouris has nothing to disclose. Dr. Wang holds stock and/or stock options in MedImageMetric LLC.

Successful Use of Subcutaneous Immunoglobulin in Chronic Neurology Patients (P07.217)

Objective: To report the use of 20% proline-stabilized subcutaneous immunoglobulin (SCIG; Hizentra®) in 2 patients with myasthenia gravis (MG) and 1 patient with chronic inflammatory demyelinating polyneuropathy (CIDP) for whom intravenous immunoglobulin (IVIG) was poorly tolerated or ineffective. Background Guidelines suggest the use of IVIG for treatment of MG and CIDP. However, some patients experience intolerable adverse events or lack of efficacy with IVIG administration. SCIG therapy is used and tolerated in immunodeficient patients. The high volume used in neurologic disease has previously limited SCIG use. Hizentra is the highest concentration SCIG available (20% IgG), allowing for reduced volumes. Design/Methods: Patient 1 is a 14 year-old boy with CIDP who experienced severe headaches and vomiting for up to 8 days after IVIG treatment (1 g/kg/mo) interfering with daily activities. Patient 2 is a 35 year-old female with MG who experienced intolerable headaches with maintenance IVIG (1 g/kg/mo), resulting in poor compliance. Patient 3 is a 13 year-old girl with MG whose symptoms were not improving after IVIG (0.5 g/kg/mo). Results: Patient 1 is treated with 250 mg/kg/wk Hizentra (25 ml/site/4 sites, 2X/wk) and reports improved strength and ability to participate in daily activities, with no adverse effects. Patient 2 is treated with 250 mg/kg/wk Hizentra (25 ml/site/2 sites, 2X/wk) and reports improved energy and MG symptoms, with no adverse effects. Patient 3 is treated with 125 mg/kg/wk (20 ml/site/3 sites, 1X/wk) and reports improved energy, with no adverse effects. Conclusions: SCIG was well tolerated and improved symptoms and quality of life in neurology patients intolerant or unresponsive to IVIG. More research is needed to further assess efficacy in chronic neurological diseases. SCIG should be considered as an alternative to IVIG in certain patients. Disclosure: Ms. Zampelli has received personal compensation for activities with CSL Behring. Dr. Zacek has received personal compensation for activities with CSL Behring. Ms. Levasseur has received personal compensation for activities with CSL Behring as a consultant.

Longitudinal Cognitive Functioning and Antiretroviral Therapy Use among HIV+ Persons in Uganda (P01.261)

Objective: To investigate the effects of combination antiretroviral therapy (ART) on 12-month change in cognitive functioning among HIV+ persons in Uganda. Background No studies have examined the association between ART use and longitudinal neurocognitive performance among HIV+ individuals in Uganda. Design/Methods: Seventy-seven HIV+ persons (62% women, mean age=37 years, mean education=8 years, mean CD4 count=235 cells/μL) were recruited from the Infectious Diseases Clinic at Makerere University, Uganda. They underwent detailed medical and neurobehavioral evaluations at baseline and 12 months later. Thirty- one individuals initiated ART sometime after their baseline visit (“ART+” group) due to having CD4 counts Results: There were no differences between the ART+ and ART- groups on gender (% women= 65% vs. 61%), age (mean=39 vs. 36 years), or education (mean=8 vs. 8 years). The ART+ group showed significant improvements, between baseline and 12 months, on several neuropsychological tests including WHO-AVLT total score (p=.003) and short delay (p=.008), Color Trails 1 (p=.015) and 2 (p Conclusions: ART use is associated with improvements in cognitive functioning among HIV+ persons in Uganda. However, these improvements did not appear to be higher than those seen among HIV+ individuals who did not initiate ART. Possible reasons for this include practice effects as well as improvements in mood and overall quality of life among the ART- group. Supported by: NIH grant MH083465. Disclosure: Dr. Okonkwo has nothing to disclose. Dr. Nakasujja has nothing to disclose. Dr. Robertson has received personal compensation for activities with Abbott and GSK as a consultant. Dr. Skolasky has nothing to disclose. Dr. Katabira has nothing to disclose. Dr. Musisi has nothing to disclose. Dr. Sacktor has nothing to disclose.

Phase IV Vision Study Evaluates Retinal Structure and Function in Adult Patients with Refractory Complex Partial Seizures Treated with Vigabatrin (P07.255)

Objective: To evaluate change in retina structure and function in vigabatrin-naive patients, we initiated a prospective, 1-year open-label trial in patients requiring vigabatrin treatment. Background An important safety issue for vigabatrin is risk of bilateral concentric constriction of visual fields. Design/Methods: ∼80 patients with rCPS for ≥1 year (with ≥2 seizures/month averaged over prior 3 months) will be enrolled at ∼25 US sites. Patients must have failed ≥3 prior therapies for lack of efficacy and must be receiving concomitant AEDs. Vigabatrin-naive patients ≥18 years of age will have visual static perimetry and optical coherence tomography (OCT) assessments at baseline, and 3, 6, 9, and 12 months following vigabatrin initiation. Key endpoints include change from reference value in field width (static perimetry), and change from reference value in retinal nerve fiber layer thickness (OCT and macular thickness OCT). After commencing vigabatrin, patients are assessed every 3 months through automated static perimetry (both standard 30-2 and horizontal meridian full field), OCT, and ancillary exploratory visual endpoints such as visual acuity, color vision, and visual fields by Tangent Corner Test. If deficits are discovered, investigators conduct benefit/risk assessments with patients. Results: By October 2011, 8 sites had been initiated. Screening was initiated for 8 patients. Five were screen failures, and three patients were enrolled. Of these three, two are ongoing study participants, and one was an early termination (seizures returned to baseline rate and patient was discontinued following benefit/risk assessment). One patient had abnormal baseline OCT results (before vigabatrin therapy), emphasizing that patients may have pre-existing afferent visual system conditions. Conclusions: This study is designed to provide a better definition of onset and progression of peripheral visual field defects, to assess the risk of developing vision loss during first year of exposure, and to evaluate OCT for monitoring retinal changes. Supported by: Lundbeck Inc. Disclosure: Dr. Sergott has received personal compensation for activities with Pfizer, Serono, Lundbeck, and Centocor as a speaker and consultant. Dr. Sergott has received personal compensation in an editorial capacity for Current Opinion in Neuro-Opthamology. Dr. Faught has received personal compensation for activities with Pfizer Inc, UCB Pharma, Ortho-McNeil Pharmaceutical, Inc., Valeant Pharmaceuticals, Ovation Pharmaceuticals, Inc., GlaxoSmithKline, Inc., Abbott Laboratories, Inc., and Novartis as a consultant or speaker. Dr. Faught has received research support from Eisai Inc., Marinus, Ortho-McNeil Pharmaceutical, Inc., and Schwarz Biosciences. Dr. Torri has received personal compensation for activities with Lundbeck Research USA as an employee. Dr. Wesche has received personal compensation for activities with Lundbeck Research USA, Inc as an employee.

