This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 1

The Spastic Paraplegia Rating Scale (SPRS)

Endorsed by ERN-RND 26072018

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

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Introduction to the European Reference Network for Rare Neurological Diseases (ERN-RND)

ERN-RND is a European Reference Network established and approved by the European Union ERN-RND is a healthcare infrastructure which focuses on rare neurological diseases (RND) The three main pillars of ERN-RND are (i) network of experts and expertise centres (ii) generation pooling and dissemination of RND knowledge and (iii) implementation of e-health to allow the expertise to travel instead of patients and families

ERN-RND unites 32 of Europersquos leading expert centres in 13 Member States and includes highly active patient organizations Centres are located in Belgium Bulgaria Czech Republic France Germany Hungary Italy Lithuania Netherlands Poland Slovenia Spain and the UK

The following disease groups are covered by ERN-RND

bull Ataxias and Hereditary Spastic Paraplegias bull Atypical Parkinsonism and genetic Parkinsonrsquos Disease bull Dystonia Paroxysmal Disorder and Neurodegeneration with Brain Ion Accumulation bull Frontotemporal Dementia bull Huntingtonsrsquo Disease and other Choreas bull Leukodystrophies

Specific information about the network the expert centres and the diseases covered can be found at the networks web site wwwern-rndeu

Recommendation for clinical use

The European Reference Network for Rare Neurological Diseases strongly recommends the use of the Spastic Paraplegia Rating Scale (SPRS) as best clinical practice for the assessment and rating of patients with Spastic Paraplegia

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 2

Introduction to the European Reference Network for Rare Neurological Diseases (ERN-RND)

ERN-RND is a European Reference Network established and approved by the European Union ERN-RND is a healthcare infrastructure which focuses on rare neurological diseases (RND) The three main pillars of ERN-RND are (i) network of experts and expertise centres (ii) generation pooling and dissemination of RND knowledge and (iii) implementation of e-health to allow the expertise to travel instead of patients and families

ERN-RND unites 32 of Europersquos leading expert centres in 13 Member States and includes highly active patient organizations Centres are located in Belgium Bulgaria Czech Republic France Germany Hungary Italy Lithuania Netherlands Poland Slovenia Spain and the UK

The following disease groups are covered by ERN-RND

bull Ataxias and Hereditary Spastic Paraplegias bull Atypical Parkinsonism and genetic Parkinsonrsquos Disease bull Dystonia Paroxysmal Disorder and Neurodegeneration with Brain Ion Accumulation bull Frontotemporal Dementia bull Huntingtonsrsquo Disease and other Choreas bull Leukodystrophies

Specific information about the network the expert centres and the diseases covered can be found at the networks web site wwwern-rndeu

Recommendation for clinical use

The European Reference Network for Rare Neurological Diseases strongly recommends the use of the Spastic Paraplegia Rating Scale (SPRS) as best clinical practice for the assessment and rating of patients with Spastic Paraplegia

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 3

Disclaimer

Clinical practice guidelines practice advisories systematic reviews and other guidance published endorsed or affirmed by ERN-RND are assessments of current scientific and clinical information provided as an educational service The information (1) should not be considered inclusive of all proper treatments methods of care or as a statement of the standard of care (2) is not continually updated and may not reflect the most recent evidence (new information may emerge between the time information is developed and when it is published or read) (3) addresses only the question(s) specifically identified (4) does not mandate any particular course of medical care and (5) is not intended to substitute for the independent professional judgement of the treating provider as the information does account for individual variation among patients In all cases the selected course of action should be considered by the treating provider in the context of treating the individual patient Use of the information is voluntary ERN-RND provided this information on an ldquoas isrdquo basis and makes no warranty expressed or implied regarding the information ERN-RND specifically disclaims any warranties of merchantability or fitness for a particular use or purpose ERN-RND assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions

