AAN 2016 DAILY REPORT

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American Academy of Neurology, Vancouver, B.C., 15-21 April 2016
CONGRESS HIGHLIGHTS – WEDNESDAY EDITION

MS
Alzheimer’s disease
Parkinson’s disease

MULTIPLE SCLEROSIS
Dietary salt: Higher salt consumption was reported to be associated with increased clinical and radiological disease activity in MS patients (Farez et al. ECTRIMS 2014; abstract P351). However, three new studies have found no association between salt intake and MS. An analysis of data from the Nurses’ Health Studies reported that higher vs. lower salt intake was not associated with an increased risk of developing MS (pooled hazard ratio 0.95) (Cortese et al. AAN 2016; abstract S37.001). MS risk was also not correlated with potassium, magnesium, calcium, phosphorus and iron intake. A case-control study recently reported that sodium intake was not associated with an increased risk of MS in pediatric patients (odds ratio 1.05 for excess sodium intake) (McDonald et al. Mult Scler Relat Disord 2016;6:87-92). Moreover, an analysis of CIS patients in the BENEFIT trial found that higher salt consumption was not associated with conversion to clinically-definite MS (HR 0.92) over a 5-year period, or with clinical or radiological outcomes, such as time to first relapse (HR 0.91) or new active lesions (HR 0.98) (Fitzgerald et al. AAN 2016; abstract S37.002).

Spinal cord imaging: Lesions only in the brain are 10-fold more common in relapsing-remitting compared to primary-progressive MS, according to a retrospective analysis of 80 PPMS and RRMS patients (Dastagir et al. AAN 2016; abstract P4.170). MRIs (brain FLAIR, spinal cord T2 sequences) were obtained at a single time point. Brain only lesions were found in 25% of RRMS and 2.5% of PPMS patients. Spinal cord only lesions occurred in 7.5% of RRMS and 15% of PPMS patients. Brain plus spinal cord lesions were found in 68% and 83%, respectively. The authors noted that topographic differences between the two groups suggest that PPMS is a distinct entity from the RRMS spectrum of disease.

Alemtuzumab: Three analyses of data from the CARE-MS II extension in previously-treated patients. In years 0-5, 76% had no 6-month confirmed disability progression; 43% had EDSS improvement (Coles et al. AAN 2016; abstract P3.022). In the cohort initially randomized to beta-interferon-1a, there was a 73% reduction in ARR after switching to alemtuzumab (0.52 to 0.14), and 81% were free of 6-month confirmed disability progression (Havrdova et al. AAN 2016; abstract P3.024). MRI results after switching: 86.2% had no Gd+ lesions, and 72.1% had no new/enlarging T2 lesions (Pelletier et al. AAN 2016; abstract P3.025).

Ocrelizumab: The proportion of patients with no evidence of disease activity (NEDA) at 96 weeks in the OPERA I and II trials was 47.9% and 47.5% with ocrelizumab, compared to 29.2% and 25.1% with beta-interferon-1a SC (Traboulsee et al. AAN 2016; abstract PL02.004). NEDA was defined as no relapses, no confirmed disability progression, and no new MRI lesions (new Gd+, new/enlarging T2) at 24, 48 and 96 weeks. After week 24, >96% of ocrelizumab-treated patients had no new/enlarging T2 lesions vs. 60.8-70.9% of patients in the interferon group.

ALZHEIMER’S DISEASE
Pathology: An analysis of brain autopsies performed at the provincial neuropathology referral centre in B.C. reported that coexisting neurodegenerative and vascular pathologies are found in a majority of AD patients (Marnane et al. AAN 2016; abstract P6.221). Data on 147 biopsies of AD patients were analysed for the period 1997-2015. Overall, 78.9% had coexisting cerebrovascular disease, defined as moderate/severe arteriosclerosis (70.7%), moderate/severe cerebral amyloid angiopathy (39.5%), or cerebral infarction (lacunar, large artery-related, hemorrhagic). In addition, 26.5% had dementia with Lewy bodies, 6.8% had hippocampal sclerosis, 2% had fronto-temporal lobar degeneration, and 2% had corticobasal degeneration. About 27% had >2 pathologies in addition to AD. A separate analysis from the Einstein Aging Study found that moderate/severe vascular pathology was associated with a more rapid cognitive decline, even after adjustment for AD pathology (Ezzati et al. AAN 2016; abstract P6.222). The effect of vascular pathology on cognitive decline was greater in patients with a higher burden of AD pathology.

