P133 PROFILE OF MEDICAL CARE COSTS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS IN MEDICARE PROGRAM AND UNDER COMMERCIAL INSURANCE
Meng L1
Jordan S1
Bian A1
Andrew J1
Shefner J2
Wolff A1
Blumen H3
Iwasaki K3
Pyenson B3
aCytokinetics, Inc., South San Francisco, USA
bSUNY Upstate Medical University, New York, USA
cMilliman, Inc, New York, USA
Email address for correspondence: [email protected]
Keywords: cost, Medicare, disability
Background: Amyotrophic lateral sclerosis (ALS) is a rare disease causing progressive denervation and consequent skeletal muscle atrophy leading to weakness, fatigue, muscle weakness and death, primarily from respiratory complications. Treatment consists of modest alteration of disease progression, symptom alleviation, and supportive measures.
Objectives: The primary objective of this analysis was to characterize the medical care costs incurred for ALS patients covered by Medicare and commercial insurance. Specifically, this analysis will determine the ALS medical care costs before and after diagnosis under each program and during the transition between these two programs.
Methods: 368 ALS patients who were diagnosed between January 1, 2009 and December 31, 2010 were identified from a 5% sample of Medicare claims (2008–2011). 344 ALS patients who were diagnosed using the same methodology as the Medicare cases were also selected from the Truven Marketscan commercial database (2008–2010). The monthly claim costs were tabulated from one year before the index date until death or the end of 2011 for Medicare cases. An exponential regression was used to model the monthly cost prior to index date. Kaplan-Meier Sample Average was employed to model the lifetime cost since index date, adjusting for censored cases. Medical costs from index date to disability milestones were tabulated from the Medicare database.
Results: Both Medicare program and commercial insurance demonstrate comparable monthly cost patterns before diagnosis. The cost increased exponentially within approximately 8 months before diagnosis. The monthly claim cost dropped sharply after the diagnosis month and then increased steadily until death. ALS patients initially covered under commercial insurance and then switched to Medicare coverage had comparable patterns to patients in pure Medicare programs. Approximately 30% of ALS patients already received supportive services for disabilities at the time of diagnosis. Total cost incurred in pure Medicare programs increased rapidly and substantially with worsening disability milestones.
Discussion and conclusion: This analysis only includes Medicare and commercial costs. Out of pocket costs likely increase the economic burden significantly. The increasingly important roles of risk adjusters, reinsurance and pooling were not assessed in this analysis. Limited duration of follow-up makes many of our conclusions tentative. Nevertheless, these results provide an initial estimate of the economic burden associated with disability milestones in ALS medical care. It will be important to explore whether delaying time to disability milestones reduces costs, as agents that improve function in ALS patients are developed.
P134 THE ROLE AND VIEW OF STUDY COORDINATORS IN A MULTICENTER ALS STUDY (ALS COSMOS)
Hupf J1
Singleton J1
Klingerman S2
Cowardin C3
Rodriguez W4
Hand S4
Washington M4
Gorham N5
Lim S6
Cregan M6
Olalde H7
Duong Y-NY8
Factor-Litvak P9
Mitsumoto H1
dEleanor and Lou Gehrig MDA/ALS Research Center, Columbia University Medical Center, New York, NY, USA
eMayo Clinic, Rochester, MN, USA
fDepartment of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA
gTexas Neurology, Dallas, TX, USA
hDepartment of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA
iDepartment of Neurology, University of California, Davis, Sacramento, CA, USA
jDepartment of Neurology, University of Iowa, Iowa City, IA, USA
kDepartment of Neurology, University of California, San Francisco, San Francisco, CA, USA
lDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
Email address for correspondence: [email protected]
Keywords: observational studies, recruitment, ALS COSMOS
Background: The successful execution of multicenter observational studies falls largely on study personnel, who coordinate and implement the study protocol at study sites. The roles of study coordinators as protocol implementers and co-investigators in multicenter amyotrophic lateral sclerosis (ALS) studies, and their perspectives on both study implementation and success, have not been previously reported.
Objectives: The purpose of this study was to investigate the role and individual viewpoints of study coordinators in Columbia University Medical Center’s Multicenter ALS Cohort Study of Oxidative Stress and Disease Progression (ALS COSMOS). By identifying issues unique to both observational multicenter studies and ALS populations, this investigation aims to improve coordinator performance and overall study execution in future studies.
Methods: A 57-item survey was distributed to 24 active research coordinators (RCs) at 14 ALS COSMOS sites across the United States. Former RCs were also asked to participate. The survey covered the background and responsibilities of RCs, subject recruitment and retention, methods of execution, data management, ways to improve future studies, and general sources of satisfaction and dissatisfaction.
Results: Among the 17 respondents, the vast majority had extensive RC experience. However, only about half had ever coordinated a multicenter study. All were satisfied with pre-study training, but most agreed that training methods could be improved. Most RCs reported that coordinators had left the project mid-study, and that these departures had noticeable effects on implementation of the project. Almost all respondents noted that recruitment was relatively easy, and that PIs or co-PIs typically led recruiting efforts at patients’ first follow-up ALS clinic visits. Notable determinants for decreased recruitment were study commitments being too large and competition from clinical trials. While retention was not an issue for most sites, disease progression was the most common reason for subject drop-out. The majority of those surveyed were satisfied with the study as a whole. Nearly all respondents stated that their overall workloads fell within the range of “just right” to “overworked.”
Discussion and conclusion: Although most RCs were satisfied with the project, their responses highlighted areas for improvement. RCs often cited subjects’ declining ability to speak, write, and travel to clinic as a factor in attrition rate. Using questionnaires and rating scales designed to accommodate subjects with motor and speech deficits, and offering reimbursement for travel expenses, could facilitate continued participation. To compensate for staffing changes, a web-based training module could ease transitions between RCs, and also allow current RCs to refresh their training as needed. Lastly, more efficient distribution of workload could improve study execution, as many RCs reported feeling overworked.
Acknowledgements: NIEHS (R01ES016348), MDA Wings Over Wall Street.
P135 SOCIOECONOMIC DIFFERENCES IN FUNCTIONAL PARAMETERS AT ALS DIAGNOSIS
Factor-Litvak P1
Goetz R2
Hupf J3
Singleton J3
Mitsumoto H3
Study Group Als Cosmos3
mDepartment of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York, USA
nNew York State Psychiatric Institute and Department of Psychiatry, Columbia University, New York, New York, USA
oEleanor and Lou Gehrig MDA/ALS Research Center, Columbia University Medical Center, New York, New York, USA
Email address for correspondence: [email protected]
Keywords: epidemiology, socioeconomic, ALS COSMOS
Background: Little is known regarding characteristics associated with function at diagnosis in ALS patients.
Objective: To evaluate sociodemographic and economic differences in function at diagnosis in ALS-COSMOS, a multi-site study of ALS progression.
Methods: Data were collected at the first clinical evaluation and via telephone questionnaire. Function was measured using the ALSFRS-R and %Forced Vital Capacity (%FVC). Sociodemographic and economic indicators included age, race/ ethnic group, sex, education level, total annual income, employment status, and health insurance type. We also evaluated smoking and use of alcoholic beverages. We used linear regression, controlling for patient reported duration of symptoms.
Results: 355 patients were enrolled, of whom 324 and 325 had ALS-FRS and FVC data, respectively. Mean ALS-FRS-R and %FVC (+ standard deviation (SD)) were 36.0 (+ 6.76) and 79.2% (+ 22.6), respectively. Average age was 61.1 (+ 10.3) years. 61% were male, 11% were non-white and 6.5% were Latino. The median duration of symptoms prior to diagnosis was 11.5 months. Controlling for duration of symptoms, lower ALS-FRS-R scores were found among: males (p = 0.02); non-whites (p = 0.017); and those of Latino descent (p = 0.012), with lower education (p = 0.01); with incomes <$60,000 per year (p = 0.013) or incomes between $60,000 and $99,000 per year (p = 0.12); employed part time (p = 0.10); retired (p < 0.001) or on disability (p < 0.001); with government sponsored health insurance (p = 0.071) and missing data on alcohol use (p = 0.003). When all variables were simultaneously adjusted, lower ALS-FRS-R was associated with: non-white race (p = 0.044); Latino descent (p = 0.002); being employed part-time (p = 0.10); retired (p = 0.001); disabled (p < 0.001); and longer duration of symptoms (p = 0.037). Controlling for duration of symptoms, lower %FVC was associated with non-white race (p = 0.10); lower education (p = 0.004); part-time employment (p = 0.089); retired (p = 0.001) or disabled (p = 0.010); and having government sponsored insurance (p = 0.071). Moderate alcohol consumption was associated with higher %FVC (p = 0.055). When all variables were simultaneously adjusted, lower %FVC was associated with older age (p = 0.027), low education level (p = 0.035), retired (p = 0.063) or disabled (p = 0.021) and longer duration of symptoms (p = 0.056); higher %FVC was associated with moderate alcohol intake (p = 0.078).