Double-Blind Placebo-Controlled Trial on the Use of Acetyl-L-Carnitine for the Treatment of Amyotrophic Lateral Sclerosis (P04.151)

Objective: To assess superiority of acetyl-L-carnitine/riluzole (ALC) combination over riluzole alone on functional disability in patients with amyotrophic lateral sclerosis (ALS). Background ALS is a fatal motorneuron disease. Unlike riluzole, no disease-modifier drugs are available. ALC counteracts motor neuron death induced by toxic agents or deprivation of trophic factors and reduces disease progression in animal models. Design/Methods: Patients 40-70 years with definite or probable ALS, disease duration 6-24 months, self-supporting (ie, able to swallow, cut foods/handling utensils, and walk), and with forced vital capacity (FVC)>80% were enrolled in a pilot double-blind, placebo-controlled, parallel group trial and followed for 48 weeks. ALC 3g/day and placebo were added to riluzole 100mg/day. Primary end-point: no. patients becoming non self-supporting. Secondary end-points: changes in the ALS-FRS-R scale, MRC scale, FVC and McGill quality-of-life scale. Analysis was performed in the intention-to-treat (ITT) population, completers and completers/ compliers (ie, taking >75% of study drug). Results: 42 patients received ALC and 40 patients placebo. In the ITT population, 34 patients receiving ALC (80.9%) and 39 receiving placebo (97.5%) became non self-supporting (p=0.030). Percentages in study completers were 71.4 vs. 94.7% (p=0.064) and in “completers/compliers”, 71.4% vs. 94.4% (p=0.069). In the per-protocol analysis, percentages were 84.4 vs. 100.0% (p=0.054) and 76.2 vs. 100.0% (p=0.132)(completers & completers/compliers). At 48 weeks, ALC was associated with higher mean ALR-FRS-R scores (p=0.039) and FVC scores (p=0.016), while MRC and quality of life were no different. Adverse events were similar. Conclusions: ALC appears superior to placebo and is well-tolerated and safe. A confirmatory phase III trial is needed. (*) Italian ALS Study Group: Virginio Bonito, Paolo Buzzi, Claudia Caponnetto, Adriano Chio, Massimo Corbo, Fabio Giannini, Maurizio Inghilleri, Vincenzo La Bella, Lorenzo Lorusso, Christian Lunetta, Letizia Mazzini, Paolo Messina, Gabriele Mora, Michele Perini, Elisabetta Pupillo, Maria Lidia Quadrelli, Vincenzo Silani, Isabella Simone, Lucio Tremolizzo. Supported by: Agenzia Italiana per il Farmaco (AIFA). Sigma-Tau pharma company provided active treatment and placebo. Disclosure: Dr. Beghi has received personal compensation for activities with UCB Pharma as a speaker. Dr. Beghi has received personal compensation in an editorial capacity for Epilepsia. The Italian ALS Study Group has nothing to disclose.

Psychiatric and Neurocognitive Morbidity in Rapid-Onset Dystonia Parkinsonism (P01.225)

