P43 ALS MORTALITY IN BELGRADE /SERBIA CONTINUES TO RISE: EXAMINATION OF MORTALITY RATES 1992-2009
STEVIC Z, PERIC S, NARJANOVIC I, STOJANOVIC V, LAVRNIC D
Clinic of Neurology, School of Medicine, Belgrade, Belgrade, Serbia
Email address for correspondence: [email protected]
Keywords: mortality, trends, epidemiology
Background: A number of studies in a wide range of countries have pointed to a worldwide upward trend in ALS incidence and mortality in last 50 years. In our first epidemiological study of ALS in Belgrade the adjusted mortality rate was low: 0.29 per 100,000 population in 7-year period (1985-1991).
Objectives: The aim of this study was to determine the mortality of ALS patients from the district of Belgrade (Serbia), over a period of 18 years (1992 to 2009), paying particular attention to variation in trends by age and sex.
Methods: Annual age and gender specific mortality rates were calculated using data from hospital in- and out-patient ALS registers at the Clinic of Neurology of Belgrade, and departments of neurology in three additional clinical centers in Belgrade, 1992 to 2009 inclusive. The diagnosis of probable or definite ALS was based on the El-Escorial revised criteria. Ten age groups were used: 0-39; five-year age groups through 40-79; and over 80 years. The mortality rates were calculated by standard procedures. The probability of survival was calculated by Kaplan-Meier method.
Results: During the investigated period, 321 ALS patients were diagnosed in the district of Belgrade, Serbia. There were 192 (59.81%) males and 129 (40.19%) females, sex ratio of 1.49:1. The mean age at the onset of ALS was 57.74 ± 11.46 years (range 18-83), for males 56.97 ± 12.11 and for females 58.89 ± 10.36, without statistically significant difference between males and females. Altogether, 267(83.2%), 160 (59.9%) males and 107 (41.1%) females, died before December 31 2009. The overall mortality rate (/ 100,000) was 0.92, 1.16 for males, and 0.71 for females, with statistically significant difference between males and females (p < 0.01). The average mortality rate (/ 100,000) of ALS during the same period changed in both groups from 0.19 (1992) to 1.58 (2002), with the peak of 2.80 in 2002 for males, and 1.82 in 2001 for females. During the observed period the mortality rate of ALS in Belgrade showed increasing tendency (y = 0.524 + 0.023x, p = 0.087). When all ages were analyzed for every year, age specific mortality rates were generally low under the age of 50, rising to a peak of 65-69 years and falling for the over 80 years age group. The median survival duration was 4.145 years, 4.223 for males and 4.011 years for females, without significant difference between them.
Discussion and conclusion: Results showed that ALS mortality increased in Belgrade (Serbia) from 1992 to 2009, with the peak at 2001, for females and at 2002, for males. The most important contributing factors are better diagnosis and registration of ALS, as well as increase of life expectancy. However, real increase in the mortality of our ALS patients related to environmental factors, cannot be excluded.
P44 THE DIAGNOSTIC PATHWAY AND INTERVAL OF AMYOTROPHIC LATERAL SCLEROSIS IN JAPAN
KANO O, IKEDA K, YOSHII Y, HIRAYAMA T, IWASAKI Y
Department of Neurology, Toho University Omori Medical Center, Tokyo, Japan
Email address for correspondence: [email protected]
Keywords: diagnostic pathway, diagnostic interval, neurologist
Background: There have been several reports from different countries concerning the time to diagnosis in patients with amyotrophic lateral sclerosis (ALS). However, little is known about the relationship between the diagnostic interval and pathway in ALS.
Objectives: We sought a correlation between the diagnostic pathway and interval in ALS patients.
Methods: We made a retrospective hospital-based study, and compared the diagnostic pathway and interval in patients diagnosed as having ALS between January 1990 and April 2011. Patients were diagnosed with definite or probable ALS during this period according to the El Escorial criteria. They were stratified according to onset symptoms of ALS (bulbar (BO) and limb onset (LO)). We investigated the speciality of the first consulting physician. The time lapse was calculated between the first symptoms to the final diagnosis of ALS. Statistical analysis was carried out with the Mann-Whitney U-test.
Results: A total of 190 patients fulfilled the El Escorial criteria of ALS. The age of onset varied from 26-83 years and the average age (SD) was 60.1 (11.1). The onset form was 76 (40%) in BO and 114 (60%) in LO. The first physician visit (BO: LO) was 45%: 23% to a neurologist, 17%: 35% to a general practitioner, 13%: 35% to an orthopedist, 10%: 1% to an otolaryngologist and 10%: 5% to a neurosurgeon. The diagnostic interval (SD) from the initial symptoms was 9.0 (5.1) months in BO patients and 15.9 (5.3) in LO patients. The diagnostic interval (SD) by different pathways (BO and LO) was 7.1 (3.2) and 11.3 (4.8) months via a neurologist, 7.0 (5.3) and 13.8 (4.1) months via a general practitioner, 11.3 (4.3) and 20.2 (7.4) in an orthopedist, 8.3 (3.3) and 13.9 (4.4) months in an otolaryngologist and 9.1 (4.5) and 13.3 (3.3) months via a neurosurgeon. There were no statistical differences of diagnostic intervals by the first visit patterns among BO patients. With respect to LO patients, the diagnostic interval of an orthopedic visit was longer than that of LO patients visiting a neurologist.
