P119 VALIDATION STUDY FOR PROTEIN BIOMARKERS IN THE CSF OF ALS PATIENTS
RYBERG H1, DARKO S1, AN J1, GANCHEV P1, LUSTGARTEN J1, GOLAPAKRISHNAN V1, ROYCE NG2, LACOMIS D1, CUDKOWICZ M2, BOWSER R1
1University of Pittsburgh, Pittsburgh, PA, United States, 2Massachusetts General Hospital, Charlestown, MA, United States
E-mail address for correspondence: [email protected]
Keywords: biomarkers, mass spectrometry, proteomics, CSF
Background: We previously reported the identification of protein biomarkers in the cerebrospinal fluid (CSF) of ALS patients using mass spectrometry based proteomics. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was performed on CSF collected from 52 control and ALS subjects to identify protein peaks with diagnostic predictive value, with testing on a separate coded set of CSF samples. We further validated two of the biomarker proteins, cystatin C and transthyretin, using immunoblot and immunohistochemistry on separate groups of ALS and control subjects.
Objectives: We performed the current study to validate our initial findings using a much larger set of CSF samples.
Methods: During the past two years we collected 263 additional CSF samples from ALS and control subjects at the University of Pittsburgh School of Medicine and Massachusetts General Hospital. The subjects included ALS, Alzheimer's disease (AD), healthy control, multiple sclerosis, and other neurological diseases including FTD patients. We performed SELDI-TOF-MS on each CSF sample using two Protein chip surfaces, IMAC and Q10. Samples were run in duplicate on separate protein chips and experiments repeated three times. Mass spectra were collected from the 2,000 – 200,000 Dalton mass range.
Results: We compared the protein profiles from ALS patients to each of the other subject groups and all other subjects. We identified a total of 60 mass peaks with statistically significant alterations between ALS and control subjects (p<0.001). Similar to our prior study, cystatin C and transthyretin protein peaks were decreased in ALS when compared to control subjects. We identified a panel of proteins that predicted ALS versus control subjects with 84% overall accuracy. The putative identification for many of these protein peaks has been determined and includes proteins in protein transport and neuroprotective signalling pathways.
Conclusions: Our data validates prior results indicating decreased levels of cystatin C and transthyretin in the CSF of ALS patients. Additional protein peaks were used to create a predictive biomarker panel that identified ALS with 84% overall accuracy. We further identified specific protein mass peaks that differentiate ALS from AD subjects.
P120 PLASMA BASED PROTEIN BIOMARKERS FOR ALS
RYBERG H1, DARKO S1, AN J1, ROYCE NG2, CUDKOWICZ M2, BOWSER R1
1University of Pittsburgh, Pittsburgh, PA, United States, 2Massachusetts General Hospital, Charleston, MA, United States
E-mail address for correspondence: [email protected]
Keywords: plasma, biomarkers, mass spectrometry, proteomics
Background: Diagnostic biomarkers for ALS would greatly benefit the rapid diagnosis of the disease, aid in determining the underlying pathogenesis of ALS, and may assist in future clinical trials. Biomarkers discovery efforts typically use biofluids such as blood or cerebrospinal fluid (CSF). We previously reported the identification of protein biomarkers in the CSF of ALS patients using mass surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) based proteomics. Specific protein biomarkers were obtained that differentiated ALS from control subjects. We next wished to determine if plasma based biomarkers could be identified from the same patient populations. We obtained blood plasma samples from 62 ALS and control subjects and performed SELDI-TOF-MS to identify protein peaks with diagnostic predictive value.
Objectives: To identify protein based biomarkers in the plasma of ALS patients near the time of symptom onset, and compare these biomarkers to those found in the CSF.
Methods: We collected 62 plasma samples from 31 ALS and 31 healthy control subjects at the Massachusetts General Hospital. We performed SELDI-TOF-MS on each CSF sample using two Protein chip surfaces, IMAC and Q10. Samples were run in duplicate on separate protein chips and experiments repeated three times. Mass spectra were collected from the 2,000 – 200,000 Dalton mass range.
Results: We compared the protein profiles from ALS patients to the control subjects. We identified a total of 14 mass peaks with statistically significant alterations between ALS and control subjects (p<0.05). These proteins ranged in mass from 4.4 to 88.8 kDa. Similar to our prior CSF study, transthyretin protein peaks were altered in ALS compared to control subjects. We identified a panel of 4 protein mass peaks that predicted ALS versus control subjects with 82% overall accuracy using a classification tree analysis. We also used a machine learning algorithm and determined that the 4.4 kDa peak (p=0.0004) provided a 90% positive predictive value for ALS. The 4.4 kDa protein peak was increased in ALS patients relative to control subjects.