Objective: Elevated rates of psychiatric disease and cognitive dysfunction have been found in primary dystonias. These features have not been studied in Rapid-Onset Dystonia-Parkinsonism (RDP), DYT12. Data are presented for 47 individuals (with or without gene mutation). Background RDP is a rare form of dystonia caused by mutation of the gene encoding the alpha-3 subunit of Na+/K+-ATPase ( ATP1A3 ). RDP is characterized by abrupt onset of dystonic symptoms with features of Parkinsonism and subsequent stabilization without recovery. Psychiatric and cognitive symptoms have not been systematically studied in RDP. Design/Methods: The SCID-I and CIDI-I were administered to 47 individuals, including 27 mutation carriers (24 motor-manifesting, 3 non-motor-manifesting) and 20 family members without ATP1A3 mutation. Discrepancies in diagnoses were adjudicated by a psychiatrist blinded to mutation status, who rendered final diagnoses. Cognitive data were obtained on 43 individuals, including 23 motor-manifesting carriers, 3 non-motor-manifesting carriers, and 17 non-carrier relatives. Results: Mood disorders appear more prevalent among carriers (44%) compared to non-carriers (25%). Anxiety (44% vs. 50%) and substance use (33% vs. 32%) were similar across groups. Five individuals from three families with ATP1A3 mutation (19%) exhibited psychotic disorder. Psychotic disorder was not present among non-carriers. One non-carrier exhibited evidence of visual memory dysfunction. Gene carriers exhibited visual (17%) and verbal (22%) memory deficits. More gene carriers exhibited impairment compared to non-carriers on Trail Making B (54% vs. 12%) and Trail Making A (42% vs. 29%). Self reported rates of childhood learning difficulties (post-RDP onset) were higher among gene carriers (69% vs. 24%). Conclusions: Anxiety disorders and substance use/abuse did not differ among individuals with and without ATP1A3 mutation. Increased mood and psychotic disorders for gene carriers illustrate comorbid mental illness. Impaired memory and executive functioning is consistent with findings in other dystonias. Higher prevalence of childhood learning difficulties in gene carriers suggests non-motor manifestations prior to motor onset. Supported by: NINDS 5R01NS058949-03. Disclosure: Dr. Brashear has received personal compensation for activities with Allergan, Inc., Merz Pharma, Ipsen as a consultant. Dr. Brashear has received personal compensation in an editorial capacity for the American Academy of Neurology. Dr. Brashear will receive future royalty payments for editing a book on spasticity. Dr. Brasher has received research support from Allergan, Inc., Merz Pharma, and Ipsen. Dr. Cook has nothing to disclose. Dr. Amponsah has nothing to disclose. Dr. Hill has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Light has nothing to disclose. Dr. Suerken has nothing to disclose. Dr. McCall has received personal compensation for activities with Sepracor, Inc. Dr. Boggs has nothing to disclose. Dr. Stacy has received personal compensation for activities with Allergan, Inc., Biogen Idec, General Electric, Novartis, Osmotica, Teva Neuroscience, and Synosia. Dr. Stacy has received research support from Ceregene, Impax, Neuraltus, Novartis, Schering-Plough, and the Parkinson Study Group. Dr. Ozelius has nothing to disclose. Dr. Sweadner has nothing to disclose.

Treatment with Rasagiline Improves the Quality of Sleep in Patients with Parkinson's Disease: Results of the Rasagiline Effect on Sleep Trial (REST) (S52.006)

Objective: To evaluate the impact of rasagiline treatment on sleep disturbances in Parkinson Disease. Background Sleep dysfunction in PD is common affecting some 60–98% of patients. Sleep disorders include excessive daytime sleepiness, sleep attacks, advanced sleep phase syndrome, nocturnal awakenings, and REM sleep behaviour disorder – each having a significant impact on patient quality of life. Design/Methods: This was an open-label, multi-center, single-arm study in patients with PD who were considered suitable for treatment with rasagiline as monotherapy or adjunct therapy (0.5 or 1.0 mg once daily per Canadian label). Subjects were assessed at baseline and after 2 months of treatment using the Parkinson9s Disease Sleep Scale (PDSS) to assess overall sleep quality and Epworth Sleepiness Scale (ESS) to assess daytime sleepiness. Results: 110 PD patients were treated with rasagiline (mean age 67 years; disease duration 4.3 years) and 97 completed the two visits; most had a Hoehn and Yahr Stage of 2 and received rasagiline as adjunct therapy. Treatment with rasagiline improved mean ± SD PDSS scores from 96.2 ± 21.6 at baseline to 105.5 ± 21.93 at 2 months (treatment effect 9.1 ± 18.7 points, p=0.003 [n=97]), denoting an improvement in sleep experience. Analysis by item revealed significant differences from baseline in overall quality of sleep, nocturnal restlessness, nocturnal motor symptoms and sleep refreshment (p Conclusions: In this open-label study, two months treatment with rasagiline improved sleep experience in patients with PD. Supported by: Teva Canada Innovation. Disclosure: Dr. Panisset has received personal compensation for activities with Teva Neuroscience, Novartis, Allergan, and Merz.Dr. Panisset has received research support from Teva Neuroscience, Novartis, and Allergan. Dr. Chouinard has received personal compensation for activities with Teva Neuroscience, Novartis, Shires, and Prestwick. Dr. Chouinard has received personal compensation in an editorial capacity from Novartis. Dr. Chouinard has received research support from Novartis, Teva Neuroscience, Elan Corporation, Schering-Plough Corporation, Merck & Co., Inc., Kyowa, and Amarin.

Loss of White Matter Microstructural Integrity Is Associated with Adverse Neurological Outcome in Tuberous Sclerosis Complex (S28.003)

Objective: To study the microstructure of long range connections and its relation to neurological phenotype in Tuberous Sclerosis Complex (TSC) Background TSC is a genetic neurocutaneous syndrome in which cognitive and social-behavioral outcomes for patients vary widely in an unpredictable manner. The cause of adverse neurological outcome remains unclear. We investigated the hypothesis that disordered white matter and abnormal neural connectivity are associated with adverse neurological outcome. Design/Methods: Structural and diffusion magnetic resonance imaging was carried out in 40 subjects with TSC (age range 0.5 – 25 years, mean age 7.2 and median age 5 years), 12 of whom had autism spectrum disorders (ASD), and in 29 age-matched controls. Tractography of the corpus callosum was used to define a 3-dimensional volume of interest. Regional averages of four diffusion scalar parameters of the callosal projections were calculated for each subject. These were the average fractional anisotropy (AFA) and average mean, radial and axial diffusivity (AMD, ARD, AAD). Results: Subjects with TSC had significantly lower AFA and higher AMD, ARD and AAD values compared to controls. Subjects with TSC and ASD had significantly lower AFA values compared to those without ASD, and compared to controls. TSC subjects without ASD had similar AFA values compared to controls. Conclusions: Diffusion tensor scalar parameters provided measures of properties of the three-dimensional callosal projections. In TSC, changes in these parameters may reflect microstructural changes in myelination, axonal integrity, or extracellular environment. Alterations in white matter microstructural properties were associated with TSC and larger changes were associated with TSC and ASD, thus establishing a relationship between altered white matter microstructural integrity and brain function. Disclosure: Dr. Peters has nothing to disclose. Dr. Sahin has received personal compensation for activities with Novartis as a consultant. Dr. Sahin has received research support from Novartis. Dr. Vogel-Farley has nothing to disclose. Dr. Jeste has nothing to disclose. Dr. Nelson has nothing to disclose. Dr. Gregas has nothing to disclose. Dr. Prabhu has nothing to disclose. Dr. Scherrer has nothing to disclose. Dr. Warfield has nothing to disclose.