Discussion: The diagnosis of ALS is achieved by examination and a series of investigations designed to exclude other clinical syndromes. One of the most important things in ALS patients is an early diagnosis so that the rapid diagnosis provides the best quality of life for ALS patients and their caregivers. The present study indicated that more than half of ALS patients did not visit a neurologist at the first consultation. As compared to LO patients visiting a neurologist, the final diagnosis of ALS was delayed for more than 6 months in LO patients visiting an orthopedist.
Conclusion: LO patients visiting an orthopedist as the first physician took a longer time to be diagnosed than LO patients visiting a neurologist.
P45 DOES RETROVIRUS INFECTION CAUSE AMYOTROPHIC LATERAL SCLEROSIS?
VERMA A
University of Miami Miller School of Medicine, Miami, Florida, USA
Email address for correspondence: [email protected]
Keywords: retrovirus, HIV, antiretroviral therapy
Background: The cause of sporadic ALS is unknown. Retroviral infection as a cause of ALS has been proposed because of the HTLV-1 associated corticospinal tract disease and presence of reverse transcriptase activity in sera of ALS patients. Over the last 20 years, 25 cases of ALS or ALS-like syndrome have been reported in HIV-1 (HIV) infected individuals; however, the causal relationship of HIV infection to ALS is uncertain.
Objective: To describe 5 cases of ALS in patients with HIV infection and review the previously reported similar cases in order to compare and contrast with classical sporadic ALS.
Setting: A multidisciplinary ALS center and Neuro-AIDS clinic at a tertiary care university hospital.
Methods: We investigated and prospectively monitored five patients who had developed ALS during the course of their HIV disease. These five cases and 20 previously reported cases were categorized by El Escorial criteria for the level of certainty of ALS diagnosis. The clinical features, disease course, laboratory findings, and response to therapy in HIV-associated ALS were reviewed for comparison and contrast with the characteristics of sporadic ALS.
Results: The clinical course of ALS in our five patients resembled clinically definite ALS in two cases, primary lateral sclerosis (PLS) in two cases, and progressive muscular atrophy (PMA) in one case. Some of these cases are reported elsewhere (J Neurol Sci 2006;240:59–64; Neurology 2008;70:575–77). There was clinical or laboratory evidence of neural structure involvement outside motor system in two cases. Two patients (one each of PLS and PMA) improved in motor deficit following effective retroviral therapy. A review of 20 other reported cases revealed clinically definite ALS in 6 cases and probable or possible ALS in 14 cases. Motor deficit commenced at different stages of the HIV disease; in 7 cases, HIV infection was discovered at the time of ALS diagnosis. CD4 cell count ranged from 2 to 560 cells/mm3. HIV-associated ALS syndrome generally occurred at younger age, clinical progression was faster, and 8 of 10 cases responded to antiretroviral therapy. Autopsy findings in three fatal cases (one definite ALS) exhibited pathology outside the motor neuron pool.
Conclusions: ALS in patients with HIV infection can be a fortuitous occurrence or a retrovirus-driven ALS-mimic syndrome. Five cases of HIV infection in our cohort of approximately 1450 ALS cases over a 12-years period is comparable to the background HIV prevalence in South Florida. The El Escorial diagnosis in the majority of HIV-associated ALS did not rise to clinically definite level of ALS. Although a causal relationship of HIV infection to classical ALS is uncertain, the recovery following effective antiretroviral therapy in many patients underscores the importance of recognition and treatment of ALS-mimic syndrome in HIV-seropositive individuals.
P46 DO MOTOR NERVE BIOPSIES HELP SEPARATE ALS/MND FROM MOTOR NEUROPATHY?
FOWKES M1, SHTILBANS A1, TING J1, LANGE D1
1Cornell University/Hospital For Special Surgery, New York, NY, USA, 2Mount Sinai School of Medicine, New York, NY, USA
Email address for correspondence: [email protected]
Keywords: motor neuropathy, motor nerve biopsy, conduction block
Background: The diagnosis of multifocal motor neuropathy with conduction block is defined by the presence of conduction block in two or more nerves in areas not prone to compression. Identifying patients with MMN without conduction block lacks such a specific signature yet IVIG responsiveness is just as robust.
Objective: Describe the spectrum of pathological changes in “motor nerves” in patients with MMN/CB and IVIG responsive MMN without CB. We also identified patients with amyotrophic lateral sclerosis (ALS) to describe findings on motor nerve biopsy in these patients.
Methods: A retrospective study was performed of all patients having a biopsy of motor nerve (median supplying the pronator or obturator supplying the gracilis) from 2001 and 2008.
Results: Fifty two patients were identified. Seventeen had ALS; 11 had MMN with multifocal conduction block. Others had motor neuropathy without definite multifocal conduction block (n = 4) and other neuromuscular disorders (n = 21). Thin large diameter axons were prominent in 4/11 MMN patients and 1/17 ALS patients (greater than 30% of all large myelinated axons were thinly myelinated). Large groups of small axons (groups = 5 axons or more clustered together; small axons: < 4.5 microns in greatest diameter) occurred in 7/11 MMN patients with a predominance of groups being composed of small axons. No patient had large clusters of mixed large and small axons composed of greater than 8 axons of nerve fibers and thinly myelinated axons were rare compared to fascicles of ALS. Onion bulbs were seen in 2/11 patients. Thinly myelinated fibers and large groups of axons may support the presence of MMN and not ALS.
