Amyotrophie Lateral Selves Quantitative Assessment of Neuromuscular Deficit in ALS Patricia L. Andres, M.S, P.T..* Linda M. Thibodeau, P-.A.,¢ Loren: J. Finison, Ph-D.,4 and Theodove 1. Munsat, M.D.§ Accurate measurement is as essential in clinical research as it is in basic research. The valiity of data resulting from an investigation depends in great part on the measurement tools avaihble, Each year hundreds of thousands of dollars are spent on dinial trials in neuromuseu using measurement techniques of questionable accuraey.. Curt ‘of measuring neuromuscular deficit include subjective elements and Tack the sensitivity to detect small but meaningful change in deterioration ancl therapeutic efficacy. Accirate, objective measurement tools are needed to document the natural hstory of progressive diseases, such as ALS, and thus provide clues to etiology and pathogenesis.” ALS is a disease of progressive damage to upper motor neurons and lower motor neurons resilting in the loss of voluntary motor function and subsequent the loss of functional capacity.*** Despite major technologie advances in our ability todiagnose specific neuromuscular diseases, current methods to quantitate de‘cit in ALS remain primitive, Unfortunately, there are no precise chemical markers or electrophysiologic techniques available to document disease progression. Therefore, motor neuron loss must be measured by indirect methods, ‘This article describes various techniques used to measure strength and function in ALS, particularly our testing protocol, the Tufts Quantitative Lecturer ta Newslony ‘Reveuch Physi Therapie stant {Asuodate Clieal Profesor, Department of Comunity Health; Statistica Consultant iDimetor, Nouromeiar Research Unt Prfeor of Nerology Frum te Neuromuscular Research, Unit Department of Neurology, Tult-New England ‘Medical Center, Baton, Massachnstis, Supported by grams fiom the Muscular Dystophy Assodaton and NIH Grant CRC No, ‘MoaRRiebes Nenroloie Cline Va. 8, Na. 1, Fey 1957 135136 Parmicia Le ANDRES ET AL Neuromuscular Exam. It will aso address basie considerations in designing test batteries for measuring deficit in neuromuscular diseases, SUMMARY OF CURRENT METHODS ‘Traditional methods of evaluating ALS patients include the clinical neurologic exam, manual musele test (MMT),*" 2" rating seales,**"® and timed functional activites.* ** MMT and ‘rating scales: produce ordinal data. That is, categories are arranged in ranked order, but intervals between rankings are not eaval. For example, spasticity can be described as L: mild 2: moderate, or 3s severe. Muscles in the mild category have less spasticity than those in the moderate category, but the difference between mild andl ‘moderate is not necessarily the same as between moderate and severe, In addition, a muscle with mild spasticity is not equal to all other muscles graded mild, Standard statistical analyses based on means are not legit imately applied to ordinal data, as the individual scores are not evenly spaced. Ordinal data permits only analysis of Frequencies.* Manual Muscle Test MMT, the most commonly used test of muscle strength, was originally developed’ by Lovett to evaluate isolated weakness associated with polion iyelits It is a standardized grading system in which strength is subjec- lively graded according to the patients ability to move against gravity and hold agsinst the examiner's manual resistance." Several groups, including the Medical Research Counecil,® Kendall and Kendall," and Daniels and Worthingham,” have devised variations on the MMT technique MMT is deficient in several respects. Its quantitative capacity is limited because ordinal data is produced. Grading is subjective, and scoring is influenced by the examiners strength and the weight of the patient's Timb, Finally, the number of grades is Hinited, Beasley* demonstrated the deficiencies of MMT by comparing it sith ‘quantitative isometric force measurement of both normal subjects ‘with neuromuscular delieit, He showed thatthe force generated by muscles graded in the same MMT grade can vary as much as 40 per cent. As a ‘muscle remains in the same grade until it reaches a “eritical” level, the use Of MMT in a longitudinal stady may falsely indicate plateaning or stepwise progression when, in fact, strength is declining in a Hinear manner Functional Rating Seales Functional seales are widely used in assessing neuromuscular deficit 21.40 They are easily performed and broadly reflect clinically relevant functional disturbances. However, they are relatively insensitive to the degree of motor neuron loss; they produce ordinal data and rely on the subjective judgment of the examiner. Functional scales can provide such formation as the number of patients who improve or worsen, but they do not show how much or how fist deterioration takes place 'e most commonly used funtion seale in assessing ALS deficit is (LS Score” designed by Norrs.