PARKINSON’S DISEASE
Phase I results: A phase I study has examined the use of nilotinib, a tyrosine kinase inhibitor (TKI), in PD with dementia and Lewy body dementia. Nilotinib is currently used for the treatment of chronic myelogenous leukemia. Twelve subjects with late-stage PD or Lewy body dementia were randomized to nilotinib 150 or 300 mg/day for 6 months (Pagan et al. AAN 2016; abstract S40.005). There were significant improvements in motor and non-motor symptoms assessed with UPDRS I-IV and Timed Up and Go, as well as improvements in cognition (MMSE, SCOPA-cog), speech and language fluency, and autonomic function (constipation, urinary incontinence, orthostatic hypotension). Nilotinib significantly reduced CSF levels of p-tau231, p-tau181 and beta-amyloid42/40, as well as biomarkers of neuronal death (neuron-specific enolase, S100B) (Moussa et al. AAN 2016; abstract S40.006). Pre-clinical studies have reported that nilotinib promotes alpha-synuclein clearance by inhibiting Abl tyrosine kinase activity (Mahul-Mellier et al. Hum Mol Genet 2014;23:2858-2879).

American Academy of Neurology, Vancouver, B.C., 15-21 April 2016
CONGRESS HIGHLIGHTS – TUESDAY EDITION

MS
Traumatic brain injury
Migraine

MULTIPLE SCLEROSIS
Teriflunomide: Final analysis of the phase II extension study of teriflunomide (up to 12.9 years, 1136 patient-years): annualized relapse rate (ARR) remained low with teriflunomide 14 mg (0.188) and 7 mg (0.256) (Kremenchutzky et al. AAN 2016; abstract P3.027). The proportion relapse-free during the extension was 51.5% and 39.5%, respectively. EDSS scores were stable. There were no new/unexpected adverse events.

A prospective study evaluated brain volume change in 30 RRMS patients treated with teriflunomide and 20 healthy controls (Zivadinov et al. AAN 2016; abstract P3.062). At 12 months, the percent change in whole brain volume was -0.50% with teriflunomide vs. -0.38% in healthy controls; differences were not significant. Nonsignificant differences were also seen in percentage change in cortical volume (-0.80% vs. -0.31%) and thalamic volume (-0.22% vs. -0.03%).

Dimethyl fumarate: In the ENDORSE extension of phase III studies, for the subset who received MRIs, the mean percent brain volume change (PBVC) was -0.34%/year over a 6-year period for the DMF 240 mg BID group (Kappos et al. AAN 2016; abstract P3.061). Over the four years of ENDORSE, the change from baseline in PBVC was not significantly different for the BID/BID and placebo/BID groups.

Alemtuzumab: The long-term follow-up of the phase II CAMMS223 trial found that ARR remained low at 10 years (0.07) and 76% were free from 6-month sustained disability progression (Coles et al. AAN 2016; abstract P3.053). Overall, EDSS score from baseline was stable or improved in 78%. During the extension, 65% received a third course, 12% received a fourth course and 10% received a fifth course.

Retinal nerve fibre layer (RNFL) thickness as assessed by optical coherence tomography (OCT) shows progressive thinning in MS patients with and without optic neuritis. A Canadian analysis reported that RNFL thickness increased in 26 patients treated with alemtuzumab for two years (Nguyen et al. AAN 2016; abstract P3.083). The mean increase in RNFL thickness was 1.5 μm during treatment; the average change was 2.3 μm after excluding values after a new/recent episode of optic neuritis.

Cladribine: Efficacy results from the two-year extension of the phase III CLARITY trial (Giovannoni et al. AAN 2016; abstract P3.028). Placebo subjects received cladribine 3.5 mg/kg; the cladribine groups were re-randomized 2:1 to cladribine 3.5 mg/kg or placebo. ARR in subjects receiving cladribine 3.5 mg/kg for four years was 0.10 versus 0.15 for those in the 3.5 mg/kg group re-randomized to placebo for the extension. The proportion relapse-free was similar for the two groups (81.2% and 75.6%). Median EDSS scores and time to 3-month confirmed EDSS progression were comparable across all groups.