All patients with motor neuropathy had prominent findings in one or more of the following: Large groups of small diameter fibers, focal loss of large diameter axons, and axonal clusters. No patient with ALS had multiple findings and only one had moderate amounts of groups. Our findings suggest that motor nerve biopsy showing large axonal clusters of greater than 8 axons composed of a mixture of numerous large thinly myelinated axons and associated small axons strongly supports the presence of MMN and not ALS. Small axonal clusters or patchy large groups of small axons is more supportive of ALS.
P47 DEFINING FAMILIAL ALS: A WORLDWIDE SURVEY
BYRNE S1,2, HARDIMAN O1,2
1Trinity College, Dublin, Ireland, 2Beaumont Hospital, Dublin, Ireland
Email address for correspondence: [email protected]
Keywords: familial ALS, survey
Introduction: Familial amyotrophic lateral sclerosis (FALS) is clinically indistinguishable from sporadic amyotrophic lateral sclerosis (ALS). A recent meta-analysis reported that the rate of familial amyotrophic lateral sclerosis (FALS) among ALS cases was 5%. Only 6% (2/33) of studies included in the meta-analysis provided a definition for FALS.
We hypothesized that the definition for FALS differs among neurologists working in the field of ALS.
Method: We set out to test this hypothesis by designing and administering an online questionnaire to clinicians involved in the diagnosis and management of ALS.
Results: There were 78 respondents from 15 countries. 62.3% of respondents were male. 71.6% of the respondents were neurologists with the remainder being traineeneurologists and clinical geneticists. 84.5% had a special interest in ALS.
Respondents were asked whether or not they thought that there was a standard definition among neurologists for FALS. One-third of total respondents thought that neurologists were using the same definition for FALS (32.4%, 23/71). There was a statistically significant difference when subgroup-analysis based on country of practice was carried out: 52%(13/25) of respondents from North America thought that there was a standard definition for FALS in use among neurologists in comparison to 19.4% (7/36) of respondents from Europe (p = 0.017).
Respondents were given five definitions for FALS and asked which matched the definition for FALS that they use in the clinical setting. There was no consensus among the respondents but the preferred definition for FALS was ‘a patient with ALS with either a first or second degree relative also with ALS (39.7% 27/68).
Respondents were then asked to look at eight pedigrees and give their clinical opinion on whether the kindred constituted FALS or not.
In cases where there was a clear autosomal dominant pattern of inheritance the level of consensus was high. In over half of the pedigrees more than a third of respondents chose the maybe option. 60.6% (43/71) respondents gave answers that differed to the definition that they had previously stated that they used in clinical practice.
65.3% (47/72) of respondents stated that they routinely carry out genetic testing on patients who had a family history of ALS.
80.3% (57/71) of respondents agreed that a consensus meeting would be helpful in defining FALS.
Conclusion: The results of this study show that there is no clear consensus among neurologists as to what constitutes FALS. Respondents agree that there is a clear need for a consensus meeting on the standard definition of FALS. A standard definition for FALS will make entry into epidemiological and genetic studies more transparent and will in turn permit more accurate comparison between geographic regions.
P48 A MODEL FOR PREDICTING ALS DISEASE PROGRESSION
KATZ J, MILLER R, MOORE D
California Pacific Medical Center, San Francisco, USA
Email address for correspondence: [email protected]
Keywords: prognosis, phenotypes, ALSFRS-R
Background: Studying the frequencies that patients with phenotypes marked by isolated limb involvement progress into phenotypes that also affect respiratory and bulbar muscles could be useful in developing predictive outcome models for ALS. The transition from limb-only to bulbar or respiratory phenotypes can then be used to model survival, directly from the time that the respiratory or bulbar decline begins.
Objectives: To present the first part of this predictive model. The model, based on the ALSFRS-R, first defines “limb-only” impairment states, and then uses them to predict transit times to “late” respiratory and bulbar phenotypes.
Methods: We used data from 412 subjects in the WALS clinical trial of minocycline. We defined a limb-only phenotype when ALSFRS-R scores suggested the total absence of respiratory or bulbar impairment (at enrollment). This included 125 patients who had respiratory and bulbar subscale scores of 11 or 12 and FVC > 90% at entry.
This limb-only group was then further subdivided into four subgroups based on the gross and fine motor subscores. The groups were defined as follows: L0: no impairments (i.e. FINE and GROSS = 11 or 12), L1: fine impairment alone (i.e. FINE < 11, GROSS = 11 or 12), L2: gross impairment alone (FINE = 11 or 12, GROSS < 11), and L3: impairment in both. We then determined the transit times to the onset of respiratory or bulbar decline (defined as these subscores falling to 10 or less or by the FVC dropping by 10% or more from its baseline.
Results: The 125 patients included 4 L0; 21 L1; 17 L2; and 83 L3 (for further analysis, we did not include L0 since the number was too small). Those in L3 proved to be the fastest decliners in each of the three categories. At six months, FVC drops of at least 10% from baseline had developed in (L1, L2, L3) 63%, 48%, 28%; bulbar subscore declines in 44%, 43%, and 17%; and respiratory subscore drops in 48%, 43%, and 11%. Statistically, testing over the whole study duration of 13 months, times to FVC drop did not differ significantly (p = 0.17) by ANOVA of the three groups, while those for respiratory (p = 0.01) and bulbar (p = 0.02) were significant. Interestingly, on direct comparison of FINE V GROSS, L1 had greater risk for respiratory (p = 0.08) and bulbar (p = 0.09) impairment than L2.
