P174 PATIENT CARE COORDINATION AT CAROLINAS NEUROMUSCULAR/ALS – MDA CENTER: DISEASE-SPECIFIC CARE CERTIFICATION
BLYTHE A1, WILLIAMS NM1, BLACK KJ1, NICHOLS MS1, WRIGHT KA1, BRAVVER E 1,2, DESAI U1, BROOKS BR1
1Carolinas Medical Center - Department of Neurology, Charlotte, NC, United States, 2University of North Carolina - Chapel Hill School of Medicine Department of Neurology, Chapell Hill, NC, United States, 3University of North Carolina - Charlotte Department of Kinesiology, Charlotte, NC, United States
E-mail address for correspondence: anne.blythe@carolinashealth care.org
Keywords: The Joint Commission, performance meaures, outcome measures
Background: DSC certification by The Joint Commission (TJC) has been designed to recognize disease management programs for superior quality. A fore-runner of these programs in neurology has been the Primary Stroke Center Certification developed in collaboration with the American Stroke Association which depends on a Stroke Core Measure Set and Stroke Performance Measure Requirements based on the Brain Attack Coalition's guidelines. Longitudinal analysis of stroke diagnosis, treatment and outcome is the key determinant of certification and re-certification. DSC Certification is currently a voluntary process. At the heart of DSC certification is a formal review of patient care data according to established guidelines. In the past, many ALS clinics participated voluntarily in ALS CARE which was a paper-based documentation of patient care encounters longitudinally that permitted assessment of each ALS Clinic's adherence to the 1999 American Academy of Neurology (AAN) ALS Practice Parameter (1) and benchmarks for ALS care provided in the real world (2, 3). In parallel, the ALS Association CenterSM Program voluntarily certified ALS Centers based on the facilities and personnel available but did not require a longitudinal analysis of patient outcomes. The recently released expanded 2009 AAN ALS Practice Parameter (4) will be the basis for developing ALS DSC certification with TJC together with the ALS Research Group (ALSRG) in collaboration with the AAN.
Objective: Implement the first three core performance measures of the ALS DSC certification profile and collect quantitative patient data for outcomes assessment in a large ALS Clinic in the Department of Neurology situated in the third largest public healthcare system in the United States - Carolinas Healthcare System.
Methods: Ambulatory care nurse meetings with allied health staff and professional staff reviewed standardized performance measures and identified cognitive, psychiatric, and falls performance measures based on validated clinimetric scales which were implemented in intake, follow-up, and multidisciplinary clinics.
Results: Consensus regarding cognitive, psychiatric and falls performance measures required implementation of several meetings to review validation parameters and integrate the clinimetric scales with the electronic medical record. Collecting performance measures in each patient increased clinical encounter time by 8%. Collating performance measure outcomes in each patient required additional administrative time measured at 1-2% per patient for three performance measures.
Conclusions: Initiating three performance measures in an ALS clinic requires increased encounter time and increased administrative time. Increased complexity of the performance measures, coupled with increased analysis in real time of the outcomes identified by these performance measures has led us to identify increased time needs for ALS DSC certification. Implementation of additional performance measures will require attention to increased efficiencies at the clinic level.
Supported by: Carolinas ALS Endowment, Pinstripes Foundation, Carolinas Healthcare Foundation, Muscular Dystrophy Association/ALS Division
References:
- Miller RG, Rosenberg JA, Gelinas DF, et al. Neurology. 1999;52(7):1311–1323.
- Bradley RG, Anderson F, Gouda N, et al. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(4):240–244.
- Miller RG, Anderson F, Brooks BR, et al. Ann Neurol. 2009;65 Suppl 1:S24–S28.
- Miller RG, Jackson CE, Kasarskis EJ, et al. Neurology. 2009; 73(15):1218–1233.
P175 COGNITION – AFFECT – BULBAR – RESPIRATORY – UPPER AND – LOWER EXTREMITY CLINICAL STAGING IN AMYOTROPHIC LATERAL SCLEROSIS PATIENTS: CROSS-SECTIONAL ANALYSIS AT FIRST CLINIC VISIT IN 264 PATIENT VALIDATION COHORT
BROOKS BR1,4, SANJAK MS1,5, BRAVVER E1,4, BOCKENEK WL2,6, DESAI U1,5, LINDBLOM SS3, PACCICO T6, WARD AL1, DUFFY K1, WRIGHT AK1, WILLIAMS NM1, NICHOLS MS1, BLACK KJ1, O'NEILL M1, LANGFORD V1,5, WALGREN K1, RUSSO P1, BLYTHE A1
1Carolinas Medical Center - Department of Neurology, Charlotte, NC, United States, 2Carolinas Rehabilitation - Department of Physical Medicine, Charlotte, NC, United States, 3Carolinas Medical Center - Department of Internal Medicine, Charlotte, NC, United States, 4University of North Carolina - Chapel Hill - Department of Neurology, Chapel Hill, NC, United States, 5University of North Carolina - Charlotte - Department of Kinesiology, Charlotte, NC, United States, 6University of North Carolina - Chapel Hill - Department of Physical Medicine and Rehabilitation, Chapel HIll, NC, United States
E-mail address for correspondence: benjamin.brooks@carolinas healthcare.org
Keywords: disease specific certification, patient outcomes, performance measures
Background: Advances in ALS classification have depended upon El Escorial, Airlie House and Awaji criteria for the diagnosis. However, the need is increasing for a comprehensive assessment of disease involvement (staging) and disease severity (grading) in each patient to define the appropriate disease endo-phenotype. Early attempts at staging (1, 2, 3) were not sufficiently comprehensive nor based on established criteria. There is a need for ALS disease staging which will provide a format for ALS Disease Specific Certification by the Joint Commision based on assessment of performance measurements at individual ALS Clinics. ALS specific treatments have been developed for different features of the disease and need to be implemented at the specific stage.
Objective: Evaluate an ALS disease staging system that organizes disease-associated anatomical or domain (behavior, function) involvement together with progression milestones to provide a validated description of the extent of ALS involvement so that results of treatments may be compared and understood.
