THEME 5 IMPROVING DIAGNOSIS, PROGNOSIS AND DISEASE PROGRESSION

P105 PROGNOSTIC FACTORS FOR SURVIVAL IN AMYOTROPHIC LATERAL SCLEROSIS PATIENTS IN SERBIAN POPULATIONP

Stevic Z¹

Kostic-Dedic S¹

Rakocevic-Stojanovic V²

Basta I¹

Dedic V¹

Lavrnic D³

^aClinic of Neurology, Belgrade, Serbia

^bDepartment of Neurology, CHC Zvezdara, Belgrade, Serbia

^cEuropean Centre for Peace and Development, Belgrade, Serbia

Email address for correspondence: [email protected]

Keywords: amyotrophic lateral sclerosis, survival analysis, prognostic factors

Background: A variety of prognostic factors have been associated with a shorter survival including older age at onset, female sex, bulbar onset, and short time elapsed from first symptoms to diagnosis. Accurate information about prognosis of ALS is useful to patients, families, and clinicians.

Objectives: The aim of the study was to determine the survival and prognostic factors of ALS patients in Belgrade district (Serbia), over a period of 17 years (1992–2009).

Methods: A retrospective analysis has been carried out on all ALS patients collected by analyzing hospital in- and outpatient registers at the Clinic of Neurology, Clinical Center of Belgrade and in other three clinical centers in Belgrade from January 1992 to December 2009. The diagnosis of probable or definite ALS was based on the El-Escorial revised criteria. Demographic and clinical data, including age at onset, age at diagnosis, the time between onset and diagnosis, the site of onset (spinal vs bulbar), site of onset of motor neuron involvement, treatment (riluzole, PEG, and NIV), and time of death were recorded for all patients. ALS Functional Rating Scale-Revised (ALSFRS-R) was used at the initial evaluation to assess motor function. Each patient was regularly followed up during the disease. Survival time was defined as the time from the onset of symptoms until the death. All statistical analyses of the association between clinical manifestations and the survival pattern were analyzed using the SPSS 17.0 software.

Results: During the analyzed period, 325 ALS patients were diagnosed in Belgrade district. The mean age of the onset for all examined ALS patients was 57.74 ± 11.46 years (range: 25–83 years) and the mean age at diagnosis was 59.21 ± 11.26 years. There were 267 (82.15%) deaths during the study period, 160 (59.92%) men and 107 (40.07%) women. There were 194 (80.49%) patients with spinal onset and 73 (86.90%) patients with bulbar onset. The mean survival was 4.35 ± 0.20 years and the median survival was 3 ± 0.14 years (36 ± 1.68 months). Overall survival from symptom onset was 3 years in 197 (60.6%), 5 years in 68 (20.9%), 10 years in 48 (14.8%) patients and more than 10 years in 10 (3.1%) patients. The cumulative probabilities of survival in a 2-year, 5-year, and 7-year intervals were 71%, 24%, and 17%, respectively. In multivariable Cox proportional hazards regression models, factors which significantly and independently were associated with prognosis included age at onset, diagnostic delay ALFRS score, and use of riluzole.

Conclusion: These findings are consistent with other population-based studies and confirm that older age, shorter diagnostic delay, and ALSFRS score below 39 are strong predicators of poor prognosis of ALS. Treatment with riluzole improves ALS survival.

106 ELEVATED CREATINE KINASE IS ASSOCIATED WITH A BETTER PROGNOSIS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS

Rafiq M¹

Lee E²

Bradburn M¹

McDermott C¹

Shaw PJ¹

^dSheffield Institute for Translational Neuroscience, Sheffield, UK

^eThe school of health and related research, Sheffield, UK

Email address for correspondence: [email protected]

Keywords: creatine kinase, prognosis, energy requirements

Background: Creatine kinase (CK) is an enzyme found in skeletal muscles, myocardium and brain (CK-MM, CK-MB, and CK-BB isoenzymes, respectively). In these tissues with high energy requirements, CK catalyses the conversion of phosphocreatine to creatine generating adenosine triphosphate. Elevated CK-MM is considered a marker of muscle damage. In the past, CK has been used to differentiate between myopathic and neurogenic disease, higher CK being associated with myopathic disease. It is recognised that CK may be mildly to moderately elevated in patients with amyotrophic lateral sclerosis (ALS). An obvious explanation of raised CK in ALS is striate muscle atrophy resulting from degeneration of the innervating motor neurons. Another possible explanation is that compensatory upregulation of this enzyme may provide an energy substrate in a hypercatabolic condition. The reason that CK elevation occurs in a proportion of ALS cases, the precise cause and its behaviour with disease progression is unknown.

Objectives: To determine (1) whether ALS patients with raised CK differ from patients with normal CK; (2) the implications of raised CK on disease outcome or prognosis; (3) whether CK level mirrors disease progression or activity and, if so, can it be used to monitor disease progression or response to therapeutic interventions?; and (4) Whether the magnitude of muscle enzyme release can be used to predict the magnitude of muscle functional impairment.

Methods: This is an observational cohort study using the clinical database from the Olesoxime (TRO19622) investigational medicinal product trial. This trial involving 512 patients with ALS was conducted across 15 European centres (2009–2011). The patients were followed up at three monthly intervals for 18 months, with monitoring of biochemical and haematological parameters, including CK. The steering committee of TROPHOS (the Biotechnology company developing Olesoxime) kindly provided the database from the Olesoxime trial to conduct this study.

Results: Baseline CK was raised in 52% of the participants; mean CK 257 ± SD of 239 IU/L. Mean CK in male participants was significantly higher than in females (p < 0.001). Mean CK was significantly higher amongst participants with limb onset ALS compared to participants with bulbar onset ALS (p < 0.001). There was no significant difference in CK levels between upper limb and lower limb onset disease (p = 0.746). A higher CK level was associated with significantly better survival, even when adjusted for prognostic co-variants (p = 0.005).

Conclusions: CK level is a prognostic factor for survival in ALS, independent of its association with site of disease onset. This finding suggests that CK may be involved as a defence mechanism in the face of the metabolic stress of ALS. CK levels cannot be used to predict the disease severity or manual muscle scores at any time point. This study highlights the potential usefulness of CK as a prognostic marker in ALS.

P107 MYOCARDAL INFARCTION AND TAKO-TSUBO CARDIOMYOPATHY IN FEMALE PATIENTS WITH BULBAR AMYOTROPHIC LATERAL SCLEROSIS: A POSSIBLE RELATIONSHIP?

Morelli C¹

Verde F^1,2

Doretti A^1,2

Ticozzi N^1,2

Altieri A¹

Tiloca C^1,3

Maderna L^1,2

Messina S¹

Silani V^1,2

^fDepartment of Neurology and Laboratory of Neuroscience-IRCCS Istituto Auxologico Italiano, Milan, Italy

^g“Dino Ferrari” Center, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano, Milan, Italy

^hDoctoral School in Molecular Medicine, Department of Sciences and Bio-Medical Technologies, Università degli Studi di Milano, Milan, Italy

Email address for correspondence: [email protected]

Keywords: Tako-Tsubo, myocardal infarction, autonomic dysfunction

Background: There are few reports of cardiac involvement in amyotrophic lateral sclerosis (ALS), even if dysfunction of the sympathetic nervous system influencing the cardiac function has been described. Moreover, there is evidence in the literature that ALS is associated with a favorable cardiovascular risk profile. Here we discuss a possible risk for cardiac involvement in women with bulbar ALS.

Objectives: To report three female patients with bulbar ALS presenting an acute myocardal infarction and one presenting Tako-Tsubo syndrome (TTS), a reversible cardiomyopathy frequently precipitated by a stressful event, with clinical presentation indistinguishable from a myocardial infarction.

Case reports: Patient (Pt) 1(Pt 1), a 52-year old woman, was found to have an asymptomatic subacute apical ischemia and an apical mural thrombus. Considering her compromised nutritional status, 16 days later she underwent a PEG. Shortly after the procedure she presented a serious desaturation and died.

Pt 2, a 77-year old woman was diagnosed as having a silent ischemic heart disease. 12 days later a PEG was performed without complications.

Pt 3, a 62-year old woman, 30 hours after PEG insertion presented a myocardal infarction, treated with Percutaneous Transluminal Coronary Angioplasty (PTCA). She died 14 months later from sudden death.

Pt 4, a 60-year old woman, presented TTS 24 hours after PEG placement with an excellent recovery.

Results: Interestingly, all the four patients were women affected by ALS with bulbar onset. All required PEG as a result of being seriously nutritionally compromised. Pts 1 and 4 had a mild hypertension, well controlled by therapy. Pt 1 was a smoker. Pt 2 had hypercholesterolemia, whilst Pt 3 did not present any major vascular risk factor. None of them had respiratory insufficiency.

Discussion and conclusion: In the general population males are known to have a greater risk for cardiovascular diseases than females, but in a 10-year experience in our ALS Center, we have never observed an acute myocardial ischemia in a male ALS patient, even if we detect subtle ECG alterations in ALS very frequently.

Patients affected by bulbar ALS might have an increased risk of heart ischemia because of a more severe autonomic dysfunction, already reported in ALS with bulbar signs, compared with ALS without bulbar involvement, or through a subclinical intermittent hypoxia. Moreover, the beneficial vascular risk profile associated with ALS and the consequent reduced portion of male patients with vascular risk factors might unmask a gender susceptibility to heart ischemia in this disease.

References:

• Oey PL, Vos PE, Wieneke GH et al. Muscle Nerve 2002;25(3):402–8.
   Google Scholar
• Sutedja NA, van der Schouw YT, Fischer K et al. J Neurol Neurosurg Psychiatry 2011;82(6):638–42.
   PubMed Web of Science ®Google Scholar

P108 MAXIMAL INSPIRATORY PRESSURE (MIP) AND FORCED VITAL CAPACITY (FVC) CORRELATE WITH DISABILITY LEVELS AT TIMES OF ALS DIAGNOSIS

Ilieva H

Vora N

Simpson E

Methodist Hospital, Houston, Texas, USA

Email address for correspondence: [email protected]

Keywords: FVC, MIP, disease progression

Objectives: To compare the rate of disease progression and disability in ALS patients who differ in their initial forced vital capacity (FVC) and maximal inspiratory pressure (MIP) values at times of diagnosis.

Background: Respiratory function is a known predictor of individual survival. The AAN practice parameters uses FVC less than 50% as an indication for NIPPV initiation. MIP is also assessed in current clinical practice. Although, FVC is routinely used as a measure of pulmonary status and selection criteria for clinical trials, others have found MIP to be a more sensitive measurement of pulmonary function.

Methods: A database review of patients diagnosed with definite or probable ALS from 2010–12. Variables studied include age, gender, FVC, MIP, DeltaFS, preslope, ALSFRS and AALS at times of diagnosis and duration of disease. ANOVA analysis was used for comparison of the three groups based upon FVC and MIP at time of diagnosis. Group 1: FVC > 50% and MIP > 60 cm H₂O; Group 2: FVC > 50% and MIP < 60cm H₂O; and Group 3, FVC < 50% and MIP < 60 cmH2O (p < 0.05).

Results: One hundred and five patients were studied (61.4 ± 11.4 years; 48% F; 34% bulbar). FVC and MIP at diagnosis were 78.5 ± 23.7%, −55.7 ± 23.1 cm H₂O, respectively. Group 1 (n = 39) were 33% female and 26% bulbar. Group 2 (n = 54) were 63% female and 35% bulbar. Group 3 (n = 10) were 30% female and 70% bulbar. For Group 4 (FVC < 50%, MIP > 60 cm H₂O, n = 2) the small number limited analysis. There was no difference between groups for rate of progression at time of diagnosis. There was a statistically significant difference between groups for initial AALS score (p = 0.001) and preslope (p = 0.045) with Group 1 having the slowest rate of progression and lower disability score, and Group 3 the fastest progression and higher disability score.