Discussion and conclusion: Variables reflecting sociodemographic characteristics are associated with functional severity of ALS at enrolment. These relationships are possibly due to general doctors not referring patients to tertiary care clinics at early stages or use of an informal care system (ie, by relatives in the home) for patients with mild to moderate symptoms.
Acknowledgements: NIEHS (R01ES016348) & MDA Wings Over Wall Street.
P136 FACTORS AFFECTING LONGITUDINAL FUNCTIONAL DECLINE AND SURVIVAL IN AMYOTROPHIC LATERAL SCLEROSIS PATIENTS
Watanabe H1
Atsuta N1
Nakamura R1
Hirakawa A2
Watanabe H1
Ito M1
Katsuno M1
Izumi Y3
Morita M4
Tomiyama H5
Taniguchi A6
Abe K7
Mizoguchi K8
Kano O9
Kuwabara S10
Imai T11
Aoki M12
Kaji R3
Nakano I13
Sobue G1
pDepartment of Neurology
qBiostatistics Section, Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan
rDepartment of Clinical Neuroscience, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
sDivision of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
tDepartment of Neurology, Juntendo University School of Medicine, Tokyo, Japan
uDepartment of Neurology, Mie University Graduate School of Medicine, Tsu, Japan
vDepartment of Neurology, Okayama University Graduate School of Medicine, Okayama, Japan
wDepartment of Neurology, National Hospital Organization, Shizuoka-Fuji National Hospital, Fujinomiya, Japan
xDepartment of Neurology, Toho University Omori Medical Center, Tokyo, Japan
yDepartment of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
zDivision of Neurology, National Hospital Organization, Miyagi National Hospital, Miyagi, Japan
aaDepartment of Neurology, Tohoku University School of Medicine, Sendai, Japan
abDepartment of Neurology, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan
Email address for correspondence: [email protected]
Keywords: ALS registry, ALSFRS-R, survival
Background: Functional decline and survival are equally important for evaluating the clinical course of amyotrophic lateral sclerosis (ALS) patients. However, although the factors that affect survival have been well analysed, factors that affect functional decline have not been well demonstrated.
Objectives: The aim of this study was to elucidate the clinical factors affecting functional decline and survival in Japanese ALS patients.
Methods: We constructed a multicentre prospective cohort of ALS patients and included 451 sporadic ALS patients in the analysis. We longitudinally utilized the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) as the functional scale, and we determined the timing of events such as the introduction of a tracheostomy for positive-pressure ventilation and death in the included patients. We employed a joint modelling approach to identify prognostic factors for functional decline and survival (Citation1, Citation2).
Results: Age at onset was a common prognostic factor for both functional decline and survival (p < 0.001, p < 0.001, respectively). Female gender (p = 0.019) and initial symptoms, including upper-limb weakness (p = 0.010), lower-limb weakness (p = 0.008) or bulbar symptoms (p = 0.005), were related to early functional decline, whereas neck weakness as an initial symptom (p = 0.018), non-use of riluzole (p = 0.030) and proximal dominant muscle weakness in the upper extremities (p = 0.01) were related to a shorter survival time. A decline in ALSFRS-R score correlated with a shortened survival time (p < 0.001).
Discussion and conclusions: The factors affecting functional decline and survival in ALS patients were common in part but different to some extent. This point of difference has not been previously well recognised but is informative in clinical practice and in conducting trials.
Acknowledgements: We thank all the patients with ALS who participated in this study. We also thank all the doctors and staff who participated in this work. This study was supported by Health and Labour Sciences Research grants from the Ministry of Health, Labour and Welfare of Japan, and grants-in-aid for Scientific Research (grant number 25461277) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. A part of this study is the result of “Integrated Research on Neuropsychiatric Disorders” carried out under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan.
References:
- Rizopoulos D. Boca Raton: Chapman and Hall/CRC, 2012.
- Therneau T, Grambsch P. Berlin and Heidelberg: Springer, 2000.
P137 DETECTION OF BETA-N-METHYLAMINO- L-ALANINE IN A LAKE SURROUNDED BY CASES OF AMYOTROPHIC LATERAL SCLEROSIS
Stommel E1
Caller T1
Henegan P1
Cox P2
Haney J3
Metcalf J2
Powell J2
Banack S2
acNeurology Department, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
adInstitute for Ethnomedicine, Jackson, WY, USA
aeDepartment of Biological Sciences, University of New Hampshire, Durham, NH, USA
Email address for correspondence: [email protected]
Keywords: cyanobacteria, BMAA, environmental risk factor
Background: A cluster of amyotrophic lateral sclerosis (ALS) cases has been previously described bordering Lake Mascoma in Enfield, NH, with an incidence of ALS approximating 25 times that of the baseline incidence of ALS reported throughout most industrialized nations. We hypothesize that the high rate of ALS might be associated with cyanobacterial blooms that have the potential to produce the neurotoxin beta-N-methylamino-L-alanine (BMAA), implicated as the cause of Guam’s high rate of ALS (Citation1). Lake Mascoma has a well-established history of blooms and the cyanobacterial liver toxin, microcystin (MC), has been found in abundance as have species of cyanobacteria capable of producing BMAA.
Objectives: To analyze plankton, fish and aerosol samples from Lake Mascoma for the presence of BMAA, the BMAA isomer 2,4-diaminobutyric acid (DAB) and MC.
Methods: Muscle, liver, and brain tissue samples from a Lake Mascoma carp were collected and tested for both free and protein-bound BMAA and DAB (Citation2, Citation3). Aerosol samples were collected using a portable air sampler and glass fiber filters. Filters were examined with fluorescence microscopy and PCR to detect cyanobacterial presence and analyzed for BMAA, DAB, and MC (Citation4).
Results: In carp brain (n = 3) the free BMAA and DAB concentrations measured were 0.03 μg/g ± 0.025 SD and 0.01 μg/g ± 0.002 SD respectively; protein bound BMAA was 0.03 μg/g ± 0.025 SD and protein-bound DAB was not detected (ND). In carp liver (n = 3) total BMAA and DAB were 1.28 μg/g ± 0.034 and ND respectively. In carp muscle (n = 1) BMAA and DAB were 1.27 μg/g and ND respectively. No cyanobacteria could be detected in the air filters by fluorescence microscopy or PCR analysis for 16S genes using cyanobacterial 16S primers CYA359F and CYA781R. These results suggest that either cyanobacteria were not present, or the biological material had degraded. BMAA was detected in the air filters that underwent a solid phase extraction, as were both BMAA isomers DAB and N-(2-aminoethyl) glycine (AEG). MC in muscle and kidney tissue was ND and in liver (three replicate sets of tissue) were 5.9, 6.3 and 6.3 ng microcystins/g liver wet weight or 59, 63 and 63 ng MC/g liver dry weight.
Conclusions: These results demonstrate that a putative cause for ALS, BMAA is present in an environment that has a documented cluster of ALS. The modes of exposure are discussed as are synergistic mercury toxicity and the implications and potential role for mitigation.
- Cox, PA Banack SA, and Murch SJ. Proc Natl Acad Sci USA. 2003. 100(23): 13380–3.
- Banack SA, Caller TA, and Stommel EW. Toxins (Basel), 2010. 2(12): 2837–50.
- Masseret E. et al. PLoS One, 2013. 8(12): e83406.
- Carey CC, Haney JF, and Cottingham KL. Environ Toxicol. 2007. 22(3): 337–9.
P138 INCREASED TUMOR NECROSIS FACTOR-A IN THE SKIN OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS–AN IMMUNOHISTOCHEMICAL STUDY
Fujikura M
Ono S
Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan
Email address for correspondence: [email protected]
Keywords: immunohistochemistry, skin, tumor necrosis factor-α (TNF- α)
Background: The studies of skin from patients with amyotrophic lateral sclerosis (ALS) have shown unique pathological and biochemical abnormalities. The lack of bedsore formation even in the terminal stages in ALS patients is considered characteristic. Tumor necrosis factor-alpha (TNF-α) is a major inflammatory cytokine that elicits a wide range of biological responses. TNF-α mediates its biological effects through activation of two distinct receptors, TNF-R1 and R2. TNF-α receptors are constitutively expressed on both neurons and glia in the central nervous system (CNS). Several studies have designated TNF-α as a pathogenic mediator in many CNS diseases with an inflammatory component. Although TNF-α can mediate motor neuron death, its role in disease pathogenesis remains unclear. Despite these findings it is unknown whether TNF-α-positive (TNF-alpha+) structures are present in the skin of patients with ALS.
Objectives: To study TNF-α in the skin of ALS patients.