™ It consists of 34 items rated 0 to 3 the "Quavrtrarive Assessuenr oF Neunowuscutan Drricrr ALS 137 (0 = no use, L = very limited, 2 = useful but impaired, 3 ‘normal composite seore i 100. The items include functional activities and neurologic signs such as chewing, rolling, feeding, breathing, reflexes, and plantar responses, As subjective reflex testing weighted equally with Such essential finetions as breathing and swallowing, the score is a doubtful index of disease progression. In addition, the sensitivity of the seale is limited because only fonr grades are used and thus fewer options are available. For example, compromised breathing must be either graded tusefal but impaired (2) or very limited (1). Finally, no reliability or validity studies of the ALS Score have been published. ‘Timed Functional Activities Several investigators have included timed functional activites in their test batteries to measure neuromuscular deficit * * This approach Produces interval data that can be analyzed using parametric statistics. ‘Avo, timed tests are more objective and reduce examiner bis. “Timed tests reflect impaired physical function and ean providea general indication of improvement of deterioration. However, they may not always provide the best means of charting disease progression. Certain tasks may Fequire a eritieal number of motor units and the time required for theit performance may not cage until this evita level is reached. Figure 1 lustrates the decline in arm strength (maximal isometric force) eompared to the decline in the ably 10 dial a phone number and place pexs in a Soar sis Ut long sepa detente in nar bho, timed hand activities Ampped of sharply at a certain point. In addition, timed activites may be infuenced by environmental or other factors texteral 0 the disease proces. Figure 2 shows that timed ambulation, for instance, may actually improve dramatically when tho typo of assistance is changed. 4.57 tived nand function and arn strength over tine “ seo 9601000 060 1100 1160 120012501300, ays since disease coset Figure 1. In this patient ere & « contauous ines decline in arm atensth while timed han neton dopa of sharply er approsinatly dy 110,138, Partita Le ANDRES EA no alo abs she alo sho ohn obo so sags sine sisease Oat igure 2 thi raph teats ted wal et of single patient over te. The pase ‘anbslated independent unt day 100 err, when he started sing x alg walker, Then ter day 00 (arrow) the patent eld no Tonger se the walker and depended pasa tstctance to ambulte, Several investigators have reported the use of timed Funetional activities to measure change in ALS drug trial." * Timed activities may be of eater value in acute studies than in longitudinal studies because environ- ‘mental fitrs and eral levels are uniely to influence the fet of the ng ‘Quantitative Strength Measurement Strength is dependent upon many factors including type of contraction isometric, isotonic, isokinetic), speed of contraction, length-tension rela- tionship, neuronal discharge, and cross-sectional area of muscle and moti- vation.” Recently developed quantitative methods to measure strength Involve either isokinetic oF isometric testing ‘An isokinetic dynamometer (for example, Cybex 11* and Kin-Comf) contains a preset speed-controlling mechanism that offers resistance pro- portional to the dynamic tension developed by the exereising limb." The torque produced by a limb as it moves throughout the range of motion is, recorded. The device produces accurate interval readouts andl measures torque throughout the entire range of motion while controlling velocity High test-retest reliability was demonstrated in children testing 10 large muscle groups. Isokinetic dynamometers have several. disadvantages, however. Their cost may be prohibitive at $25,000 to $35,000, Cybex adjustment is difficult, making measurement of several diferent muscle groups laborious. Also, muscles with less than Fair-+ strength cannot be tested through the full are of motion because the limb is too weak to exert force against the machine's moving lever arm, ‘There are several instruments for quantitating maximal voluntary Isometric force, ‘These include spring balances, cable tensiometers, hy “Gybex Dison of Lumex, In, 2100 Smithtown Ave, Rovonkoms, NY Chater Corp, 101 Mem Dr, BO Box 4287, Catan, IN‘Quavrexrive Assessunr ov NEUROMUSCULAR Devicrr i ALS 129 raulie myometers, and various types of strain gauges." Isometric testing has the advantage of eliminating velocity and muscle length as variables.” 