Conclusions: The study confirms FVC and MIP are associated with rate of progression and level of disability at time of diagnosis. The study also shows a significant number of patients with FV > 50% have MIP’s < 60 cm H₂O. Additional analysis will be performed looking at MIP, FVC, NIPPV, the actual rate of progression, and survival.

P109 ASYMMETRY OF MOTOR DYSFUNCTION IN AMYOTROPHIC LATERAL SCLEROSIS: THE EFFECT OF LIMB DOMINANCE

Devine M^1,2

Heggie S¹

McCombe P^1,2

Kiernan MC^3,4

Henderson R¹

ⁱDepartment of Neurology, Royal Brisbane and Women’s Hospital, Herston, Brisbane, QLD, Australia

^jThe University of Queensland, St Lucia, Brisbane, QLD, Australia

^kNeuroscience Research Australia, Randwick, Sydney, NSW, Australia

^lPrince of Wales Clinical School, University of New South Wales, Randwick, Sydney, NSW, Australia

Email address for correspondence: [email protected]

Keywords: handedness, limb dominance, clinical phenotype

Background: A key feature of amyotrophic lateral sclerosis (ALS) is asymmetric onset and spread of upper (UMN) and lower motor neuron (LMN) degeneration. The preferential involvement of a particular limb and side of the body may reflect underlying developmental or stress-induced vulnerabilities.

Objective: Our aim was to investigate the relationship between limb dominance and the onset and spread of both UMN and LMN dysfunction in ALS. This expands our prior pilot study (1) by relating onset and spread to the clinical phenotype.

Methods: A structured questionnaire was used to determine the pattern of onset and spread of weakness or disability in 156 consecutive patients with clinically probable or definite ALS, from two tertiary referral centres. The clinical severity of UMN and LMN signs in each limb was also quantified based on clinical examination (2) applied within 12 months of diagnosis or first evidence of limb involvement.

Results: Of the 156 patients, 55% were males and 93% had sporadic disease. Onset site was upper limb in 30%, lower limb in 42% and bulbar in 28%. Upper limb onset of ALS was more likely to occur in the dominant side in right-handed patients. In right-handed patients with initial weakness in a left-sided limb, the direction of disease spread was more likely to remain ipsilateral (p = 0.008). In non-right-handed patients, 67% of upper limb onset was either left-sided or bilateral. The distribution of clinical UMN signs between limbs was also affected by handedness, whereas spread of LMN dysfunction between limbs appeared independent of dominance. There was also a tendency toward early spread of hyperreflexia to limbs unaffected by clinical LMN involvement.

Conclusions: These findings are consistent with an early cortical process underlying spread of disease in patients with ALS who have clinical evidence of UMN involvement. The relationship between handedness and UMN dysfunction may reflect underlying developmental vulnerabilities in the central nervous system, which are exposed in ALS.

Acknowledgements:

We would like to acknowledge Helen Woodhouse, Nicole Hutchinson and Eleanor Ramsey for their assistance with this project.

References:

• Devine M, Woodhouse H, McCombe P, Henderson R. The relationship between limb dominance, disease lateralization and spread of weakness in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2013;14: 150–1.
   PubMed Web of Science ®Google Scholar
• Ravits J, Paul P, Jorg C. Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology 2007;68: 1571–5.
   PubMed Web of Science ®Google Scholar

P110 IS THYROID HORMONE ABNORMALITY A PROGNOSTIC FACTOR OF AMYOTROPHIC LATERAL SCLEROSIS?

Zheng Z

Huang R

Chen X

Shang H

Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China

Email address for correspondence: [email protected]

Keywords: amyotrophic lateral sclerosis, thyroid hormone, survival

Objectives: To determine the correlation of thyroid hormones and survival in amyotrophic lateral sclerosis (ALS).

Methods: We conducted a prospective cohort study in a group of ALS patients enrolled from May 2006 to January 2013. Level of fasting serum thyroid hormones including free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were determined at the time of enrolment, and were separated into quintiles based on their distribution of the ALS patients. Survival was calculated as the duration between the onset of first symptom and death (or tracheotomy, permanent ventilation) or at the time of analysis if alive. Chi-square and Cox regression tests were used to estimate the possible correlation between thyroid hormones and ALS survival.

Results: We enrolled a total of 341 patients with probable or definite ALS, with balanced baseline demographic data among quintiles. The Chi-square test showed that lowered level of serum FT4 was correlated with increased survival in ALS, however, the significance failed to maintain in Cox proportional hazard analysis. There was no statistical difference in survival among patients with different levels of TSH and FT3.

Conclusions: Disturbed level of thyroid hormone does not correlate with longer survival in ALS. There should be no necessity to correct the abnormal levels of thyroid hormone unless it reaches medical needs.

Acknowledgements:

The authors thank the patients and their families for their participation in the study. The present study was supported by the National Science Fund of China (Grant No. 30973149) and the Science and Technology Bureau Fund of Sichuan Province (No. 2010SZ0069).

P111 OCULAR MOTOR APRAXIA: AN UNCOMMON EARLY SIGN IN AMYOTROPHIC LATERAL SCLEROSIS

Morelli C¹

Ticozzi N^1,2

Doretti A^1,2

Verde F^1,2

Altieri A¹

Lafronza A¹

Poletti B¹

Girotti F¹

Ciammola A¹

Messina S¹

Silani V^1,2

^mDepartment of Neurology and Laboratory of Neuroscience-IRCCS Istituto Auxologico Italiano, Milan, Italy

ⁿ“Dino Ferrari” Center, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli studi di Milano, Milan, Italy

Email address for correspondence: [email protected]

Keywords: ocular motor apraxia, dementia, ALS-plus

Background: Acquired ocular motor apraxia (AOMA), never described in amyotrophic lateral sclerosis (ALS), is characterized by loss of voluntary control of saccades and smooth pursuit. AOMA is also a characteristic feature of ataxia-oculomotor apraxia (AOA), a neurodegenerative disease caused by mutations in the APTX (aprataxin, AOA1) and SETX (senataxin, AOA2) genes.

Objectives: To report six patients with ALS also presenting AOMA, two of which at an early disease stage.

Case Reports:

• Case 1: a 62-year-old woman presented an extrapyramidal syndrome at the age of 62 (DaTSCAN was compatible with Parkinson's disease). Three years later she developed ALS and dementia. Progressive fixation of gaze, ocular and eyelid apraxia appeared at the age of 67. Brain MRI showed frontal posterior and parietal areas cortical atrophy; liquoral Aß42 was decreased.

• Case 2: a 77-year-old male was diagnosed as having ALS. Seven months after the onset he developed dementia, ocular and eyelid apraxia. Brain MRI showed frontal and parietal lobes cortical atrophy. Liquoral total tau protein was increased. He became comatose in 2 months and died 9 months after onset.

• Case3: a 63-year-old woman, affected by primary lateral sclerosis (PLS), three years after the onset presented ocular apraxia and severe limitation of upper and lateral gaze. Neuropsychological examination revealed an impairing of executive functions and agraphia.

• Case 4: a 71-year-old woman affected by PLS developed ocular apraxia 16 years after the onset of the disease.

• Case 5: a 45-year-old man presented ALS associated with parkinsonism. Ten months later he developed ocular apraxia and a severe slowing of saccades. Brain MRI and neuropsychological assessment were normal. DaTSCAN was compatible with Parkinson's disease. No mutation was found in MAPT, LRRK2, GRN, ATXN2 (SCA2) and TBP (SCA 17) genes. Liquoral total tau protein was normal.

• Case 6: a 57-year-old woman affected by ALS presented ocular apraxia and a severe limitation of upper gaze 6 months after the onset of ALS. A slight impairment of the mnesic function was detected. A brain MRI showed a mild hyperintensity of the corticospinal tracts. CSF analysis and an 18-F-DOPA PET were normal.

Results: ALS with associated atypical parkinsonism was diagnosed in Cases 1 and 5. ALS-FTD and PLS-FTD were diagnosed respectively in Cases 2 and 3. PLS and ALS were diagnosed respectively in Cases 4 and 6. No mutation was found in the analyzed ALS-associated genes (SOD1, TARDBP, ANG, FUS, C9ORF72, and SETX) and APTX gene. All the patients presented oculomotor apraxia, never reported in ALS.

Discussion and conclusion: Oculomotor function may be impaired in ALS through frontal and parietal lobes involvement, in particular in ALS with cognitive impairment. Early detection of oculomotor apraxia might assume a negative prognostic significance, possibly being associated with an ALS-plus syndrome.

P112 CIRCULATING MIR-1285 AND MIR-29B AS POTENTIAL BIOMARKERS FOR AMYOTROPHIC LATERAL SCLEROSIS

Cai B

Fan D

Peking University Third Hospital, Beijing, China

Email address for correspondence: [email protected]

Keywords: plasma, microRNA, diagnostic biomarker

Objective: To identify novel biomarkers using microRNA (miRNA) expression profiles in plasma from patients with amyotrophic lateral sclerosis (ALS), and assess their diagnostic values for ALS.

Methods: miRNA expression levels in plasma were determined in five ALS patients and five healthy control subjects using an miRNA microarray from Applied Biosystems Inc. (ABI). Differentially expressed miRNAs in the two groups were screened. The results from the miRNA microarray analysis were validated by real-time quantitative polymerase chain reaction (RTqPCR) in 74 ALS patients and 53 healthy control subjects. The diagnostic performance of miRNAs for ALS was estimated by the receiver operating characteristic (ROC) curve.

Results: Screening using the ABI miRNA microarray revealed that the expression levels of miR-1285, miR-29b, miR-194, and miR-1290 in plasma were different between ALS patients and healthy control subjects. Using larger sample sizes, the results from the validation indicated that the differences in miR-1285 (0.74 ± 0.06 vs. 1.52 ± 0.14, p = 7.0978*10⁻⁶) and miR-29b (37.63 ± 7.07 vs. 15.25 ± 2.16, p = 0.0025) between ALS patients and healthy control subjects were statistically significant. When the relative expression level of miR-1285 was used to diagnose ALS, the area under the ROC (AUC) was 0.734. If the diagnostic threshold was set at 0.9537, both the sensitivity and the specificity were high and the values were 70.3% and 73.6%, respectively. The AUC of miR-29b was 0.669 and the values for sensitivity and specificity were 68.4% and 62.7%, respectively.

Conclusions: The miR-1285 expression levels in ALS patient plasma samples were significantly decreased, while the miR-29b expression levels were significantly increased. These two miRNA species could become diagnostic biomarkers for ALS.

P113 UNTARGETED METABOLOMICS IN CEREBROSPINAL FLUID OF PATIENTS WITH MOTONEURON DISORDERS: DIAGNOSIS PREDICTION TO AN EXTERNAL POPULATION

Blasco H^1,2

Corcia P^2,3

Pradat PF⁴

Emond P^2,5

Antar C^1,2

Veyrat-Durebex C^1,2

Moreau C⁶

Devos D⁶

Mavel S²

Gordon PH⁴

Andres CR^1,2

Nadal-Desbarats L^2,5

^oCHRU Bretonneau, Laboratoire de Biochimie et Biologie Moléculaire, Tours, France

^pINSERM U930, Université François Rabelais, Tours, France

^qCHRU Bretonneau, Centre SLA, Tours, France

^rAPHP, Fédération des Maladies du Système Nerveux, Centre Référent Maladies rares SLA, Paris, France

^sPPF, Université François Rabelais, Tours, France

^tCHRU Lille, service de Neurologie, Lille, France

Email address for correspondence: [email protected]

Keywords: motor neuron disorders, metabolomics, Nuclear Magnetic Resonance

Background: The diagnosis of Motor Neuron Disorders (MNDs) is often delayed principally due to the absence of reliable diagnostic biomarkers. Metabolomics, a relevant approach to the identification of disease markers, provides metabolic profiles from biological fluids analysis. Nuclear Magnetic Resonance (¹H-NMR) is a robust analytical platform to perform such analysis. Although biomarker studies provided relevant findings, robust validation is missing to improve the confidence to diagnosis in clinical practice. The aim of this study was to provide a CSF signature of MND patients by ¹H-NMR and to evaluate the performance criteria of such pattern in the prediction of diagnosis from an independent population.