Methods: Skin biopsy specimens were taken from the left biceps from 21 sporadic ALS patients (61.4 ± 9.2 years) and 20 control subjects with other neurologic disorders (63.6 ± 6.7 years). Routine formalin-fixed paraffin-embedded 6 μm sections were immunostained according to standard techniques. A densitometric analysis was performed using an image analysis system.
Results: Immunohistochemistry for TNF-α demonstrated cytoplasmic activity in the epidermis and in some blood vessels and glands. The proportion of TNF-α-positive (TNF-α+) cells in the epidermis in ALS patients was significantly higher (p < 0.001) than in controls. There was a significant positive relationship (r = 0.87, p < 0.001) between the proportion and duration of illness in ALS patients, but there was no such relationship in control subjects. The optical density of TNF-α+ cells in the epidermis in ALS patients was markedly stronger (p < 0.001) than in controls. There was a significant positive relation (r = 0.70, p < 0.001) between the immunoreactivity and duration of illness in ALS patients. In addition, there was an appreciable positive correlation (r = 0.59, p < 0.01) in ALS patients between the proportion of TNF-α+ cells and the optical density of these cells, but with no correlation in controls.
Discussion and conclusions: The increased TNF-α immunoreactivity of skin does not reflect nutritional status-or activity-dependent skin remodeling. From these considerations, our results as to the increase of TNF-α immunoreactivity of skin in ALS might indicate an augmentation of TNF-α content due to reduced degradation, increased synthesis, and/or increased binding of circulating TNF-α by skin components. These data suggest that changes in TNF-α identified in the skin of ALS patients are likely to be related to the disease process and that metabolic alterations of TNF-α may take place in the skin of patients with ALS.
P139 WERE NUTRITIONAL FACTORS ASSOCIATED WITH HIGH INCIDENCE OF ALS IN THE K AREA?
Okamoto K1
Kihira T2
Kokubo Y3
Kuzuhara S4
afAichi Prefectural University School of Nursing and Health, Nagoya, Japan
agKansai University of Health Sciences, Osaka, Japan
ahGraduate School of Regional Innovation Studies, Mie University, Tsu, Japan
aiSuzuka University of Medical Science, Suzuka, Japan
Email address for correspondence: [email protected]
Keywords: nutritional factor, epidemiology, K area
Purpose: The aim of this study was to explore nutritional factors to look for the explanatory clues of the high incidence of ALS in the K area from comparisons with the area free from ALS (control area) together with the results of a population-based case-control study conducted in Japan.
Method: A cross-sectional population-based survey was conducted for adults aged ≥ 15 years living in K area and control area in 2003, and for adults aged ≥ 60 years living in O area in 2011. A case-control study was conducted with incident 183 ALS cases and 407 controls. Dietary information was obtained by a self-administered food frequency questionnaire (FFQ), consisting of 97 commonly eaten food and beverage items. Frequency of food consumption was classified into two categories as follows: less frequent (‘never/seldom’ or ‘less than once a week’ ‘1–3 days a week’), and frequent (‘4–5 days a week’ or ‘almost every day’). Dried fish was classified into two categories as follows: less frequent (less than once per week), and frequent (‘almost every day’). The differences of means were tested with analysis of variance, and of the distribution of proportions with the chi-square test.
Results: In 2003, the proportion of subjects with frequent intake of dried fish was significantly higher in K area than in control area, and was the highest among the other food consumption. That was also significantly higher in the time of 15 years old than in the time of survey (2012). That in K area (67.9%) was the highest in the area (Aichi cases, Aichi controls, control area, O cho) to have used for the comparison, and was the lowest in Aichi controls (18.7%). In case-control study, higher frequency of dried fish consumption was associated with an increased risk of ALS (1.2 and 1.9, respectively, p = 0.004). Frequent intake of dried fish consumption was significantly associated with an increased risk of ALS, even after adjusting for confounding factors (low vs. high, adjusted OR: 4.8 (95%CI; 3.60–10.3)).
Conclusion: The present results suggested that habitual frequent intake of dried fish may have triggered the development of ALS in the K area, given that our case-control study from which time and a place differ also showed similar findings to the K area.
P140 BMAA ANALYSIS IN THE BRAINS OF AMYOTROPHIC LATERAL SCLEROSIS/PARKINSONISM-DEMENTIA COMPLEX OF THE KII PENINSULA OF JAPAN
Kokubo Y1
Banack S2
Morimoto S3
Murayama S3
Togashi T4
Cox PA2
Kuzuhara S5
ajKii ALS/PDC Research Center, Mie University, Graduate School of Regional Innovation Studies, Mie, Japan
akThe Institute for Ethnomedicine, UT, USA
alTokyo Metropolitan Geriatric Hospital, Tokyo, Japan
amMarine Biosystems Research Center, Chiba University, Chiba, Japan
anSuzuka University of Medical Science, Mie, Japan
Email address for correspondence: [email protected]
Keywords: Kii ALS/PDC, Guam ALS/PDC, BMAA
Background: Amyotrophic lateral sclerosis/parkinsonism-dementia complex of the Kii peninsula of Japan (Kii ALS/PDC) is a unique tauopathy with fronto-temporal dementia. There is a hypothesis that β-N-methylamino-L-alanine (BMAA), which was produced by cyanobacteria, was a trigger for Guam ALS/PDC. The purpose of this study was to examine BMAA in the brains of Kii ALS/PDC.
Objective: Five patients with Kii ALS/PDC (3 ALS, 2 PDC, men 1:4 women, average age: 69.8 years old, average duration of the illness: 7.4 years), two classical ALS and three age-matched normal control were submitted for the study.
Method: To detect BMAA, free and hydrolyzed amino acid extracts from each brain were analyzed using liquid chromatography-tandem mass spectrometry (LC/MS/MS), high-performance liquid chromatography (HPLC), and a Hitachi amino acid analyzer (AAA).
Result: BMAA was detected in ten samples using the HPLC and in six samples using the LC/MS/MS. BMAA was not detected constantly in the brains of Kii ALS/PDC.
Discussion and conclusion: This suggests that the role that BMAA plays as a trigger for Kii ALS/PDC is unclear. Further research is necessary to understand the possible role of BMAA as a trigger in Kii ALS/PDC as the results clearly differ in BMAA content from previously analyzed ALS/PDC brain samples from Guam.
Acknowledgment: The authors thank Ms. Jyunko Karita for her clerical assistance.
P141 IS PARENTAL SURVIVAL ASSOCIATED WITH THE RISK OF AMYOTROPHIC LATERAL SCLEROSIS? - EXPLORING THE FITNESS HYPOTHESIS
Visser AE
Seelen M
de Graaf JA
Hulsbergen AFC
Veldink JH
van den Berg LH
University Medical Center Utrecht, Utrecht, The Netherlands
Email address for correspondence: [email protected]
Keywords: fitness theory, parental survival
Background: There is evidence for an association of a higher phenotypic fitness and an elevated risk of amyotrophic lateral sclerosis (ALS). This ‘fitness theory’ was supported by recent findings that relatives of ALS patients had a reduced risk of cardiovascular diseases.
Objective: To study this fitness hypothesis, we assessed whether parents of ALS patients live longer than parents of controls.
Methods: In a population-based case control study, information regarding age and cause of death of parents was obtained from the Prospective ALS study the Netherlands (PAN) database. Univariate and multivariate Cox regression analysis was used to determine whether survival of the parents of participants was associated with ALS, stratified by mothers and fathers.
Results: 575 sporadic ALS patients and 1082 controls participated in the study. This resulted in data of 1064 parents of patients and 2127 parents of controls. None of the survival analyses were associated with ALS (all p-values > 0.05, all HRs 1.02–1.08).
Conclusion: In this population-based case control study no association between the age of death of parents and the risk of ALS has been found. When parental age of death is a reliable proxy for ‘familial’ cardiovascular fitness, these results do not support the hypothesized fitness theory.
P142 BLOOD LEAD, BONE TURNOVER, AND SURVIVAL IN AMYOTROPHIC LATERAL SCLEROSIS
Fang F1
Peters TL1,2
Beard JD2
Umbach D2
Keller J3
Mariosa D1
Allen K4,5
Oddone E5
Ye W1
Sandler DP2
Schmidt S5
Kamel F2
aoKarolinska Institutet, Stockholm, Sweden
apNational Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
aqWestat, Durham, NC, USA
arDurham VA Medical Center, Durham, NC, USA
asDuke University Medical Center, Durham, NC, USA
Email address for correspondence: [email protected]
Keywords: lead, bone turnover, survival
Objectives: To assess the impact of blood lead and bone turnover status on the survival of US military veterans with amyotrophic lateral sclerosis (ALS).
Methods: We conducted a survival analysis among 123 ALS patients enrolled in the National Registry of Veterans with ALS during January-September 2007. Patients were followed from date of diagnosis to death or July 25, 2013. The association of blood lead and plasma biomarkers of bone formation (PINP) and bone resorption (CTX) with ALS survival were estimated by hazard ratios (HRs) derived from Cox models after adjustment for age at diagnosis, site of symptom onset, ALS functional rating scale, and diagnostic delay. Blood lead, plasma CTX and PINP were mutually adjusted for one another.