Methods: Domain definition was based on literature cross-sectional samples of 40-2456 patients at different stages and previously presented (4). The development cohort consisted of 264 unselected ALS patients from a large MDA/ALS Center who were analyzed cross-sectionally and prospectively to validate six (6) staging domains. Stage 0 - normal function; Stage - 1 no treatment; Stage 2 - no or minimal treatment; Stage 3 and 4 - treatment; Stage 5 - severe disease; Stage 6 - Hospice eligible.
Results: At the first clinic visit ALS patients above stage 0 or 1 were - Cognitive (C)-impaired (15%), behavior-impaired (4%), -mixed (2%); - Affect(A)-pseudobulbar (10%), -depressed (13%), -mixed (9%); - Bulbar(B)-speech-impaired (5%), swallow-impaired (14%), -mixed (25%); - Respiratory (R) -impaired (30%), -assisted (9%); - Upper Extremity (UE)-impaired (31%), -dependent (14%), -mixed (6%) and - Lower Extremity(LE)-impaired (19%), -dependent (21%). C-patients (16.7%) and A-patients (26.5%) were spread throughout B, R , UE and LE domains. B-patients (18.9%) and R-patients (28.7%) free of C- and A-involvement were distributed through UE and LE domains. The remaining UE- and LE-patients had no C-, A-, B- and R-involvement. Progression from initial stages through later stages proceeded over 2-4 years.
Conclusions: ALS staging permits definition of disease involvement over 6 domains on a per patient basis. Further validation is proceeding with a second validation cohort to confirm this staging system.
Supported by: Carolinas Healthcare Foundation, Carolinas ALS Research Fund, Pinstripes Foundation, Muscular Dystrophy Association.
References:
- Dal Bello-Haas V, et al. Phys Ther. 1998 Dec;78(12):1312–24.
- Strand EA, et al. Dysphagia 1996;11:129–139.
- Sinaki M, Mulder DW. Mayo Clin Proc. 1978;53(3): 173–8.
- Brooks BR, et al. Neuroepidemiology 2010;34:273.
P176 INITIAL DESIGN AND EVALUATION OF A NEW CLINICAL ASSESSMENT TOOL TO QUANTIFY MOTOR DEFICITS IN ALS PATIENTS: THE MADRID QUANTITATIVE NEUROMUSCULAR ASSESSMENT, MAQUINA
MORA JS, VALERA F, MACÍAS AI, HURTADO F, MARÍN S, MINAYA FJ, MASCÍAS J, CHAVERRI D
ALS Unit, Hospital Carlos III, Madrid, Spain
E-mail address for correspondence: [email protected]
Keywords: clinical-assessment, timed-tests, impairment-quantification
Background: In clinical practice and trials different scales (e.g. ALSFRS-R) or tests (e.g. QMA) are used to evaluate ALS motor deficits. None is fully satisfactory. Waiting for the adequate biomarker, a permanent search for new clinical assessment tools is warranted.
Objectives: The final objective is to develop and validate a new clinical ALS assessment tool, MAQUINA (Madrid Quantitative Neuromuscular Assessment). The first step was to identify or design the most adequate tests to study, and then to evaluate them, in order to design a protocol of a limited number of easy use tests, with few technical drawbacks, prolonged applicability, and acceptable time duration.
Methods: A series of stages were followed: 1) Literature Search. Most important medical databases were searched and reviewed for published tests. A Focal Group of experienced ALS neurologists and physiotherapists selected or designed best tests for initial study based on best evidence and clinical experience; 2) An evaluation of those tests was done in up to 35 ALS patients by those professionals. Quantitative evaluation included number and percentage of technical drawbacks and tests failures, and time spent. Qualitative evaluation labeled each test 0 to 3 for facility of use, technical drawbacks, duplicity, prolonged applicability and time consuming. Best rated non duplicated tests were finally selected to compose MAQUINA.
Results: Timed bulbar tests pataka (10-repetition) and count (up to 10-count), and arm tests arm pedalling (10-rounds) and marbles (10-marbles move) were of easy use and moderate technical drawback or failure in advanced disease. Pegs was rejected for duplicity and lower reliability. Three up&go leg test variants had moderately high technical drawbacks and test failures, the up&3m walk test being best rated and so selected. Similar ratings were obtained leg pedalling (10-rounds). Palm tapping and sole tapping (10-repetition) had higher technical drawback or failure in advanced disease. Technical adjustments in legs tests were made to extend time of use. Total performance time of finally selected tests is 20 minutes.
Conclusions: Based on best evidence and clinical experience, eleven timed tests, three in right and left sides, were preselected and evaluated. Eight were selected based on least technical drawbacks, duplicity or time consumed and prolonged applicability. Reliability studies are described in another communication. Comparison with current quantified muscle assessment tests and functional scales and validation of the MAQUINA protocol is under way.
Acknowledgment: Work supported by Fundación Mutua Madrileña.
P177 INTER- AND INTRA-RATER RELIABILITY OF DESIGNED TESTS TO ASSESS ALS PATIENTS WITHIN THE MADRID QUANTITATIVE NEUROMUSCULAR ASSESSMENT, MAQUINA
MORA JS, MACÍAS AI, VALERA HF, HURTADO F, MARIN S, HERNÁNDEZ M, MORAN Y, SALAS T
ALS Unit, Hospital Carlos III, Madrid, Madrid, Spain
E-mail address for correspondence: [email protected]
Keywords: clinical-assessment, timed-tests, impairment-quantification
Background: A battery of timed tests to quantify motor deficits in ALS patients is being designed. Quantitative and qualitative evaluation of facility of use, technical drawbacks and time applicability was done in preselected tests for bulbar, arms and legs impairment. Reliability, validation and comparison studies are necessary to consider this battery a useful tool for clinical practice and trials.
Objectives: To analyze inter- and intra-rater reliability of eleven initially preselected timed test to determine best tests for inclusion in MAQUINA.