Method: CSF samples, collected at the time of diagnosis suffering from motor neuron conditions and controls were analysed by ¹H-NMR. We split the cohort in an 80/20 ratio to provide a training set and a test set. A multivariate analysis (OPLS-DA) was performed on the training set before the prediction diagnosis step on the test set. This experiment was repeated 10 times for assessment of the performance criteria of the diagnosis prediction. Finally, we identified the most discriminating compounds of the metabolome profile.

Results: CSF from 95 MND patients and 85 controls were analysed and discriminating profile between both groups was highlighted. We obtained correct OPLS-DA models characterized by R²X > 22%, R²Y > 93%, Q² > 66%, and a correct diagnosis prediction with probability mean of 99.31% in the training set. Diagnosis prediction on the test set showed correct performance with 78.9% sensitivity, 76.5% specificity, 78.9% predictive positive and 76.5% predictive negative values. Among the discriminating compounds, we identified threonine, histidine and metabolites of branched chain amino-acids that are linked with pathophysiological ways of MND.

Discussion and conclusion: This analysis confirmed that CSF screening using ¹H-NMR is relevant to provide a metabolic signature and to identify promising biomarkers for the diagnosis of ALS. To our knowledge, this is the first metabolomic study in neurological disease based on metabolome profile analysis to predict a diagnosis on an independent validation.

P114 SPORADIC ALS: A SPINAL FLUID PATHWAY DISORDER?

Smith R¹

Ravits J²

Bowser R³

^uCenter for Neurologic Study, La Jolla, CA, USA

^vUniversity of California, San Diego, La Jolla, CA, USA

^wBarrow Neurological Institute, Phoenix, AZ, USA

Email address for correspondence: [email protected]

Keywords: disease progression, hypothesis, cerebrospinal fluid pathway

Objective: To propose an alternative hypothesis for the propagation of ALS.

Background: It is proposed that the onset of ALS is local and that progression is regional (1,2). However, exceptions are notable. For example, recent studies report that 15% of patients with lower limb onset subsequently develop bulbar symptoms 93, 4) and that a large percentage of patients with bulbar onset (38% and 28%, respectively) next develop lower limb symptoms.

Discussion: To account for these exceptions we propose that propagation is mediated by the circulation of spinal fluid. Further, we suggest that ALS represents a CSF pathway disorder preferentially impacting the brainstem and spinal cord which are in close proximity to CSF.

Additionally, the relative sparing of the cerebral hemispheres may represent a dosage effect. Considering the ventricular volume (120 cc), a noxious substance released into the cerebral ventricles would be diluted, relative to the mass of the brain (1400 g), and well tolerated. However, tissue exposure would be enhanced as CSF passed into the fourth ventricle and ultimately into the subarachnoid space surrounding the spinal cord. Accordingly, the brunt of the disease would be borne by neurons and non-neuronal cells in proximity to the CSF pathway. Local variation could result from obstructions to the flow of CSF or other factors. But established locally, contiguous spread would proceed as described (5, 1, 3, 4).

Several disparate clues are compatible with our assumption. Firstly, absorption of CSF from the arachnoid villi decreases with age (6). This offers a possible explanation for the increased incidence of ALS in older persons. Secondly, a number of molecules, including proteins and oligonucleotides, are robustly taken up by motor neurons and non-neuronal cells from the CSF (7). Finally, CSF from ALS patients is toxic to motor neurons in in vitro models (8).

Conclusions: The notion that ALS represents a CSF pathway disorder leads to several lines of research that could provide insight into the cause of ALS. Firstly, it suggests that the study of CSF may lead to the cause(s) of sporadic ALS. Secondly, it suggests that an effort to identify the sources of potentially toxic molecules that find their way into the CSF may shed further light on the origins and spread of the disease.

References:

• Ravits JM, La Spada AR Neurology 2009;73.10: 805–811.
   Google Scholar
• Polymenidou L, Cleveland D Cell 2011: 147.3: 498–508.
   Google Scholar
• Fujimura-Kiyono C, Kimura F, Ishida S et al. J of Neurology, Neurosurgery & Psychiatry 2011;82.11: 1244–249.
   Google Scholar
• McKenery M, Yu H, Lee H et al. AAN Annual Meeting 2013; P06.130.
   Google Scholar
• Brooks B, Can J Neurol Sci. 1991;18: 435–8.
   Google Scholar
• Albeck MJ, Skak C, Nielsen PR et al. J Neurosurg 1998;89: 275–278.
   PubMed Web of Science ®Google Scholar
• Smith RA, Miller TM, Yamanaka K et al. JCI 2006;116;8: 2290–96.
   Google Scholar
• Tikka TM, Vartiainen NE, Goldsteins G et al. Brain 2002;125: 722–31.
   PubMed Web of Science ®Google Scholar

P115 PHASE 2 SELECTION TRIAL OF HIGH-DOSAGE CREATINE (CRE) AND TWO DOSAGES OF TAMOXIFEN (TAM) IN AMYOTROPHIC LATERAL SCLEROSIS (ALS)

Atassi N¹

Macklin E¹

Jackson K¹

Berkley J¹

Simpson E¹

Yu H¹

Walker J¹

Simmons Z²

David W¹

Barkhaus P⁴

Simionescu L⁵

Dimachkie M⁶

Pestronk A⁷

Salameh J⁹

Weiss M⁸

Bravver EK³

Brooks BR³

Schoenfeld D¹

Shefner JM⁵

Cudkowicz M¹

^xMassachusetts General Hospital, Boston, MA, USA

^yPenn State Hershey Medical Center, Hershey, PA, USA

^zCarolinas Medical Center, Charlotte, NC, USA

^aaMedical College of Wisconsin, Milwaukee, WI, USA

^abSUNY Upstate Medical University, Syracuse, NY, USA

^acUniversity of Kansas, Kansas City, Kansas, USA

^adWashington University St. Louis, St. Louis, MO, USA

^aeUniversity of Washington, Seattle, WA, USA

^afUniversity of Massachuesetts Medical Center, Worcester, MA, USA

Email address for correspondence: [email protected]

Keywords: clinical trial, creatine, tamoxifen

Background: Preclinical and preliminary clinical data suggest that high dosages of creatine and tamoxifen may be beneficial for people with amyotrophic lateral sclerosis (ALS). Selection design trials can speed the search for effective treatments by screening multiple drugs against each other and choosing the winner for testing against placebo.

Objectives: To select the best of three treatments (creatine (CRE) 30 g/day, tamoxifen (TAM) 40 mg/day, TAM 80 mg/day) based on safety, tolerability, and efficacy profiles.

Methods: This was a double-blind, randomized, three-arm selection trial, following 60 subjects with ALS from nine centres over 9 months. Subjects were randomized 1:1:1 to: CRE 30 g, TAM 40 mg, and TAM 80 mg. Eligibility criteria include ALS duration less than 36 months and vital capacity ≥ 50% of predicted. The primary efficacy endpoint was mean rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score using a random slopes model with adjustment for time from first symptom to diagnosis, limb vs. bulbar onset, and baseline vital capacity (VC). Secondary efficacy endpoints included rates of decline in VC and muscle strength measured by hand held dynamometry (HHD). Missing data were treated as missing at random conditional on the observed data and our model assumptions.

Results: Sixty eligible subjects were randomized. Tolerability: the overall rate of drug discontinuation was higher in the CRE 30g group (64%) compared to the TAM 40 mg (43%) and TAM 80 mg (41%) (p = 0.047). Safety: a total of 16 serious adverse events (SAE) occurred during the study (CRE 30 g: 23%, TAM 40 mg: 14%, and TAM 80 mg 29%) and none was considered to be related to study treatments. Nine participants died (CRE 30 g: 14%, TAM 40mg: 10%, and TAM 80 mg: 24%). The CRE group had a higher rate of gastrointestinal adverse events and two subjects had elevated serum creatinine levels. Efficacy: the rate of decline of ALSFRS-R was numerically slower in the tamoxifen 80 mg group (CRE 30g: − 0.9, TAM 40 mg: − 1.0, TAM 80 mg: − 0.7 point/month) and the rate of decline of VC was numerically slower in the Tamoxifen 40 mg group (CRE 30 g: − 3.4, TAM 40 mg: − 2.9, TAM 80 mg: − 3.3 point/month). The differences in ALSFRS-R and VC rates of decline were not statistically significant. Muscle strength in the upper and lower extremities measured by HHD declined at a slower rate in the tamoxifen 80 mg group followed by tamoxifen 40 mg and creatine 30 g groups (p = 0.002).

Conclusions: Tamoxifen 40 and 80 mg dosages are well tolerated in ALS and treatment with tamoxifen showed a slower decline in muscle strength in a dose-dependent fashion. A future trial is needed to test the efficacy of tamoxifen 80 mg against placebo in people with ALS.

Acknowledgements:

We would like to thank the ALS Therapy Alliance for funding this trial and Avecina for providing creatine. We would also like to thank members of the Data Safety Monitoring Board (Lorne Zinman, Rebecca Betensky, Seward Rutkove, Nancy Berliner), site investigators and evaluators, and study monitors (Dafna Rebibo, Meghan Hall, Mary Lou Watson) at the Northeast ALS Consortium (NEALS).

P116 SAFETY OF DEXPRAMIPEXOLE FOR THE TREATMENT OF ALS: RESULTS FROM THE RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY, EMPOWER

Hebrank G

Khemani S

Bozik M

Knopp Biosciences Inc., Pittsburgh, PA, USA

Email address for correspondence: [email protected]

Keywords: dexpramipexole, safety, EMPOWER

Background: In a two-part phase 2 study, dexpramipexole (25–150 mg twice daily) was well tolerated for 9 months or less, with dose-dependent trends in slowing the rate of functional decline and reducing mortality in amyotrophic lateral sclerosis (ALS). EMPOWER is an international, prospective, randomized, double-blind, placebo-controlled phase 3 trial of dexpramipexole in familial or sporadic ALS.

Objective: To evaluate the safety of dexpramipexole in a phase III study of patients with amyotrophic lateral sclerosis (ALS), the EMPOWER trial, and determine if dose-limiting toxicities were present.

Methods: EMPOWER randomized 942 subjects with familial or sporadic ALS to treatment with dexpramipexole or placebo. Patients (18–80 yrs) with symptom onset 24 months or lesser before randomization, slow vital capacity 65% or more of predicted, and no history of or current neutropenia were included. Patients were randomized (1:1) to dexpramipexole 150 mg or placebo twice daily for 12–18 months. Patients on a stable dose of riluzole for 60 days or more before study start and those not taking riluzole were eligible. Safety was evaluated by monitoring adverse events (AE) and laboratory evaluations throughout the study.