Effect of Intravenous Immunoglobulin Treatment on Pregnancy and Postpartum-Related Relapses in Multiple Sclerosis: A Prospective, Rater-Blinded Analysis (P06.185)

Objective: To evaluate relapse rate and disease progression under immunomodulatory treatment with intravenous immunoglobulin (IVIg) during pregnancy and postpartum period. Background Medical treatment of pregnant and nursing women requires special attention. Licensed disease-modyfying drugs for the treatment of MS should be avoided or are hitherto contraindicated during gestation, pregnancy or lactation. Intravenous immunoglobulin (IVIg), might be the only immunomodulatory treatment that can be recommended for women with MS during this period of life considering safety aspects of the fetus or the newborn. Design/Methods: We analysed 70 women with relapsing remitting MS (RRMS) and 66 pregnancies for at least 12 month after delivery. IVIg administration differed for group 1 and 2 as follows. Group I (n=40) patients were treated with IVIg before gestation, during first trimenon of pregnancy and during postpartum period. Group II (n=24) patients were treated with IVIg starting in between 24 hours after delivery and during lactation. Group III (n=6) patients were untreated during pregnancy and lactation. Relapse rates per woman per year before, and disease progression during and after pregnancy were analysed for the described patient groups. Results: Increase of relapse rate after delivery and relapse rates during first and second trimenon like known from historic cohorts (“Pregnancy in MS group”, Confavreux et al. 1998) turns out lower during IVIg-treatment. We could not find a significant difference considering the relapse rate after delivery depending on the described IVIg-treatment groups. Pregnancy and IVIg-treatment do not exert an influence on disease progression. No serious adverse events were recorded under IVIg treatment. Conclusions: IVIg-treatment for RRMS patients during lactation is an effective option to reduce the incidence of postpartum-related relapses. Further multi-center investigations to prove these data with higher numbers of patients are desirable. Supported by: Analysis was not supported. Disclosure: Dr. Winklemann has received personal compensation for activities with Bayer Pharmaceuticals Corporation and Merck-Serono as a speaker. Dr. Benecke has received personal compensation for activities with Ipsen, Allergan, Inc., and Merz Pharma. Dr. Zettl has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience. Dr. Zettl has received research support from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis Pharmaceuticals, Inc., and Teva Neuroscience.

The Importance of Stress as a Trigger Factor in Childhood Migraine: An Italian Study (P04.254)

Objective: To determine the prevalence of stress reported as a migraine trigger in a pediatric population and to describe the role of different reported trigger factors. We also evaluate the influence on stress of age, gender, headache subtype, psicosocial variables. Background Stress is frequently reported as a headache trigger, both in adult and pediatric sufferes, but is not clearly characterized in pediatric population. Design/Methods: Through a semi-structured interview, parents of 150 pediatric out-patients assessed at San Raffaele Hospital in one year, were asked to provide a detailed clinical history and evaluate the importance and the significance of stress in their children9s headache, specifying the type and frequency of trigger factors on a headache diary. Children suffering from anxiety, depression or any other psychiatric disorder were excluded. Results:72% of patients reported a significant level of stress in determining headache (85% migraine and 13% of tensive-type headache), for a median of 10 days/month on a diary. Different stress trigger factors were recognized in relationship with school (78%), missed sleeping hours (68%), family (25%), travelling (20%), environmental factors (10%), extra-curricular activity(29%), life-events (10%), unidentified trigger factors (20%). Stress resulted more frequent in children between 6 and 11 years old. No difference for sex, family status, parents educational level, living environment, comorbidities.Stress associated symptoms were evident in 50% children. Conclusions: In this monocentric study, we characterized headache triggers reported in 72% by parents as generical “stress factors” in an Italian metropolitan area. Proper individualized counselling of children and their parents is auspicable in order to better copy with stress. Disclosure: Dr. Dalla Libera has nothing to disclose. Dr. Colombo has nothing to disclose. Dr. De Feo has nothing to disclose. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe.

Logopenic Variant of Primary Progressive Aphasia in Lewy Body Dementia: Beyond Alzheimer's Disease (P05.038)