Methods: Up to thirty-five ALS patients were examined by two physiotherapists trained in the standardized tests protocol. The patients were examined twice by each examiner in random order and established times. The exam included 2 timed tests of bulbar impairment, 4 of arms and 5 of legs impairment, three of them in right and left sides. Five standardized tests to quantify muscle strength in selected arm and in leg muscle groups, and 1 test of respiratory function were also analyzed, for further comparison studies. The Kappa index was used to determine inter-rater reliability, with 95% CI. Statistical analyses to establish absolute and relative proportions were carried out with SPSS 15.0 for Windows. Reliability analysis was obtained using an index of acceptable Kappa (0.6–0.8).
Results: Bulbar impairment tests, pataka and count, had very good inter- and intra-rater agreements, (Kappa 0.8–1.00). Arms impairment tests palm tapping and pedaling had very good inter- and intra-rater agreements, marbles had very good intra-rater and good inter-rater (Kappa 0.6–0.8) agreements, and pegs had moderate (Kappa 0.4–0.6) intra-rater and fair (Kappa 0.2–0.4) inter-rater agreements. Legs impairment tests sole tapping, pedaling, and up&3m walk had very good inter- and intra-rater agreements, up&1m walk and up&go had very good intra-rater and good inter-rater agreements. Slow vital capacity measurements had very good intra- and inter-rater agreements. Quantified knee flexion and extension and grip strength had very good intra- and inter-rater agreements, elbow flexion and extension had good intra- and inter-rater agreements. No significant differences were observed between dominant and non-dominant limb.
Conclusions: 1) The intra- and inter-rater reliability was good to very good (Kappa above 0.6) in all tests preselected for MAQUINA, except in pegs for arm impairment and so it was excluded; 2) Comparison studies with most frequently used ALS clinical assessment tools, ALSFRS-r and QMA quantified muscle strength, to validate a protocol for MAQUINA, are under way.
Acknowledgment: Work supported by Fundación Mutua Madrileña.
P178 SIT TO STAND AND STAIR CLIMBING ARE MORE SENSITIVE THAN 25 FOOT WALK TEST AND TIMED UP AND GO IN PREDICTING PROGRESSION IN AMBULATORY AMYOTROPHIC LATERAL SCLEROSIS PATIENTS
SANJAK M1,2, GANDHI RB1, RUSSO P1, DESAI U1,3, BRAVVER E1,3, BROOKS BR1,3
1Carolinas Medical Center Department of Neurology, Charlotte, NC, United States, 2Department of Kinesiology, University of North Carolinas, Charlotte, NC, United States, 3Department of Neurology, University of North Carolina, Chapel Hill, NC, United States
E-mail address for correspondence: Mohammed.Sanjak@carolinas healthcare.org
Keywords: outcome measure, sit to stand test, stair climbing test
Background: Evaluation of functional motor impairments in ALS patient is necessary for proper clinical decision making, natural history, and efficacy of therapeutics. ALSFRS-R and forced vital capacity (FVC) are among the most used tools for this purpose. Timed functional tests such as sit to stand (STS), stair climbing (SC), 25 foot walk test (25FWT) and time up and go (TUG) are quantitative, reliable, and easy to perform and frequently used in other neurodegenerative diseases but they are less commonly applied in ALS.
Objective: To compare the rate of progression in ALSFRS-R total and its sub scores of walking, stair, and respiratory function with the rate of decline in STS, SC, 25FWT, and TUG in 16 ambulatory ALS patients.
Methods: Sixteen ambulatory patients were evaluated by ALSFRS-R, FVC, and timed mobility tests consisting of STS, SC, 25FWT, at baseline, and were followed every 3 months up to 9 months. ALSFRS-R and FVC, 25FWT and TUG were evaluated using standard procedures. STS was evaluated as the time it took the patient to stand up 3 consecutive times from seated position. TUG was evaluated as the time it took the patient to stand up from standard chair with arm rest, walk 3 meters, and return to the chair with without assistance. Stair climbing was evaluated as the time it took the patients to go up and down 4 steps. ALSFRS-R and FVC were evaluated following standard procedures. Change in functional outcome measure was calculated as percent change from baseline.
Results: STS and SC decrease significantly faster than the 25FWT, TUG ALSFRS-R over the 9 month period. This observation is separately validated and supported by faster decline in the stair than the walking ALSFRS-R sub scores. ALSFRS-R respiratory sub score was slightly faster and declined more uniformly than measured FVC.
Discussion and conclusions: Staging of ALS is one of the determinant factors in selecting appropriate outcome measures to evaluate progression and interventions. Different components of the motor function are lost at different rates depending on the stage of ALS. In ambulatory ALS patients, the loss of the ability to stand up and climb stairs (‘antigravity functional activities’) are lost faster and earlier than walking. Antigravity activities like climbing stairs and standing up require a greater number and larger motor units to work which are known to be lost earlier; this may be the reason for faster progression in ALS compared to just walking. These functional outcome measures may be used to evaluate intervention in the early stage of the disease, and for small pilot studies in phase I or II clinical trials. In a large, long period efficacy trials (ie Phase III trials), the ALSFRS-R scale seems to be superior and include items that appropriately reflect changes in most aspects of motor function.
P179 ADMINISTERING AND INTERPRETING A CLINICAL BULBAR SCALE FOR ALS
BALL L1, PATTEE G2
1East Carolina University, Greenville, NC, United States, 2University of Nebraska Medical Center, Omaha, NE, United States
E-mail address for correspondence: [email protected]
Keywords: bulbar, clinical evaluation, dysarthria
Background: The CBS is designed to quickly and effectively assess bulbar functioning of PALS in early stages and throughout disease duration. In addition to the clinical detail of this bulbar scale, its intended design is for use across multiple clinic visits to objectively monitor the progression of bulbar motor (speech and swallowing) features in ALS clinical trials. Critical to identification of bulbar symptoms is specification of features characteristic of upper motor neuron (UMN) and/or lower motor neuron (LMN) impairment. In many cases, the ALS Team speech-language pathologist (SLP) evaluates speech and swallowing function during each clinic visit, however, these data often are reported in summary or descriptive form, with few objective results/data documented. The CBS considers interactions between ALS and contextual factors, defining levels of disability including body structures (lips, tongue, palate, pharynx), functions (speech, swallowing), activities (intelligibility, rate, intonation, naturalness, aspiration risk, inefficient dietary intake), and participation (communication effectiveness, community interactions, social networks/dining, employment/volunteer activities, telephone use).