Results: The safety of dexpramipexole observed in EMPOWER was similar to previous studies. Most subjects in the dexpramipexole and placebo-treated groups reported an AE (97% dexpramipexole and 96% placebo). Similar incidences of AEs were observed for both treatment groups with respect to severity; AEs considered moderate or severe (81% dexpramipexole and 80% placebo); AEs considered severe (39% dexpramipexole and 40% placebo); serious adverse events (SAEs) (47% dexpramipexole and 50% placebo); subjects who discontinued study treatment due to an AE (11% dexpramipexole and 8% placebo); subjects withdrawing from the study due to an AE (13% dexpramipexole and 13% placebo). More subjects treated with dexpramipexole 150 mg BID experienced AEs related to study treatment (46%) than those who were treated with placebo (32%). Consistent with previous reports, the incidence of neutropenia was higher in participants treated with dexpramipexole (8%) compared with those who received placebo (2%). The most common adverse events (at least 5% incidence and 2% more than placebo) were constipation, nausea, and weight decreased; insomnia; muscular weakness; cough; dizziness; dry mouth; neutropenia; upper respiratory tract infection; and neck pain. The incidence of deaths in the treatment groups was similar, 19% of subjects in the dexpramipexole group and 22% of subjects in the placebo group.

Conclusion: Dexpramipexole was well tolerated in EMPOWER with comparable overall incidences of SAEs, discontinuations due to AEs, and withdrawals due to AEs between the dexpramipexole and placebo groups. No previously unidentified safety issues emerged compared with the earlier phase 2 study of dexpramipexole. No dose-limiting safety signals were observed.

P117 EMPOWER SUBJECTS WITH EL ESCORIAL DEFINITE ALS EXHIBITED SIGNIFICANT BASELINE DIFFERENCES INDEPENDENT OF DISEASE DURATION AND EXPERIENCED SIGNIFICANTLY WORSE OUTCOMES

Petzinger T¹

Mather J¹

Archibald D¹

Zhang B²

Brooks BR³

Bozik M¹

^agKnopp Biosciences Inc., Knopp Biosciences Inc., USA

^ahMacroStat, Inc., Hockessin, DE, USA

^aiNeurology Carolinas Medical Center - University of North Carolina School of Medicine - Charlotte Campus, Charlotte, NC, USA

Email address for correspondence: [email protected]

Keywords: El Escorial Criteria, dexpramipexole, EMPOWER

Background: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease characterized by variable clinical presentation and course, increasing the challenge of both clinical management and clinical research. A baseline diagnosis of El Escorial Criteria (EEC)-definite ALS, involving at least three affected regions, is generally associated with worse outcomes. However, it remains controversial whether this solely represents an advanced stage of disease progression or whether EEC-definite ALS may signal a distinct disease subtype associated with diffuse presentation.

Objectives: Subjects (n = 942) in one of the largest controlled studies ever conducted in ALS, the Phase 3 trial of dexpramipexole in ALS (EMPOWER), were retrospectively analyzed according to their baseline EEC classification to assess differences in disease progression.

Methods: Baseline demographics, ALS history, and clinical laboratory values of subjects with definite ALS (EEC-definite, n = 303) were compared to all other subjects (EEC-not definite, n = 639). In the placebo population only (n = 468), on-study changes in efficacy measures and clinical laboratory values were compared between EEC-definite subject n = 156) and EEC non-definite subjects n = 312).

Results: At baseline, EEC-definite subjects were significantly younger (55.789 years vs. 57.659 years, p = 0.0175) and significantly more likely to be female (40.9% vs. 33.3%, p = 0.0243) than EEC-not definite subjects. EEC-definite subjects entered the study with a significantly faster mean pre-study progression rate, as measured by, average monthly decline on the ALS Functional Rating Scale-Revised (−0.80 vs. − 0.71, p = 0.0163); a lower mean baseline ALSFRS-R score (36.7 vs. 38.9, p < 0.0001); significantly reduced mean baseline predicted slow vital capacity (85.6% vs. 90.4%, p < 0.0001); significantly lower mean plasma creatinine (68.4 μm/l v. 71.3 μm/l, p = 0.010). Importantly, there was no difference in mean baseline duration of ALS symptoms (15.3 months vs. 15.2 months, p = 0.6252). Over the course of EMPOWER, EEC-definite placebo subjects had significantly worse outcomes on the primary outcome measure, a Combined Assessment of Function and Survival (CAFS, 468.0 vs. 405.9, p = 0.014) and on ALSFRS-R slopes (−1.37 v. −1.06, p < 0.001), while showing a trend toward increased mortality (19.1% v. 16.1%, p = 0.092). EEC-definite subjects also showed a significantly greater reduction from baseline in mean serum creatinine (−16.4 μm/l vs. −12.5 μm/l, p = 0.0056).

Discussion and conclusion: EEC-definite EMPOWER subjects exhibited significant differences from not-definite subjects consistent with more advanced disease at baseline and more rapid on-study progression, confirming that this classification is associated with worse outcomes. However, EEC-definite diagnosis was not an indicator of the duration of disease in EMPOWER, raising doubts that EEC-definite ALS represents solely a stage of progression and suggesting a potential avenue for identifying a specific ALS subtype associated with diffuse presentation. Significance differences in age, gender, and serum creatinine levels exhibited by EEC-definite subjects suggest additional opportunities for investigation.

P118 CREATININE IS A BIOMARKER OF DISEASE SUBTYPE, DISEASE PROGRESSION AND DRUG RESPONSE IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS IN THE PHASE 3 EMPOWER STUDY

Petzinger T¹

Mather J¹

Archibald D¹

Boyd S¹

Dworetzky S¹

Zhang B²

Brooks BR³

Bozik M¹

^ajKnopp Biosciences Inc., Knopp Biosciences Inc., USA

^akMacrostat, Inc., Hockessin, DE, USA

^alNeurology Carolinas Medical Center - University of North Carolina School of Medicine - Charlotte Campus, Charlotte, NC, USA

Email address for correspondence: [email protected]

Keywords: creatinine, dexpramipexole, biomarker

Background: ALS is a progressive, heterogeneous neurodegenerative disease with a highly variable clinical course, including survival ranging from a few months to 10 years or more. Validated ALS biomarkers are badly needed to aid diagnosis, measure and predict disease progression and serve as potential surrogate markers of drug response. Without an effective method for measuring disease burden and drug activity, developing effective therapies in treating ALS continues to be elusive. Changes in creatinine levels have been correlated with disease progression and creatinine may be a promising biomarker candidate in ALS.

Objective: To determine if creatinine levels at baseline and changes in creatinine levels over the course of EMPOWER correlate with ALS classification by El Escorial criteria (EEC) and with dexpramipexole-treatment (dex-treated).

Methods: EMPOWER, one of the largest ALS clinical trials ever conducted, enrolled 942 ALS patients. The primary objective of the study was to evaluate the effectiveness of dexpramipexole 300 mg/day. Baseline creatinine levels were compared for participants with definite (n = 303) and not-definite (n = 639) ALS by EEC. Correlations between change from baseline in creatinine levels and the rate of disease progression as measured by the slope of ALSFRS-R at Month 12 were also evaluated. Finally, the effect of dexpramipexole on changes in creatinine levels through Month 12 (time averaged difference) was also evaluated.

Results: Baseline levels of creatinine in subjects with EEC definite ALS were significantly lower than the EEC not- definite group (EEC definite 68.4 μm/l, EEC not-definite 71.3 μm/l, p = 0.0096). During EMPOWER, the slope of creatinine decline (mixed-effects repeated-measure model) was significantly increased in placebo-treated subjects with EEC definite ALS (n = 156) compared with EEC not-definite ALS (n = 312) at Month 12 (EEC definite, –16.4 μm/l, EEC not definite –12.5 μm/l, p = 0.0056). Treatment with dexpramipexole also significantly reduced the decline from baseline (time averaged difference) in plasma creatinine over 12 months (2.71 μm/l, p < 0.001) compared with placebo in patients with EEC definite ALS. The effect of dexpramipexole on creatinine further increased in the EMPOWER subgroup of EEC definite participants receiving concomitant riluzole (3.16 μm/l, p < 0.001), and the EEC definite, concomitant-riluzole and short-symptom duration (< 18 months) subgroup (4.71 μm/l, p < 0.001) where a near-significant improvement with CAFS (416.7/347.7, p = 0.059) was also seen. The significance of this creatinine-sparing effect increased after adjusting for weight change in dex-treated and placebo-treated participants.

Discussion and conclusion: Baseline creatinine levels and changes from baseline in creatinine levels were significantly correlated with ALS classification by EEC and with disease progression by EEC. Treatment with dexpramipexole also significantly reduced the rate of creatinine decline compared with placebo in EMPOWER, including after adjusting for weight change in dex-treated and placebo-treated participants. The creatinine-sparing effects of dexpramipexole increased with increasing disease severity by EEC classification and symptom duration, and correlated with increasing clinical improvement.

P119 EQUIVALENCE OF HISTORICAL CONTROL DATA BETWEEN LARGE ALS TRIALS: SHOULD WE BE PAYING MORE ATTENTION TO THIS DATA?

Katz J

Moore D

CPMC, San Francisco, USA

Email address for correspondence: [email protected]

Keywords: clinical trial, historical placebo, PROACT database

Background: Over the past few years, the field of ALS has seen several agents prove ineffective in large randomized clinical trials. These studies followed smaller screening trials that showed promise. A more efficient approach is needed to accelerate the identification of useful agents and exclude ones destined to fail. Gaining trust in historical control data would strengthen earlier studies by providing a trove of information for predicting outcomes.

Objectives: To demonstrate that historical placebo outcomes are stable over time, and predictable, as long as data is controlled for differences in inclusion criteria between different trials.

Methods: We compared mean functional declines between placebo patients from the WALS clinical trial of minocycline (MINO, conducted from 2003–5) and from the Talampanel trial (TAL, 2008–10). The TAL data were provided by the PROACT database. These were the two largest trials with data that used the ALSFRS-R. The studies had different baseline inclusion criterion, to ensure we were comparing identical cohorts, we excluded subjects that did not fit the largest overlapping set of criteria that fit both studies. These included: symptom duration less than 3 yrs, at least 4 months follow-up, vital capacity greater than 70% and FRS respiratory subscale 10 or greater. We compared baseline features, and used a linear mixed-effects model over the entire length of the studies to compare differences in mean slopes of the ALSFRS-R.

Results: We included 159 MINO and 191 TAL subjects. The slope declines were nearly identical: −1.02 per month (−1.14, −0.90) for MINO and −1.00 per month (−1.11, −0.89) for TAL (p = 0.83). We also analyzed the subset of patients with symptom duration of less than 2 yrs, and the mean slope declines were MINO −1.13 per month (−0.99, −1.27) and TAL–1.10 per month (−0.97, −1.22) (p = 0.78). There were also no differences when controlling for the effect of symptom duration on outcomes within each study (using a locally weighted least squares regression of slope on symptom duration). Baseline ALSFRS-R were (39.0 ± 4.4 MIN v 38.9 ± 4.7 TAL). TAL patients had slightly longer symptom duration than MIN (18.4 months v 17.0).

Discussion and conclusion: The mean functional declines from these two studies, conducted 5 years apart, appear to be nearly identical and suggest the rate of disease progression is stable. ALS trialists would benefit from considering historical comparisons which improve power, especially when the data can be trusted by showing it yields predictable results over time. Historical control data can augment small concurrent randomized control trials, which run their own risk of outcomes being subject to random statistical variations. These may lead to overly optimistic efficacy predictions. Estimating the expected range of mean functional decline, based on a given set of inclusion criteria, could have raised a caution flag on early trials of dexpramipexole and TAL where the early placebo control cohorts progressed more rapidly than would be predicted.