2304 However, the examiner must be carefully trained to assure that the limb position and stabilization are standard.""® Hand-held myometers and electronic strain gauges are widely used to {quantitate isometric force. Hand-held myometers have been used in studies {0 measure neuromuscular deficit, yiekling exellent test-retest reliability.” ‘Their pocket size and portability ae advantageous, but a major disadvantage is that the maximum force recorded is limited by the strength of the texaminer, who must be able to hold against the patients resistance. The hand-held myometer is therefore not suitable for measuring minor degrees of weakness in large adulls. Also, it does not produce a hard copy of results Several Investigators have used strain-gauges to measure isometric force." ® Their main advantages are that (1) a hard copy of the test results is produced and (2) the subject is pulling against an immovable rap, rather than against the force of the examiner (Fig. 2) DEVELOPMENT OF THE TUFTS QUANTITATIVE NEUROMUSCULAR EXAM We have developed a standardized test battery to quantitate neuro: muscular deficit in ALS, the Tufts Quantitative Neuromuscular Exam Figute 3. metric ree measurements performed on a standard ection table with aminaenoprights and aijostble ngs A'spon strap poxtoned on the lib ne Table Yor devas on pining The stp i connected tothe san gige, whi gon a nme upright The strap and ral gauge ema pore with is tumadocd Uy the aun af deteaton win Ch sri ange Tot pled (Hevlet-Pakerd nplfers adel 62164, 481 Nis Oslo Aves Tacos, Calor) and recorded on the sp chat recorder ewe Packard Medel No. 080,130 Paricts Le ANDRES ET Al ‘Table 1, Pubwonry Function Testing erm 20 Forced vial capacity (best of two a) Callin survey sprometer™ Masini vantary entation waren B Goliog tne, Baites, Many (TONE). Used to test over 250 patients with ALS, th E has heen utilized in several drug trials.» ®* Our tost protocol (Tables 1 through 4) evolved Irom several years ol experience in collecting and analyzing data to assure reliability and validity. As part of this process, many items have been dropped, added, or modified over the past decade, ‘An important principle in designing a test batery is that the protocol must address specific research questions. The TONE was developed to measure the rate of disease progression in ALS and to determine how much change occurs in a given time period. Test items that produce interval data were required to allow adequate statistical analysis. If one is more {interested in funetional outeomes, tests that produce ordinal data (MMT, grading scales) may be appropriate, Analysis of ordinal data, however, can only indicate general improvement or decline in performance. The following summarizes our efforts to establish reliability and validity of the TONE. Reliability Reliability refers to the consistency or reproducibility of a measure- ment.® Thus, when all variables are held constant, it is assumed that change reliably measured from one trial to the next reflects true change in the disease state. Test-retest variation is a function not only of testing or measurement error but also human performance variation.* Positioning, instructions to the patient, verbal encouragement, muscle contraction relaxation time, and stabilization can influence the results.» Such variables ‘ean be somewhat controlled during isometrie strength testing when strict standardized procedures are followed. However, despite minimizing testing terror, it may be impossible to limit human performance variation to less than 5 per cent. ‘Table 2 Timed Motor Actiitios esr ee ure NEEDED once ip ate “Stopwatch Speech ster“ Stopwatch one ding Singh dil Completing the ligt Tht ant lane, stopwatch ‘umber 164.7172 Let han Pen tet Purdue pegboard. uber of pgs pla in Tht han “epateh ‘i soond at har Timed ot walk State Grossing the 1 