Discussion: Isolated gross motor impairment predicts the longest transit time to respiratory and bulbar involvement, likely reflecting the distance of lumbosacral myotomes from respiratory or bulbar muscles. More importantly, our work suggests that clinical phenotypes can be determined from the FRS can be useful for predicting outcomes. This work is only one step in a larger model that considers the survival once respiratory or bulbar begin to decline and accounts for the rate of progression and other baseline findings to predict survival.
P49 PREDICTORS OF INCREASE IN SEVERITY AMONG JAPANESE AMYOTROPHIC LATERAL SCLEROSIS PATIENTS BY DISCRIMINANT ANALYSIS
OKAMOTO K, KIHIRA T, KUZUHARA S, KOKUBO Y
Aichi Prefectural University, School of Nursing & Health, Nagoya, Japan
Email address for correspondence: [email protected]
Keywords: discriminant analysis, prognosis, prevention
Objective: It is important to select individuals at high risk of increase in severity of amyotrophic lateral sclerosis (ALS) earlier to maintain quality of life and mental health for both patients and their caregivers. Prognostic factors for increase in severity have not been well documented. We constructed a predictive model to discriminate patients at a higher risk of increase in severity in Japanese ALS patients, using linear discriminant analysis.
Methods: Data were collected for 183 ALS patients diagnosed by EI Escorial World Federation of Neurology criteria who got informed consent to participate in a case-control study and the follow-up one year later. A structuredself-administered questionnaire specifically designed for this case-control study was distributed and collected by mail in both patients and controls. We asked patients to recall their lifestyle within the 3 years before the onset of ALS. Assessment of increase in severity was compared between joining the study and one year later based on self-report of caregivers. Change in increase in severity was categorized into two groups: stable (better or same) and worse. Stepwise linear discrimination analysis was used to construct a predictive model to select individuals who have a higher risk of increase in severity, using variables with a significant difference of p < 0.05 by t-test and chi-square test.
Results: Proportion of males, age at onset (age 65 and over), short duration of ALS, much mental imbalance, type A behaviour, symptom at ALS onset, i.e. bulbar onset and limb onset, much stress, less daily intake of green-yellow vegetables and loss of purpose in life were significantly higher in worse group than in stable group. Among those factors, the stepwise discriminant analysis selected the 3 predictor variables (male, short duration of onset, much mental imbalance) and yielded a statistically significant function (λ = 0.5; χ2 = 10.5, df.3, p < 0.001). This function showed that the rate of correct prediction was 89.6 % for change in increase in severity.
Conclusion: The calculated discriminate function based on the above 3 predictor variables (male, short duration of onset, much mental imbalance) is useful for detecting individuals at high risk of increase in severity and preventing its development among ALS patients. Prospective studies are needed to confirm the validity and feasibility of the model for earlier screening for increase in severity among ALS patients.
P50 GLUCOSE AND HIGH DENSITY LIPOPROTEIN: POOR PROGNOSTIC FACTOR IN AMYOTROPHIC LATERAL SCLEROSIS
HUANG R, CHEN Y, CHEN K, SONG W, PAN P, LI J, SHANG H
Department of Neurology, West China Hospital, SiChuan University, Chengdu, Sichuan, China
Email address for correspondence: [email protected]
Keywords: glucose, high density lipoprotein, prognosis
Background: Studying the energy metabolism of amyotrophic lateral sclerosis (ALS) patients leads to better understanding of the pathogenesis of ALS and offers a new perspective to the treatment for ALS patients. Plasma markers of energy metabolism were identified in ALS patients in Southwest China.
Methods: A total of 138 ALS patients (85 males and 53 females), from the Department of Neurology of West China Hospital of Sichuan University from 2005-2010 were included in the study. Venous blood samples were collected after 12-hour overnight fasting and tested in the lab of West China Hospital of Sichuan University. Information on functional rating scale scores was provided by family members, caregivers, and family physicians.
Results: The mean onset age of the patients was 50.35 ± 12.36 years and the mean disease duration was 19.35 ± 17.23 months. Ninety-one patients were spinal onset and 47 patients were bulbar onset. Overall, the mean levels of uric acid (304.25 ± 68.10μmol/L), triglyceride (1.61 ± 0.53 mmol/L), cholesterol (4.85 ± 0.90 mmol/L mmol/L), high density lipoprotein (1.42 ± 0.26 mmol/L), low density lipoprotein (2.84 ± 0.62 mmol/L), and glucose (4.79 ± 0.57 mmol/L) were normal in plasma. However, the high density lipoprotein (P = 0.001, R = 0.58) and glucose (P = 0.002, R = 0.69) were correlated with onset age and the glucose was negatively correlated with functional rating scale score (P = 0.006, R = -0.62).
Conclusion: Low level of glucose and high density lipoprotein may be an important risk factor for decreased survival time.
P51 CSF NEUROFILAMENT LIGHT CHAIN LEVELS AT DIAGNOSIS CAN PREDICT PROGRESSION TO GENERALIZED AMYOTROPHIC LATERAL SCLEROSIS
TORTELLI R1, COPETTI M2, CAPOZZO R1, CORTESE R1, D'ERRICO E1, LEO A1, MASTRAPASQUA M1, RUGGIERI M1, PELLEGRINI F2, SIMONE IL1, LOGROSCINO G1
1Department of Neurological and Psychiatric Sciences, University of Bari, Bari, Italy, 2Unit of Biostatistics, IRCCS “Casa Sollievo della Sofferenza” – Hospital, San Giovanni Rotondo (FG), Italy
Email address for correspondence: [email protected]
Keywords: biomarkers, generalization time, prognosis
Background: The natural history of ALS is characterized by clinical heterogeneity. Biomarkers are needed to improve prediction of prognosis. Neurofilament subunits (NFs) are the major structural components of axons and CSF neurofilament light chain (NF-L) levels have been proposed to monitor motor neuron damage. In ALS the prediction of prognosis is usually based on death as the outcome measure. The conversion from bulbar or spinal ALS to generalized ALS is a critical moment and an alternative prognostic outcome.