Results: By the end of study, 93 of the ALS patients (75.6%) had died. In the fully adjusted model, a one-unit increment in log2-transformed blood lead (ie, a doubling of lead concentration) was associated with a 1.59-fold risk of death (95% confidence interval (CI): 1.11–2.26) among the ALS patients. Similarly, a doubling of plasma CTX concentration was associated with a 1.66-fold risk of death (95% CI: 1.11–2.46). On the contrary, a doubling of plasma PINP concentration was associated with a 0.56-fold risk of death (95% CI: 0.39–0.80). No clear interactions were observed between these biomarkers and other ALS prognostic indicators.
Discussion and conclusion: Our results suggest that blood lead and plasma bone turnover biomarkers are independent predictors of ALS prognosis. Moreover, given the ease of measurement, bone turnover status may be of special clinical interest.
P143 APPLICATION OF A STAGING SYSTEM TO THE PROACT DATABASE POPULATION
Heiman-Patterson T
Dey S
Alexander G
Deboo A
Drexel University College of Medicine, Philadelphia, Pa, USA
Email address for correspondence: [email protected]
Keywords: staging, survival, PRO-ACT database
Background: Validated staging systems for ALS can increase understanding of the disease prognosis, help with resource management and research design. Recently, a staging system was proposed for ALS in a UK population (Citation1) using clinical milestones for disease progression. Milestones were defined as: symptom onset in one region (bulbar, upper limb, lower limb or diaphragmatic) (Stage 1); diagnosis (2a); involvement of a second region (2b); third region (3); gastrostomy (4a); non-invasive ventilation(4b). These stages/milestones occurred at predictable times when examined over the course of the illness with Stage 2a at 35%; stage 2b at 38%; stage 3 at 61%; 4a at 77% ; 4b at 80%. To date this staging system has not been validated in any other populations.
Objectives: To validate this proposed staging system in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, a multi-national de-identified ALS database.
Methods: We reviewed 8672 cases within the PRO-ACT database and identified 100 subjects with data spanning diagnosis to death in order to compare the stage durations between a global population and the UK population. We identified the percentage of time in each stage for both bulbar and limb onset, demographics and survivals in order to compare the results of the two populations. Survival analysis included Kaplan-Meier plots and results between the PRO-ACT subjects and UK subjects were analyzed with t-tests using the means and sd.
Results: The PRO-ACT subjects included 66 limb onset (24 F, 42M), and 34 bulbar onset (20F, 14M). The average age of onset overall was 58.25 years(Y) (60.5 Y F, 55Y M), 56.7Y (51.6Y M, 60Y F) for bulbar onset and 59.8Y (58.7Y M, 61.8Y F) for limb onset. For PRO-ACT subjects 2a occurred at 29%, 2b at 55%, 3 at 76 %, 4a at 75 % and 4b at 82 % through the disease course. When compared to the UK population, 2a occurred earlier in the disease course (p = 0.0007). Also more time was spent between stages 2a and 2b in the PRO-ACT subjects (p < 0.0001); but by stage 4 (a and b): there was no significant difference with both populations having gone through 75% of their disease course (p > 0.05). Overall, survival was similar in both.
Conclusion: The clinical staging system was easily applied to the global ALS population represented in the PRO-ACT database and although there were differences in early stage disease, both populations had gone through about 75% of the disease course by Stage 4a and 4b. While further validation in prospective studies will be needed, we agree that this staging system holds promise in guiding prognosis, use of resources and clinical research.
Acknowledgements: Funded by the ALS Hope Foundation.
Reference:
- Roche JC. et al. Brain (2012) 135:847–852.
P144 AGE-PERIOD-COHORT ANALYSIS OF TRENDS IN ALS INCIDENCE
Tobin K
Hardiman O
Trinity College Dublin, Dublin, Ireland
Email address for correspondence: [email protected]
Keywords: age-period-cohort, incidence, partial least squares regression
Background: Many studies have shown an increase in rates of incidence and death from ALS over time (Citation1,Citation2). Investigation of age-period-cohort effects is often used to explain temporal trends in incidence. A number of methodological approaches exist for this type of analysis, each with its own set of assumptions and constraints. Here we apply the novel approach of partial least squares regression (PLSR).
Objective: To look at the effects of age, time of diagnosis and birth cohort to explore trends in incidence using PLSR.
Methods: Estimating the distinct impact of age, period and cohort effects on changes to an outcome such as incidence is a frequently discussed issue in the analysis of healthcare trends. By definition, these three variables are perfectly correlated (age+ cohort = period) which leads to the well-known identification problem in linear models. Traditional regression methods cannot be used with these three covariates without imposing additional constraints, which may be unreasonable or difficult to interpret. The PLSR model overcomes the identification problem and facilitates the estimation of the relative effects of age, period and cohort on the incidence of ALS. Our dataset is a national population based register of ALS.
Results: As expected, analysis showed a significant age effect with incidence of ALS increasing with age. No significant association was found between year of diagnosis and incidence (period effect). The non-linear PLSR model showed a significant cohort effect with increased incidence for those born between 1912–1916 (Coefficient: 0.32, CI: 0.17–0.46), 1927–1931 (Coefficient: 0.43, CI: 0.24–0.62) and 1932–1936 (Coefficient: 0.35, CI: 0.21–0.49).
Discussion and conclusion: Our analysis shows a significant cohort effect on incidence in this population. Further research will be necessary to explore the potential cause of this trend. Possible explanations may be excess exposure to some environmental risk factor in early life, or some unknown workplace hazard.
Conclusion: Through the use of PLSR modelling it is possible to analyse age-period-cohort effects simultaneously and estimate their relative impact on ALS incidence over time (Citation3). These results can be used in planning future studies on the cause of ALS.
References:
- Sejvar JJ. et al. Neuroepidemiology 2005; 25(3):144–152.
- Fang F. et al. Arch Neurol. 2009; 66(4):515–519
- Tu Y-K, Davey Smith G, Gilthorpe MS. PLoS ONE 2011;6(4).
P145 AGGREGATION OF NEUROPSYCHIATRIC DISEASE IN AMYOTROPHIC LATERAL SCLEROSIS KINDREDS: EVIDENCE OF CLUSTERING WITHIN FAMILIES.
O’Brien M1,2
Heverin M2
Byrne S2
Elamin M1,2
Hardiman O1,2
atDepartment of Neurology, Beaumont Hospital, Beaumont, Dublin, Ireland
auAcademic Neurology Unit, Trinity College Dublin, Dublin, Ireland
Email address for correspondence: [email protected]
Keywords: neuropsychiatry, C9ORF72, genetics
Background: Amyotrophic lateral sclerosis (ALS) is known to be associated with frontotemporal dementia in 14% of cases. A wider spectrum of neurodegenerative and neuropsychiatric disease is increasingly recognized in association with ALS (Citation1).
Aim: To determine whether psychiatric conditions occur with greater frequency within individual ALS kindreds.
Methods: Data from a previously published family history study was interrogated. The study also included a further 138 ALS patients diagnosed from 2012, with age and gender matched controls. Kindreds from ALS patients and controls in which at least one first degree relative was reported to have a neuropsychiatric illness were identified.
Results: Extensive family histories from 302 ALS patients, encompassing 5838 first or second degree relatives, and 221 controls encompassing 5950 first/second degree relatives were included. 119 (36%) of ALS kindreds and 51 (23%) of control kindreds had at least one first or second degree relatives with a history of schizophrenia, psychosis, suicide, depression, alcoholism or autism (p < 0.005). 12.6% (38) of ALS kindreds and 5.4% (12) of control kindreds had 3 or more family members with neuropsychiatric illness (p < 0.004). Conditions that were over-represented in the ALS kindreds included schizophrenia (n = 24, p = 0.01), suicide (n = 30, p = 0.001), autism (n = 12, p = 0.02). No differences in size of kindred/number of first vs second degree relatives was observed between ALS and control families.
C9ORF72 repeat expansion data was available for 186 (62%) ALS patients. 13% of ALS patients with a family history of neuropsychiatric disease had the C9ORF72 repeat expansion.
Conclusion: Aggregation of neuropsychiatric disease within ALS kindreds is driven by over-representation in individual kindreds. While the C9ORF72 repeat expansion accounts for a proportion of these kindreds, additional families negative for the C9ORF72 repeat expansion also exhibit a strong neuropsychiatric signal suggesting the presence of at least one addition gene associated with both ALS and neuropsychiatric disease in the Irish population.
Reference:
- Byrne et al. Ann Neurol. 2013; 74: 699–708.