ot maker (Patent seated ia 38.6 an high lay a Font of Heh ale) ‘Model 3300, J-A Piston Corp, New Yor, New YorkQuavrrrarive Assesses oF Netnowuscutan Destcr ALS 131 ‘Table 3. Newonuscular Functional Performance Seale Speed Trott patent oak nner etrmty Plies «8:5 om cube wong Oa kg in 12S cm square box Lower extremity Interview ard observe patent smbolte 7 Normal Sly showed, some suring of Evidence of dysartri, sowed rte, ely nerd (Geveraly dye, may have ‘eto tli Dyna el Yo wnderstand, Dut sme pias undersea Dysarts aly 2 few wow coder = Une, sooveral communication seve bg wed a en mal {Gan Somplt, but wth ‘omen tecgiee ‘Canta bt canna complete Unable Unlined community ambultor sina gat ater Independent community ambulstr ‘ih or witout device, detectable ‘tt devious [dependent howcholdambultos ‘wth or thot devices, ma ed Sisto rar limited omy “nuit with Supervision ‘sted ambulation the homes tated trates Sted fr 3 ted ‘Nina sist transfersParmicis L, ANDRES EF AL. ie ‘gs os “THE-266 29" SmaINON sD NI jn u| WouIsOSs ZU! oMTMHUEN TET MEL “A Tracy SopaUY so "og Seog DE ow 2003 os 8908 06 w 0m sup 2009 omg open dy xd serene soar soyepunet spur amas 0518 mC mata eras ip sang weeny 0 sony os w mpnes owing a ensop 0 eand Dorspiets eng epg res any eg oaosaa wm Bay Beapen, Pa104 EO fo POHPTF AMPE,‘Quanrrixtive AssessuNT oF NeuHOMUSCULAK Desicrt wy ALS 133 High reliability is often incorrectly assumed if dere is high test-retest correlation. Te should be noted that a correlation coefficient of 1.00 des ‘not mean thatthe values of the Krst and second tals are identical. Rather itimeans that they are pefetly matched. That i all first and second values Ihave the same relative relation to each other. To. more fully assess reproducility, It is. preferable to use per cent change of intraclass Carrelaton coelficient (IOC) with interval data and per cent agreement with ordinal data To studying the testretst reliability of the TONE, 10 patients with ALS and 35 normal subjets were ested twice within ato Shou period Data were analyzed using both correlations and per cent variation, a shown in Tables 5 through 8. Intrarater test-retest correlations ranged between t = 0181 and 0.98 (mean absolute variation = 6.4. per cent) for normal subjects; and = 0.92 and 0.99 (moan absolut variation = 8.9 per cent) for ALS patients, Intaiter testretest corelations ranged between ¥ = 10.70 and 0.99 (mean absolute variation = 7 per cent) for normal subjects and ¥ = 0,92 and 0.96 (mean absolute varation 7.4 per cent) for ALS patients “These results illustrate that different information can be obtained from the same data using two different analyses. Though correlations were higher for ALS patients, the normal contiols showed lest per cent testretest variation. ‘This is most likely because the normal subjects were a more hhomogencous group, whereas the patients with ALS had a wider spread in their performance. Therefore, though the patients individually changed from test to retest moro than the normal subjects, they more closely ‘maintained their relative postion compared with normal subjects who were Lightly clustered. In adtition, our resulls demonstrated no dliflerence Ipetween intra and interrater reliability. indicating high consistency tn the testing procedure. This sguests that test-retest variation i due to subjeet performance variation, rather than ervor in the testing method Many investigators have demonstrated similar reliability using strain gauges." 2 * Wiles and Kami tested knee extensor strength in 20 Patients with neuronvuseular diseases and found a test-retest correlation of ‘Table 5. Analyse of 3 to Sshour Tost-Retst for Toned Actvtios and Pubmonary Punction: Intrarater Testing TT etenee- «ne = “tal 036 9 a1 Phone R ba os Sa Phone L 95 om a Pegard R oss on 4 goad ost om ike ve bs O99 a4 vy bs om 103 er aie (Prom Anvires PL, Hdl We Fini Ly ot ok Qumaittive ator ssement anyotrophi lateral leon Neurology 3457-98, 1968 wth persion)1m Parmicas Le ANDRES ET AL ‘Table 6. Analysis of 9- to S-Hour Test-Retst for Isometrie Force: Intrarter Testing NORA CoNTON T= 35) Taseanenn n= 1 Te ___Fercowthange pr __‘For ent cana ‘honk fx ny 3 om 32 Shaler ex on a om bo Slams ext oo zo oo 5 Shney ext L 0. bo 30 Ell fer om 5a oo Elbow fe 096 a3 bap Eto ex 096 bs ba Elbo et I Das 52 bar Grp bas ta ba Gap be bao Hip ex R 095 Das Hip ext bas her ip flex oar h@ ip fee bas 9 Kee ee sr 4 Ke eat nes 4% 8 Ke fx O98 O98 46 Knee