Conclusions: We have identified specific protein peaks in the plasma that differentiate ALS from healthy control subjects. Further studies are required to validate these findings and expand them to include additional ALS and other disease control groups.
P121 QUANTITATIVE SIT-TO-STAND (STSV), 360 DEGREE AXIAL ROTATION (AXRV) AND WALKING (WLKV) VELOCITY IN AMYOTROPHIC LATERAL SCLEROSIS (ALS)-PROSPECTIVE NATURAL HISTORY OF THE COMPONENTS OF THE TIMED UP AND GO TEST INCLUDING CORRELATION WITH FALLS, ADAPTIVE EQUIPMENT NEEDS AND SURVIVAL
BROOKS BR1, SANJAK M1, PEPER SM2, HOUDEK AM3
1Carolinas Neuromuscular/ALS-MDA Center, Charlotte, NC, United States, 2University of Wisconsin School of Medicine and Public Health, Madison, WI, United States, 3William S Middleton Memorial Veterans Affairs Medical Center, Madison, WI, United States
E-mail address for correspondence: [email protected]
Keywords: Outcome Measure, Rehabilitation, Postural Reflexes
Objective: Perform a factor analysis of the independent constitutive components of the Timed Up-and-Go test, which is proposed as an outcome measure for clinical trials in ALS.
Background: Quantitative Sit to Stand (STSv), 360 Degree Axial Rotation (AXRv) and Walking Velocity (WLKV) were prospectively determined in 227 ALS (129 M; 98 F) at each clinic visit over 9–108 months follow-up.
Methods: STSv is determined by measuring the time (seconds) from the command “stand” to the subject achieving a totally erect stance and dividing the distance from the chair seat to the upright position (2 feet) by this time to give the STSv (Ft/sec). AXRv is determined by measuring the time (seconds) from the command “turn” to completion of a full 360 degree axial rotation clockwise or counter-clockwise resuming the starting stance with the feet in the same starting position. Angular velocity represented as degrees/sec is transformed to Ft/sec by assuming the stance is represented by a radius of 0.5 foot yielding a circumference of 2π-r (3.1 Ft). AXRv is provided in comparable units by dividing the circumference distance travelled by the time to complete the axial rotation. WLKv is determined by measuring the time from “start” to the completion of a 30 Ft walk performed as quickly as the patient safely can. STSv, AKRv, WLKv were analyzed by descriptive statistics cross-sectionally and longitudinally. Changes in STSv, AXRv and WLKv were correlated with sex, age, site of disease onset, spasticity, milestones including more than 2 falls monthly, use of adaptive equipment (cane, walker, wheelchair) and survival (MediCalc).
Results: In subjects with no neurological diagnosis, median 50% STSv is 2.4 Ft/sec with 25–75th quartile range: 1.8–3.2 Ft/sec, median AXRv is 1.8 Ft/sec with 25–75th quartile range: 1.4–2.2 Ft/sec and median WLKv is 7.0 Ft/sec with 25–75th quartile range: 5.4–8.4 Ft/sec. STSv is decreased to a greater degree than AXRv and WLKv in early ALS. AXRv in ALS patients requiring a cane is decreased to greater extent than STSv and especially WLKv. STSv and AXRv together are much more decreased than WLKv in ALS patients requiring a walker. Wheel chair dependent ALS patients have a significantly decreased and usually non-measurable STSv, AXRV and WLKv. Five Year survival is 36% in ALS patients. The proportion of ALS patients with STSv, AXRv and WLKv greater than 50% predicted is comparable at two years.
Conclusions: Timed Up-and-Go Test may be studied through its components. Transformation to STSv, AXRv and WLKv indicates that Sit-To-Stand and Axial Rotation are more severely affected in ALS patients than Walking. STSv and AXRv are more severely decreased than WLKv with development of dependency on cane or walker.
P122 THE DIFFERENT MECHANISMS OF DYSPHAGIA IN BULBAR AND PSEUDOBULBAR PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS (ALS)
TOMIK B1, LORENS K2, TOMIK J3, ZAWISLAK D1, OSTROWSKA M1, PAWLIK W2, SKLADZIEN J3, SZCZUDLIK A1
1Department of Neurology, 2Department of Physiology,, 3Department of Otolaryngology, Jagiellonian University, Medical College, Krakow, Poland
E-mail address for correspondence: [email protected]
Keywords: dysphagia, mechanisms, manometry
Background: Swallowing mechanism in ALS patients has not been systematically studied. The oesophageal manometry (OM) can be an objective, manometric method for oesophageal peristalsis failure detection in ALS patients. There is some evidence that lesions of the pseudobulbar tract are more responsible for dysphagia due to ALS.