P146 CLUSTER ANALYSIS OF ALS RISK IN IRELAND
Rooney J1
Heverin M1
Vajda A1
Crampsie A2
Tobin K1
Byrne S1
Mclaughlin R1
Staines A3
Hardiman O1,4
avTrinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
awSchool of Geography, Planning and Environmental Policy, University College Dublin, Dublin, Ireland
axSchool of Nursing and Human Sciences, Dublin City University, Dublin, Ireland
ayBeaumont Hospital, Dublin, Ireland
Email address for correspondence: [email protected]
Keywords: Spatial epidemiology, cluster analysis, relative risk
Background: We have recently conducted a Bayesian spatial risk analysis of prospectively gathered data of incident cases over a 17.5-year period (Citation1).
Objectives: To perform formal cluster analysis of the Irish ALS population based Register.
Methods: 1,693 cases of ALS in Ireland from January 1995 to December 2013 were identified from the Irish ALS register. Census data were used to calculate an average population for the period and standardized incidence rates (SIRs) were calculated for 3,355 areas based on Electoral Divisions. Bayesian conditional auto-regression was applied to produce smoothed relative risks (RR). SaTScan was run using a Poisson probability based discrete scan statistic to detect clusters of statistically high risk, and SaTScan to identify areas of low risk.
Results: Smoothed maps revealed no overall geographical pattern to ALS incidence in Ireland, although several areas of localized increased risk were identified, and two larger areas, in Clare and Kilkenny, showed lower RR. Formal cluster analysis confirmed these two low risk areas as statistically significant clusters: Clare (Observed: 0 Expected: 13.5, RR = 0.0, P = 0.025); Kilkenny (Observed: 57 Expected: 105, RR = 0.53, P = 0.015). None of the areas identified by Bayesian smoothing to have localized high risk were identified as significant high-risk clusters using current methodology.
Discussion and conclusion: The absence of significant high-risk clusters in the republic of Ireland contrasts previous findings of significant high-risk clusters by others (2, 3, 4). The finding of statistically significant low risk areas has not been previously reported for ALS in European countries. We postulate that historical differences in local genetic admixture may account for these findings. Further studies are underway to investigate possible associations between ALS risk and genetic epidemiology.
Acknowledgements: We acknowledge Neil McCluskey, NCRI, and the National Cancer Registry of Ireland for their expertise and the use of modified OSI shapefiles generated for the All Ireland Cancer Atlas. We would also like to acknowledge Ordnance Survey Ireland for granting us copyright to reproduce OSI shapefiles (Permit No. MP 0008613).
References:
- Rooney J. et al. PLoS One 2014 May 27; 9(5):e9655.
- Turabelidze G. et al. Neurotoxicology 2008 Jan; 29(1): 81–6.
- Scott KM. et al. Neuroepidemiology 2009 Jan; 32(2): 81–8.
- Caller T. et al. ALS. 2009 Jan; 10 Suppl 2(June):101–8.
P147 ATXN2POLYQ INTERMEDIATE REPEAT IS A MODIFIER OF ALS PHENOTYPE IN A POPULATION BASED STUDY
Calvo A1,2
Moglia C1
Canosa A1,9
Brunetti M3
Barberis M3
Restagno G3
Conte A4
Bisogni G4
Marangi G5
Moncada A5
Lattante S5
Zollino M5
Sabatelli M4
Bagarotti A6
Corrado L6
Mora G7
Bersano E8
Mazzini L8
D’Alfonso S6
Chiò A1,2
azALS Center, ‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Torino, Italy
baAzienda Ospedaliero Universitaria Città della Salute e della Scienza, Torino, Italy
bbLaboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy
bcNeurological Institute, Catholic University of the Sacred Heart, Roma, Italy
bdInstitute of Medical Genetics, Catholic University of the Sacred Heart, Roma, Italy
beDepartment of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), ‘Amedeo Avogadro’ University of Eastern Piedmont, Novara, Italy
bfSalvatore Maugeri Foundation, IRCSS; Scientific Institute of Milano, Milano, Italy
bgDepartment of Neurology, ‘Amedeo Avogadro’ University of Eastern Piedmont and Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy
bhUniversity of Genova, Genova, Italy
Email address for correspondence: [email protected]
Keywords: ataxin 2(ATXN2), phenotype, population-based study
Background: An intermediate-length (CAG) expansion (encoding 27–33 glutamines, polyQ) in ataxin 2 (ATXN2) gene, already known as the cause of spinocerebellar ataxia type 2 (SCA2), has been found to be related to an increased risk of developing ALS. The clinical characteristics of patients with this expansion remain poorly investigated.
Objectives: The aim of this study was to analyze the frequency of intermediate polyQ expansion in the ATXN2 gene in a population-based cohort of Italian patients (discovery cohort), with an in-depth assessment of their clinical and prognostic characteristics, and to replicate the findings in an independent cohort of consecutive patients from an ALS tertiary center (validation cohort). We assessed survival of patients with ATXN2 polyQ expansion compared with patients with normal length expansion.
Methods: PolyQ expansions were assessed in 672 patients incident in Piemonte and Valle d’Aosta regions, Italy, during the 6-year period from 2007 to 2012 (discovery cohort); controls were 509 neurologically healthy subjects, resident in the study area, age- and gender-matched to cases. The validation cohort includes 661 patients consecutively admitted between 2001and 2013 in the ALS Clinic Centre of the Catholic University in Rome, Italy. Diagnostic criteria were identical to those of the discovery cohort. Genomic DNA was isolated from peripheral blood lymphocytes using a standard protocol. The ATXN-2 CAG repeat in exon 1 was amplified using a fluorescent primer and sized by capillary electrophoresis on an ABI 3130 genetic analyzer. We considered as cut-off a repeat size ≥ 31. All ALS cases of both cohorts were also tested for SOD1, TARDBP, FUS, ANG and C9ORF72. Familial ALS patients were also tested for OPTN.
Results: In the discovery cohort the frequency of ≥ 31 polyQ ATNX2 repeats was significantly more common in ALS cases (19 patients vs. 1 control, p = 0.0001; odds ratio 14.8, 95% confidence interval, 1.9–110.8). Patients with an increased number of polyQ repeats have a shorter survival than those with < 31 repeats (median survival, polyQ ≥ 31, 1.8 years, interquartile range (IQR) 1.3–2.2; polyQ < 31, 2.7 years, IQR 1.6–5.1) (p = 0.001). An increased number of polyQ repeats remained independently significant also in multivariable analysis. In the validation cohort, patients with ≥ 31polyQ repeats have a shorter survival than those with < 31 repeats (median survival, polyQ ≥ 31, 2.0 years, IQR 1.5–3.4; polyQ < 31, 3.2 years, IQR 2.0–6.4; p = 0.007).
Conclusions: We have found that an ATXN2 intermediate polyQ repeat is a significant risk factor for ALS; it is correlated to a spinal phenotype and is associated to a shorter survival. Disease-modifying therapies targeted to ATXN2 represent a promising therapeutic approach for a devastating disease such as ALS; possible strategies may be the use of antisense oligonucleotides, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeats.
P148 PROGNOSTIC FACTORS FOR ALS IN PATIENTS FROM EMILIA ROMAGNA, ITALY: A POPULATION BASED STUDY
Mandrioli J1
Georgoulopoulou E1
Fini N1
Biguzzi S2
Sette E3
Salvi F4
Pietrini V5
Guidi C6
Terlizzi E7
Rizzi R8
Casmiro M9
Liguori R10
Ravasio A11
D’Alessandro R12
biDepartment of Neuroscience, St. Agostino-Estense Hospital, MODENA, Italy
bjDepartment of Neurology, Bufalini Hospital, CESENA, Italy
bkDepartment of Neurology, St. Anna Hospital, FERRARA, Italy
blDepartment of Neurology and IRCCS Istituto delle Scienze Neurologiche di Bologna, BOLOGNA, Italy
bmDepartment of Neuroscience, University of Parma, PARMA, Italy
bnDepartment of Neurology, Forlì Hospital, FORLI’, Italy
boDepartment of Neurology, G. Da Saliceto Hospital, PIACENZA, Italy
bpDepartment of Neurology, IRCCS Arcispedale Santa Maria Nuova, REGGIO EMILIA, Italy
bqDepartment of Neurology, Faenza and Ravenna Hospital, RAVENNA, Italy
brDepartment of Biomedical and Neuromotor Sciences, and IRCCS Istituto delle Scienze Neurologiche di Bologna, BOLOGNA, Italy
bsDepartment of Neurology, Infermi Hospital, RIMINI, Italy
btNeuroepidemiology Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, BOLOGNA, Italy
Email address for correspondence: [email protected]
Keywords: population based registry, survival, prognostic factors
Background: Although the mean survival of ALS patients from symptom onset is often reported to be 3–5 years, published studies report a wide range of outcomes, that narrows when considering population based studies (median survival from onset to death: 20–36 months).We performed a population-based study focusing on ALS survival and possible prognostic factors.