fee ase a9 so Dorner ry on 40 Doras 1 Os 0s ur i = Hexion Ea = erenaim (From Andres PL, Hedland W. Faison Ly etal: Quantiave motor asset in ‘unpotophic ater! sclerosis: Newoagy SBCTAIST- DA, 186 wth ermisin.) able 7. Analysis of 3- to 5-Hour Test-Retest for Tuned Actielties and Pulmonary Function: Interrater Testing Toma conrwnis(e = 10) panne = 1) Tem a Per cat hana a erent change = os BI am oa ta on ts os 03 Phone ® Om 26 3s a Phone L 08 aT 000 a Pega on 62 009 19 Pega L om 54 098 a1 re 004 so om % ANY 03 a bop uu er Le ket (rom Andves PL, Hedland W, inion L, eta: Quantitative motor asessment in snnyoroic teal selves, Newtelogy SATN7-04, 1086 wth pean,Quavrrnynive Assrssweser or NeunoMUSCULAR DEFICIT IN ALS 135 “Table 8. Analysis of 3 to S-Hour Test Retest for Inmerie Fore: Intersraer Testing Tom connan f= 10) ras = 10) Tew 7_Per cont change = __Perent chan a Shoulder er L095 3 om Shoulder ek 098 33 098 Shoulder et LOST 52 090 Ew fe 8 099 ar aa Ew fe ost Ba aa Bl ex 98 7B 7 Elbo et 99 87 a8 np 098 58 om Gal oor 6s om ip ext 0.98 sa oot Hip et Le ‘090 89 ba Hip es hs er bas ip es 1 ot wo ba Knee ext it 9 ts a8 Knee ett aut 80 98 Knee fx oot 1 oa Knee fs L ot 56 ost Dean | REL 1 oar Dovaiieron L_—O.85 Ba oar = whe Lake fix = Henon (from Andee PL, Hedland W, inion L, e sk Quunttate motor aueunent fa sunyotophic trl sero, Neuro 367/897-81, 1988, with perio = 0.57. With five examiners measuring 32 muscles, inter-rater coefficient fof variation was 12.8 per cent. Scott et al. tested knee extensor strength (Of 12 boys with DMD an observed a test-retest correlation coefficient over 1.5 hours ofr = 0.91 To be valid, a test must measure what it Is supposed to measure. Because no method currently exists to measure motor neuron loss directly, true validation of test methods to quantitate deficit in ALS is not possible. Validity is best assessed by comparing the test protocol with a universally accepted standard. Unfortunately, no such standard exists for quantitating deficit in ALS. Therefore, validity must be assessed through theoretical ‘constructs "The major component of the TQNE is measurement of voluntary isometric force. Its theoretical framework assumes that a change in maximal fsometric force is diredly related to motor neuron loss, Sobue et al.” demonstrated a high correlation (r = 0.84) between the number of motor neurons at autopsy and muscle strength tested 2 to 6 months before death. Edwards," using myothermal measurements, has demonstrated in normal subjects and patients that the quadriceps ean be made to contract as fully jn a maximal voluntary isometric contraction as in a maximum stimulated136 Parwtets Le ANDNES Ev AL ‘5 negascores over tine for patient # 3 a) see MESA ea ee Tae days singe disease onset Figure 4, The decline ny ve fnctons of «sng patent over tne. The slopes appear ears parallel contraction. Therefore, measurement of maximal isometsic contraction is dlinically the most direct means of ascessing the amount of functional muscle ‘We have included pulmonary function tests, diadochokinetc speech rates, and timed functional activities in the TQNE, because these categories provide adjunctive information about changes in functional capacity com- monly seen in ALS. These tests are measures of the seqquclae of strength loss and thus provide less direc evidence of disease progression. To validate them, we charted decline in these functions against decline in isometric strength.” A close correlation was found, and, therefore, the validity of these tests was established using isometric strength loss as the standard measure (Fig. 4). ‘Content validity addresses the minimal scope a measurement must have in order to adequately reflect the variable of interest.” Originally, the ‘TONE consisted of more than 70 items and took 2 hours to complete. ‘To improve efficiency while retaining comprchensiveness, a factor analysis was performed to identify redundant items, Those that were closely clustered by factor analysis were climinated. Items of low reliability. oF minimal clinical use were also dropped. As shown in Tables 1 through 4, the test protocol now consists of 25 quantitative items yielding interval data. that measure motor performance and three graded items yielding ordinal level data tha judge fonction abit; The test akes about 48 minutes to complete, SPECIFIC TEST CATEGORIES Pulmonary Funetion Progressive respiratory impairment is the primary cause of death in