Objective: We investigated the mechanisms of oesophageal dysphagia in ALS patients with mainly bulbar (BP) or pseudobulbar clinical presentation (PBP).
Material and Methods: 28 (BP = 13 and PBP = 15) sporadic ALS patients with clinical evidence of dysphagia, fulfilling WFN criteria, from Krakow MND Centre, were involved in the study.
The standard transnasal OM was performed in all subjects studied and 20 healthy volunteers (control group) using a flexible catheter with the solid state transducers. The parameters were measured automatically and visualised by the computer system. Swallows were initiated with 5 to 10 ml of water (wet swallows) and saliva (dry swallows) and repeated at 30 second (sec) intervals in all subjects. We compared the upper oesophageal contractile amplitude and duration, rest pressure of the upper oesophageal sphincter, negative pressure of the oseophageal body, propagation of peristaltic waves, the upper oesophageal contractile velocity in ALS patients with BP or PBP and also control subjects.
Results: ALS patients studied had significant abnormalities in all parameters measured by OM as compared to controls. In BP cases we noticed: the upper oesophageal contractile amplitude-max. 38.6±6 mmHg (mean:17±5), the mean upper oesophageal contractile duration-1.4±0.2 sec., rest pressure of the upper oesophageal sphincter-12±2.4 mmHg, the occurrence of the negative pressure of oseophageal body-all cases studied, propagation of peristaltic waves-8 out of 13, the upper oesophageal contractile velocity-2 cm/sec. In PBP cases we detected: the upper oesophageal contractile amplitude-max: 98.6±19 mmHg (mean: 67±15), the mean upper oesophageal contractile duration-5.2±1.5 sec., rest pressure of the upper oesophageal sphincter-55±17 mmHg, the occurrence of the negative pressure of oseophageal body-3 out of 15, propagation of peristaltic waves-3 out of 15, the upper oesophageal contractile velocity-4.3 cm/sec.
Summary: OM procedure allows us to objectively distinguishing dysphagia in ALS patients due to mainly bulbar or pseudobulbar syndrome which could be important for revealing the cases with high risk of aspiration. Our results are in line with data suggesting that dysphagia in ALS cases is mainly associated with progressive degeneration of the corticobulbar pyramidal fibers.
P123 A CLINICAL BULBAR SCALE FOR ASSESSMENT & MONITORING OF CHANGE IN ALS
BALL LJ1, PATTEE GL1, GESKE J1, GREEN JR2, BEUKELMAN DR2
1University of Nebraska Medical Center, MMI, Omaha, NE, 2University of Nebraska, Lincoln, NE, United States
E-mail address for correspondence: [email protected]
Keywords: bulbar, scale, clinical, speech
Background: Persons with ALS (PALS) experience rapid progression of spastic-flaccid dysarthria. A clinical bulbar scale would provide a means of identifying UMN and LMN features observed in speech, and evaluate swallowing status. The scale would include timed verbal capacity, sentence intelligibility, communication effectiveness, UMN and LMN features, and swallowing. Timed verbal capacity has been identified as deficient among a subset of PALS. Sentence intelligibility is used to objectively measure speaking performance. Speaking rate is an effective indicator of pending reduction in intelligibility; however, the above evidence does not provide a timeline for predicting speech loss. PALS report that communication effectiveness is functionally impaired when sentence intelligibility is below 90%. When intelligibility declines to 80%, verbal communication is completely ineffective. These features, combined with clinical speech signs, comprise a proposed bulbar scale.
Objectives: A clinical scale for identifying bulbar dysfunction associated with ALS is proposed for use in identification and longitudinal monitoring. Initial face validity and reliability analyses will be completed.
Method: A Kaplan-Meier estimator was used to calculate survival from longitudinal speech intelligibility and rate scores, or PALS’ “speech lifetime”. Data were obtained from a clinical ALS database of 173 PALS over 380 sessions. Participant characteristics included: 94 male:79 female; 52 bulbar:121 spinal onset; Mean = 61 years, range 38–72. Speech characteristics were obtained for analysis (e.g., examination date, percent sentence intelligibility, speaking rate). Kaplan-Meier estimates were calculated to evaluate survival of functional speech based on rate and sentence intelligibility. The survival estimate of speech was determined for 50% intelligibility, the level at which participants indicate speech is no longer functional. A second calculation of survival at 80% was based on communication effectiveness ratings obtained from PALS who indicated this level as when speech becomes ineffective.