Methods: Individual protocol items will be presented with data illustrating change with specific data points (eg, speaking rate, intelligibility, communication effectiveness). The relationship between speaking rate and intelligibility across time illustrates a non-normal trajectory but consistent change among bulbar and spinal onset ALS. Participants with ALS (n = 133) completed CBS components and results will be presented in this session.
Results: These data indicate a potential need for augmentative communication interventions when speaking rate reaches the 120–130 words per minute level, regardless of current level of intelligibility. Kaplan Meyer survival functions calculated to illustrate survival of functional speech indicate an abbreviated survival of only 308 days for individuals with spinal onset and 123 days with bulbar onset. Communication effectiveness ratings by persons with ALS and communication partners illustrate agreement in perceived limitation and that PALS experience reductions in communication effectiveness even while intelligibility remains relatively unimpaired (90–95%).
Discussion and conclusions: Indications for use of the CBS include consistent quantification of clinical bulbar data, which may be obtained in approximately 20 minutes. The data may be used clinically to predict need for interventions such as augmentative/alternative communication and PEG. The data may also be collected longitudinally to assess change in bulbar functions, rate of change, and slope of change within individual subjects or across a larger population of persons with ALS.
P180 BULBAR-RESPIRATORY ALS
CONTE A1, DEL GRANDE A1, LUIGETTI M1, MADIA F4, MELEO E2, TONALI PA1,3, SABATELLI M1
1Catholic University, Department of Neurosciences, Institute of Neurology, Rome, Italy, 2Catholic University, Department of Respiratory Physiology, Rome, Italy, 3Don Carlo Gnocchi Foundation, Rome, Italy, 4Complesso Integrato Columbus, Rome, Italy
E-mail address for correspondence: [email protected]
Keywords: prognosis, bulbar onset, phenotype
Background: In about 25% of ALS patients the disease starts with bulbar symptoms and signs. Though Progressive Bulbar Palsy is no longer regarded as a distinct entity, bulbar-onset ALS shows peculiar clinical features, including older age of onset, female predominance and worse outcome. Any bulbar feature at onset and older age are consistently reported to be independently associated with poorer survival. There are several explanations for shorter survival in bulbar-onset ALS, including early respiratory muscle involvement, aspiration pneumonia, malnutrition, older age.
We have observed in some patients a ‘Bulbar-respiratory’ phenotype, characterized by bulbar onset ALS with early and severe respiratory involvement.
Objective: The aim of our study is to analyze clinical features of ALS patients with ‘Bulbar-respiratory’ phenotype.
Methods: We reviewed our ALS population with a bulbar onset and we selected those patients who had severe respiratory involvement (FVC<50% of the predicted value) without or with very slight (MRC>4) limb weakness during the follow-up period.
Results: In our series of 705 sporadic ALS patients, 206 (29.2%) had a bulbar onset. Twenty nine patients (14%) developed the Bulbar-respiratory phenotype. In patients with this subtype, the age of onset ranged from 45 to 83 years (mean 67.8, median 69); the male-to-female ratio was 1.4; the median survival was 25 months. In the remaining 177 bulbar onset ALS the mean age of onset was 62.3 years (P=0.01) and the median was 65 (range 24-84); the male-to-female ratio was 0.72; the median survival was 33 months. Using Kaplan-Meyer survival analysis we observed that disease duration was significantly shorter in 206 bulbar onset ALS with respect to 498 spinal onset ALS patients (32 months vs 43 months, P=0.009). However when bulbar-respiratory patients were excluded from the bulbar onset ALS, this difference was not statistically significant.
Discussion and conclusions: Patients with bulbar-respiratory phenotype disclosed different age of onset and gender distribution with respect to classic bulbar onset ALS, suggesting a distinct entity. Our data suggests that early respiratory involvement in a subgroup of patients is the main contributor to worse prognosis in bulbar onset ALS. Motor neuron degeneration in ALS is an orderly and sequential process, most likely spreading from one region to contiguous anatomic ones. In the ‘Bulbar-respiratory’ ALS phenotype, neuronal degeneration starts in bulbar motor neurons and spreads in a rostro-caudal direction to involve phrenic nuclei and the intercostal muscles sparing those of the upper limbs. This peculiar pattern of spread suggests a primary involvement of the limbic motor control system which projects to the motor neurons innervating bulbar and respiratory muscles, throughout the Periaqueductal Gray (PAG) and the nucleus retroambiguous (NRA).
P181 LIMB DOMINANCE AND LATERALITY OF ONSET IN ALS: A PATHOGENIC ROLE FOR EXERCISE OR CLUE TO A CORTICAL VULNERABILITY?
TURNER M1, WICKS P2, BROWNSTEIN C2, MASSAGLI M2, TORONJO M3, TALBOT K1, AL-CHALABI A3
1Oxford University, Oxford, United Kingdom, 2Patientslikeme.com, Boston, United States, 3King's College London, London, United Kingdom
E-mail address for correspondence: [email protected]
Keywords: onset, spread, handedness
Background: Attempts to identify whether physical exercise is implicated in the aetiology of ALS have provided inconsistent results. Hyper-stimulation of SOD1 rats accelerated motor neuron death and induced contiguous spread of disease (1). If physical use of a limb were important in defining the site of onset then handedness might be expected to influence the side of upper limb-onset disease, and footedness likewise in lower limb-onset ALS.
Objectives: To test the null hypothesis that concordance of handedness and footedness is unrelated to laterality of upper limb or lower limb onset respectively.
Methods: ALS patients registered with an internet-based support site were invited to complete an online questionnaire concerning site of onset of symptoms, and their dominant hand and foot. A binomial test of proportions was used.
Results: A total of 343 ALS patients with limb-onset disease were studied. For upper limb-onset patients the concordance for side of onset and handedness was high (64%; P<0.0006). For lower limb-onset patients concordance for side of onset and footedness was absent.