P120 AEROBIC CYCLE ERGOMETER ACCORDING TO HEART RATE RESERVE (HRR) IN AMYOTROPHIC LATERAL SCLEROSIS REHABILITATION

Zuccarino R¹

Cellotto N¹

Vignolo M¹

Bandettini di Poggio M²

Truffelli R¹

Giove E¹

Cipollina I¹

Dotta M¹

Bagnoli E¹

Caponnetto C³

^amNeuromuscular/ALS-MDA Rehabilitation Center, NeMO, La Colletta Hospital, Arenzano, Genova/Liguria, Italy

^anDepartment of Neurosciences Santa Corona Hospital, Pietra Ligure, Savona/Liguria, Italy

^aoDepartement of Neurology, Ophtalmology, Rehabilitation, Genetics and Maternal and Child Sciences – AOU San Martino – IST, Genova/Liguria, Italy

Email address for correspondence: [email protected]

Keywords: exercise, cycle ergometer

Background: Despite the clinical relevance of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) the best type of exercise and its effect on rehabilitation in this population are not well understood.

Objectives: To determine the safety and exercise treatment-effect size of submaximal aerobic repetitive rhythmic exercise mediated by cycle ergometer for patients with amyotrophic lateral sclerosis (ALS).

Methods: Ten patients were enrolled. Functional status was evaluated by: ALS Functional Rating Scale-Revised (ALSFRS-R); percentage of predicted vital capacity (VC); oxygen consumption using Heart Rate Reserve (HRR); Medical Research Council scale (MRC) for upper and lower limb strength. Data were collected at baseline; at the end of 4 week; and after washout period of 4 months. The participants underwent submaximal aerobic repetitive rhythmic exercise mediated by cycle ergometer performed twice every day, for 6 days a week, for 4 weeks.

Results: No dropouts or adverse event were observed after cycle ergometer treatment. Safety measures showed stability in ALSFRS-R score during the study interval. Three patients showed the same score in ALSFRS scale from the beginning, three a variance of 1 point, two 3 points, one 4 points and one a variance of 7 points. Also in MRC scale, nine patients showed stability and only one showed a worsening on average of 1 point, in lower limb. Finally VC showed five patients with the same percentage from the beginning, two showed a worsening of 10%, two a worsening of 14% and one 20% less.

Discussion: Cycle ergometer exercise is tolerated, and safe. The treatment supported work capacity and follow up showed that ALS patients should be treated at least three times every year.

Conclusions: Repetitive rhythmic exercise using cycle ergometer should be evaluated further in larger studies to determine the stability of function in relation to the rate of progression of the underlying ALS.

References:

• Bello-Haas et al. A randomized controlled trial of resistance exercise in individuals with ALS. Neurology 2007;68: 2003–2007.
   PubMed Web of Science ®Google Scholar
• Chiò et al. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 2005;128: 472–476.
   PubMed Web of Science ®Google Scholar
• Drory et al. The value of muscle exercise in patients with amyotrophic lateral sclerosis. Journal of the Neurological Sciences 2001;191: 133–137.
   PubMed Web of Science ®Google Scholar
• Kaspar et al. Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. Annals of Neurology 2005;57: 649–655.
   Google Scholar
• Liebetanz et al. Extensive exercise is not harmful in amyotrophic lateral sclerosis. European Journal of Neuroscience 2004;20: 3115–3120.
   PubMed Web of Science ®Google Scholar
• Mahoney et al. Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis. Muscle Nerve 2004;29: 656–662.
   PubMed Web of Science ®Google Scholar
• Sanjak et al. Supported treadmill ambulation for amyotrophic lateral sclerosis: a pilot study. Arch Med Rehabil 2010;91: 1920–9.
   PubMed Web of Science ®Google Scholar

P121 THE USE OF EYE-TRACKER-BASED NEUROPSYCHOLOGICAL TESTS FOR THE IDENTIFICATION OF C9ORF72 EXPANSIONS CARRIERS AMONG ALS PATIENTS

Poletti B^1,2

Carelli L¹

Solca F¹

Lafronza A¹

Ticozzi N^1,2

Ratti A.^1,2

Tiloca C^1,2

Calini D¹

Meriggi P³

Cipresso P⁴

Pedroli E⁴

Lulé D⁵

Ludolph AC⁵

Riva G⁴

Silani V^1,2

^apDepartment of Neurology and Laboratory of Neuroscience -IRCCS Istituto Auxologico Italiano, Milan, Italy

^aqDepartment of Pathophysiology and Transplantation, University of Milan, Milan, Italy

^arICT & Biomedical Technology Integration Unit, Centre for Innovation and Technology Transfer (CITT), Fondazione Don Carlo Gnocchi Onlus, Milan, Italy

^asApplied Technology for Neuro-Psychology Lab, IRCCS Istituto Auxologico Italiano, Milan, Italy

^atDepartment of Neurology - University of Ulm, Ulm, Germany

Email address for correspondence: [email protected]

Keywords: C9orf72, neuropsychological tests, eye-tracker

Background: Over the past decade growing evidence supports a continuum between Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). The recently discovered hexanucleotide repeat expansions (RE) in the C9ORF72 gene appears to be the most common genetic cause of familial ALS and FTD, and has also been found in a significant number of apparently sporadic cases (1). A bulbar-onset disease and a more severe cognitive-behavioural impairment have been reported in ALS patients with C9ORF72 expansion (2). These findings highlight the importance of a combined genetic-cognitive screening in ALS, in order to better define genotype-phenotype associations and improve therapy and care. However, neuropsychological (NP) assessment is problematic in moderate-severe stages of ALS, due to motor-verbal impairment. Eye-tracking (ET) has been preliminarily used in ALS to administrate cognitive testing (3,4).

Objectives: To investigate the use of motor-verbal free NP measures, administered by means of the ET technology, for identifying C9ORF72 RE carriers in ALS patients.

Methods: We enrolled 31 patients with probable or definite ALS according to the El Escorial revised criteria. C9ORF72 RE detection was performed using a two-step protocol including a repeat-primed PCR as already described (5). A short battery composed by the adapted versions of cognitive tests focusing on frontal and executive functions, was administered with the ET; patients also underwent a cognitive screening based on traditional paper and pencil tools (Frontal Assessment Battery; Montreal Cognitive Assessment). Patients were divided in two groups according to genetic status; a linear discriminant analysis (LDA) was used to verify if traditional and ET-based measures were useful to discriminate between groups.

Results: Five patients were found to carry RE, while 26 were wild-type. The LDA showed that 97.3% of original grouped cases were correctly classified with traditional tools and 86.3% with ET-based ones. When considering all measures, the classification correctness increased up to 100%, classifying correctly all cases in the two groups.

Discussion and conclusion: The ET technology is suitable to be employed in moderate-severe stage of ALS; we demonstrated that the use of a short ET-based cognitive battery increases the accuracy in the identification of RE carriers up to 100%, with a specific discriminating power similar to that of traditional measures. This supports the introduction of ET-based cognitive tests in the clinical evaluation of ALS, especially in presence of verbal-motor impairment.

Acknowledgements:

research support was provided by the eBrain project, funded by the Lombardy Region.

References:

• DeJesus-Hernandez M et al. Neuron 2011.
   Google Scholar
• Byrne S et al. Lancet Neurol 2012.
   Google Scholar
• Donaghy C et al. J Neurol 2009.
   Google Scholar
• Poletti B et al. Neurological Science 2009.
   Google Scholar
• Ratti A et al. Neurobiol Aging 2012.
   Google Scholar

P122 AN ASSESSMENT OF PAIN REPORTS IN ALS USING THREE LARGE DATA SETS

Stephens H¹

Felgoise S²

Walsh S³

Simmons Z¹

^auPenn State Hershey Medical Center, Hershey, PA, USA

^avPhiladelphia College of Osteopathic Medicine, Philadelphia, PA, USA

^awALS Association Greater Philadelphia Chapter, Philadelphia, PA, USA

Email address for correspondence: [email protected]

Keywords: pain, assessment, physical function

Background: Pain has been reported in 50–70% of patients with ALS. This pain can be due to musculoskeletal causes, cramps, or spasticity. The ALS Specific Quality of Life-Revised (ALSSQOLR) instrument is a validated QOL measure. One item within the measure addresses pain by asking “how much of a problem has pain been in the last 7 days” using a scale of 0 (no problem) to 10 (tremendous problem).

Objectives: To examine the frequency and distribution of patient-reported problematic pain scores.

Methods: A retrospective review was carried out of 3 large research data sets used to collect ALSSQOLR, ALS Functional Rating Scale-Revised (ALSFRSR), and demographic data from ALS patients. This included a multicenter dataset collected at 12 US academic ALS clinics in 2006 (DATA1) as part of a validation study of the ALSSQOLR, and two national survey data sets of ALS patients who completed questionnaires in 2007 (DATA2) and 2009 (DATA3) in surveys comparing those who attended multidisciplinary clinics to those who did not. We created pain problem severity categories based on patient problem ratings: 0 = no problem; 1–3 = mild problem; 4–6 = moderate problem; and 7–10 = severe problem. Pearson product-moment correlations between pain and ALSFRSR were calculated.

Results: There were 389 patients in DATA 1, 381 in DATA2, and 385 in DATA 3. All three data sets had similar distributions of gender (approximately 60% male), site of disease onset (25% bulbar, 75% limb), and mean age (approximately 57 years). Mean ALSFRSR in the 3 sets was: 33/48 (DATA 1), 26/48 (DATA 2) and 28/48 (DATA 3). Mean ratings of pain were 2.2 (SD = 2.7) in DATA 1, 2.7 (SD = 2.9) in DATA 2, and 2.6 (SD = 2.8) in DATA 3. The three data sets show similar distributions of pain report scores: DATA 1 (no problem = 40%, mild = 34%, moderate = 16%, severe = 10%); DATA 2 (no problem = 33%, mild = 36%, moderate = 15%, severe = 16%); and DATA 3 (no problem = 34%, mild = 36%, moderate = 16%, severe = 14%). A negative correlation (p < 0.05) of ALSFRSR and pain was present in all samples r = − 0.16 (DATA 1), r = − 0.15 (DATA 2), and r = − 0.14 (DATA 3).

Discussion and conclusion: Three distinct data sets collected over 3 years report similar patterns of pain assessment by ALS patients. Poorer physical function was associated with more problematic pain, consistent with previous studies. While on average, ALS patients report pain to be a mild problem, 30% report that pain is a moderate to severe problem. Additional large, prospective studies to characterize the nature, distribution, and severity of pain in ALS would aid in the development of systematic approaches for pain management.

P123 USE OF VETERANS SPECIFIC ACTIVITY QUESTIONNAIRE [VSAQ] TO ESTIMATE EXERCISE TOLERANCE IN AMBULATORY AMYOTROPHIC LATERAL SCLEROSIS (AMBALS) PATIENTS

Sanjak MS^1,2

Holsten SE¹

Super M²

Langford VL¹

Bockenek Wl^1,3

Bravver EK¹

Desai UG¹

Lindblom SC^1,3

Paccico TJ^1,3

Lucas Nw^1,3

Smith NP¹

^axCarolinas Medical Center – Carolinas HealthCare System, Department of Neurology, Neuroscience and Spine Institute, Charlotte, NC., USA

^ayDepartment of Kinesiology, University of North Carolina, Charlotte, NC., USA

^azUniversity of North Carolina School of Medicine – Charlotte Campus, Charlotte, NC., USA

Email address for correspondence: [email protected]

Keywords: exercise tolerance, physical actvities, metabolic equivalent

Background: Many ALS patients want to know whether they can exercise and how much exercise they should do. Exercise prescription should be tailored to each patient's tolerance and functional capacity. The cardiopulmonary exercise test (CPET) is an established procedure used to assess an individual’s tolerance to exercise by directly measuring peak oxygen uptake. The application of CPET in an ALS multidisciplinary clinic would be time consuming, requires elaborate equipment, and technical training. Physical activity symptom questionnaires have been used to estimate patient’s tolerance and functional capacity for the development of an exercise prescription. The VSAQ (1) is validated instrument used to estimate exercise capacity that consists of physical activities (PA) listed in progressive order according to their energy demand estimated by metabolic equivalents (METs). The MET values associated with each activity are in general agreement with the American College of Sport Medicine Compendium of Physical Activities (2). One MET is defined as the amount of oxygen consumed at rest, generally equal to 3.5 ml/kg/min. Therefore, the numbers of METs express the energy cost of PA as a multiple of the resting metabolic rate.