Results: Data identified speaking rate as an early predictor of bulbar dysfunction. PALS show a decline in intelligibility preceded by a speaking rate decline. Months post ALS diagnosis did not prove predictive of speech loss in either bulbar or spinal ALS. Results indicate 50% intelligibility survival function for all participants (M = 578.88 days, Median = 590) was approximately 1.5 years. The 80% intelligibility survival for bulbar ALS (M = 245.91 days, Mdn =241) was shorter than that for spinal ALS (M = 522.92 days, Mdn = 301). Data will illustrate survival functions for speaking rate.
Discussion: Intelligibility alone is not an adequate identifier of bulbar speech symptoms in ALS. This study provides the first speech survival times of PALS. Spinal onset PALS have longer speech survival than bulbar; but more importantly, dysarthria onset is preceded by changes in speaking rate and communication effectiveness that are imperceptible during clinical interactions. Validity and reliability of the bulbar scale will be presented, with research and implications discussed.
P124 MEASURES OF MAXIMUM PERFORMANCE OF SPEECH-RELATED TASKS IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS
YAMINI BK, SHIVASHANKAR N, NALINI A
National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
E-mail address for correspondence: [email protected]
Keywords: Duration, rate, dysarthria
Background: Measures of maximum performance of speech-related tasks are often used to determine the efficiency of the oral –vocal motor system.
Objectives: To evaluate measures of maximum performance of speech-related tasks in Amyotrophic lateral sclerosis (ALS).
Methods: Participants of the study included 70 patients with ALS (46 spinal onset and 24 bulbar onset) and 58 healthy volunteers (controls). The patients and controls were compatible with reference to age (25–73 yrs), gender and four Indian vernacular languages (native speakers of Kannada, Tamil, Telugu; and Hindi speakers of Indo-Aryan language background). All participants were tested on each of the following tasks i.e. Maximum Phonation Duration (MPD) of (a); Maximum Frication Duration (MFD) of (s) and (z); Diadochokinetic (DDK) rate of (pa), (ta), (ka) and (pataka); and articulatory precision of (pa), (ta) and (ka) during the task of DDK rate.
Results: Mean age (years) of patients was 49.47± 10.56 and controls was 47.48± 11.08. M: F- 3.4:1. Spinal onset: bulbar onset ALS- 2.3:1. In spinal onset group, mean durations of speech symptoms and limb symptoms were 3.89± 5.05 and 17.26±12.61 months respectively. In bulbar onset group, mean durations of speech symptoms and limb symptoms were 13.90± 12.12 and 4.13± 5.83 months respectively. Overall mean duration of illness was not significantly different among patients speaking the four vernacular languages.
Mean MPD (seconds) of (a) for patients was 11.87± 6.1 while in controls, it was 19.33± 6.28. Mean MFD (seconds) for (s) was 5.53± 5.44 in patients and 11.76± 4.91 in controls. Mean MFD for (z) was 6.34± 6.61 seconds in patients while in controls, it was 14.27± 4.41. Mean DDK rate (syllables per second) of (pa), (ta), (ka) and (pataka) in patients was 4.25± 1.8, 4.17±1.94, 3.98± 1.92 and 6.04± 2.9 respectively; and in controls was 6.69± 0.77, 6.96± 0.84, 6.59± 0.74 and 8.94± 1.35 respectively.
A significant difference (p< 0.05) in the performance was observed for all parameters between control group and the patient group; control group and the spinal onset group; control group and bulbar onset group. A significant difference between spinal onset and bulbar onset groups was also evident on all the parameters except MPD. There was no significant difference in the DDK rates of (pa), (ta), (ka) and (pataka) in the patient group across the four different languages. While the articulatory precision was observed in 67.1%, 41.4%, 61.5% and 55.7% of patients during DDK rate of (pa), (ta), (ka) and (pataka) respectively, it was present in all controls.
Discussion and Conclusion: These measures of maximum performance of speech-related tasks can be used clinically to detect deficiencies in the speech motor control in patients with both bulbar and spinal onset patterns of ALS while evaluating for dysarthria.
P125 LARYNGOLOGICAL DETECTION OF THE EARLY BULBAR SIGNS IN LIMB ONSET AMYOTROPHIC LATERAL SCLEROSIS PATIENTS
TOMIK J1, TOMIK B2, WIATR M1, SREK P1, ZWOLINSKA G2, ZAWISLAK D2, OLES K1, OSTROWSKA M2, SZCZUDLIK A2, SKLADZIEN J1
1Department of Otolaryngology, 2Department of Neurology, Jagiellonian University, Medical College, Krakow, Poland
E-mail address for correspondence: [email protected]
Keywords: videostroboscope,voice, analysis
Background: Not many data concerning the laryngological evaluation of sporadic Amyotrophic Lateral Sclerosis (sALS) patients exist. The bulbar symptoms of sALS include problems with spoken communication (dysphonia, dysarthria), difficulty with the management of swallowing, saliva production and aspiration of the airways. These patients are occasionally seen by otolaryngologists. The first clinical presentation of sALS could be usually on limb or bulbar level only, however the occurrence of preclinical phase of the disease is suggested.