Objective: To describe a patient affected by the logopenic variant of primary progressive aphasia (lv-PPA) with a clinical evolution towards dementia with Lewy bodies (DLB). Background Lv-PPA is a progressive language disorder characterized by slow speech, word finding problems, sentence repetition and comprehension deficits, and relative sparing of motor speech, grammar, and single-word comprehension. Brain atrophy is located at the left temporo-parietal junction. Biological and neuropathological studies suggest that the main cause of lv-PPA is Alzheimer9s disease (AD). Design/Methods: Clinical, cognitive and language data were acquired in a 65-years-old patient with lv-PPA (right-handed man, disease duration at presentation 24 months). Furthermore, we analyzed cerebrospinal fluid (CSF) biomarkers, structural MRI, brain Single-photon emission computed tomography (SPECT) and dopamine transporter (DAT)-scan. Results: For the first two years (2006-2008), the patient demonstrated isolated language deficits with typical logopenic profile. In 2008: MRI was normal and SPECT showed hypoperfusion in left posterior temporal and inferior parietal regions. CSF analysis revealed a non-AD profile, with normal levels of beta-amyloid, tau and phosphorylated tau. On the basis of these elements, the diagnosis of lv-PPA was made. Two years later, visual hallucinations, cognitive fluctuations and parkinsonian signs appeared; neuroleptic medication was not tolerated. DAT-scan demonstrated a bilateral DAT loss. The second SPECT showed a posterior extension of cortical hypoperfusion including parietal, temporal and occipital regions, with involvement of the left primary visual cortex. Accordingly with this clinical and imaging evolution, the clinical diagnosis of DLB was made. Conclusions: We provided clinical, imaging and biological findings showing that the lv-PPA is not necessarily related to AD pathology. Hence, the medical community should not systematically lump together lv-PPA and AD. Conversely, DLB should be considered as a heterogeneous disease, which can initially present with a progressive aphasia profile, namely lv-PPA. Supported by: Dr. Migliaccio was funded by the Neuropole de Recherche Francilien (NeRF). Disclosure: Dr. Migliaccio has nothing to disclose. Dr. Roue-Jagot has nothing to disclose. Dr. Dubois has received personal compensation for activities with Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen as a consultantDr. Dubois has received personal compensation for serving on the advisory board of Bristol-Myers Squibb, Roche, Elan, Eli Lilly, Eisai, and Janssen.Dr. Dubois has received research support from Novartis and Sanofi-Aventis. Dr. Teichmann has nothing to disclose.

Updated Incidence of Progressive Multifocal Leukoencephalopathy in Natalizumab-Treated Multiple Sclerosis Patients Stratified by Established Risk Factors (S41.001)

Objective: To quantify progressive multifocal leukoencephalopathy (PML) risk in multiple sclerosis (MS) patients considering or receiving natalizumab using three risk factors: anti-JC virus (JCV) antibody positive serostatus, prior immunosuppressant use, and natalizumab treatment duration. Background PML, an opportunistic brain infection caused by JCV, occurs primarily in patients who are immunocompromised or have received immunomodulatory therapies, such as natalizumab. Anti-JCV antibody positive status, prior immunosuppressant use, and natalizumab treatment duration are PML risk factors in natalizumab-treated patients. Design/Methods: Data from natalizumab postmarketing sources and clinical studies were used to estimate PML incidence in natalizumab-treated MS patients by anti-JCV antibody status (positive or negative), prior immunosuppressant use (yes or no), and duration of natalizumab treatment (1–24 or 25–48 months). Results: As of September 2011, 159 PML cases were confirmed among 92,105 patients exposed to natalizumab in the postmarketing setting. PML risk was lowest in anti-JCV antibody negative patients (estimated at ≤0.10 per 1000 [95%CI:0–0.56] or ≤0.17 per 1000 [95%CI:0.00–0.94], assuming one hypothetical PML case testing anti-JCV antibody negative prior to diagnosis, and exposures ≥1 natalizumab dose or ≥18 natalizumab doses, respectively). PML risk was highest in patients with all three risk factors, anti-JCV antibody positive status, prior immunosuppressant use, and 25–48 months of natalizumab treatment (9.8 per 1000; 95%CI:7.0–13.4). Conclusions: This analysis, representing approximately 178,000 patient-years of natalizumab experience, demonstrates that discrete MS subpopulations can be identified at greater or lesser PML risk based upon the presence or absence of risk factors using an algorithm capable of discerning an approximate 100-fold difference in risk between the highest and lowest risk groups. The use of anti-JCV antibody status in this quantitative algorithm marks the first use of a safety biomarker for risk stratification to inform treatment decisions in MS. Studies are ongoing to further characterize the PML risks presented in this analysis. Supported by: Biogen Idec Inc. and Elan Pharmaceuticals, Inc. Disclosure: Dr. Bloomgren has received personal compensation for activities with Biogen Idec as an employee. Dr. Richman has received personal compensation for activities with Biogen Idec as employees.Dr. Richman holds stock and/or options in Biogen Idec, which sponsored research in which Dr. Richman was involved as an investigator. Dr. Hotermans has received personal compensation for activities with Biogen Idec as an employee.Dr. Hotermans holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Hotermans was involved as an investigator. Dr. Subramanyam has received personal compensation for activities with Biogen Idec as an employee. Dr. Subramanyam holds stock and/or stock options in Biogen Idec. Dr. Natarajan has received personal compensation for activities with Biogen Idec as an employee. Dr. Lee has received personal compensation for activities with Biogen Idec as an employee. Dr. Plavina has received personal compensation for activities with Biogen Idec as an employee.Dr. Plavina holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Plavina was involved as an investigator. Dr. Scanlon has received personal compensation for activities with Biogen Idec as an employee. Dr. Sandrock has received personal compensation for activities with Biogen Idec as an employee. Dr. Sandrock holds stock and/or stock options in Biogen Idec. Dr. Bozic has received personal compensation for activities with Biogen Idec. Dr. Bozic holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Bozic was involved as an investigator. Dr. Bozic holds stock and/or stock options in Biogen Idec.