METHODOLOGY

The endorsement process has been performed by the Disease group for Ataxia and Hereditary Spastic Paraplegias of ERN-RND

Disease group for Ataxia and Hereditary Spastic Paraplegias

Disease group coordinators

Caterina Mariotti16 Rebecca Schuele-Freyer14

Disease group members

Healthcare professionals Segolene Ayme1 Enrico Bertini2 Kristl Claeys3 Maria Teresa Dotti4 Alexandra Durr1 Antonio Federico4 Josep Gaacutemez5 Paola Giunti6 David Goacutemez-Andreacutes5 Kinga Hadziev7 York Hellenbroich8 Jaroslav Jerabek9 Mary Kearney10 Jiri Klempir11 Thomas Klockgether12 Thomas Klopstock13 Norbert Kovacs7 Ingeborg Kraumlgeloh-Mann14 Berry Kremer15 Alfons Macaya5 Bela Melegh7 Maria Judit Molnar8 Isabella Moroni16 Alexander Muumlnchau8 Esteban Muntildeoz17 Lorenzo Nanetti16 Andreacutes Nascimento17 Mar OCallaghan17 Damjan

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 4

Osredkar18 Massimo Pandolfo19 Joanna Pera20 Borut Peterlin18 Maria Salvadoacute5 Ludger Schoumlls14 Deborah Sival15 Matthis Synofzik14 Franco Taroni16 Sinem Tunc8 Bart van de Warrenburg21 Judith van Gaalen21 Martin Vyhnaacutelek9 Michegravel Willemsen21 Ginevra Zanni2 Judith Zima7 Alena Zumrovaacute9

Patient representatives Lori Renna Linton10 Cathalijne van Doorne10

1 Assistance Publique-Hocircpitaux de Paris Hocircpital Pitieacute-Salepeacutetriegravere France Reference Centre for Rare Diseases Neurogeneticsrsquo 2 Pediatric hospital Bambino Gesugrave Rome Italy 3 University Hospitals Leuven Belgium 4 AOU Siena Italy 5 Hospital Universitari Vall dHebron Spain 6 University College London Hospitals NHS Foundation Trust United Kingdom 7 University of Peacutecs Hungary 8 Semmelweis University Hungary8 Universitaumltsklinikum Schleswig-Holstein Germany 9 Motol University Hospital Czech Republic 10 Patient representative 11 General University Hospital in Prague Czech Republic 12 Universitaumltsklinikum Bonn Germany 13 Klinikum der Universitaumlt Muumlnchen Germany 14 Universitaumltsklinikum Tuumlbingen Germany 15 University Medical Center Groningen Netherlands 16 Foundation IRCCS neurological institute Carlo Besta ndash Milan Italy 17 Hospital Cliacutenic i Provincial de Barcelona y Hospital de Sant Joan de Deacuteu Spain 18 University Medical Centre Ljubljana Slovenia 19 Universiteacute libre de Bruxelles Belgium 20 University Hospital in Krakow Poland 21 Stichting Katholieke Universiteit doing business as Radboud University Medical Center Nijmegen Netherlands

Endorsement process

bull Mapping of used disease scales by disease group ndash June ndash December 2017 bull Proposal for endorsement of rating scale by ERN-RND disease group coordinators ndash

15052018 bull Discussion in ERN-RND disease group during annual meeting ndash 08062018 bull Consent on endorsement of disease scale during ERN-RND annual meeting 2018 ndash

08062018 bull Consent on endorsement by whole disease group ndash 13072018

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 5

SCALE

(1) Walking distance without pause Due to history walking aids allowed

0 Normal unlimited 1 Abnormal exhaustion due to spasticity after more than 500m 2 Walking distance less than 500m 3 Walking distance less than 10 m 4 Unable to walk

(2) Gait quality Patient is asked to walk as fast as possible a 10 meter distance including one turn