Methods: From 2009 onwards, a prospective registry, involving 9 provinces, 11 local health units, and 17 neurological departments, has been collecting all cases of incident ALS among residents in Emilia Romagna region (population 4.4 million inhabitants). For each patient, the main demographic and clinical information were collected by the caring physicians and input in a dedicated website at diagnosis. In addition a further case report form has been completed during each patient follow up. Clinical characteristics, services access, accepted procedures, and date of tracheostomy and death have been included in the follow up case report form.
Results: From 1.1.2009 to 31.12.2013 in Emilia Romagna 566 patients (M: F = 1.2) received a new diagnosis of ALS. Mean age at onset was 66.4 years. Median overall tracheostomy-free survival from onset was 50 months, 37 months from diagnosis. Based on univariate analysis, factors related to survival were: age at onset, site of onset, diagnostic delay, degree of diagnostic certainty according to El Escorial Revised Criteria (EEC-R), and dementia. In the Cox-multivariable model, the factors independently related to a longer survival were age at onset (HR 1.3, p < 0.01), dementia (HR 1.4, p < 0.01), respiratory onset (HR 2.4, p = 0.01), definite ALS at diagnosis according to EEC-R (HR 1.9, p < 0.01), clinically probable ALS at diagnosis according to EEC-R (HR 1.5, p < 0.01).
Discussion and conclusions: This population based study confirms the well-known prognostic role of clinical features, such as age at onset, respiratory onset, and dementia together with the degree of certainty of diagnosis (the more certain, the worse disease course). Procedures did not result in disease prolongation, possibly in relation to the greater disease severity in patients requiring respiratory or nutritional support. These confirmatory findings provide evidence that population-based studies are the most reliable settings for epidemiological and clinical studies on ALS.
P149 EPIDEMIOLOGY OF AMYOTROPHIC LATERAL SCLEROSIS IN ISRAEL (1997–2013)
Weil C1
Shalev V1,2
Herzel E1
Chodick G1,2
buMaccabi Healthcare Services, Tel Aviv, Israel
bvSackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Email address for correspondence: [email protected]
Keywords: prevalence, incidence, survival
Background: Globally, the incidence and prevalence of amyotrophic lateral sclerosis (ALS, or motor neurone disease) are estimated at 1.9 and 4.5 per 100,000 population, respectively (Citation1). There is a need for real-world data on the epidemiology of ALS/MND in Israel.
Objectives: We aimed to determine the prevalence and incidence of ALS/MND in a large Israeli health maintenance organization, and to describe patient characteristics and survival.
Methods: The study was conducted using the computerized databases of Maccabi Healthcare Services, which include up to 20 years of data on 2 million members (25% of the Israeli population). Patients with ALS were identified by diagnosis code (ICD-9 335.2) from a GP or relevant specialist. Prevalence and incidence rates were adjusted to the age distribution of the WHO standard population. Kaplan-Meyer analysis was used to assess patient survival during the period 1997–2013. Demographic and clinical characteristics of prevalent patients (2013) were compared to a control group of ALS-free MHS members matched (1:5) on age (± 5 y) and sex.
Results: Between 1997 and 2013, a total of 456 MHS members were diagnosed with ALS, corresponding to an age-adjusted incidence rate (per 100,000) of 1.7 (95% CI: 1.6–1.8). In 2013 (n = 226), the age-adjusted prevalence rate (per 100,000) was 10.9 (95% CI: 9.5–12.5). The mean age was 58.1 ± 17.5 (59% male). Compared to the control group (n = 1130), patients with ALS had a lower proportion of chronic conditions, such as overweight (26.1% vs.34.0%; p = 0.024), diabetes (12.4 vs. 18.0%; p = 0.042) and CKD (11.9 vs. 17.0%, p = 0.060). During the total follow-up period, 224 (49.0%) of patients with ALS died; the median survival time was 4.6 years (95% CI: 3.3–5.9 y). Approximately 40% of patients survived for at least 8 years after diagnosis and more that 20% survived beyond 10 years.
Discussion and conclusion: The results of this large population-based study indicate that the prevalence of ALS in Israel is relatively high, while the incidence rate is similar to previous international reports (Citation1). One explanation may be relatively higher survival rates for patients with ALS in Israel compared to Western countries. In line with previous studies, the present study suggests that patients with ALS may have a lower prevalence of chronic comorbidities than the general population (Citation2–3).
Conclusion: Based on the present study, there were at least 750 patients living with ALS in Israel at the end of 2013. Further research is needed to investigate factors that may contribute to the survival of patients with ALS in Israel.
References:
- Chio A. et al. Neuroepidemiology 2013; 41:118–130.
- Komer S. et al. Eur J Neurol. 2013; 0(4):647–54.
- Lekoubou A. et al. BMC Res Notes. 2014; 7:171.
P150 THE LONG SAGA OF A VCP GENE MUTATION IN A LARGE FAMILY
Blumen S1,2
Gonzales-Perez P3
Drory V4,5
Brown JRR3
bwHillel Yaffe Medical Center, Hadera, Israel
bxRappaport Faculty of Medicine, the Technion, Haifa, Israel
byUniversity of Massachusetts, Worcester, MA, USA
bzTel-Aviv Sourasky Medical Center, Tel Aviv, Israel
caTel Aviv University, Tel Aviv, Israel
Email address for correspondence: [email protected]
Keywords: valosin-containing protein (VCP), myopathy, bulbar
Background: Mutations in the valosin-containing protein (VCP) gene may produce autosomal dominant inclusion body myopathy (IBM), Paget disease of the bone, frontotemporal dementia and familial ALS in different combinations (Citation1).
Objectives: To present the long term follow-up of a large, three generation family with “pseudo-myopathic” ALS and the diagnostic challenges preceding the final identification of a novel, causative, VCP mutation (Citation2).
Family Study: We followed for 13 years a large Arab - Israeli family in which seven members, in three generations, presented sequentially with a complex, slowly progressive neurological phenotype. Since adolescence affected individuals had insidious onset of nasal voice. However, at presentation, at the age of 38, most features in the index patient and his siblings suggested primary muscle involvement: hyperlordosis, proximal weakness, involvement of thoracic paraspinal muscles and moderately elevated CPK. Motor and sensory nerve conduction studies were normal and EMG displayed both neuropathic and myopathic features. At that stage a quadriceps muscle biopsy was not conclusive. Only four years later, proximal and distal muscle wasting with fasciculations, new bulbar symptoms (mild dysphagia) and pyramidal signs in four limbs suggested motor neuron disease. Pompe disease, hexosaminidase A deficiency and SOD1 mutations were excluded. After more than seven years from presentation four brothers (from the second generation) required wheelchairs and, one up to three years later, three among them required respiratory assistance. The index patient is alive on a respirator at 13 years since presentation while two of his brothers died at eight and ten years from presentation. Two patients developed also Parkinsonian features. Cognition and affect were normal in all. The final diagnosis of a point mutation (p.R191G) in the VCP gene was possible only with genetic linkage analysis and whole exome sequencing in two affected brothers (Citation2).
Discussion and conclusion: The long term follow-up of this large family exemplifies the difficulties in discriminating between primary muscle and motor neuron diseases in certain, complex, ALS phenotypes. It also shows that early bulbar features do not always predict a rapidly progressive disease. Finally, our experience stresses the importance of whole exome sequencing as an invaluable diagnostic tool for unusual phenotypes in large families.
References:
- Johnson JO. et al. Neuron 2010; 68(5):857–64.
- Gonzalez-Perez P. et al. Neurology 2012; 79:2201–2208.
P151 THE GERMAN PRE-SYMPTOMATIC ALS RISK-CARRIER STUDY (GPS-ALS) 2014
Weydt P
Madinger M
Knehr A
Böhm S
Görges M
Kassubek J
Weishaupt JH
Ludolph AC
Ulm University, Ulm, Germany
Email address for correspondence: [email protected]
Keywords: presymptomatic, familial ALS, gene carrier
Background: Recent advances in the understanding of genetic factors underlying familial and sporadic ALS creates important new challenges and opportunities for both the patient community and the clinical and basic researchers. Through genetic testing of symptomatic ALS patients with and without a family history of the disease, first degree relatives can be identified that hold a 50% risk of carrying an ALS-causing gene. Clinical characterization of these presymptomatic risk- carriers offers the possibility to study the earliest, subclinical phases of the disease and thus identifying biomarkers and critical therapeutic intervention points.
Methods: ALS-gene risk carriers are recruited from first degree relatives of ALS patients with known gene mutations (C9ORF72, SOD1, FUS, TDP-43 and others). Regardless of the actual gene status the risk carriers are offered a panel of annual exams consisting of a clinical exam, tissue collection (blood, CSF and others), imaging studies, metabolic test and cognitive exams. The participants and the examiners are blinded to the gene status. Non-mutation carriers serve as internal controls. Genetic counselling is offered to interested parties. A structured phone interview 1 week after the enrolment is used to assess psychosocial effects of the study participation.