Objective: To determine whether a questionnaire-based method using the VSAQ is a practical tool to estimate exercise capacity in ambALS.

Methods: Thirty ambALS patients completed the VSAQ. Patients were instructed to identify which PA would be associated with cardiovascular symptoms (fatigue, chest pain, or shortness of breath). The ALS Functional Rating Scale-Revised (ALSFRS-R), forced vital capacity (FVC), 25-foot walk test (25FWT), timed-up-and-go (TUG) were performed; 19 patients completed a 6 minutes walk test (6MW). Pearson’s correlations were used to test for linear relationships between the VSAQ (predicted MET) with the other outcome measures.

Result: Significant correlation was observed between METs and the ALSFRS-R (r = 0.578, p ≤ 0.001), mainly due to its correlation with the gross motor subscore (r = 0.65, p ≤ 0.001), but not with bulbar, fine motor, or respiratory subscores. AmbALS patients with higher MET were faster in TUG and 25FWT (r = −0.625, p≤.0.001 and r = −0−.484, p≤.0.001 respectively), and walked further in 6MW (r = 0.56, p < 0.001). No correlation was found between METs and FVC.

Discussion and conclusion: VSAQ is a practical tool to estimate exercise capacity of ambALS patients and may be used for safe exercise prescription to define PA that might be tolerated by the ambALS patients. Estimated exercise capacity of ambALS patients predicted by VSAQ correlated with timed functional measures of motor function and ALSFRS-R, but not with FVC or the respiratory and bulbar subscores of the ALSFRS-R.

Acknowledgements:

Carolinas ALS Garden of Hope Funds, Carolinas ALS Research Fund, Pinstripes ALS Foundation, Mike Rucker ALS Care Fund, Carolinas HealthCare Foundation, NC Jim “Catfish” Hunter Chapter - ALSA, MDA - ALS Division.

References:

• Myers J et al.Am Heart J 2001;142: 1041–6.
   PubMed Web of Science ®Google Scholar
• Ainsworth BE et al.Med Sci Sports Exerc. 2011;43(8): 1575–81.
   Google Scholar

P124 VALUES: A NATIONAL MULTICENTER STUDY EVIDENCING GENDER DIFFERENCES IN THE BEHAVIORAL VARIANT OF FRONTOTEMPORAL LOBAR DEGENERATION IN AMYOTROPHIC LATERAL SCLEROSIS

Flaherty C¹

Brothers A³

Hoffer D²

Harrison M²

Yang C¹

Legro R¹

Simmons Z¹

^baPenn State College of Medicine, Hershey, PA, USA

^bbPenn State Harrisburg, Middletown, PA, USA

^bcUniversity of Colorado, Fort Collins, CO, USA

Email address for correspondence: [email protected]

Keywords: bvFTLD, gender, HRT

Background: Behavioral variant Frontotemporal Lobar Degeneration (bvFTLD) has three recognized subtypes that reflect different patterns of deterioration: Disinhibited (DIS), Apathetic (APA), and Stereotypic (STE) subtypes (1). We hypothesized that with emergence of bvFTLD, female gender would be associated with a more anterior and bilateral pattern of neurodegeneration, characterized by a less florid presentation.

Objectives: To investigate gender differences in incidence rates and pattern of symptomology of the three bvFTLD subtypes in the ALS population as they emerge.

Methods and materials: One hundred and six subjects (53 male) from 14 ALS clinics were evaluated cross-sectionally with the caregiver rating Frontal Behavioral Inventory. Gender groups were equivalent for IQ, while females were older (male, mean = 57.1, female, mean = 62.5; p = 0.013) and males more educated (male mean = 15.5, female mean = 14.3; p = 0.018). We evaluated subtype gender differences by independent t tests. We evaluated gender associated traits by Spearman rho correlational analysis.

Results: A significantly greater proportion of males evidenced the DIS subtype (p < 0.001), with three of the five inclusive traits evidenced in males to a statistically significantly greater degree: loss of insight (p < 0.001); Jocularity (p = 0.009), and Impulsivity (p = 0.005). For the female subgroup, incidence rates for moderate-severe levels of concreteness (98.7%) and perseveration (79.8%) were markedly lower, while personal neglect (120.2%) was markedly higher. For concreteness, a significant correlation was found for the male subgroup with impulsivity (p < 0.001), while a significant relationship was found for the female group with indifference (p < 0.001). For the female subgroup, significant relationships were also detected between personal neglect and all other traits evaluated: Indifference (p < 0.001); impulsivity (p = 0.013); jocularity (p = 0.013); concreteness (p = 0.012).

Discussion and conclusion: From a review of the human neuroimaging literature across a broad spectrum of related disciplines, and based upon our pattern of findings, we have generated a model of FTLD onset consequent to disruption to the ventral tegmentum – ventral striatum – forebrain dopaminergic neural system (2). We propose a novel therapeutic approach applying the gonadal steroid hormones to attenuate the FTLD prodrome in relatively young ALS individuals in or just post-menopause or andropause (2).

References:

• Neary D, Snowden JS, Mann DM. Cognitive change in motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). J Neurol Sci 2000;180: 15–20.
   PubMed Web of Science ®Google Scholar
• Flaherty C, Brothers A, Hoffer D, Harrison M, Legro RS, Yang C, Simmons Z. Neurodegen Dis Manage (Under review).
   Google Scholar

P125 CLINICALLY MEANINGFUL CHANGE ON THE ALSFRS-R

Ratti E¹

Berry J¹

Hudgens S²

Cudkowicz M¹

Kerr D³

^bdMassachusetts General Hospital, Boston, Massachusetts, USA

^beHealthcare Analytics, Boston, Massachusetts, USA

^bfBiogen Idec, Cambridge, Massachusetts, USA

Email address for correspondence: [email protected]

Keywords: ALSFRS-R, outcome measure, clinical research

Background: ALS is heterogeneous in location of onset and rate and pattern of spread. The ALS Functional Rating Scale-Revised (ALSFRS-R) is an outcome measure with four functional domains focused on bulbar, respiratory and gross and fine motor function. A clinically meaningful change on the scale is not uniformly defined and each functional domain impacts patients’ independence and function differently. Only one prior study (1) assessed the clinical relevance of percentage changes in decline of ALSFRS-R slope. There are no evaluations of clinical meaningfulness of change in each functional domain.

Objectives: To assess the clinically meaningful threshold of change on the ALSFRS-R functional domains in the opinion of ALS expert providers.

Methods: Thirty-eight ALS experts, all members of the Northeast ALS Consortium (NEALS) were gathered in person to evaluate the clinical meaningfulness of changes in functional domains on the ALSFRS-R. Participants evaluated 48 questions/scenarios and rated changes as not-, minimally-, moderately-, or very clinically meaningful. Questions were presented as either ALSFRS-R score changes in each functional domain or changes presented as clinical passages corresponding to changes in the ALSFRS-R. Changes were in either individual functional domains or across multiple domains.

Results: When changes were presented as ALSFRS-R scores, a slight majority of providers rated a 2-point change moderately or very clinically meaningful (MVCM) in the gross-motor (58% of respondents) and bulbar (53%) domains; in the fine-motor domain, a minority of respondents rated 2 points as clinically meaningful (42%). In the respiratory domain, a clear majority rated a 2-point change as MVCM (70%); Three-point changes (but not two point changes) were rated as MVCM by the majority of respondents when the changes involved multiple functional domains. When offered clinical passages, the majority of experts rated the following changes as MVCM: ≥ 2 points (bulbar and respiratory domains) and ≥ 4 (fine motor domain). The majority of respondents rated a change of 3 points, but not 4 points, as MVCM in the gross motor domain.

Discussion and conclusion: ALS experts rated changes similarly whether presented as cases or numerical changes in the ALSFRS-R. Interestingly, smaller changes in bulbar and respiratory functional domains were considered more clinically relevant than in other domains. This suggests that perhaps changes in the total ALSFRS-R score should be adjusted for the domains affected prior to statistical analysis in trials. This could impact power calculations and trial results, providing trial analyses that are more clinically meaningful and better account for disease heterogeneity.

Acknowledgements:

Biogen Idec provided the audience response system and part of data analysis.

Reference:

• Castrillo-Viguera C, Grasso DL, Simpson E et al. Clinical significance in the change of decline in ALSFRS-R. ALS 2010;11: 178–180.
   Google Scholar

P126 STATISTICAL CONSIDERATONS IN THE PRIZE4LIFE DATA MINING CONTEST INVOLVING PREDICTING ALSFRS

Schoenfeld D¹

Hayden D¹

Zach N²

Kueffner R⁴

Leitner M³

^bgMassachusetts General Hospital, Boston, MA, USA

^bhPrize4Life, Tel Aviv, Israel

^biPrize4Life, Cambridge, MA, USA

^bjLudwig-Maximilians-University, Munich, Germany

Email address for correspondence: [email protected]

Keywords: data mining, clinical prediction, crowd-sourcing

Background: Two non-profits, PRIZE4LIFE and DREAM, organized a contest for the development of a predictor of a patient’s outcome to guide clinical management and reduce the size of clinical trials.

Objectives: We describe the statistical issues in the design and evaluation of this contest and report some of the results.

Methods: Contestants were given a training data set to develop predictors which were tested on a test data set. There was an intermediate round where contestants could repeatedly test their solution on a validation data set. These data sets were drawn from the large PROACT database of data from ALS clinical trials. The contestants used data from a patient’s first three months to predict the change in ALSFRS in the next nine months. The root-mean-squared-error was used to compare the solutions.

In this study, we required that predictions be computable from an individual patient’s data, rather than the entire data set. The mean square error from the test data set for each contestant is unbiased. But the best of these mean squared errors of would be biased if the difference between leading entries were due to chance. This bias was estimated by taking bootstrap samples from the test data set, using each bootstrap sample to determine the winner and testing the winner’s solution against the observations that were not in the sample. To assess the usefulness of the prediction we simulated clinical trials by adding a treatment effect to the elements of the test data set.

Results: A total of 1073 participants entered the challenge, 37 submitted algorithms, and 12 entered the final round. Two finalists were disqualified because their predictions depended on the entire data set. The six best contestants were not significantly different. Two contestants were selected as winners. The winning entries reduced the variance of ALSFRS changes by 17%. The extent of over-fitting was minor.

The use of the top predictor could reduce trial sample size by 22%. Although various laboratory tests were available for prediction, the past disease progression was identified by all predictors as the best predictor for the future progression

Discussion: The number of contestants participating in the final round may have been reduced by the difficulty of manipulating the data set and by the leader board. Many of the statistical problems did not materialize. It will be necessary to reduce the length of the lead in period if we intent to use these predictions to reduce the sample size of clinical trials. Since the potential reduction in sample size is only 20% large clinical trials are necessary in ALS.