Objective: To evaluate if CSF NF-L levels may predict the time to conversion to generalized ALS.
Methods: NF-L assay was performed in CSF samples. A two-site solid phase sandwich ELISA was used to measure NF-L levels. This method has a detection limit of 31 ng/L with a variability intra assay CV% < 6 and inter assay CV% < 9. Neurological status was assessed by revised ALS Functional Rating Scale (ALSFRS-r). We considered the “time to conversion to generalized ALS (TTG)” as the time of symptoms spreading from spinal or bulbar localization to both. We used the median CSF NF-L to dichotomize the sample (subjects with CSF NF-L levels above or below the median). Spearman test was used to assess correlations between variables. Kaplan-Meier analysis (Log-rank method) was used to compare the effect of CSF NF-L levels on TTG. Cox regression model was used for univariate and multivariate analysis (adjusting for age, gender and ALSFRS-r at baseline).
Results: We enrolled 37 sporadic ALS patients with a median age of 55.5 years (range: 36.5-76.8), median disease duration at time of lumbar puncture of 12.1 months (range: 2.2-142.5). The median of NF-L levels was 5000 ng/L (range: 668.7-10000). The median of the TTG was 16.5 months (range: 0-79). CSF NF-L levels were inversely correlated to TTG (rs = -0.65; p = 0.0001). Kaplan-Meier analysis showed shorter TTG in patients with high NF-L levels (Log-rank test Chi-squared = 14.8, p = 0.0001). In the Cox regression model NF-L levels predict the TTG with a HR = 1.28 (95% CI 1.11-1.48, p = 0.0006). Multivariate Cox regression model suggested that patients with high NF-L levels have a risk five times higher than patients with low NF-L levels (HR = 5.8, 95% CI 2.2-16.7, p = 0.0005) to progress to generalized ALS.
Discussion and conclusion: In this pilot study CSF NF-L levels predict a shorter time to conversion from symptom onset to generalized ALS. The use of TTG as an intermediate end point could give us information about the progression in the early stages of the disease. Further studies are needed to confirm these preliminary results using CSF-NF-L as a biomarker of disease progression.
P52 THE IMPAIRMENT OF THE OXIDATIVE STATUS CORRELATES WITH SEVERITY OF THE DISEASE IN ALS PATIENTS
LUNETTA C, MAESTRI E, MELAZZINI MG, CORBO M
NEuroMuscular Omnicentre, Milan, Italy
Email address for correspondence: [email protected]
Keywords: oxidative status, thiols, severity of disease
Background: Several mechanisms have been proposed to account for the progressive motor neuron degeneration, including oxidative stress, neurofilament damage, mitochondrial abnormalities, glutamate-mediated excitotoxicity, and altered responses to hypoxia. Since increased levels of oxidative stress have been found not only in nervous but also in peripheral tissues of familial and sporadic ALS patients, many studies have been addressed to relate the presence of increased oxidative stress to reduced antioxidant defenses also in peripheral tissues of these patients. However, the majority of these data showed conflicting results, due to patients’ heterogeneity in terms of disease time onset and course.
Objective: In this work we assayed the oxidative status in ALS patients. In fact although it is not yet established if oxidative stress is a cause or a consequence of the neurodegenerative process, the different capacity of each subject to respond to increased oxidative stress may account for the heterogeneity of the ALS patients in terms of clinical course, disease duration and response to pharmacological treatment.
Patients and methods: We performed the derivatives-reactive oxygen metabolites (d-ROMs) test for the measurement of free radical metabolites, the biological antioxidant potential (BAP) to assess the antioxidant power of the serum, and the thiol antioxidant barrier (SHp) test for the measurement of total thiol group concentration in ALS patients’ sera. We also evaluated the plasma glutathione (GSH), which is the most important intracellular buffer for redox status. To perform the above tests we utilized the commercially available d-ROMs, BAP and -SHp tests (Diacron International, Grosseto, Italy), respectively, and the automated clinical chemistry analyser SYNCHRON, CX9 PRO (Beckman Coulter, Brea, CA, USA). Plasma reduced GSH was determined by high-pressure liquid chromatography (HPLC).
Results: We consecutively recruited 91 patients (mean age 64 + /-12 years; median disease duration 35 months) at NEuroMuscular Omnicentre (NEMO) in Milan. In 69% of patients the d-ROMs test showed a marked increment of free radical metabolites. Moreover, in 83% of ALS patients the SHp test showed a severe reduction of total thiol groups concentration. Finally, all of the above markers were not correlated with the clinical features of ALS patients, except for the plasma GSH concentration that was significantly correlated with disability, as measured by ALSFRS-r total score (r = 0.46, p = 0.002).
Discussion: Our results showed a significant impairment of oxidative activity with a marked increment of free radical metabolites levels and depletion of thiol levels in the majority of ALS patients. Among the clinical features, only the severity of the disease was strongly correlated with plasma glutathione.
Conclusion: Interestingly, our results are in favour of an oxidative imbalance in the ALS population, from the early phase of disease.