Clinical Characteristics of Parkinsonism in Frontotemporal Dementia Syndromes Associated with Mutations in MAPT, PGRN, C9ORF72 (P06.075)

Objective: To compare and contrast the features of parkinsonism in cases with different genetic mutations associated with frontotemporal lobar degeneration (FTLD). Background FTLD has been associated with mutations in the microtubule associated protein tau ( MAPT) , progranulin (PGRN) and the GGGGCC hexanucleotide repeat expansion in the open reading frame 72 on chromosome 9 ( C9ORF72 ). Several of affected individuals with an FTLD syndrome exhibited parkinsonism. The specific features of parkinsonism associated with these mutations have not been well-characterized. Design/Methods: Using data collected prospectively on the UPDRS during the course of yearly visits, we analyzed all the parkinsonian features of the patients affected by one of the three mutations. Results: We compared 14 cases with C90RF72 , 12 with PGRN and 12 with MAPT that had parkinsonism. A symmetric akinetic-rigid parkinsonism phenotype was present in the majority of the cases. Hypomimia and bradykinesia were the most common features. Tremor was present in 5% of the cases with C90RF72 , 18% with MAPT , and absent in all cases with PGRN . None in whom levodopa therapy was administered benefited from treatment. Conclusions: Although some variability exists, among those with familial FTLD associated with mutations in C90RF72, PGRN and MAPT mutations, the parkinsonian features are typically akinetic rigid and symmetric without a significant presence of tremor. Supported by: Grants AG016574, AG006786, the ALS Association, and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer s Disease Research Program of the Mayo Foundation. Disclosure: Dr. Savica has nothing to disclose. Dr. Graff-Radford has received personal compensation for activities with Codman as a participant on a scientific advisory board. Dr. Graff-Radford has received personal compensation in an editorial capacity for the Neurologist. Dr. Graff-Radford has received research support from Janssen Pharmaceuticals, Inc., Pfizer Inc, Medivation, Inc., Forrest Laboratories and Allon Therapeutics Inc. Dr. DeJesus-Hernandez has nothing to disclose. Dr. Knopman has received personal compensation for activities with Lilly Pharmaceuticals as a data safety monitoring board member. Dr. Knopman has received personal compensation in an editorial capacity for Neurology. Dr. Knopman has received research support from Elan, Forest, and Baxter. Dr. Adeli has nothing to disclose. Dr. Boot has nothing to disclose. Dr. Kuntz has received research support from Cephalon, Inc. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare. Dr. Rutherford has nothing to disclose. Dr. Baker has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Boeve has nothing to disclose.

A Neurotrypsin Resistant Agrin Fragment (NT-1654) Reverts Both Impaired Performance and Muscle Pathology in Transgenic Mice Modelling Sarcopenia (P07.195)

Objective: to investigate the involvement of the neurotrypsin/agrin system in human sarcopenia and to test the therapeutic potential of an engineered indigestible agrin fragment in a transgenic animal model of sarcopenia. Background Sarcopenia, is an age-related muscle dysfunction leading to frailty, disability and reduced life expectancy. Neuromuscular junctions9 (NMJs) degeneration is one of the putative pathogenic factors. Agrin is a key protein in the development and homeostasis of NMJs. Agrin cleavage by the agrin-specific neuronal serine protease neurotrypsin releases a 22 kDa (CAF) fragment incapable of synaptogenesis. Mice over-expressing neurotrypsin (SARCO mice) are characterized by loss of weight, muscle mass and strength, conspicuous degradation of NMJs and elevated serum levels of CAF. These abnormalities are accompanied by muscle pathology typical of human sarcopenia. Thus, SARCO mice provide a valuable tool to study agrin-dependent sarcopenia and to test potential treatments. We have recently found in two separate studies, significantly elevated levels of CAF in about 50 % of sarcopenia patients. Design/Methods: An agrin fragment (NT-1654) has been engineered to prevent its further cleavage by neurotrypsin. NT-1654 retains both Acetylcholine Receptors clustering capabilities and the key functions of full-length agrin. SARCO mice displaying a sarcopenia like syndrome were treated for 3 weeks with daily subcutaneous injections of NT-1654. Results: Treated mice reverted back to perform as WT mice in terms of body weight and grip strength. Muscle pathology (soleus muscle) also reverted toward the normal pattern, showing reduction of centrally nucleated fibers, increased number of fibers and more homogeneous fiber size. Hybrid fibers co-expressing fast and slow myosin heavy chains, typical of aged muscle (also observed in SARCO mice), were absent after treatment. Conclusions: These results suggest that agrin-dependent sarcopenia can be treated in a mouse model and offers a promising perspective for treatment of agrin-related sarcopenia in patients. Supported by: Part of this work has been supported by European Union Grants (Eurostars program). Disclosure: Dr. Fariello has received personal compensation for activities with Neurotune as a consultant. Dr. Fariello holds stock and/or stock options in Neurotune. Dr. Kucsera has received personal compensation for activities with Neurotune as an employee. Dr. Kucsera holds stock and/or stock options in Neurotune. Dr. Hettwer has received personal compensation for activities with Neurotune as an employee.Dr. Hettwer holds stock and/or stock options in Neurotune. Dr. Dahinden has received personal compensation for activities with Neurotune as an employee. Dr. Vrijbloed has received personal compensation for activities with Neurotone AG.