Results: > 30 participants have been enrolled. As expected, C9ORF72 and SOD1 are the most common ALS associated mutations in our cohort. Acceptance of the individual test was high (> 90%), except lumbar puncture (> 50%). The data and biosamples are being made available to researchers looking for wet and dry biomarkers.
Discussion and conclusion: This ongoing study offers the opportunity to investigate the early, presymptomatic (prodromal) phase of ALS while at the same time empowering the growing community of people aware of their risk of developing ALS to participate in the quest for a cure.
P152 THE EPIDEMIOLOGY AND TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS IN CANADA: NEW INSIGHTS FROM THE CANADIAN NEUROMUSCULAR DISEASE REGISTRY
Hegedus J1
Korngut L1,2
Zinman L2,3
Johnston M1,2
Benstead T2,4
Briemberg H2,5
Dupré N2,6
Genge A2,7
Grant I2,4
Hader W2,8
Johnston W2,9
Kalra S2,9
Massie R2,7
Melanson M2,10
O’Connell C2,11
Schellenberg K2,12
Shoesmith C2,13
Wee J2,10
Worley S2,10
cbCalgary ALS and Motor Neuron Disease Clinic, South Health Campus, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
ccCanadian Neuromuscular Disease Registry Investigator Network, Calgary, Canada
cdALS Clinic, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
ceDivision of Neurology, Dalhousie University, Halifax, Nova Scotia, Canada
cfDivision of Neurology, University of British Columbia, Vancouver, British Columbia, Canada
cgDepartment of Neurological Science CHA-Enfant-Jésus, Laval University, Quebec City, Quebec, Canada
chALS Program, Montreal Neurological Institute, Montreal, Quebec, Canada
ciDepartment of Physical Medicine and Rehabilitation, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
cjDivision of Neurology, University of Alberta, Edmonton, Alberta, Canada
ckDepartments of Medicine and Physical Medicine and Rehabilitation, Queen's University, Kingston, Ontario, Canada
clStan Cassidy Centre for Rehabilitation, Fredericton, New Brunswick, Canada
cmSection of Neurology, University of Manitoba, Winnipeg, Manitoba, Canada
cnClinical Neurological Sciences, Western University, London, Ontario, Canada
Email address for correspondence: [email protected]
Keywords: registry, epidemiology, Canada
Background: The Canadian Neuromuscular Disease Registry (CNDR) was launched in 2011 with the primary goal of improving access to and facilitating enrolment in clinical trials. The secondary goal was to improve our understanding of the epidemiology of neuromuscular diseases across Canada, as well as to determine regional differences in diagnosis and treatment.
Objectives: The aim of the present study was to perform a descriptive statistical analysis of the amyotrophic lateral sclerosis (ALS) population registered in the CNDR as of April 2014.
Methods: Patients with ALS were recruited into the registry through adult ALS clinics or by self-registration through the CNDR National Office. Data collection at routine visits has been outlined previously (Citation1). For the present study, data from all captured ALS clinic visits for registered ALS patients was accessed. We reviewed data on 358 patients.
Results: The mean age of the study population was 63.5(+/+ 12.2) years. The majority of patients were male (61%) and 88% of patients were from urban locations. In our population the site of disease onset was limb-onset in 69% (199/288) of patients, bulbar-onset in 20% (58/288) and the remaining patients had either cognitive onset (0.3%), respiratory (0.6%), mixed onset (8%) or unknown onset (2%). The average percent predicted forced vital capacity (% FVC) at the last clinic visit was 73.8% (standard deviation +/+ 25.4). Average ALSFRS-R score at enrolment was 26 (SD +/+ 10). We found that 93% of the patients were registered with the Canadian ALS society. Data was available on 311 patients with respect to riluzole use revealing that 209 (67%) were currently taking riluzole whereas 8% reported previous use, 5% declined use and 2% were unknown regarding their riluzole status. There was regional variability with riluzole use, with 21 patients out of 54 (39%) in the Province of Alberta actively using riluzole as compared to 163 patients in the Province of Ontario using riluzole out of 220 (74%). Across the country 47 of 311 patients (15%) were actively involved in a clinical trial, with 15 (5%) having been past clinical trial participants. Only 11% of the ALS patients had personal directives (19 women and 22 men).
Discussion and conclusion: Information regarding 358 patients across Canada was collected and presented in this study in order to provide the first nation-wide epidemiological survey of ALS.
Acknowledgements: This abstract was compiled on behalf of the CNDR Investigator Network.
Reference:
- Korngut L. et al. Can J Neurol Sci 2013. 40: 698–704.
P153 PREVALENCE OF AMYOTROPHIC LATERAL SCLEROSIS (ALS) IN THE UNITED STATES, OCTOBER 19, 2010 – DECEMBER 31, 2011
Mehta P
Horton K
Antao V
ATSDR/CDC, Atlanta, GA, USA
Email address for correspondence: [email protected]
Keywords: prevalence, United States, demographics
Background: In October 2010, the federal Agency for Toxic Substances and Disease Registry (ATSDR) launched the congressionally-mandated National ALS Registry to collect and analyze data regarding persons with ALS (PALS) in the United States. ALS, also known as Lou Gehrig's disease, is a progressive neuromuscular disease that usually leads to death within 2–5 years of diagnosis. The initial symptoms of ALS vary and may include muscle weakness in upper or lower extremities along with difficulty speaking, walking, and fatigue and eventual death. The main goals of the Registry are to determine the incidence and prevalence of ALS within the United States, characterize the demographics of those living with ALS, and identify the potential risk factors for the disease.
Objective: To summarize the prevalence of persons with ALS in the United States from October 19, 2010 – December 31, 2011.
Methods: As ALS is not a reportable disease in the United States, the National ALS Registry uses a two-pronged approach to help identify all cases of ALS in the country. The first approach utilizes existing national administrative databases (Medicare, Medicaid, Veterans Health Administration (VHA) and Veterans Benefits Administration (VBA)) to identify prevalent cases. The second method uses a secure web portal to identify cases not included in the national administrative databases. PALS who register via the web portal have the opportunity to complete surveys that may lead to a better understanding of the potential risk factors for ALS (eg, genetics, environmental and occupational influences).
Results: Findings from the National ALS Registry's first report will be presented at the ALS/MND International Symposium in Brussels, December 2014. Descriptive statistics on the prevalence rates of ALS in the US, along with demographics of cases and survey completion rates will be presented.
Conclusion: This report summarizes the prevalence of ALS from PALS from October 19, 2010 – December 31, 2011. This is the first ever effort to identify ALS cases on a national population basis in the United States. The preliminary surveillance results capture ALS prevalence but do not reflect all incident cases, since the ALS diagnosis date was not captured via the national administrative data sets. The establishment of the National ALS Registry will allow for analysis of prevalence of this disease as well as assess potential risk factors that may cause ALS.
P154 AMYOTROPHIC LATERAL SCLEROSIS (ALS) RE-ADMISSIONS AT CAROLINAS HEALTHCARE SYSTEM - HIGHER THAN STROKE RE-ADMISSIONS
Brooks BR1,4
Nichols MS1
Lindblom SS3,4
Pacicco TJ3,4
Bockenek WL2,4
Sanjak MS1,5
Ward AL1,6
Lucas NM1
Smith NP1
Belcher SL1
Lary C1
Nemeth J1
Russo PC1
Bravver EK1,4
Desai UG1,4
Story JS1,4
Holsten SE1
Fischer MP1
Langford VL1
Wright KA1
coCarolinas Neuromuscular/ALS-MDA Center - Carolinas Medical Center - Department of Neurology – Carolinas Healthcare System Neurosciences Institute, Charlotte, North Carolina, USA
cpDepartment of Physical Medicine and Rehabilitation - Carolinas Rehabilitation, Charlotte, North Carolina, USA
cqDepartment of Internal Medicine - Carolinas Medical Center, Charlotte, North Carolina, USA
crUniversity of North Carolina School of Medicine – Charlotte Campus, Charlotte, North Carolina, USA
csDepartment of Kinesiology, University of North Carolina - Charlotte, Charlotte, North Carolina, USA
ctCabbarus College of Health Sciences - Occupational Therapy, Concord, North Carolina, USA
Email address for correspondence: [email protected]
Keywords: hospital admissions, in-patient mortality, medical co-morbidities
Objective: To compare ALS re-admissions prevalence with stroke re-admissions.
Methods: 622 home-visit ALS patients (48% M; 52% F) were monitored prospectively compared with 834 stroke patients.