ALS,"*and most ALS test protocols include some measurement of pulino-(Quasrrrarive AssessMenr oP NEUROMUSCULAR DEFICIT WN ALS 137 ry fanetion***** However, a decline in pulmonary function may be influenced by factors such as emphysema, congestive heart failure, and asthma, as well as by muscular weakness. We have therefore limited our pulmonary studies to expratory volumes (sce Table 1), though others have also tested inspiratory pressures." ® Test-retest correlations were high, and variation between tests was generally under 10 per cent Bulbar Function We tested bulbar function (sce Table 2) by measuring speech rates in the manner deseribed by Fletcher." This technique has been used previ- ously in ALS drug trials**! Other investigators have also sed a descriptive ‘scale for chewing and swallowing *=® or videotape esophagrams.”” Wo found that measuroment of speech rates provides a quick, reproducible, and sensitive indicator of disease progression ‘Timed Functional Activities ‘Timed activities (see Table 2), such as phone dialing, the pegboard test, and the timed alk, are inchided as assessments of upper motor neuron (UMN) function, Direct clinical measurement of UMN loss is not yet possible, but timed tests may provide indirect evidence, as spastic manifest by decreased speed of movement and decreased ability to alternate ‘movement.® Efforts wero made to design timed test items to reduce the ‘effects of pure lower metor neuron (LMN) weakness. This was done by ‘sing, small loads and shert time intervals Direct quantitative testing of spasticity continues to present « chal- lenge, Quaiative sales have been used fo aes pst in ALS 2% Norris graded stretch reflexes, plantar responses, and leg. “rigidity.” Engel! focused on the patient's ability to perform bieyclestike movement, the presence of conus, and the agility of walking. However, their methods produce ordinal data and have not been validated. Neuromuscular Functional Performance Seale A functional scale was included in the TONE to provide a broad description of a patient's functional status (see Table 3). However, these data are not inchided in our statistical analysis ‘Maximal Isometric Force Strain gauges produce accurate and valid interval data by which to ‘measure isometrie force (we Table 4)“ *! We have used the device for this reason and also because the limb is positioned at 90 degrees, which allows longitudinal studies despite contractures. In addition, testing at mic- range serves to limit the effects of gravity and improve standardization. Our strain gauge provides a reliable linear signal sensitive to 0.5 ke, and able to tolerate up to 100 ky, Because the examiner is not required to provide any resistance, the contraction force can be accurately measured in patients with very weak or very strong musculature.138 Parmcts fe ANDRES ETAL COMPOSITE SCORES (MEGASCORES) Rationale Individual data items were grouped into relevant categories. Scores within each group were transformed and averaged into composite values of “mezascores.” Data were grouped into megascores for several reasons. First, the number of individval items in the test battery are too numerous for elficient analyses. Rach patient can be assessed in 31 different ways at ‘each visit, and as longitudinal testing involves many patients, the amount ‘of data would be overwhelming. Second, the creation of composite scores increases the reliability of measurement by balancing measurement errors, By averaging several individual scores into one, the reliability of the composite measure will be higher than any one component taken alone, ‘Third, composite scores reduce erroncons “significant” findings by reducing the number of statistical comparisons. When many items are measured and analyzed separately, the probability i high that one will produce a "signil= jeant” effect by chance alone, Finally, we wanted to summarize function by neurologic region Statistical Methods Grouping ems. A factor analysis was performed on data from a tandom visit for each of the 176 patients with ALS in our data bank, to determine the patterning of test-item intercorreations. Items regionally ‘and functionally related were also factor analytically related. This allowed the creation of five megascores titled pulmonary function, bulbar function, timed hand actcitos, isometric arm force, and tsometric leg force (Table 9) Standardizing Scores. Individual raw scores were transformed