Obstructive Sleep Apnea in Idiopathic Intracranial Hypertension: Comparison with Matched Population Data (P07.261)

Objective: To compare the prevalence and severity of obstructive sleep apnea (OSA) in idiopathic intracranial hypertension (IIH) patients with the prevalence and severity from matched population data. Background Patients with IIH frequently have coexisting OSA. However, it is unclear if the prevalence and severity of OSA is greater in IIH patients than would be expected given their other risk factors for OSA (e.g., obesity). Design/Methods: We included patients with a new diagnosis of IIH who satisfied modified Dandy criteria and underwent overnight polysomnography. We collected demographic data, anthropometric data, and the apnea-hypopnea index (AHI) from polysomnography. We also calculated the expected AHI for our patients, based on their age, sex, race, BMI, and menopausal status, using a model derived from 1741 randomly-sampled members of the general population with overnight in-lab polysomnography scored using similar criteria. We compared the obtained AHI values to those predicted by the model using a paired t-test. Our study had 80% power to detect a 10 unit change in AHI at α = 0.05. Results: We included 24 IIH patients, of which 20 were female (83.3%), 13 were Caucasian (54.2%), and 11 were African-American (45.8%). Patient age ranged from 16-54 yrs (median = 32 yrs; mean±SD = 32±10 yrs). Body mass index ranged from 27.3-45.9 (median = 39.5; mean±SD = 38.1±5.3). AHI from the sleep studies ranged from 0-63.3 (median = 3.3; mean±SD = 9.4±15.8). Predicted AHI ranged from 2.1-14.5 (median = 5.4; mean±SD = 5.9±3.0). The AHIs from the sleep studies were not significantly different from those predicted by the population-derived model (p = 0.14). Conclusions: The prevalence and severity of OSA in IIH patients is no more than would be expected for their age, sex, race, and BMI. It remains unclear if the presence or treatment of coexisting OSA influences the clinical course of IIH. Supported by: In part by a departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc., New York, by core grant P30-EY06360 (Department of Ophthalmology), and by K23-EY019341 (Dr. Bruce). Dr. Newman is a recipient of the Research to Prevent Blindness Lew R. Wasserman Merit Award. Disclosure: Dr. Thurtell has nothing to disclose. Dr. Trotti has nothing to disclose. Dr. Bixler has nothing to disclose. Dr. Rye has received personal compensation for activities with GlaxoSmithKline, Boehringer Ingelheim Pharmaceuticals, UCB Pharma, and Jazz Pharmaceuticals as a consultant, advisor, or speaker. Dr. Bliwise has received personal compensation for activities with Ferring Pharmaceuticals as a consultant. Dr. Newman has received personal compensation for activities with Biogen Idec. Dr. Biousse has nothing to disclose. Dr. Bruce has nothing to disclose.

Oculofaciopalatal and Lingual Myoclonus with Two Separate Generators Following Brainstem Stroke (P07.146)

Objective: To describe a unique neurophysiological study in a patient with oculofaciopalatal and lingual myoclonus following brainstem stroke. Background Oculofaciopalatal myoclonus is a syndrome characterized by rhythmic pendular vertical eye movements with synchronous contraction of the soft palate. It is often seen in the context of brainstem infarction or hemorrhage causing damage to the triangle of Guillian-Mollaret, and may causes oscillopsia. We report a case of oculopalatofacial myoclonus secondary to a brainstem stroke, who was noted to also have asynchronous and independent lingual myoclonus. Design/Methods: Case report. Results: A 52 year old man suffered brainstem infarction. On examination, he had a one and a half syndrome and left sided lower motor nerve facial palsy, as well as quadriplegia,and sensory loss in the right hemibody and left face. Rhythmic, synchronous upward contraction of the eyes, palate and face were noted, as well independent rhythmic tongue contractions independent and asynchronous to the oculopalatofacial myoclonus. Polymography of multiple cranial and limb muscles was performed to characterize these movements. Synchronous, rhythmic myoclonic bursts were seen at a frequency of 1.5-2 Hz in the orbicularis oculi, mentalis, palatal muscles and sternocleidomastoid. However, myoclonic bursts in the lingual muscles were noted to occur asynchronously with these other muscles, at the same frequency but with variable latency. Conclusions: Lingual myoclonus has been described in the literature to occur in an idiopathic fashion, and in isolated case reports, with Arnold-Chiari malformations, brainstem tumors and as epileptic phenomena. We believe that in our patient with oculopalatofacial and independent, asynchronous lingual myoclonus, the neurophysiological evaluation demonstrates the presence of a second generator causing rhythmic tongue movements, completely independent and asynchronous from the classic generator of oculofaciopalatal myoclonus. This is a novel description in our patient. Disclosure: Dr. Lysenko has nothing to disclose. Dr. Bhat has nothing to disclose. Dr. Rosenberg has nothing to disclose. Dr. Chokroverty has received personal compensation for activities with Elsevier and Cephalon. Dr. Chokroverty has received personal compensation in an editorial capacity for Sleep Medicine Journal.

The Role of Prolactin on B Cell Regulation in Multiple Sclerosis (P02.127)

Objective: To evaluate the role of Prolactin in MS pathogenesis. Background Hyperprolactinemia has been associated with different autoimmune diseases in humans. Moreover, increased levels of Prolactin have been found in experimental MS models and administration of prolactin antagonists suppressed disease. Design/Methods: Ninety-two patients with relapsing remitting MS were examined, fifty-eight during remission and 32 during exacerbations. Forty healthy age and gender-matched subjects served as controls. Prolactin, JAK2, Stat1, Stat3, Stat5, BAFF, and Bcl-2 were measured by ELISA. Prolactin receptor and IRF-1 expression were assessed using RT-PCR. Anti-MOG antibodies were measured by ELISPOT. Results: Prolactin levels were higher in MS subjects compared to controls (p= 0.01). However, no differences were found in men, and no association was found between disease activity and Prolactin levels. B and T cells isolated from both MS patients and controls expressed Prolactin receptor, which were upregulated by estrogens. B cells isolated from MS patients demonstrated higher JAK2/Stat pathway activation and IRF-1 expression. Likewise, B cells stimulated in vitro with Prolactin showed increased JAK2 and IRF-1 expression, and Stat protein phosphorylation. Anti-MOG antibodies, BAFF and Bcl-2 levels were significantly higher in MS patients compared to healthy subjects, findings reproduced by culturing CD19+, and CD19+CD5+ B cells in the presence of Prolactin. Moreover, prolactin antagonists blocked these effects, suggesting Prolactin may enhance autoreactive B cells survival. Finally, Prolactin induced CD40 expression on B cells, suggesting it may rescue autoreactive B cells, possibly through recruitment of T cell support. Conclusions: Prolactin can promote B cell autoreactivity in MS through different mechanisms, mediated by the JAK2/Stat pathway. Prolactin influence over the hormonal milieu may have implications on pathogenic immune responses in MS. Disclosure: Dr. Correale has received personal compensation for activities with Merck Serono Argentina, Biogen Idec, Novartis, and from Teva Neuroscience as a speaker. Dr. Farez has nothing to disclose. Dr. Ysrraelit has nothing to disclose.