The phase II ONWARD trial evaluated the efficacy of adding cladribine 3.5 mg/kg in patients with breakthrough disease while on a beta-interferon (Montalban et al. AAN 2016; abstract P3.029). Patients had >1 relapse in the prior 48 weeks of interferon therapy; 14.5% had SPMS. ARR was significantly lower with the combination compared to interferon monotherapy (0.12 vs. 0.32). There was also a benefit with the combination in RRMS/active SPMS patients with respect to MRI measures of disease activity (Gd+ lesions, active T2 lesions, combined unique active lesions).

Secondary-progressive MS: An international study interviewed 16 clinicians about how they diagnosed SPMS (Ziemssen et al. AAN 2016; abstract P2.156). Progression to SPMS was commonly associated with a gradual worsening of symptoms (13 of 16 clinicians), lack of recovery (10/16), increased symptom severity (9/16), and presence of new symptoms (9/16). Also considered were new MRI lesions (8/16) and absence of relapses (7/16). Worsening symptoms most commonly involved vision, cognition, balance and ambulation. Time to confirmation of SPMS ranged from <6 months to >1.5 years.

TRAUMATIC BRAIN INJURY (TBI)
Psychiatric sequelae: TBI is associated with an increased risk of psychiatric sequelae, according to a database analysis of health records in California, Florida and New York for the period 2005-2012 (Merkler et al. AAN 2016; abstract P3.341). TBI was defined according to ICD-9 criteria and was classified as mild (discharged from Emergency department), moderate (inpatients not requiring mechanical ventilation) or severe (inpatients requiring mechanical ventilation). A total of 1.23 million patients with TBI were identified: 1,007,494 with mild TBI, 202,063 with moderate TBI, and 26,717 with severe TBI. The incidence rate ratio (IRR) of psychiatric sequelae was higher after mild (1.39), moderate (1.25) and severe (1.35) TBI compared to before TBI.

MIGRAINE
Migraine and emotional abuse: The prevalence of childhood abuse was examined for 14,484 adults (ages 24-32 years) from wave 4 of the National Longitudinal Study of Adolescent Health (Tietjen et al. AAN 2016; abstract S26.003). Three items asked respondents to recall emotional, physical and sexual abuse. Overall, 14.2% of the sample reported a migraine diagnosis. Childhood abuse was recalled by 60.5% of migraine patients versus 49.0% of the non-migraine sample. Childhood abuse increased the risk of migraine by 55%. Emotional abuse had the strongest effect on migraine (odds ratio 1.52); this effect was reduced but remained significant when controlled for depression and anxiety (OR 1.33).

American Academy of Neurology, Vancouver, B.C., 15-21 April 2016
CONGRESS HIGHLIGHTS – MONDAY EDITION

MS
Dementia
ALS
Epilepsy

MULTIPLE SCLEROSIS
Natalizumab: A high percentage of CD8+ cells may be associated with an increased risk of disease reactivation following natalizumab discontinuation (Bertolotto et al. AAN 2016; abstract P2.063). Reactivation risk was lower with a higher CD4+ percentage or higher CD4+/CD8+ ratio.

Fingolimod: Report from Japan that fingolimod suppresses bone resorption, which may benefit MS patients with osteoporosis (Miyazaki et al. AAN 2016; abstract P2.072). Fingolimod-treated patients had lower levels of uNTx (urinary type I collagen cross-linked N-telopeptide), a marker of bone resorption, compared to untreated MS patients and healthy controls. The authors previously reported that fingolimod reduced arthritis development, in part through inhibition of prostaglandin E2 production by synovial cells, in a mouse rheumatoid arthritis model (Tsunemi et al. Clin Immunol 2010;136:197-204).