P127 EVALUATING THE PENN STATE HERSHEY COMMUNICATION AND TREATMENT PREFERENCE TOOL

Walsh S¹

Stephens H²

Simmons Z²

^bkALS Association Greater Philadelphia Chapter, Philadelphia, PA, USA

^blPenn State Hershey Medical Center, Hershey, PA, USA

Email address for correspondence: [email protected]

Keywords: treatment goals, communication, evaluation

Background: As ALS progresses, patient’s goals of treatment often change. An understanding of these goals is essential for framing treatment decisions. Patients often believe that completion of an advance directive is by itself sufficient and may fail to realize that conditions anticipated by advance directives rarely develop in ALS, and that advance directives are only one piece of the planning process. We developed the Penn State Hershey ALS Communication and Treatment Preference Assessment (PSHCTPA) to document patient’s completion of legal documents related to end of life, preferences for information, services, and treatments for ALS, and thoughts about living well with the disease.

Objectives: To conduct a pilot trial of the PSHCTPA in order to permit evaluation of this instrument by patients with ALS and by ALS clinic staff.

Methods: During a 3-month period, the PSHCTPA and a research summary sheet were mailed to patients one month before their ALS Clinic appointments. The clinic physician and nurse reviewed the form with the patient in clinic. Both patients and ALS clinic staff completed evaluations of the instrument.

Results: The PSHCTPA was sent to 95 ALS clinic patients, 27 of whom completed it. Mean age was 65 years (SD 11.1), mean ALSFRSR 26.9 (SD = 11.1), and average disease duration 73 months (range = 13–265). Fourteen patients completed anonymous evaluations of the form. 85% reported no difficulty completing the form. 86% indicated that completing the form helped them communicate their wishes to the ALS clinic team and all thought that use of the form would improve the care received from the ALS team. 79% felt that communication and treatment preference assessment was an important topic to discuss. When asked how often the form should be reviewed in the ALS clinic: 36% reported “at every ALS clinic”; 36% reported “every other ALS clinic”; 7% reported “yearly”; 21% indicated “at the discretion of the ALS team”. Clinic staff reported that the form was useful in clarifying treatment goals, providing an opportunity to give resources on advance directives and other legal documents, and discuss mechanical ventilation and other end-of-life goals and decisions.

Discussion and conclusion: Patients found the form to be useful as part of their ALS care. Staff found the form to be helpful, particularly in clarifying treatment goals. Engaging with patients consistently and in a manner sensitive to their personal style of communicating and receiving end-of-life care is difficult in a busy ALS clinic. This form encourages patients to discuss end-of-life care as a routine part of their ALS clinic visit, enhances understanding of treatment goals by patients and the health care team, and may improve care by facilitating discussion of these goals.

P128 FIBEROPTIC ENDOSCOPY EVALUATION OF SWALLOWING IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS

Linhares Filho TA¹

D’Ottaviano FG¹

Rocha MSG¹

Andrade HMT¹

Alves PCL^1,2

Tabacow MEC¹

Pereira LO¹

Sierra HNM²

Stanich P²

Oda AL²

Oliveira ASB²

^bmHospital Santa Marcelina, São Paulo/SP, Brazil

^bnFederal University of São Paulo, São Paulo/SP, Brazil

Email address for correspondence: [email protected]

Keywords: deglutition, deglutition disorders, endoscopy

Background: An early diagnosis of swallowing disorders in patients with Amyotrophic Lateral Sclerosis (ALS) is important to allow patients to have a proper therapeutic approach according to clinical symptoms. The endoscopic evaluation of swallowing is an image examination that provides indirect informations about oral phase and pharyngeal phase of swallowing, and also laryngeal and pharyngeal structures in relation to motility and sensitivity.

Objective: To evaluate the swallowing of patients with ALS using fiberoptic endoscopic evaluation of swallowing (FEES).

Methods: A transversal historical cohort study in 11 patients with ALS; Six male (54.5%) and Five female (55.5%); median age 61.7 years. The period of disease reported was 26.0 ± 14.6 months and the period of diagnose of the neurological disease was 13.9 ± 12 months. These patients underwent anamnesis and FEES.

Results: All patients presented bulbar symptoms, 81.8% (9) were feeding orally and 18.2% (2) used alternative methods via nonexclusive feeding (nasogastric tube). All patients had, at least, one phase of swallowing altered, but only 72.7% had swallowing complaints. The preparatory phase was altered in 63.6% and the oral and pharyngeal phases in 100% of individuals, despite of the consistence of the food. The laryngeal penetration or tracheal aspiration was observed in 90.9% of the patients during the pharyngeal phase of swallowing of liquid.

Discussion: The endoscopic evaluation of swallowing can assess every food consistency and can still be carried out in bedridden patients or even those using alternative feeding devices and respiratory devices, increasing its options of diagnosis and continuance. The premature spillage is more often with thin liquid texture, it is the major cause of tracheal aspiration even in the early stages of the disease with light changes in the oral muscles. The laryngeal penetration or tracheal aspiration of food can indicate inability to control food bolus, a reduction in the elevation of hyoid–larynx complex, a decrease in the contraction of the pharyngeal constrictor muscle and or presence of residues in valecule and piriform recesses, exposing the patient to the risk of bronchoaspiration.

Conclusion: The oral and pharyngeal phases are the most frequently altered in patients with ALS. The laryngeal penetration or tracheal aspiration occurred more frequently during pharyngeal phase of swallowing of liquid. Despite the absence of any swallowing complaint, the deglutition disorder is frequent in ALS, so that it is mandatory to investigate the dysphagia in these patients.

P129 PRIMARY LATERAL SCLEROSIS: ARE THE PRINGLE CRITERIA STILL VALID?

Wais V

Rosenbohm A

Ludolph AC

Dorst J

Department neurology, University Ulm, Ulm, Baden-Württemberg, Germany

Email address for correspondence: [email protected]

Keywords: Pringle criteria, primary lateral sclerosis, diagnostic criteria

Objective: Since primary lateral sclerosis (PLS) is mainly a clinical diagnosis validity of its diagnostic criteria is crucial. For 20 years the Pringle criteria has been commonly used for this purpose; however, the validity of the Pringle criteria has never been investigated.

Methods: In this study, we reviewed the Pringle criteria in the context of our database of 76 patients who were diagnosed in specialised motoneuron outpatient clinics.

Results: We found that the Pringle criteria cannot be applied to most of the patients. For example, the beginning of the disease, PLS patients frequently showed an asymmetrical clinic presentation. Further observations have been made, some of them, based on the new scientific insights which have been discovered in the last years, contradict the Pringle criteria and will be discussed.

Conclusion: Based on diagnostic assessment of our large cohort of PLS patient, we suggest a new diagnostic pattern based on our results and considerations.

P130 AN EVALUATION OF NEWLY DIAGNOSED PATIENT NEEDS: LESSONS LEARNED FROM PATIENTS AND FAMILIES

Klapper J¹

Walsh S¹

Schwartz S¹

Hill S¹

Simmons Z²

^boALS Association Greater Philadelphia Chapter, Philadelphia, PA, USA

^bpPenn State Hershey Medical Center, Hershey, PA, USA

Email address for correspondence: [email protected]

Keywords: diagnosis, coping, patient services

Background: The ALS Association Greater Philadelphia Chapter patient service staff sought to understand the needs of newly diagnosed patients and their families during the period shortly after diagnosis. Many services and programs are available, but there is no information on the usefulness of these services to patients and families.

Objectives: To seek information about coping behaviours and services utilized by patients and family members in the first 6 months following diagnosis of ALS.

Methods: An evidence based practice model was utilized. A review of the literature did not identify research addressing these specific needs during the 6-month period following diagnosis. A focus group of expert clinicians in ALS care (social workers, a nurse, and a counsellor) developed a survey. Persons with ALS (PALS) diagnosed in the previous 2 years and their family members were contacted by email or via the postal service and asked to complete the survey.

Results: Four hundred and seventeen people were contacted by conventional mail with a response rate of 22.2%, whereas 278 were contacted by email with a response rate was 23.7%, giving a total response rate of 22.8%. 50.3% of respondents were PALS and 49.7% were family members. There were no significant differences between the PALS or family groups on any items. Responses were therefore combined. The most helpful services were the first clinic visit (79%) information (59%) and support groups (22%). 80% sought information outside of the physician appointment, with the internet as most common source. Only 31% wished to meet others during this period. Responses to what helped coping during this period were, from most to least frequent responses: (1) Friends and family; (2) ALS Clinic visit; (3) Gathering information; (4) Spiritual life; (5) Own perspective; and (6) Avoidance. When asked what else would be helpful, only 50% responded and those responses were split between an in-person, or web-based seminar, ‘webinar’. Only 2.2% reported attending a newly diagnosed seminar, responding that they did not do so because it was inconvenient (43%); they were not aware (38%); or they were not ready (33%).

Discussion and conclusion: PALS and their families have similar coping experiences and behaviours in the first 6 months following diagnosis. The primary coping strategies focus on information seeking, expert medical care at a multidisciplinary clinic and connecting with others. The results of this survey are being used to evaluate and guide services for the ALS chapter.

P131 FALSE POSITIVE DIAGNOSIS OF AMYOTROPHIC LATERAL SCLEROSIS: A TWO-YEAR RETROSPECTIVE COHORT STUDY IN TURIN

Cammarosano S¹

Ilardi A¹

Canosa A¹

Moglia C¹

Manera U¹

Bertuzzo D¹

Mongini T²

Calvo A¹

Chiò A¹

^bqALS Center

^br‘Rita Levi Montalcini’ Department of Neuroscience, University of Torino, Torino, Italy

Email address for correspondence: [email protected]

Keywords: ALS, misdiagnosis, atypical features

Aims: To verify how many cases of alleged ALS referred to the Turin ALS Center for diagnosis confirmation received a different diagnosis, and to assess their characteristics.

Methods: The Turin ALS center is the reference center for ALS in Piedmont region. All subjects referred to the center from 1 January 2011 to 31 December 2012 with an alleged diagnosis of ALS have been included in the study. All subjects underwent a complete diagnostic work-up, including brain and cervical MRI scan, neurophysiological examinations and other exams when deemed necessary, according to EFNS guidelines for ALS.

Results: Out of a total of 390 patients referred to our ALS Center, 296 received a final diagnosis of ALS and 27 a diagnosis of non-ALS MNDs (ie progressive muscular atrophy, primary lateral sclerosis, monomelic MND, and post-polio syndrome). Sixty-seven patients (17.2%) were reclassified as having other disorders, the most common being cervical myelopathy and myopathies. The 296 patients meeting the eligibility criteria included 124 women and 172 men and had a mean age at onset of 63.1 years (men: 62.4; women: 64.2). The presentation was spinal in 194 cases (65.5%) and bulbar in 99 cases (33.5%). The 27 patients meeting a diagnosis of non-ALS MND included 13 women and 14 men; the mean age at onset was 54.7 years (men: 58.0; women: 53.3). The 67 patients affected by other diseases included 42 men and 25 women; their mean age at onset was 53.7 years (men: 51.8; women: 56.9). The most frequent diagnoses were cervical myelopathies and extrapyramidal disorders (men) and myopathies (women). The male/female distribution showed no significant difference among the three groups (p = 0.61). Patients not confirmed as affected by ALS were significantly younger (p < 0.05) and showed generalized asthenia (p < 0.05), atypical symptoms (p < 0.05), and symmetrical disturbances (p < 0.05) as presentation symptoms.

Conclusions: In our series, 17.8% of patients referred as ALS were reclassified to be affected by other disorders, higher rate than that previously reported in other population-based studies. In our study, misdiagnosis was more frequent in young men and the most common confounding symptom was symmetrical weakness at the lower limb muscles. In the absence of a definitive diagnostic test, the diagnosis of ALS is clinically based. All suspected ALS patients should undergo electrophysiological testing by an experienced neurophysiologist while imaging is required in some presentations, such as limb-onset without bulbar involvement, or symptoms and signs isolated to the bulbar region. Failure to progress as expected or the development of atypical features should prompt reconsideration of the diagnosis in order to exclude treatable ALS mimics.