Objective: The aim of the study was to detect the early, preclinical signs of bulbar dysfunction in limb onset sALS patients.
Material and Methods: We have included 24 limb onset sALS patients, diagnosed in the Department of Neurology, Jagiellonian University, Medical College in Krakow; using the El Escorial Criteria (1998). None of patients presented any bulbar symptoms or signs in the neurological examination.
To detect the early bulbar dysfunction the videostroboscope examination with analysis of the acoustic parameters of the voice were performed in sALS cases and results were compared with 20 healthy persons (control group).
Results: In 17 out of 24 patients studied we have noticed-slowness of one / both vocal folds (VF) – (7 patients), the lack of their complete closure during phonation (5 patients) and unilateral decrease of VF tension with limited abduction as well as VF decrease mobility (5 patients).The evidence of shorter phonation time (PT) was detected in 5 out of 24 patients (range: 8 – 18 sec.). The abnormal frequency of the voice (range: 80 – 180 Hz) was detected in 7 patients. The analysis of the Jitter and Shimmer parameters have presented statistical significance difference (p< 0.001) as compared to the control group. The voice analysis have showed: roughness voice (5 patients), breathiness voice (5 patients) and asthenicity voice (2 patients). The details of the voice analysis will be presented.
Conclusions: The results of our study have highlighted the occurrence of early signs of bulbar dysfunction, especially nerve/s vagus lesion, before clinical presentation of bulbar failure in limb onset sALS patients. The laryngological examination can be very useful in the estimation of the early bulbar presentation in ALS patients.
P126 VOWEL SPACE AREA IN PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS
YAMINI BK, SHIVASHANKAR N, NALINI A
National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India
E-mail address for correspondence: [email protected]
Keywords: vowel triangle, vowel space area, languages
Background: Quadrilateral with the English corner vowels (a), (i), (u) and (ae) has a smaller space area in speakers with Amyotrophic Lateral Sclerosis (ALS) Citation[1]. However, (ae) is not observed in the linguistic repertoire of all Indian languages.
Objectives: To determine the vowel space area formed by three vowels in ALS.
Method: 64 patients (Men: Women- 3.92: 1) participated. Among men, 38 had spinal and 13 had bulbar onset. Among women, 7 had spinal and 4 had bulbar onset. They included native speakers of Kannada (15 men, 9 women), Tamil (10 men and 2 women) and Telugu (9 men) languages; and Hindi speakers (17 men, 2 women) of Indo-Aryan background. Age and language compatible 54 healthy volunteers (44 men and 10 women) were the controls.
Words were chosen from the articulation tests of Kannada, Tamil, Telugu and Hindi languages. The language of the articulation test used for participant depended upon his/her linguistic category. Participants either read or repeated words which had the vowels (a), (i) and (u) in predetermined word positions. The first formant frequency (F1-Hertz) and second formant frequency (F2-Hertz) of vowels were obtained using the software- ‘speech science lab’. F1 and F2 values for each of the three vowels of each language were plotted separately graphically for both men and women. A vowel triangle was drawn connecting the plots and the vowel space area (Hertz squared) in the triangle was determined using a mathematical equation and averaged.
Results: For Kannada speaking men, vowel space area was 88,831.37 in spinal onset, 1,36,122.78 in bulbar onset and 3,35,098.2 in controls. For Kannada speaking women, area was 2,76,044.15 in spinal, 1,60,630.14 in bulbar and 3,23,360.15 in controls. For Tamil speaking men, area was 90,298.72 in spinal and 1,44,473.52 in controls. For Tamil speaking women, area was 4,16,791.95 in spinal and 1,78,272.37 in controls. For Telugu speaking men, area was 1,16,683.41 in spinal, 1,15,274.67 in bulbar and 2,05,106.44 in controls. For Hindi speaking men, area was 2,14,348.28 in spinal, 65,179.55 in bulbar and 2,55,361.89 in controls. For Hindi speaking women, area was 2,95,737.05 in bulbar and 3,66,480.35 in controls.
Data suggested that average vowel space area in both spinal and bulbar onset groups, in both genders, is less than area in gender compatible controls irrespective of the language except in one comparison. Bulbar onset groups of Hindi and Telugu speaking men; and Kannada and Hindi speaking women had least area in their respective comparisons.