Dimethyl fumarate: Two analyses of the incidence of lymphopenia with DMF were presented. An analysis of U.S. health records (n=1014) reported a mean 28-32% decrease in absolute lymphocyte count (ALC) at 12 months (Wenten et al. AAN 2016; abstract P2.098). The incidence of severe lymphopenia (ALC < 500 cells/mcL) was 6%; mean time to severe lymphopenia was 9 months. The incidence of severe lymphopenia was higher (13%) in a U.S. single-centre study (n=250) (Romba et al. AAN 2016; abstract P2.101). Older patients may have a higher risk of severe lymphopenia.

DMF had no effect on the pharmacokinetics of an oral contraceptive (norgestimate/ethinyl estradiol; Ortho-Tri-Cyclen and generics) when the drugs were coadministered in healthy volunteers (Zhu et al. AAN 2016; abstract P2.097). Mean plasma concentrations of norelgestromin (the primary metabolite of norgestimate), ethinyl estradiol and progesterone were comparable with and without DMF.

Cladribine: In the CLARITY trial of cladribine 3.5 or 5.25 mg/kg, the proportion of patients free of Gd+ lesions was 86.8% and 91.0%, respectively, compared to 48.3% with placebo; the proportion with no active T2 lesions was 61.7%, 62.5% and 26.1% (Comi et al. J Neurol 2013;260:1136-1146). For the two-year extension, the placebo group received cladribine 3.5 mg/kg, and the cladribine groups were re-randomized to cladribine 3.5 mg/kg or placebo (Comi et al. AAN 2016; abstract P2.114). The proportion with no Gd+ lesions was 85.1-89.9% for patients on continuous cladribine, and 73.0-80.2% for the placebo/cladribine group. The proportion with no active T2 lesions was 37.6-43.7%, and 27.6-34.4%, respectively, at week 120 of the extension.

Ocrelizumab: There is a low incidence of anti-drug antibodies to ocrelizumab (Song et al. AAN 2016; abstract P2087). The analysis included >96% of patients enrolled in the OPERA I/II trials of RRMS. The prevalence of anti-ocrelizumab antibodies was 0.6% (5/798) prior to drug exposure. The incidence of treatment-emergent anti-drug antibodies was 0.4% (3/807).

Adherence: Canadian MS clinics report that 27.5% of patients receiving an injectable DMT in the period 2010-2013 had poor adherence (McKay et al. AAN 2016; abstract P2.067). Mild disability (EDSS < 2.5), disease duration >5 years and alcohol dependence were nonadherence risk factors.

DEMENTIA
Cholinesterase inhibitor/memantine combination: A pooled analysis of two 24-week trials (n=1056) of combined ChEI/memantine was performed to determine the areas of functioning that benefited (Alva et al. AAN 2016; abstract P2.218). At week 24, there were significant improvements in grooming, conversing, and finding belongings with combination therapy versus ChEI alone. The combination was significantly associated with less decline in four subscales: basic ADLs; higher-level ADLs requiring communication/comprehension skills; simple praxis; and praxis items requiring visuo-spatial and memory skills.

AMYOTROPHIC LATERAL SCLEROSIS
Nuedexta ALS treatment trial: Dextromethorphan/quinidine 20/10 BID (Nuedexta) demonstrated efficacy in patients with pseudobulbar affect secondary to dementia in the open-label PRISM II trial (Doody et al. CNS Spectr 2015; epublished October 16, 2015). A new multicentre crossover study randomized 60 patients with ALS to dextromethorphan/quinidine or placebo for one month (Smith et al. AAN 2016; abstract P2.224). There was a significant improvement in self-reported Center for Neurologic Study-Bulbar Function Scale (CNS-BFS) scores at one month with treatment versus placebo (mean score 53.45 vs. 59.31). All three domains of bulbar function (speech, swallowing, salivation) responded to treatment; the effect on speech rate and swallowing time were not statistically significant. Treatment effects were independent of the presence or absence of pseudobulbar affect.

EPILEPSY
Colour me compliant: Capsule colour may influence treatment adherence in clinical trials (Stack et al. AAN 2016; abstract P2.037). A survey of 96 patients with epilepsy presented with five capsule colours (grey, caramel, maroon, white and yellow) found that 48% found at least one colour was unacceptable. The most objectionable: grey, caramel and maroon.