Discussion: This is potentially consistent with the hypothesis that exercise influences pathogenesis in ALS, since routine physical demands on the upper limb are heavily influenced by limb dominance, whereas in the lower limbs the commonest function is standing or locomotion, using both legs equally.
There may also be a cortical vulnerability underlying upper limb-onset laterality. The ‘split hand’ phenomenon is postulated to reflect cortical organisation (2), presumed to be part of the evolution of fine hand control (3). There is evidence for greater connectivity in the dominant motor cortex with respect to handedness. In relation to the observations of early cortical hyperexcitability in pre-symptomatic ALS patients (4), a study in relation to handedness in healthy subjects demonstrated a shorter cortical silent period (reflecting reduced inhibitory function) in the dominant hand (5).
Conclusions: Exercise may influence site of onset in ALS, but the neocortical connectivity involved in the evolution of human dexterity may also harbor a specific vulnerability to the ageing motor system.
References:
- Lepore AC, Tolmie C, O’Donnell J, et al. Neurobiol Dis. 2010.
- Weber M, Eisen A, Stewart H, Hirota N. J Neurol Sci. 2000; 180(1–2):66–70.
- Eisen A. Muscle Nerve. 2009;40(2):297–304.
- Vucic S, Nicholson GA, Kiernan MC. Brain. 2008;131 (Pt 6):1540–50.
- Priori A, Oliviero A, Donati E, Callea L, Bertolasi L, Roth-well JC. Exp Brain Res. 1999; 128(3):390–6.
P182 LOWER EXTREMITY AMYOTROPHIC DIPLEGIA: PREVALENCE AND PATTERN OF WEAKNESS
DIMACHKIE M1,2, MUZYKA I1, BAROHN R1,3, KATZ J4, JACKSON C5, KISSEL J6, ZHAO X-S6, WANG Y1, MCVEY A1, DICK A1, PASNOOR M1, MOZAFFAR T7, ENSRUD E8, ROSENFELD J9
1The University of Kansas Medical Center, Kansas City KS, United States, 2The University of Texas-Houston, Houston TX, United States, 3The University of Texas-Southwestern, Dallas TX, United States, 4California Pacific Medical Center, San Francisco CA, United States, 5The University of Texas-San Antonio, San Antonio TX, United States, 6The Ohio State University Medical Center, Columbus OH, United States, 7The University of California-Irvine, Orange CA, United States, 8The Boston VA Medical Center, Boston MA, United States, 9Carolinas Medical Center, Charlotte NC, United States
E-mail address for correspondence: [email protected]
Keywords: lower extremity amyotrophic diplegia, progressive muscular atrophy
Objective: To identify the prevalence of lower extremity amyotrophic diplegia (LAD) at a US academic center, describe the pattern of weakness, and provide comparative data from 8 additional major US academic institutions.
Background: We previously described LAD, a leg onset variant of progressive muscular atrophy (PMA). LAD weakness is confined to the legs for at least 2 years and there are no upper motor neuron signs.
Design and methods: Observations from nine US academic institutions were combined resulting in the identification of 26 patients with the LAD presentation. We analyzed patient medical records at the University of Kansas Medical Center (KUMC) with the lower motor neuron (LMN) presentation, focusing on 10 LAD cases.
Results: Of 318 subjects identified in the KUMC Neuromuscular Research Database, 82% (260) had amyotrophic lateral sclerosis (ALS), 1.9%(6) had familial ALS, 6.6% (21) had primary lateral sclerosis, and 31 had LMN disease. Of these 31 cases, 16 had PMA, 5 had brachial amyotrophic diplegia, while 10 had LAD. The mean LAD age of onset was 59 years with a male/female ratio of 2.3/1. Onset was asymmetric in 8/10, without side predilection. We identified a pelviperoneal pattern of weakness (sparing of knee extension and/or ankle plantar flexion) in 5 cases, diffuse leg weakness in 2, and distal predominant weakness in 3. All 10 patients had electrodiagnostic findings consistent with motor neuron disease confined primarily to the lower extremities. We also present data comparing the KUMC LAD cases to those from other major academic neuromuscular centers. At last follow up, the weakness progressed to involve the arms in 7/26 LAD cases. During the follow up, 2/26 cases died from progression to typical ALS. Overall, the mean survival of LAD cases is 96 months.
Discussion: Marie-Patrikios described the pseudopolyneuritic form of ALS in 1918 which is a LMN syndrome confined to legs. We provided a modern description of this syndrome in 2002 and coined the term LAD. Wijesekera et al in 2009 described the flail leg syndrome (FLS) which is characterized by progressive distal leg weakness and atrophy. Their case definition is somewhat different from LAD since FLS cases may have pathologic stretch reflexes and remain confined to the legs for 1 year. LAD represents 3.5% of motor neuron disorders at KUMC which is comparable to the 3–6.3% described by Wijesekera et al. Both LAD and FLS predominantly affect men. The mean survival from the London series, Melbourne series and our series are respectively 76, 91 and 96 months.
Conclusions and relevance: The natural history of LAD differs from typical forms of ALS and PMA. LAD is a slowly progressive disorder that accounts for a third of LMN disease cases. An asymmetric pelviperoneal pattern of weakness should heighten the suspicion of LAD.
P183 BODY MASS INDEX AND SURVIVAL IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS
KOSTIC S1, STEVIC Z2, DEDIC V3, LAVRNIC D2, STOJANOVIC RAKOCEVIC V2, BASTA I2
1CHC Zvezdara, Belgrade, Serbia, 2CHC Serbia, University, Belgrade, Serbia, 3Technical Faculty, University, Kragujevac, Serbia
E-mail address for correspondence: [email protected]
Keywords: BMI, hyperlipidemia, survival
Background: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Median survival from symptom onset is about 3.5 years, but some patients survive more than 5 years. Hyperlipidemia has been reported to have a protective effect in ALS patients but not in all studies.
Aim: To determine the status of lipids in patients with ALS and investigate whether lipid contents may have an impact on disease progression and survival.
Method: Blood concentrations of triglycerides, cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) and body mass index (BMI) were measured in 323 ALS patients. All patients were diagnosed as probable or definite ALS according to revised El Escorial revised criteria, at the Institute of Neurology, Belgrade, Clinical Centre of Serbia. Survival was assessed by Kaplan-Meier method.