Discussion and Conclusion: Tongue height and tongue advancement determine the said formant frequencies which in turn determine vowel production. The finding of reduced area in ALS in most of the comparisons suggest inadequate lingual mobility and inturn impaired articulation of vowels and is more so in bulbar onset.Citation[1]
P127 NOVEL CLINICAL OBSERVATIONS ON POSTURAL ORIENTATION IMPAIRMENTS EARLY IN THE COURSE OF AMYOTROPHIC LATERAL SCLEROSIS (ALS)
SANJAK M, DUFFY K, BRAWER E, BROOKS B
The Carolinas Neuromuscular/ALS-MDA Center, Department Of Neurology, CHS, Charlotte, NC., United States
E-mail address for correspondence: [email protected]
Keywords: Balance, Fall, Vistibular impairment
Background: Falls are a common occurrence in ALS patients and may occur before weakness is apparent. Quantification of balance deficit, which may lead to falls and/or injuries, is not completely established in ALS patients. Balance deficit may result from damage within the sensory systems (vision, somatosensory, and vestibular) which provide the patient with spatial orientation, from pathology in the central sensory structures necessary for the interpretation and selection of sensory information for balance control, or in the corticospinal tract and associated cortico-bulbar-spinal pathways that permit motor corrections. In ALS clinics, a variety of tests have been used to assess the balance status of ALS patients. The balance subscale of the Tinetti Performance Oriented Mobility Assessment (POMA-B), the Timed Up-and-Go Test, and the Functional Reach (FR) are among the most frequently used to assess the balance status in ALS patients.
Objectives: To identify balance deficit early in the course ALS.
Methods: We employ the Modified Clinical Test of Sensory Integration and Balance (mCTSIB), in addition to the POMA-B and FR. The mCTSIB requires patient to stand still for 30 seconds on solid ground (1) with eyes open (SG EO) (Three sensory systems available for balance (vision, vestibular, somatosensory) then (2) with eyes closed (SG EC) (vestibular and somatosensory available, vision absent). These two conditions are included in the POMA-B. The patients then are required to stand on foam (3) with eyes open (F EO) (vision and vestibular available, somatosensory compromised) and then (4) with eyes closed (F EC) (vestibular available. vision absent, somatosensory) compromised).
Result: In early diagnosed ALS patients, who are ambulatory without any assistive devices and who report fear of falling (FF) but have not fell, the mCTSIB is more sensitive to postural imbalance. POMA-B scores were 15 – 16; FR scores were 9 – 15 indicating no apparent risk of falling, but tested patients who tolerated standing on SG EO, SG EC, and F EO with minimal or no sway, developed imbalance with near falling when standing on F EC.
Discussion and Conclusions: Apparent vestibular impairment is indicated early in ALS patients with FF and may not be detected by the commonly used balance scales. Early detection of this impairment should help clinician to develop treatment protocol to rehabilitate this impairment and to teach ALS patients the proper compensation to avoid falls ALS patients seem to compensate by increasing reliance on vision and somatosensory senses. ALS patients seem to sense this early loss in apparent vestibular system function and compensate by slowing their movement, and assume forward head and trunk posture to increase fixation to maintain the center of mass within the base of support (camptocormia). This strategy may protect patients from falls in the short term, but it may lead to deconditioning of the balance system and the postural righting reflexes needed for proper balance to avoid fall. Further studies of the sensory and motor control of balance in ALS are needed.
P128 CLINICAL PHENOTYPIC ANALYSIS OF X-LINKED RECESSIVE INHERITED SPINAL AND BULAR MUSCULAR ATROPHY IN CHINA
LI C, YE J, LIAO Z, YANG J, WANG X
Neurology department of Xuan Wu hospital, the Capital Medical University, Beijing, China
E-mail address for correspondence: [email protected]
Keywords: Kennedy's disease, gene detection, China
Spinal and bulbar muscular atrophy (SBMA) was first described by Kennedy in 1968, and Spada et al found that SBMA was caused by an expansion of a CAG repeat in the the first exon of androgen receptor gene. The first family of SBMA confirmed by gene linkage analysis in Chinese mainland was reported in 2006,and another two families reported in 2007. We collected five patients from four families pseudo-diagnosed as SBMA from June to December, 2007. They all have an expansion of a CAG repeat in the androgen receptor gene confirmed by PCR-gene sequencing. This report analyses the clinical phenotype and electrophysiology features of SBMA.
Objective: To analyse the clinical features of X-linked spinal and bulbar muscular atrophy confirmed by gene detection in Chinese.
Methods: Five patients from four families pseudo-diagnosed as SBMA were collected. Four of them have family history. They are all han people from Chinese mainland. Xq11–12 androgen receptor (AR) gene was detected by PCR-sequencing directly. Twenty normal Chinese were chosen as the control group. According to the primer sequence designed by La Spada et al, a CAG repeat in the the first exon of androgen receptor gene was amplified by PCR. The primer sequence: template strand: 5′2TCCAGAATCTGTTCCAGAGCG2 TGC23′, Crick strand: 5′2GCTGTGAAGGTTGCTGTTCCT2CAT23′. The symptoms, physical examination of nervous system, electromyogram and creatine phosphokinase were analysed.