P132 PHENOTYPE AND GENOTYPE STUDIES OF ALS CASES IN ALS-ASI FAMILIES

Corcia P^1,2

Blasco H²

Biberon J²

Couratier P³

Deschamps R⁴

Desnuelle C⁵

Viader F⁶

Pautot V⁷

Maugin D⁷

Salachas F⁸

Meininger V⁸

Camu W⁹

Vourc’H P²

^bsCENTRE SLA, TOURS, France

^btUMR Inserm U930, Université François-Rabelais de Tours, TOURS, France

^buCentre SLA, Limoges, France

^bvDepartment of Neurology, Fort de France, France

^bwcentre SLA, Nice, France

^bxcentre SLA, Caen, France

^bycentre SLA, Angers, France

^bzFédération des Maladies du Système Nerveux, Centre Référent Maladie Rare SLA, Hôpital de la Pitié-Salpêtrière, PARIS, France

^caCentre SLA, Montpellier, France

Email address for correspondence: [email protected]

Keywords: phenotype, co-occurrence, SMA

Background: Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the most prevalent motor neuron affections in adulthood and childhood, respectively. Since both conditions are characterized by lower motor neuron degeneration and several reports mentioned occurrence of both disorders within the same family, a common genetic factor to both conditions was suspected. Currently, there is no evidence for a main role of SMN genes in such co-occurrence and the phenotype of these cases has never been well described.

Objectives: To determine the phenotype and genotype of these ALS cases.

Methods: We performed a retrospective study on 11 ALS cases from nine families in which cases of ALS and SMA co-exist. For all ALS cases, gender, age of onset, site of onset and duration of the disease were collected. After written informed consent, SOD1, TARDBP, FUS, C9ORF72 and VAPB genes were screened in the samples. A quantitative SMN gene copy number was also performed in all cases.

Results: In our cohort, there were 8 familial ALS (FALS) comprising 6 men and 5 women, with a mean age of onset of 58.5 years. Site of onset ranged from bulbar (1 case), upper limb (1 case) and lower leg (9 cases). Seven cases died after a mean duration of disease was 18.3 months, the remaining four were still alive after a median duration of 72 months. Three mutations were found in three different pedigrees: two in the SOD1 gene (G147N, E121G) and one in the c9ORF72 gene (number of GGGCGG repeat > 30). 3 out of the11 had abnormal SMN1 copy numbers.

Discussion and conclusion: Since the phenotype of these cases matched for that of classical FALS, theses co-occurrences, more frequent than expected, might support searching for other genetic factors and strengthens the oligogenic hypothesis of MND.

P133 CLINICAL AND MOLECULAR CHARACTERIZATION OF A COHORT OF PATIENTS WITH DISTAL MOTOR NEURONOPATHY

Riva N¹

Scarlato M¹

Scarlino S¹

Del Bo R²

Comi GP²

Corbo M³

Penco S³

Ferrari M⁴

Foglio A⁴

Grimaldi LM⁵

Comi G¹

Nobile-Orazio E⁶

Marrosu MG⁷

Gerevini S⁸

Bolino A¹

Previtali S¹

^cbDepartment of Neurology and Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy

^ccDino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy

^cdMedical Genetics, Department of Laboratory Medicine, Niguarda Ca’ Granda Hospital, Milan, Italy

^ceLaboratory of Clinical Molecular Biology, Diagnostica e Ricerca San Raffaele, Milan, Italy

^cfDepartment of Neuroscience AUSL n.2, Caltanissetta, Italy

^cgDepartment of Neurological Sciences, University of Milan; 2nd Neurology, IRCCS Humanitas Clinical Institute, Milan, Italy

^chDepartment of Neurology, University of Cagliari, Cagliari, Italy

^ciDepartment of Neuroradiology San Raffaele Scientific Institute, Milan, Italy

Email address for correspondence: [email protected]

Keywords: distal SMA, lower motor neuron disease, diagnosis

Background: Within the vast spectrum of Lower Motor Neuron Syndromes, the distal hereditary motor neuropathies/neuronopathies (dHMN) represent a genetically heterogeneous group of diseases characterized by distal muscle weakness and atrophy, and no or minor sensory abnormalities. However, 80-90% of patients with dHMN carry a mutation in an as-yet undiscovered gene.

Objectives: Here we present the clinical, pathological and molecular findings of patients presenting with motor neuropathy evaluated for the four most frequent genes responsible for dHMN: small heat shock protein 1 and 8 (HSPB1 and 8), glycyl-tRNA synthetase (GARS), Berardinelli-Seip Congenital Lipodystrophy type 2 gene (BSCL2), and senataxin (SETX).

Methods: For all patients, demographic characteristics, family history, disease duration, and site of onset were recorded. The contribution of additional diagnostic tests, including sensory or motor nerve biopsy and brachial plexus magnetic resonance imaging (MRI), has also been considered.

Results: A total number of 37 unrelated patients were evaluated (Males: 13 and Females: 24). Family history was positive for five patients, while consanguinity was observed in three patients. Mean age at onset was 33.9 years ± 20.7; mean disease duration was 12.9 years ± SD: 11.3. The site of onset was at the upper limbs for 9 patients (24.3%) and lower limbs for 28 patients (75.7%).

The molecular analysis identified mutations in four patients in three different genes. Of note, two mutations in SETX were identified in two young males previously diagnosed as multifocal motor neuropathy.

Moreover, we found a previously reported mutation in the BSCL2 gene in a 13-year-old boy presenting with progressive upper limb weakness. We also identified a previously reported mutation in the HSPB1 gene segregating in a large Sardinian pedigree with a variable clinical phenotype ranging from CMT2 to dHMN and spastic paraplegia. Interestingly, the following alternative diagnosis was formulated at subsequent follow-up for five patients: inclusion body-myositis (supported by motor nerve and muscle biopsy), diffuse sporadic spinal muscle atrophy (supported by motor nerve biopsy), flair-arm syndrome (two patients), and Hyrayama disease (supported by brachial plexus MRI).

Discussion and conclusion: Our case record confirms a similar percentage, of detection-rate for mutations in dHMN genes, when compared to the literature. Moreover, we suggest that genetic screening should be considered in the context of a complex diagnostic approach, in order not to overlook other possible diagnoses.

References:

• Dierick I, Baets J, Irobi J et al. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. Brain. 2008;131: 1217–27.
   PubMedGoogle Scholar
• Rossor AM, Kalmar B, Greensmith L, Reilly MM. The distal hereditary motor neuropathies. J Neurol Neurosurg Psychiatry. 2012;83: 6–14.
   PubMed Web of Science ®Google Scholar

P134 THE CLINICAL CHARACTERISTICS OF ALS PATIENTS IN DIFFERENT ETHNIC GROUPS

Kwan J

Vintayen E

Zilliox RL

Russell J

Diaz-Abad M

University of Maryland, Baltimore, MD, USA

Email address for correspondence: [email protected]

Keywords: ethnic groups, disease progression, prognosis

Background: The incidence and prevalence of ALS has been reported to be lower in non-White ethnic groups compared to Caucasians in the United States (1,2). Other studies have suggested that there is a difference in the mortality in non-White ALS patients compared to that of Caucasian ALS patients (3). The cause for these differences between ethnic groups is unknown and may be related to variations in the genetic background. The clinical characteristics that may reflect the genetic variability in non-White ALS patients have not been well described.

Objective: The aim of this study is to compare the clinical characteristics of ALS patients in different ethnic groups.

Method: A retrospective chart review was conducted for all patients diagnosed with ALS at University of Maryland ALS Clinic between 2007 and 2013. Information extracted include: ethnicity, gender, revised El Escorial diagnostic criteria classification at the time of diagnosis, date of symptom onset, date of diagnosis, site of symptom onset, clinical measures of motor function, ALSFRS-R, forced vital capacity, and riluzole use. The rate of disease progression was calculated as follows: (ALSFRS-R score at first time point evaluation – ALSFRS-R score at last time point)/follow-up interval in months.

Results: The medical records for 86 ALS patients were reviewed. There were 72 (83.7%) non-Hispanic Caucasian patients and 14 (16.3%) non-White patients. There were 12 African American patients, one Asian patient, and one Hispanic patient. There were 39 (45%) women and 47 (55%) men. Fifty-five (64%) patients had limb onset ALS and 29 (33.7%) patients had bulbar onset ALS. The frequency of bulbar onset ALS was greater in Caucasian patients compared to that of non-White patients (p = 0.048). The rate of disease progression was similar in non-White ALS patients compared to Caucasian ALS patients. There were no other significant demographic or clinical differences between non-White and Caucasian ALS patients.

Conclusion: Non-White ALS patients may be underrepresented in a typical academic medical center ALS clinic. Most non-White ALS patients have limb onset ALS which may confer a more favourable prognosis and partly account for the lower mortality in this group of patients.

References:

• Cronin S, Hardiman O, Traynor BJ. Ethnic variation in the incidence of ALS: a systematic review. Neurology. 2007 Mar 27;68(13): 1002–7.
   Google Scholar
• Annegers JF, Appel S, Lee JR, Perkins P. Incidence and prevalence of amyotrophic lateral sclerosis in Harris County, Texas, 1985–1988. Arch Neurol 1991;48: 589–593.
   PubMed Web of Science ®Google Scholar
• McCluskey K, McCluskey L. Racial disparity in mortality from ALS/MND in US African Americans. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5(suppl): 73–78.
   Google Scholar

P135 URIC ACID IN AMYOTROPHIC LATERAL SCLEROSIS: NO EFFECT ON OUTCOME IN A POPULATION-BASED SERIES

Moglia C

Bertuzzo D

Manera U

Cammarosano S

Galmozzi F

Cugnasco P

Calvo A

Chiò A

ALS Center, University of Torino, Torino, Italy

Email address for correspondence: [email protected]

Keywords: ALS, uric acid, prognosis

Background: Elevated uric acid levels have recently been found to be associated with slower disease progression in several neurodegenerative disorders (Parkinson’s disease, Huntington’s disease, and multiple system atrophy). There are limited and uneven results in ALS.

Methods: ALS patients resident in Piemonte and seen between 2007 and 2011 have been considered for the study. Blood biochemical factors studied included glucose, creatinine, creatine kinase, uric acid, cholesterol, triglycerides, HDL, LDL, albumin, bilirubin, TSH, fT3, fT4, and electrolytes (Na, K, Cl, Mg, and Fe). Serum samples were obtained at the time of diagnosis and immediately processed. The median time from onset to diagnosis was 8 months. All biochemical analyses were performed in the same laboratory. The mean outcome measure was survival time, calculated as tracheostomy-free survival. Levels of biochemical factors were stratified into quartiles, based on the distribution of the results. Since some biochemical values significantly differed between genders, stratification was performed separately for men and women. In Cox multivariable analysis (stepwise backward), clinical factors known to be related to survival were considered as covariates (ie age at onset, site of onset, FVC, ALSFRS-R score, BMI, diagnostic delay, and riluzole use).

Results: A total of 312 patients were included (169 men and 143 women; mean age at onset 65.5 years ± 10.3. Uric acid levels were higher in men than in women (5.3 ± 1.3 vs. 4.4 ± 1.2, p = 0.0001). In univariate analysis, uric acid levels were not correlated with survival both in men and in women, although men with the highest quartile of acid uric levels showed a 2-year longer median survival than all other quartiles. In Cox multivariable analysis, uric acid level did not prove to be an independent prognostic factor both in men and in women.

Discussion: We have found no evidence of a specific effect of uric acid levels on ALS outcome in a population-based series of ALS patients.