P53 NATURAL HISTORY OF PURE UPPER MOTOR NEURON DISEASE/DYSFUNCTION (PUMND)
PASMANTIER M, LEE Y-W, CAMPANELLA C, WEIMER L, MITSUMOTO H
Columbia University, New York, NY, USA
Email address for correspondence: [email protected]
Keywords: PLS, natural history, EMG
Background: Primary lateral sclerosis (PLS) begins with pure upper motor neuron disease/dysfunction (PUMND) and, by definition, it remains as PUMND throughout its entire disease course. According to the current criteria, the diagnosis of PLS cannot be made until PUMND is sustained for at least 36 to 48 months after symptom onset. Our critical review of all the reported PLS autopsy studies in the past suggests that true PUMND based on strict pathological and EMG criteria may be exceedingly rare. When lower motor neuron dysfunction (LUMND) develops in patients with PUMND, the term UMN-dominant ALS, is applied. How often we encounter PUMND among all new MNDs and how often PUMND evolves into UMN-dominant ALS is not well-known. Understanding the natural history of PUMND appears to be essential for defining the relationship between amyotrophic lateral sclerosis (ALS) and PLS.
Objective: To determine the proportion of PUMND among all newly seen MND/ALS cases and the early evolution of PUMND cases based on clinical and EMG changes.
Methods:We retrospectively reviewed 622 cases of MNDs newly seen in a 4-year period between 2003 and 2007 and identified 33 patients with PUMND (5.3%). We excluded cases with spastic paraplegia or incomplete medical records. Retrospective analyses were made in 22 cases (3.5%) which satisfied PUMND of undetermined cause based on clinical, extensive laboratory studies and electrophysiological data.
Results: Of the 22 cases, 7 cases (32%) were later classified as UMN-dominant ALS (UMN-D ALS) because of new denervation on EMG (on average 50 months after symptom onset and ranging 25 - 102 months). Out of these UMN-D ALS cases, 2 (29% of UMN-D) developed LMND at 82 and 102 months after symptom onset. Thirteen cases (59%) remained as PUMND evidenced by one or more repeated normal EMGs (average 55 months), whereas 2 cases (9%) were based on clinical findings alone (no repeated EMG). Among these PUMND cases, 5 have not reached the 48 month cut-off period to be called PLS.
Discussion and conclusions: Our study shows PUMND is generally rare among MNDs. Although the majority of the PUMND cases developed LMND within 48 months of symptom onset, nearly 30% of these cases developed LMND after 48 months and up to 102 months, implying that LMND may develop in a good proportion of PUMND cases at some point in its course. This observation indeed makes PLS a rare disease. We still do not know if ALS and UMN-D ALS are biologically different, and if UMN-D ALS and PLS are different. To answer these questions, we need a large, prospective, long-term, and multicenter natural history study of PUMND, which is essential to understanding the relationship between ALS and PLS.
Project funded by MDA
P54 CLINICAL FEATURES IN AMYOTROPHIC LATERAL SCLEROSIS SUBTYPES: A HOSPITAL-BASED REGISTRY STUDY
Dong Y, Chen Y, Dong Q, Jiang Y, Wu J
Huashan Hospital, Fudan University, Shanghai, China
Email address for correspondence: [email protected]
Keywords: subtypes, duration to fasciculation, progression
Background: Amyotrophic lateral sclerosis (ALS) is difficult to diagnose, with a progressive fatal course and unknown aetiology.
Objectives: To explore epidemiology and clinical features of different subtypes of ALS.
Methods: Between January 1st 2000 and August 31st 2010, 63 patients who were diagnosed with ALS at Huashan Hospital were recruited. Data on demographics, risk factors, clinical features, physical and neurological examinations, EMG, laboratory, neuroimaging and ALS Functional Rating Scale (ALSFRS) were recorded. Subtypes were classified according to the onset region of ALS, including bulbar, arms and legs. Fisher's exact test was used to compare features of ALS subtypes and multiple regression models were used based on demographic, vascular risk factors, and clinical variables.
Results: We identified 57 individuals (36 male and 21 female, sex ratio = 1.7) from our hospital in-patients with mean age of 51.3 years old. Among them, 19 patients had a history of trauma or surgery, and 42 developed symptoms symmetrically. The mean duration from onset to diagnosis was 18 months. Patients with bulbar-onset were diagnosed earlier, at a mean time of 10.58 months. Patients with arms-onset were younger and fasciculation happened earlier, with higher levels of CPK compared to the other two groups. All groups of patients were similar in ALSFRS-R, suggesting patients with legs-onset developed more slowly. In multi-regression analysis, age and fasciculation were related to ALS subtypes.
Discussion: The results demonstrated the characteristic clinical profiles of subtypes of ALS patients. A striking observation in the present study is that region of onset greatly relates to clinical features, including the age, time to diagnosis, and time to fasciculation.
Bulbar onset accounted for one-fifth of all patients, who were characterized as older aged, male and more likely to be blue-collar. The incidence of bulbar onset in 20% of ALS patients has been reported with onset at an older age and with a poor prognosis in some previous studies. In our observation, they are diagnosed at an early phase, which also revealed fast progression. Patients with limb-onset took a longer time to be diagnosed than those with bulbar-onset. Those with arm-onset are younger than patients of other groups. Patients with arm-onset presented fasciculation earlier, with higher levels of CPK and LDH. In diagnosis, patients with bulbar-onset can be diagnosed earlier than that of limb onset. ALSFRS-R evaluates the daily function of patients, which is closely related to severity of the disease. Patients of each onset region are similar in ALSFRS-R scores, which suggests leg onset patients have the same ALSFRS-R scores as bulbar-onset patients at an early time from diagnosis. It was confirmed ALSFRS-R scores have a strong relationship with prognosis, suggesting bulbar onset with a poor prognosis.