Results: The frequencies of CAG repeat in the AR gene's first exon of the five patients were all higher than the control group. The mean frequency of CAG repeat in the control group was 20. In the case group, there were 47 CAG repeats in 1 patient, 50 times in 3 patients and 51 times in 1 patient. Mean age at onset was 27.8 years (15 to 46 years). Some of them were initially diagnosed as low calcium, amyotrophic lateral sclerosis, acquired neuromyotonia, progressive muscula dystrophy. Symptoms of onset were myasthenia of limbs, myospasm, tremor of hands and dysphagia. The slow progressive myasthenia of limbs, especially the lower limbs, was the main symptoms which caused the patients to visit doctor. The second cause was muscle thrilling(3/5), myotonia(3/5). Physical examination: Muscles of tongue amyotrophy, thrill(5/5), bilateral upper extremities weakness (3/5), bilateral lower extremities weakness (5/5), tendon reflex attenuated (4/5), amyotrophy (5/5), amyotrophy of proximate of bilateral upper extremities, thenar, hypothenar and rump (5/5), pathologic reflex and brain stem reflex negative(5/5), waddling gait (3/5), gynecomastia (5/5), giga-potential in electromyogram (5/5). Andrusol and growth were normal and no peripheral nerve disorders. CPK was increased in all patients (mean 496µ/l). One sporadic patient with fewer frequences of CAG repeat suffered milder clinical symptoms, and onset age was later.
Conclusions: The main clinical symptoms of five Chinese patients with SBMA are myasthenia of limbs, especially the lower limbs, and amyotrophy, particularly the upper limb-girdle muscle, muscle spasm, tremor of hands, tendon reflex attenuated mimicking peripheral nerve diseases, waddling gait and hyper CPK emia mimicking myopathy, giga-potential in electromyogram mimicking anterior horn diseases, gynecomastia without abnormal andrusol and growth.
P129 LATE ONSET BRACHIAL MONOMELIC AMYOTROPHY
JUNTAS MORALES R, PAGEOT N, CAMU W
University Hospital of Montpellier, Montpellier, France
E-mail address for correspondence: [email protected]
Keywords: Hirayama late onset
Background: Brachial monomelic amyotrophy or Hirayama disease is a benign lower motor neuron disorder affecting mainly young patients, with a male preponderance. Insidious onset of atrophy and weakness, with slow progressive evolution for 2–4 years is followed by a stationary course. Electromyographic evidence of neurogenic pattern without conduction block is typically found.
Objectives: The aim of this work is to present two cases of brachial monomelic amyotrophy of very late onset (63 and 71 years respectively). Previously reported cases of Hirayama disease typically affected young people (98% between 15 and 30 years). To our knowledge no other cases have been published at this advanced age.
Methods: We describe the clinical phenotype of two patients: age of onset, physical activity, duration of progression and clinical manifestations, including initial symptoms and neurological findings during the course of the disease. We also recorded the results of nerve conduction velocity studies, needle electromyography, Anti-GM1 antibody test and cervical magnetic resonance imaging (MRI).
Results: The first patient consulted for progressive left hand weakness appearing at the age of 63. Initially he had difficulty making precise movements, without either pain or sensitive symptoms. The neurological examination showed isolated marked left first dorsal interosseous muscle atrophy. Osteotendinous reflexes and sensory examination were normal. Motor and sensory nerve conduction studies were also normal. There were no signs of conduction block. Anti-GM1 antibodies were not present. The symptoms worsened progressively and two years later muscular atrophy had spread to all hand muscles and distal forearm (sparing brachioradialis).
EMG revealed chronic denervation in abductor pollicis brevis, abductor digiti minimi, flexor carpi radialis and first dorsal interosseus on the left side. Cervical spinal cord MRI was normal. From this moment till now, seven years later, there has not been any evolution and the motor deficit remains stable.
The second patient had identical evolution concerning this time the right side: the first sign appeared at the age of 71 and consisted of right first dorsal interosseous atrophy spreading slowly to other hand muscles and distal forearm during a period of two years. There were no conduction blocks and anti-GM1 antibodies were absent. MRI of the spinal cord was normal. He is now 77 years old and the muscular atrophy remains unchanged.
Conclusions: Although brachial monomelic amyotrophy appears typically in young patients, these two cases illustrate that the same phenotype may be seen in older people. Obviously, amyotrophic lateral sclerosis and multifical motor neuropathy must be excluded.