Results: ALS re-admissions were 17.7% (12.0–24.5%/month) annually greater than Stroke re-admissions-7.4% (1.9–11.9%/month; Chi-Square = 4.4209; p = 0.04). Pneumonias (7%) were more common in ALS re-admissions (Chi-Square = 4.6875; p = 0.03). Re-admission for falls was similar in both ALS (5%) and stroke (2%) patients. Respiratory re-admissions were significantly more common in ALS (28%) than stroke (2%) patients (Chi-Square = 29.4011; p < 0.01) as seen previously (Citation1). Cerebrovascular events occurred in 40.3% of the stroke re-admissions while none occurred in ALS re-admissions. Death during hospitalization occurred in 29.3% of ALS re-admissions (5.2% of all ALS home-visit patients) compared with 11.3% of stroke re-admissions (0.8% of all stroke patients; Chi-Square = 12.5; p < 0.01).
Conclusion: ALS patients followed in the home care setting constitute a source of significant re-admissions to an acute hospital setting (Citation2). Comparing two cohorts of comparable size identified differences in types of problems leading to re-admission and will provide a framework for planning interventions to decrease these re-admissions.
Acknowledgements: Study Supported by: Carolinas ALS Research Fund, Carolinas Healthcare Foundation.
References:
- Lechtzin N. et al. Neurology. 2001 Mar 27; 56(6):753–7.
- Canadian Institute for Health Information (Ottawa, CIHI, 2007).
P155 BLOOD LEVELS OF TRACE METALS AND AMYOTROPHIC LATERAL SCLEROSIS (ALS) IN US MILITARY VETERANS
Peters TL1,2
Beard JD1,3
Umbach DM4
Allen K5,6
Keller J7
Mariosa D2
Sandler DP1
Schmidt S8
Fang F2
Ye W2
Kamel F1
cuEpidemiology Branch, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC, USA
cvDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
cwDepartment of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
cxBiostatistics Branch, National Institute of Environmental Health Sciences, NIH, DHHS, Research Triangle Park, NC, USA
cyEpidemiology Research and Information Center, Durham VA Medical Center, Durham, NC, USA
czDepartment of Medicine and Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC, USA
daWestat Inc., Durham, NC, USA
dbDepartment of Medicine, Duke University Medical Center, Durham, NC, USA
Email address for correspondence: [email protected]
Keywords: metals, case control, epidemiology
Background: Past studies have reported higher concentrations of trace metals such as selenium (Se), zinc (Zn), copper (Cu) and manganese (Mn) in ALS cases compared to controls. Deficiencies of trace metals might also affect ALS risk, but only Zn deficiency has been studied.
Objectives: To examine associations of trace metals (Se, Zn, Cu and Mn) with ALS risk and to evaluate whether these associations differed by site of disease onset (bulbar or spinal).
Methods: We conducted a case-control study of 139 medical record-confirmed cases recruited in 2007 from the US Department of Veterans Affairs (VA) National Registry of Veterans with ALS and 229 veteran controls frequency matched to cases on age and use of VA medical care. Whole blood samples were collected in trace metal-free tubes; metals were measured using inductively coupled plasma mass spectrometry. Associations between metals and ALS risk were evaluated using unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) after adjustment for age, gender, and race/ethnicity.
Results: Blood metal levels in controls were comparable to those observed in other populations. Associations of ALS risk with Se and Zn were inverse; comparing the highest to the lowest 20%, the OR (95% CI) for Se was 0.4 (0.2–0.8, Ptrend = 0.02) and that for Zn was 0.6 (0.3–1.2, Ptrend = 0.03). Cu was associated with increased ALS risk (OR 2.5, 1.2–4.9, Ptrend = 0.01) as was Mn, but the strongest association for the latter was with the middle 20% (OR 2.3, 1.2–4.6) and there was no linear trend (Ptrend = 0.79). Additional adjustment for smoking did not change associations. Adjustment for lead attenuated the positive association with Cu (OR 1.9, 0.9–3.9, Ptrend = 0.13) but did not change associations with other metals. Both positive and inverse associations were stronger in individuals with bulbar compared to spinal onset.
Discussion and conclusion: Our study shows that higher levels of Zn and Se within the normal range are associated with decreased ALS risk after adjusting for other known risk factors. In contrast, higher levels of Cu are associated with increased ALS risk, consistent with past literature, but this relationship may be explained partly by lead. Most previous literature has focused on increased ALS risk associated with higher levels of Se and Zn. However, although we cannot exclude reverse causality, it is possible that deficiencies of these metals are also associated with ALS risk.
Acknowledgements: This work was supported in part by the Intramural Research Program of NIH/NIEHS (Z01-ES-049005) and by grants from NIH/NIEHS (R01-ES-013244) the Karolinska Institutet, and NIOSH (T42OH00867302). The National Registry of Veterans with ALS was supported by the VA (CSP #500A).
P156 SOD1 GENE MUTATIONS IN ALS PATIENTS TURKISH POPULATION
Idrisoglu HA
Polat N
Idrisoglu M
Medical Faculty, Istanbul, Turkey
Email address for correspondence: [email protected]
Keywords: Turkish population, SOD1
Background: Amyotrophic lateral sclerosis (ALS) is a fatal late onset neurological disorder characterized by motor neuron degeneration in the primary motor cortex, brainstem and spinal cord. The majority of cases are sporadic and only 5–10% have a family history. Familial ALS cases show a high heritability and this has enabled the identification of several genetic triggers, of which mutations in SOD1, FUS, TARDBP and C9ORF72 are the most frequent.
Methods: We have searched for the SOD1 gene mutation in 770 ALS patients. 700 of 770 patients were sporadic and the others were familial ALS (30 families).
Results: The SOD1 gene mutation was not detected in any family. The SOD1 gene mutation was detected in 0.5% of patients who came to the clinic with sporadic ALS. The family research of 2 patients with SOD1 gene mutation was present without the clinical and electrophysiological findings in the family members. SOD1 gene mutations were negative in our laboratory, but were positive in another laboratory in one ALS patient.
Conclusions: We observed that in both sporadic and familial ALS patients the D90A SOD1 mutation was not causative for ALS pathogenesis in the Turkish population.
The SOD1 gene mutation was found in 0.7% of 700 patients in both familial ALS and sporadic ALS cases. We also observed good progression in the patient with SOD1 gene mutation. There was no SOD1 mutation in any of the patients with familial ALS.
- Leblond CS. et al. Exp Neurol. 2014 apr 26.pii:S0014–4886(14)00115–0.
- Orrell RW. Neuromuscul disord. 2000 Jan; 10(1):63–8.
P157 NATURAL HISTORY AND CLINICAL FEATURES OF SPORADIC AMYOTROPHIC LATERAL SCLEROSIS IN CHINA: A TEN-YEAR CLINIC-BASED COHORT STUDY
Chen L
Zhang B
Tang L
Ye S
Liu X
Ma Y
Zhang H
Fan D
Peking University Third Hospital, Beijing, China
Email address for correspondence: [email protected]
Keywords: natural history, clinical features, prognostic predictors
Background: ALS is a fatal neurodegenerative disorder. The characteristics of Chinese ALS patients have not been studied yet. In this clinic-based cohort study, we aimed to provide data on natural history, clinical features and prognostic predictors of ALS in China.
Methods: Between January, 2003 and December, 2012, all patients with a diagnosis of ALS referred to and assessed at PUTH were screened with a follow-up every three months by telephone. Baseline demographic details and clinical data were collected from the patient's first visit to PUTH and follow-up visits. Survival and tracheotomy were predefined primary outcome measures. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Survival was calculated using a Kaplan-Meier analysis, survival rate was calculated using a life table analysis and predictors were identified in a Cox regression model.
Results: In the 1624 recruited cases, 1220 (75.1%) were limb-onset ALS, 227 (14.0%) bulbar-onset ALS, 126 (7.8%) FAS, 43 (2.6%) PMA and others (8 cases, 0.5%) . The overall M: F ratio was 1.7:1 and the mean age of symptom onset was 49.8 years. The overall median diagnostic delay time from symptom onset was 14.0 months (Range, 0–228). Median survival from symptom onset as determined by Kaplan-Meier analysis was 71 months. The mean onset age, sex ratio, BMI, diagnostic delay time and the median survival time were different between phenotypes. The percentage of smokers was different between phenotypes (p = 0.013). The mean onset age, the percentage of each phenotype and the median survival time were different between male and female. There were more male patients who had the history of long-time smoking, alcohol abuse, drinking tea frequently or always eating aginomoto or had contact history of harmful gas than female patients. Survival of patients was associated with sex, age of symptom onset, BMI, diagnostic delay time, phenotype of the disease, Airlie House category at presentation, residence, use of traditional Chinese medicine and contact history of pesticides.
Conclusion: Our prospective cohort study provides important information of Chinese ALS patients based on the data from mainland China for the first time, which will be helpful for neurologists in patient counselling and designing of future clinical research studies.
References:
- Das M, Patil S, Bhargava, et al. Biomaterials, 2007; 28:1918–25.
- Bhargava N, Das M, Karakoti AS, et al. J Nanoneurosci, 2009;1:130–43.