Results: Among 323 ALS patients (193 males and 130 females, with average age 58.0±10.3), 240 (74.3%) had spinal and 83 (25.7%) patients had a bulbar onset. The mean survival time from symptom onset for ALS patients with normal lipidemia, was 2.76±1.53 years. The mean survival time from symptom onset for ALS patients with hyperlipidemia, was 3.37±2.14 years. Between these two groups we did not find a statistically significant difference (P =0.22). ALS patients with abnormally elevated LDL/HDL ratio did not have significantly longer survival in comparison to the group with normal LDL/HDL ratio (3.23±1.67 vs. 2.76±1.53, P = 0.42). Higher BMI index has not statistically significant protective role in survival (4.32±3.44 vs. 3.60±2.07, P = 0.91)
Conclusion: We did not find that ALS patients with hyperlipidemia presented longer survival. Respiratory impairment is related to a decrease in blood lipids but further studies are needed to explore this finding.
P184 ALS PATIENTS ON MECHANICAL VENTILATION HAVE GREATER RISK OF CHOLECYSTITIS
OGINO M1, KITAMURA E1, OGINO Y2, MOCHIZUKI H1
1Kitasato University School of Medicine, Department of Neurology, Sagamihara, Kanagawa, Japan, 2Toshiba Rinkan Hospital, Sagamihara, Kanagawa, Japan
E-mail address for correspondence: [email protected]
Keywords: cholecystitis, mechanical ventilation
Background: We encountered several ALS patients using TPPV who experienced cholecystitis. Two of them experienced recurrence. Thus we speculated that ALS patients on TPPV might have greater risk of cholecystitis.
Objectives: To elucidate whether ALS patients on TPPV have a greater risk of cholecystitis. If so, to identify the factors that are responsible for this risk increase.
Methods: Seventeen ALS patients on TPPV and as a control group 9 patients with other neurological diseases on TPPV (4 muscular dystrophy, 1 Pompe disease, 2 central nuclear myopathy, 1 chronic progressive external ophthalmoplegia and 1 Myasthenia Gravis) and 28 long term bed ridden patients with Parkinsonism not on TPPV were analyzed. The diagnosis of cholecystitis was made based on ‘Diagnostic criteria and severity assessment of acute cholecystitis: Tokyo Guidelines’. Physical examination, blood test (WBC, CRP, GGTP, ALP) and imaging examinations (at least one of following: abdominal echogram, abdominal CT, abdominal MRI, bile duct system scintigraphy) were performed.
Results: 1) Seven out of 16 ALS patients on TPPV (6 male, one female) had cholecystitis. Two of them were cholecystitis sine concrement. Two patients had a gall bladder stone without cholecystitis. In contrast only one out of nine patients with other neurological diseases on TPPV had cholecystitis. 2) Two out of 28 longtime bed ridden patients with Parkinsonism not on TPPV had cholecystitis. 3) There were not clear differences in age, gender, BMI, serum cholesterol level, Diabetes Mellitus, calorie intake and duration of TPPV in ALS patients with or without cholecystitis.
Discussion and conclusions: Our results suggest that ALS patients on TPPV have greater risk of cholecystitis than patients with other neurological diseases on TPPV and longtime bed ridden patients with Parkinsonism not on TPPV. The reason for this risk increase is not clear. 1) ALS patients using TPPV who had cholecystitis did not have characteristics generally regarded as risk factors (female gender, obesity). 2) There were no differences between ALS patients using TPPV who had cholecystitis and those who did not. 3) Positive pressure ventilation has been reported as a risk factor of cholecystitis. Patients with other neurological diseases on TPPV seem to have a lower risk but the number of patients is too small and their age is much younger so it is difficult to eliminate the risk of positive pressure ventilation. 4) Autonomic dysfunction could cause cholecystitis but Parkinsonism patients who have autonomic dysfunction do not have high risk. 5) Tube feeding was reported to cause higher risk of cholecystitis but all of the patients were on tube feeding so again this could not explain the risk increase.
We conclude that although the mechanism is not clear, ALS patients on TPPV have a greater risk of cholecystitis. Many patients using TPPV have difficulty in communication, so we have to be careful to find cholecystitis before it becomes severe.
P185 INCIDENCE OF DEEP VEIN THROMBOSIS IN IMMOBILISED ALS PATIENTS
BORISOW N, LINKE P, HOLM T, MAIER A, DULLINGER J, BAHRKE R, MEYER T
Charité, Department of Neurology, Berlin, Germany
E-mail address for correspondence: [email protected]
Keywords: deep vein thrombosis, immobilisation, duplex sonography
Introduction: Amyotrophic Lateral Sclerosis (ALS) leads to progressive, high-grade pareses of the extremities and, as a rule, results in immobilisation. Immobilisation in the context of traumas or surgical interventions coincides with a higher incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE). In up to 20% of patients with ALS, sudden unexpected death (SUD) occurs. One possible cause of SUD is DVT in combination with PE. In ALS, the incidence of DVT as a risk factor for PE has as yet been widely unknown.
Objective: To assess deep vein thrombosis in immobilised ALS patients by using duplex sonographic examination.
Method: We conducted a prospective controlled study on duplex sonographic examinations of DVT in the lower extremities. Inclusive criteria were high-grade pareses of the legs (ALS Functional Scale - ALS-FRSr scoring <2 on the subscore for gait disturbances).
Results: The duplex sonography revealed a complete and organised DVT in 3 out of 76 patients (3.9%).
Discussion: The present study represents the first prospective, controlled study on the incidence of DVT in ALS. The DVT incidence of 3.9 % ascertained herein is lower than that detected by other authors in a retrospective study in which the incidence of DVT was 5.7%. The mere presence of DVT cannot sufficiently substantiate the high incidence of SUD associated with ALS. Other underlying causes, including autonomic failure, must be considered as central events first and foremost. Our study demonstrates that the incidence of DVT in patients with ALS is higher compared with the normal population but lower compared with patients displaying post-traumatic or post-interventional symptoms. The low incidence of DVT in ALS could be due to the protracted development of lower extremities pareses and an adaptation of the coagulation system and the venous system. Therefore, it seems that a prophylactic administration of anticoagulation drugs to immobilised ALS patients is not required.