Micro-Structural Alterations in the Brain of Well-Treated HIV+ Patients with Mild Neurocognitive Disorders: A Multi-Contrast MRI Study at High Field (S37.001)

Objective: To investigate MRI markers of subtle HIV effects on the brain. Background Mild neurocognitive disorders (MND) affect a subset of HIV+ patients under effective highly active antiretroviral therapies (HAART). The physiopathology of MND is however not clear, as well as the reasons why some well-treated patients suffer from MND while other not. Here, we used a multi-contrast MRI based approach at high field to test the hypothesis that well-treated aviremic MND+ patients present different brain micro-structural characteristics compared to MND- HIV patients and healthy controls (HC). Design/Methods: We enrolled 17 MND+ and 19 MND- patients with undetectable viremia and 14 age-matched HC. MRI acquisitions at 3T included: MP2RAGE for T1 relaxation times as well as Magnetization Transfer (MT), T2* and Susceptibility Weighted Imaging (SWI) to probe micro-structural integrity and iron deposition. Regions of interest were automatically extracted for white and gray matter (WM, GM), thalamus, basal ganglia and hippocampus. Statistical analysis used multivariate permutation-based Hotelling tests and correction for family-wise error rate. A linear discriminant analysis between MND+ and MND- patients was performed using multi-parametric MRI data (T1, MT ratio, SWI) and cross-validated with a leave-one-out test. Results: Multivariate analysis showed significant differences between MND+ and MND- patients in WM and GM (p=0.02 respectively), and between MND+ and HC in the caudate (p=0.02). Univariate analysis revealed that MND+ patients had lower MT ratio than MND- and HC, reaching significance in WM and caudate (p=0.01). The linear discriminant analysis distinguished MND+ and MND- patients with a classification quality of 0.73% after cross-validation. Conclusions: Our findings show the presence of micro-structural brain alterations in MND+ patients as compared to MND- and HC, suggesting loss of structural integrity. In addition, they suggest that multi-contrast MRI at high field may be a powerful approach to understand the physiopathology of MND and to discriminate between patients9 sub-groups. Supported by: Centre d9Imagerie BioMedicale of the University of Lausanne, the Swiss Federal Institute of Technology Lausanne, the University of Geneve, the Centre Hospitalier Universitaire Vaudois, the Hopitaux Universitaires de Geneve, the Leenaards, the Jeantet and the Stoicescu foundations and the Swiss National Science Foundation Grant PZ00P3_131914/1. Disclosure: Dr. Granziera has nothing to disclose. Dr. Daducci has nothing to disclose. Dr. Simioni has received personal compensation for activities with Gilead and Boehringer Ingelheim as a speaker. Dr. Cavassini has nothing to disclose. Dr. Roche has received personal compensation for activities with Siemens AG as an employee. Dr. Meskaldji has nothing to disclose. Dr. Michel has nothing to disclose. Dr. Calmy has nothing to disclose. Dr. Hirschel has nothing to disclose. Dr. Krueger has received personal compensation for activities with Siemens AG as an employee. Dr. Krueger has received research support from Siemens AG. Dr. Du Pasquier has received personal compensation for activities with Merck Serono, Biogen Idec, Abbott, and ViiV.

Health Related Differences among Elderly MS Patients with and without a Caregiver (P06.162)

Objective: The aim of this study is to describe the differences among elderly multiple sclerosis patients with and without an informal caregiver regarding quality of life, neuropsychological impairment, cognition, and severity of depression. Background MS is a progressive neurological illness generally beginning as relapsing/remitting, later becoming secondary progressive. Patient ability to perform activities frequently decreases and the need for informal caregiving increases. Factors associated with caregiving for persons with MS aged 60+ have not been described. Design/Methods: Three cross-sectional paper-based surveys were administered including demographics, the MS Neuropsychological Questionnaire (MSNQ), MSQLI-54, and the Beck Depression Inventory. Patients completed the Symbol Digit Modalities Test upon enrollment and caregivers completed the MSNQ.Descriptive statistics determined differences between patients with and without a caregiver. Results: 211 patients returned their first survey, 188 the second, and 179 the third. 43% of patients have SPMS and 35% have RRMS. 65% have a caregiver and 80% live with their caregiver. Those with a caregiver have a higher MSNQ score (28.7 ± 9.4 vs. 25.8 ± 7.8, p Conclusions: MS patients with a caregiver have higher levels of depression and neuropsychological impairment than those without. They also have lower levels of cognition, and physical and mental health. This has implications for patients with progressive MS as it suggests that those patients with poorer overall health and cognition will need a caregiver for daily assistance. Supported by: Bayer Pharmaceuticals. Disclosure: Dr. Buhse received personal compensation for activities with Biogen Idec, Teva Neuroscience, Bayer Pharmaceuticals, and Questcor. Dr. Buhse has received research support from Bayer Pharmaceuticals. Ms. Banker has received research support from Bayer Pharmaceuticals. Dr. Clement has nothing to disclose.