to allow equal weighting of raw values measured in diferent units or capacities tsing2 score transformations (Table 10), In order toallow equal contribution ‘of an item with a relatively small capacity such as forced vital capacity Table 9. Meunscore Compasttion Hees 1 Palonary faction HVC 1 Rd 1 Mega 2: Babar function ‘indecent: “po 1 Mega 2: Timed hand fnetion Dialing a7-dat phone number 2 Purdue pexboard tet 2 Mega 4; Arm stent loon sin gauge to measure ars meee strength 5 Jamar dynamometer 0 messre sop stent, 2 Megs 5: Lag sre letoni tn gauge to measure log sometrie tenth 0 ‘ToraL. Es‘Quawrtrarive Assesswtenr oF NeuHOMUSCULAR Davterr IW ALS 139 ‘Table 10, Example of Z-Seore Transformation and Megascore Calculation AS pom Rawiacore AUS pops nes "DN __Eauation Zoo ie oi 3s T “0.00 Mwy olen 6 -oar Megencore Calelation ‘Mesa 1 (Pulmonary fanetion) (FVC)—measured in single digits of liters—eompared with an item with a relatively large capacity such as maximal voluntary ventilation (MVV)— measured in double or triple digits of liters—the raw seores must be transformed. The equation for z-score transformation is: z= raw score ‘minus the ALS population mean divided by the ALS population standard deviation, Means and standard deviations were computed by averaging the actual score for cach item on a random visit for each of the 176 patients in the data bank. This procedure generated an ALS population mean and standard deviation for each test item in which each patient had equal weight. ‘Table 10 illustrates the use of z-seore transformations to convert FVC and MVV to comparable units. Once z scores were calculated for each item within a category (in this case FVC and MVV), the megascore was abtained by averaging the z-score items. Megascores were only calculated when all items in a group were available Uses for ALS Megascores We have used megiscores to analyze the natural history of ALS and to test therapeutic efficary of drugs. Megascores of 50 patients with ALS tested on eight or more occasions over 8 or more months were analyzed t0 determine deterioration rates and the course of the disease.*" A’ strong, linearity of deterioration was seen, as shown in Figure 4 In a study to test the therapeutic efficacy of ehronie intrathecal administration of TRH in ALS, we used megascores to calculate and compare the slopes of deterioration before and during TRH therapy.” SUMMARY Several criteria must be met in developing a test battery for ALS. First, the test items should be designed to answer the specif questions being asked. If questiors involve the amount and rate of deterioration, then the test items should generate interval data and show evidence that40 aravets L, ANDRUS ET AL they reflect change in the disease itself. Second, the reliability of the test items should be carefully determined. Are the variances due to testing errors such as inconsistent positioning or changes in verbal instructions; oF {do they reflect human perlormance variation? Third, the test items must be sensitive to small changes, and one must be able to test the very strong as well as the severely debilitated patient. “The TONE was designed to measure degree of disease progression in ALS. The major portion of the protocol consists of isometric force measure~ rent using an electronie strain gauge. Other quantitative segments include tests of pulmonary function, speech rates, aud timed activities. Using Score transformations, we have summarized these test items into five ‘megascores: pulmonary function, bulbar functon, timed hand activities, frm strength, and leg strength, Meyascores have been used to characterize the natural history of the disease and to judge therapentie offcacy ‘Quantitative methods to measure deficit in neuromuscular disease lag far behind other technologie advances in medical research. Future advances in the measurement of neuromuscular deficit depend on the commitment of researchers to invest the time and resourves necessary to develop more sensitive and reliable testing techniques. REFERENCES 1. Andres PL, Hedland W, Faison Leal: Quantitative motor asesanent in ametropic Tater sero: Newrabgy. 36707-0158, 2, Bensley WE Quaitatve te testing Paces and applications to research and ‘nial serves Arch Phys Mel Reha, 42098-45. 1961 2, Malley WO. Halt W, Caper Greta A double ind conte eal of bovine ‘aa gant romasi i ry ateral sclerosis, Nearby. 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