Acknowledgements: This study was funded by the Air Berlin Fund for ALS therapy research at the Charité and GlaxoSmithKline GmbH & Co. KG.
P186 ALS ONSET AFTER A PROLONGED TREATMENT WITH VEGF RECEPTOR INHIBITOR
MOGLIA C, CALVO A, CANOSA A, GALLO S, GIACONE S, BALMA M, CAMMAROSANO S, CHIÒ A
ALS Center, Neuroscience Department, University of Turin, Turin, Italy
E-mail address for correspondence: [email protected]
Keywords: VEGF inhibitor
Background: Vascular endothelial growth factor (VEGF) is an endothelial cell mitogen that promotes angiogenesis in response to hypoxia, in embryologic development and in pathologic conditions. Through the binding of its receptors (VEGFR1-2-3), it has neurotrophic and neuroprotective effects on neuronal and glial cells in culture and in vivo, and it can stimulate the proliferation and survival of neural stem cells. Through its angiogenic effects it also has been implicated in oncogenesis, and VEGF antagonists are being used in cancer treatment. One of the most common VEGF antagonists is Sunitinib, an oral multi-targeted tyrosine kinase inhibitor with activity against the VEGF. Sunitinib is approved for treatment of advanced renal cell carcinoma (RCC), which is one of the most highly vascularized tumors. Consistent with its multitargeted profile, sunitinib may inhibit tumor growth, cause tumor regression, inhibit pathologic angiogenesis, and inhibit metastatic progression of cancer.
Case report: We report a case of amyotrophic lateral sclerosis (ALS) occurring in a patient with renal cancer treated with sunitinib. An Italian man had an history of right-sided RCC, diagnosed in 2000 and surgically excised by a right radical nephrectomy. During 5 years of oncologic follow-up there was no evidence of recurrence. In December 2005 a total body computed tomography (CT) showed lung and cerebral lesions; therefore he was started on an oral antitumoral therapy with sunitinib (50 mg qod). In October 2006, at the age of 62, he developed rapidly progressive wasting and weakness in upper limbs, associated with dysarthria and followed by dysphagia. Three months later he was evaluated in our ALS Center. The clinical examination and the electromyographic findings suggested that he had a definite ALS, according to El Escorial criteria. He still had been taking the Sunitinib. In subsequent months, he developed lower limb dysfunction, bulbar palsy and respiratory muscle insufficiency. He died on February 2008 from acute respiratory failure, 16 months from the onset of limb weakness.
Discussion: There is reasonably convincing evidence suggesting a role for VEGF and its receptors (VEGFR1, VEGFR2 and VEGFR3) in ALS. In particular, VEGF has been shown to protect motor neurons against several insults thought to be important in the pathogenesis of ALS. Reduction in activity of VEGF, through the inhibition of VEGFR1, VEGFR2 and VEGFR3, using an antitumoral as Sunitinib, might play an important role in the development and the fast course of ALS.
P187 A POSTERIORI CONFORMAL RADIOTHERAPY USING 3D DOSIMETRIC RECONSTITUTION IN ADULT-ONSET HODGKIN SURVIVOR FOR DEFINITIVE DIAGNOSIS OF A LOWER MOTOR NEURON DISEASE
PRADAT P-F1, DELANIAN S2
1Department of Neurology, Pitié-Salpétrière Hospital, Paris, France, 2Department of Radiotherapy and Oncology, Saint-Louis Hospital, Paris, France
E-mail address for correspondence: [email protected]
Keywords: radiotherapy, Hodgkin, dosimetry
Background: Radiation-induced Lower Motor Neuron Disease (LMND) is a rare entity; its diagnosis is often difficult and may be possible only after follow-up excluding primary degenerative LMND.
Objective: To demonstrate the utility of a new method for the diagnostic of radiation-induced LMND: a posteriori conformal radiotherapy using 3D dosimetric reconstitution.
Method: Case report.
Results: A 47-year-old woman was referred in 2005 for a two-year progressive weakness of the lower limbs. The patient had been treated in 1993 for advanced-stage IV Hodgkin's disease with chemotherapy then radiation therapy. A supramediastinal mantle field followed by a subdiaphragmatic inverted Y-field including periaortic-splenic and ilio-inguinal nodes delivered 45 Gy by a 10-MV x-rays linear accelerator using equal weighting of less than 2 Gy daily fraction from anterior and posterior portals. From September 2003, she progressively developed a right, then bilateral lower limb (LL) weakness, with lower motor neuron signs and was initially diagnosed with primary muscle atrophy. Electromyography showed denervation features consistent with purely motor bilateral involvement of the L4 to S1 roots. Spinal MRI with gadolinium injection was normal. Verification of the 2D dose-surface distribution at axis made in 1999 showed no technical error, especially with a planned underdosing fields junction.
To determine if RT may have potentially injured the lumbar cord and nerves in the whole irradiated volume, an ‘a posteriori’ conformal radiotherapy with a technical reconstitution on CT-scan was performed in 2009: it showed that (a) the whole spinal cord including lumbar cord, cauda equine and plexus nerves were involved in the radiotherapy treated volumes, (b) the 3D dose-volume distribution was heterogeneous with a maximum delivered dose higher than the 45 Gy-prescribed: an unexpected 51 Gy-isodose appeared on 7 cm long and a mean 50 Gy involved 40% of the whole spinal cord.
Conclusion and discussion: Our ‘a posteriori’ 3D radiotherapy dosimetric reconstruction supported post-radiation LMND diagnosis, demonstrating the anatomical structures concerned by a neurotoxic heterogeneous radiation dose-volume. The importance of an early diagnosis is justified by the emergence of new treatments. We recently reported the efficacy of PENTOCLO combination in two patients with radiation-induced LL neuropathy with predominantly motor signs. These results led us to end the phase II clinical trial of PENTOCLO combination and plan a randomized trial.