Conclusion: Age of onset and duration to fasciculation were related to ALS subtypes in this cohort.
P55 VALIDATION OF A NEW ALS CLINICAL EVALUATION TOOL, THE MADRID QUANTITATIVE NEUROMUSCULAR ASSESSMENT, MAQUINA
MORA JS, MACIAS AI, AVENZA M, RODRIGUEZ-SANTOS F, MONGIL E, MARÍN S, SALAS T
ALS Unit, Hospital Carlos III, Madrid, Spain
Email address for correspondence: [email protected]
Keywords: clinical assessment, motor function, deficit quantitation
Background: MAQUINA was designed and proved consistent and reliable to quantify motor deficits in ALS patients (1,2). It is composed of 2 timed test of bulbar (pataka, count), 5 of arm (marbels R + L, pedalling, tapping R + L), and 4 of leg function (3m + 3m walk, pedalling, tapping R + L).
Objective: To analyze the validity of MAQUINA to quantify motor deficit in ALS patients throughout the disease by comparison with current assessment tools (ALSFRS-R, MMT, MVIC, and FVC/slowVC).
Methods: Sixty-three patients with ALS were assessed by 2 physiotherapists following the standardized MAQUINA protocol every 3 months for one year. At the same times they were evaluated by the ALSFRS-R, MMT, QMA (maximum voluntary isometric contraction of 6 UE and 4 LE selected muscle groups), and FVC/slowVC. Cronbach's alpha was used for internal consistency. Spearman's Rho Index was used to assess test retest reliability. The same Index was used to assess validity by comparing MAQUINA with the other methods. Analyses were done by SPSS15.0.
Results: The results showed high internal consistency (rxy:0.79-0.97) and a good test-retest correlation (0.97, p < 0.01). A high correlation between total MAQUINA and ALSFRS-R scores was found at initial assessment (-0.69, p < 0.01) and higher at 12 months (-0.80, p < 0.001). Other correlations were: the corresponding MAQUINA and ALSFRS-R bulbar tests (items 1 + 2 + 3) at initial assessment (-0.72, p < 0.01) and at 12 months (-0.78, p < 0.001); arm + leg tests (items 4 to 9) at initial (-0.80, p < 0.01) and at 12 months (-0.90, p < 0.01); MMT of arms at onset (-0.62, p < 0.001) and at 12 months (-0.78, p < 0.01); MMT of legs at onset (-0.53, p < 0.01) and at 12 months (-0.62, p < 0.01). There was correlation between bulbar/respiratory tests of MAQUINA and FVC or SVC at 12 months (-0.43 a -0,50, p < 0.01). Correlation with MVIC is also significant: MAQUINA arm tests with elbow flexion and extension (-0.32 to -0.7, p < 0.01) and hand grip (-0.5 to -0.7, p < 0.01), and MAQUINA leg tests with knee flexion and extension (-0.4 to 0.6, p < 0.01).
Conclusions: The MAQUINA timed battery has proved to be a reliable and valid assessment tool to quantify motor deficits over time in ALS patients, either as a single complete test or as three separate components, bulbar/respiratory, arms and legs. Further comparison analysis regarding assessment at onset and end phase of the disease are ongoing.
Work supported by Fundación Mutua Madrileña, Spain
References:
- Mora JS, Valera F, Macías AI, et al. Amyotrophic Lateral Sclerosis, 2010;11(Suppl. 1):151.
- Mora JS, Macías AI, Valera F, et al. Amyotrophic Lateral Sclerosis, 2010;11(Suppl. 1):152.
P56 AMYOTROPHIC LATERAL SCLEROSIS DASHBOARD: COGNITIVE, BEHAVIORAL, BULBAR, RESPIRATORY, ARM, LEG DOMAIN-SPECIFIC DISEASE STAGING
BROOKS BR1,5, BRAVVER E1,5, SANJAK MS1,4, DESAI UG1,5, BOCKENEK WL2,5, LINDBLOM SC3,5, PACCICO TJ3,5, WILLIAMS NM1, NICHOLS MS1, WARD AL1, LANGFORD VL1, WRIGHT KA1, HOLSTEN SE1, RUSSO PC1, BLYTHE A1, FRUMKIN LH1, WALGREN KL1, SMITH NP1, HENDERSON AM1, O'NEILL M1
1Carolinas Medical Center - Department of Neurology - Neuromuscular/ALS-MDA Center, Charlotte, NC, USA, 2Carolinas Rehabilitation - Physical Medicine and Rehabilitation, Charlotte, NC, USA, 3Carolinas Medical Center - Department of Internal Medicine, Charlote, NC, USA, 4University of North Carolina - Charlotte - Department of Kinesiology, Charlotte, NC, USA, 5University of North Carolina School of Medicine - Charlotte Campus, Charlotte, NC, USA
Email address for correspondence: [email protected]
Keywords: disease staging, El Escorial, Awaji
Background: ALS Dashboard is a new tool for analyzing disease severity within a single patient and across different patients defining involvement over 6 domains on a per patient basis.