P130 IS SPORADIC MONOMELIC AMYOTROPHY ALWAYS BENIGN?
MOGLIA C, CALVO A, GHIGLIONE P, CHIÒ A
Department of Neuroscience, Torino, Italy
E-mail address for correspondence: [email protected]
Keywords: monomelic amyotrophy, case report, disease progression
Background: Monomelic amyotrophy (MA) of lower limbs is a variant of lower motor neuron disease, generally considered benign and non progressive. We report a case of a MA with a late evolution to a fatal diffuse motor neuron disease (MND).
Case report: A 56 year old caucasian man developed wasting and weakness of the left leg. The patient had no relevant clinical or family history for neuromuscular diseases. The clinical examination revealed signs of lower motor neuron impairment, with amyotrophy, hyporeflexia, fasciculations and cramps, without upper motor neuron signs. Electromyographical (EMG) examination demonstrated a neurogenic pattern, restricted to the left lower limb muscles. Neuroradiological findings (cranial and spinal MRI scan) were negative. Blood chemistry showed normal values, except for a mildly elevated serum creatine kinase (CK). Medial gastrocnemius muscle biopsy was performed: it was suggestive of neurogenic amyotrophy. The disease course was slowly progressive for five years, followed by stabilization of symptoms. However, after a long period (11 years) of disease stability, the contralateral leg was gradually involved, with the appearance of lower motor neuron signs (amyotrophy, weakness and fasciculations). Four years later, both upper limbs, bulbar functions and respiratory muscles were rapidly and severely involved, although there were no evidence of involvement of the upper motor neuron. Within few months the patient died for acute respiratory failure.
Discussion: Our patient's initial clinical presentation had the typical features of lower extremities MA, but he developed a late progression of disease, that turned, 20 years later, to a diffuse motor neuron disease. To our knowledge no other similar cases have been described. This case demonstrated that MA may rarely evolve to a serious form of motor neuron diseases.
P131 CLINICAL AND GENETIC FEATURES OF PATIENTS WITH AMYOTROPHIC LATERAL SCLEROSIS IN SOUTH-WEST CHINA
SHANG HF, FANG DF, HE L, ZHOU D
Department of Neurology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
E-mail address for correspondence: [email protected]
Keywords: clinical features, prognosis, polymorphism
Background: Amyotrophic lateral sclerosis (ALS) is one of the most common fatal neurodegenerative disorders.
Objective: To investigate the risk and protective factors influencing onset and progression of patients with ALS in South-West China; to analyse the association of several recently reported polymorphisms including rs6587852, rs6700125, rs1470407, rs6690993, rs333662 and rs10493256 and clinical features.
Patients and Methods: All the patients diagnosed with ALS according to the El Escorial criteria from our department from May 2004 to January 2008 were included in the prospected study. Data of clinical features and outcome of patients were registered. Blood samples were collected after informed consent. The frequency of alleles was identified by sequencing and restriction analysis of the PCR products spanning polymorphism. All the patients were followed up every six months by re-examination or telephone call. Multiple linear regression was used to analyse the prognosis factor of the disease.
Results: Overall 165 patients were diagnosed with definite and probable ALS. The mean onset age was 50.8±11.3 years. In addition, 35 (21.2%) patients were younger than 40 year-old. The number of males (105, 63.6%) was significantly higher than that of females (60, 36.4%).There was no significant difference of onset age, initial symptoms, fasciculation and outcome between males and females. The initial symptom was involved in the upper limbs in 83 cases (50.3%), in the lower limbs in 48 cases (29.1%), in the bulbar in 33 cases (20.0%) and in the respiratory muscles in 1 case (0.6%). The onset age of cases whose initial symptoms involved the spinal cord (132 cases) was significantly younger than that of patients whose initial symptoms involved bulbar (33 cases) (48.9±11.1 vs 58.4±8.4). Forty patients (24.2%) were dead. The onset age of death group (56.7±8.7) was significantly older than that of survival group (48.9±11.4)(p = 0.02). The mean survival time after onset of disease was 24.3±16.7 months. The mean delay between age at onset and age at diagnosis was significantly higher in the death group than that in the survival group (12.4±10.8 vs18.3±15.7 months, p = 0.03). No association of the polymorphisms and clinical features including onset age, sex, initial symptoms, fasciculation and survival was found in 57 patients group. Positive correlation between mean delay and disease duration was found. Negative correlation between onset age, mean delay and disease duration was found.
Conclusions: Late onset is a poor prognostic factor in ALS patients. Physician should pay more attention to the patients after patients were diagnosed as ALS. No association of the polymorphisms and clinical features may due to the small number of the patients.
References
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