P188 A CASE OF AMYOTROPHIC LATERAL SCLEROSIS COINCIDENT WITH FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY
DULLINGER JS, MAIER A, LINKE P, BORISOW N, HOLM T, MEYER T
Charité – Universitätsmedizin, Berlin, Germany
E-mail address for correspondence: [email protected]
Background: Amyotrophic lateral sclerosis (ALS) and facioscapulohumeral muscular dystrophy (FSHD) are two rare neuromuscular diseases. We present a patient in whom we could detect typical features of both ALS and FSHD. Careful examinations point to a rare comorbidity of both diseases.
Case Report: In his mid-twenties, our patient developed a slowly progressive paralysis with a scapuloperoneal distribution. At the age of 59, there was a sudden progression of the paresis affecting the distal forearm extensors. At that time, a molecular genetic analysis showed a pathognomonic shortening of the repeat at the D4Z4 locus. Bearing in mind that there is a positive family history, FSHD was diagnosed.
Follow up examinations revealed a rapid decline in muscle strength resulting in a severe tetraparesis. In the neurological examination, a combined degeneration of the upper and lower motor neuron was now evident. The El Escorial Criteria for definite ALS were fullfilled and ALS was diagnosed. The patient died at the age of 61. Subsequent autopsy confirmed the clinical diagnosis of ALS showing characteristic TDP43 inclusions. Morphological changes in muscle biopsy typical of FSHD could not be detected.
Discussion: FSHD and ALS are rare neurological diseases for which different disease mechanisms are discussed. Up to now, there has been no known pathophysiological overlap between both diseases. In our patient we were able to gather several findings that suggest a comorbidity of ALS and FSHD despite its low likelihood. We also considered a pure early-onset ALS that might be associated with a D4Z4 mutation. However, taking into account all our findings, this possibility seems rather unlikely to us. Nevertheless, we cannot definitely exclude a D4Z4 mutation as a risk factor for ALS, as ALS is a multifactorial disease.
Funded by the Air Berlin Fund for ALS therapy research at the Charité.
P189 MAGNETIC RESONANCE IMAGING OF HIRAYAMA DISEASE – A MIMIC CONDITION OF MOTOR NEURON DISEASE
BEDE P1,2, HARDIMAN O1,2
1Trinity College, Dublin, Ireland, 2Beaumont Hospital, Dublin, Ireland
E-mail address for correspondence: [email protected]
Keywords: Hirayama disease, MRI, monomelic amyotrophy
Background: Hirayama disease is a monomelic amyotrophy, a benign condition of the cervical spinal cord that can mimic motor neuron disease (MND). It frequently presents with unilateral or asymmetrical upper limb weakness and atrophy in young male patients. Electrophysiological studies are not specific to the condition. Anterior displacement of the posterior wall of the cervical dural canal is thought to be the underlying pathomechanism. The recognition and establishment of the diagnosis of Hirayama disease is challenging because of confounding clinical and electrophysiological features similar to MND. Early diagnosis and prevention of flexion by a collar might prevent disease progression.
Method: Four patients with Motor Neuron Disease, 4 age-matched healthy controls and 2 young patients with suspected Hirayama disease underwent cervical spinal cord imaging. A 3.0 Tesla MRI system was used to acquire 3D high resolution structural and diffusion tensor data of the cervical spinal cord in extension and flexion. Multi-echo fast field echo (mFFE) MRI sequence was used to enhance spinal grey matter - white matter contrast.
Results: The clinical suspicion of Hirayama disease was confirmed by demonstrating marked anterior shifting of the posterior wall of the cervical dural canal with cord flattening in flexion. No similar changes have been observed on the healthy controls and motor neuron disease patients.
Conclusion: Standard non-flexion, neutrally positioned cervical spinal cord MRI might be non-specific to Hirayama disease. Dynamic myelography or flexion MRI studies are required to confirm the diagnosis.
P190 TRANSCRANIAL PARENCHYMAL SONOGRAPHY IN AMYOTROPHIC LATERAL SCLEROSIS
STEVIC Z1, PAVLOVIC A1, KUZMANOVIC A1, DEDIC V2, LAVRNIC D1
1Institute of Neurology, Belgrade, Serbia, 2Techical Faculty, University of Kragujevac, Kragujevac, Serbia
E-mail address for correspondence: [email protected]
Keywords: transcranial, ultrasonography, substantia nigra
Background: There is accumulating evidence that amyotrophic lateral sclerosis (ALS) is a multisystem degenerative disease, raising the question whether some clinical parkinsonism features are of extrapyramidal origin. Enlargement of the echogenic signal (hyperechogenity) of the substantia nigra (SN) registered by transcranial sonography (TCS) of the brain structures, has been reported a highly characteristic finding in idiopathic Parkinson's disease. TCS has not been used to assess brainstem and subcortical brain structures in ALS until now.
Aims: To investigate possible degeneration of basal ganglia in sporadic ALS (SALS) patients using TCS, and its clinical correlates.
Methods: Thirty one nondemented patients, with probable or definite ALS, according to El Escorial criteria, (19 women and 12 men, average age 59.90±8.17) were compared to 31 age-matched controls (19 women and 12 men, average age 55.22±10.89). Twenty three (74.1%) had spinal onset and 8 (25.9%) had bulbar onset of the disease. The mean duration of the disease was 2.55±2.46 (range 0.5-10 years). For TCS examinations, a color-coded phased array ultrasound system equipped with 2.5 MHz transducer (ALOK, Alpha 10, Japan),was performed through a preauricular acoustic window, with a penetration depth of 16 m and dynamic range of 45–50 dB. The ALSFRS-r was an instrument for evaluation of the functional status of patients with ALS.
Results: Unilateral SN hyperechogenity was identified in 6 (19.35%) examined ALS patients, which was marked in 2 (6.45%) and moderate in 4 (12.90%) patients. Unilateral SN marked hyperechogenity was found in 1 (3.22%) control. The mean SN echogenity was not significantly different between groups. Between the mean SN echogenity and ALSFRS-r score we registered a statistically significant negative correlation (P =0.009).
Conclusion: Our pilot study did not show significant impairment in SN in SALS patients examined with TCS.