Methods: ALS patients (199/263) at first clinic visit were categorized as El Escorial Criteria clinically definite(EECD) only (90) or Awaji clinically definite only (AwCD) (109) and staged according to the ALS Dashboard criteria. Comparisons of ≥ stage 3 disease in each domain by EECD/AwCD criteria were conducted by chi-square test with Yates correction and confirmed with Fisher's exact test.
At first clinic visit in EECD/AwCD ALS ≥ stage 3 cognitive disease was similar (8.9%/13.8%; p = 0.3968), ≥ stage 3 pseudobulbar affect (11.1%/2.8%; p = 0.0369), ≥ stage 3 depression (25.6%/10.0%; p = 0.0070), ≥ stage 3 bulbar dysfunction (45.6%/13.8%; p = 0.0001), ≥ stage 3 arm dysfunction (35.6%/8.3%; p = 0.0001), ≥ stage 3 leg dysfunction (55.6%/33.9%; p = 0.0036) were statistically significantly increased and ≥ stage 3 respiratory dysfunction was identical (7.8%/4.6%; p = 0.5209).
Results: Disease severity in some domains segregates differently with a higher proportion of ≥ stage 3 disease in EECD ALS. The proportion of ≥ stage 3 disease ranks similarly: leg > arm > bulbar > depression > pseudobulbar affect.
Conclusions: Disease severity in some domains, segregates differently with a higher proportion of ≥ stage 3 disease in EECD ALS. The proportion of ≥ stage 3 disease ranks similarly: leg > arm > bulbar > depression > pseudobulbar affect. ALS Dashboard is a new tool for analyzing disease severity within a single patient and across different patients.
P57 DYNAMIC POSTUROGRAPHY EVOKES SENSORY AND MOTOR DEFICITS LEADING TO DISEQUILIBRIUM AND PREDICTS FALLS IN AMBULATORY ASYMPTOMATIC AMYOTROPHIC LATERAL SCLEROSIS PATIENTS
SANJAK M1,2, HIRSCH M3, SKAINS R1, BRAVVER E1, DESAI U1, NORTON HJ4, BOCKENEK W1, BROOKS BR1
1Carolinas Neuromuscular/ALS-MDA Center, Charlotte, NC. 28207, USA, 2Department Of Kinesiology, University of North Carolina, Charlotte, NC. 28223, USA, 3Department of Physical Medicine and Rehabilitation, Carolinas Rehabilitation, Charlotte, NC.28203, USA, 4Department of Biostatistics, Carolinas Medical Center, Charlotte, NC.28203, USA
Email address for correspondence: [email protected]
Keywords: fall, balance, sensory integration
Background: Falls are common in ALS. Previous observation in our clinic indicates that ambulatory ALS patients who did not fall on condition 4 of the modified sensory integration and balance had excessive sway or fell in condition 5 (C5) and C6 of the computerized dynamic platform posturography - EquiTest (CDP). No comparisons with healthy controls (HC) were available.
Objectives: To identify problems in equilibrium of ALS patients compared to HC.
Methods: Nineteen ambulatory early diagnosed patients with no symptoms or history of fall or motor problems by Berg Balance Scale, Tinetti, dynamic gait index, get-up-and-go, sit to stand, and 25 foot walk tests, and 15 adults matched for age and gender (HC) performed the sensory organization test (SOT) and motor control test (MCT) using CDP. The SOT involved 6 sensory conditions © with 3 fixed support conditions (FS) and 3 sway-referenced conditions (SR); (C1) vision normal, support normal (C2) vision absent, support normal (C3) vision SR, support normal, (C4), vision normal, support SR, (C5) vision absent, support SR, (C6) vision and support SR. Equilibrium scores (ES) for each C ranging from zero (worst = fall) to 100 (best = no sway) were generated to identify sensory dysfunctions and/or abnormal sensory organization patterns (SOP). In total, 18 ES were obtained, 3 for each condition. The arithmetic mean of the 3 scores was used. MCT was evaluated by the latency of time (in milliseconds (ms) to recover from small and large forward and backward translations (2.8 and 8.0 deg/sec).
Results: Compared to HC, ALS patients exhibit: 1) Lower composite ES in C5 (51 ± 22 vs. 65 ± 11 (P ≤ 0.05); 2) Higher incident of falls during C4-C6. 7/19 (37%) vs. no falls in HC. 2 patients fell on C4, 5 patients on C5, and 6 patients on C6 (P ≤ 0.03); 3) lower vestibular SOP score among (0.51 ± 0.2 vs. 0.7 ± 0.11, P ≤ 0.03); 4) Longer latency (165.4 ± 9.9 vs.149.7 ± 9.5); 5) Fallers during CDP reported their first fall during follow-up ALS Clinic visits with a median time to first fall = 120 days sooner than non-fallers (Kaplan-Meier plot, HR = 1.9973, (95%CI = 0.6576 to 6.0664); P ≤ 0.176)).
Discussion and conclusions: Altered SOP characterized by difficulty to utilize information from the vestibular system leading to disequilibrium and fall is seen early in ALS. The vestibular influence on postural sway depends on peripheral vestibular organs, branches of the vestibular nerve to the vestibular brainstem nuclei and their connection to the cerebellum. Latency problems may indicate extra vestibular, central nervous system lesions. Efficacy of balance, ocular-vestibular and neuromuscular reeducation early in ALS needs to be explored.
Supported by: Carolinas Healthcare Foundation, Carolinas ALS Research Fund, Pinstripes Foundation, Muscular Dystrophy Association.