0 Normal 1 Mild stiffness running still possible 2 Clearly spastic gait interfering with running 3 Spastic gait requiring use of caneswalker 4 Unable to walk for a 10 meter distance even with maximal support

(3) Maximum gait speed Time for a 10 meter distance including one turn taken by stop watch

0 Normal 1 Slightly reduced (10m ge 5s) 2 Moderately reduced (10m ge 10s) 3 Severely reduced (10m ge 20s) 4 Unable to walk for a 10m distance or time ge 40s

(4) Climbing stairs 5 steps upstairs - turn - 5 steps downstairs

0 Normal needs no support of the banister 1 Mild impairment needs intermittent support of the banister 2 Moderate impairment needs permanent support of the banister 3 Severe impairment needs support of another person or additional walking aid to perform

task 4 Unable to climb stairs

(5) Speed of stair climbing Time for 5 steps upstairs - turn - 5 steps downstairs taken by stop-watch

0 Normal 1 Slightly reduced (ge 5s to perform task) 2 Moderately reduced (ge 10s to perform task) 3 Severely reduced (ge 20s to perform task) 4 Unable to climb stairs

(6) Arising from chair Patient attempts to arise from a straight-back wood or metal chair with arms folded across chest

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 6

0 Normal 1 Slow or may need more than one attempt 2 Pushes self up from arms of seat 3 Tends to fall back and may have to try more than one time but can get up without help 4 Unable to arise without help

(7) Spasticity -hip adductor muscles (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in adduction

(8) Spasticity -knee flexion (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in flexion or extension

(9) Weakness -hip abduction (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(10) Weakness -foot dorsiflexion (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(11) Contractures of lower limbs Score in supine position

minus Hip extension lumbar spine and thighs touch the underlay Hip abduction abduction up to an angle of gt60deg between the legs possible

minus Knee extension thigh and calf touch the underlay minus Ankle dorsal extension gt 10deg possible

Ankle pronation gt 10deg possible 0 No contractures 1 Mild not fixed abnormal position of one joint (unilaterally or bilaterally) 2 Fixed contracture of one joint (unilaterally or bilaterally) 3 Fixed contracture of two joints (unilaterally or bilaterally)

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 7

4 Fixed contracture of more than two joints (unilaterally or bilaterally)

(12) Pain due to SP related symptoms 0 None 1 le 50 of waking day present AND intensity 0 - 3 points on visual analogue scale 2 le 50 of waking day present AND intensity 4 - 10 points on visual analogue scale 3 gt 50 of waking day present AND intensity 0 - 3 on visual analogue scale 4 gt 50 of waking day present AND intensity 4 - 10 points on visual analogue scale

(13) Bladder and bowel function 0 Normal bladder and bowel function 1 Urinary or fecal urgency (difficulties to reach toilet in time) 2 Rare and mild urge incontinence (no nappy required) 3 Moderate urge incontinence (requires nappy or catheter when out of the house) 4 Permanent catheterization or permanent nappy

Annex - Original publication

The Spastic Paraplegia RatingScale (SPRS)

A reliable and valid measure of disease severityR Schule MD T Holland-Letz MSc S Klimpe MD J Kassubek MD T Klopstock MD V Mall MD

S Otto MD B Winner MD and L Schols MD

AbstractmdashObjective To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure diseaseseverity and progression Methods A 13-item scale was designed to rate functional impairment occurring in pure forms ofspastic paraplegia (SP) Additional symptoms constituting a complicated form of SP are recorded in an inventory Twoindependent patient cohorts were evaluated in a two-step validation procedure Results Application of SPRS requires lessthan 15 minutes and does not require any special equipment so it is suitable for an outpatient setting Interrateragreement of SPRS was high (intraclass correlation coefficient 099) Reliability was further supported by high internalconsistency (Cronbach 091) SPRS values were almost normally distributed without apparent floor or ceiling effectConstruct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative AtaxiaRating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity) Conclu-sion The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity

NEUROLOGY 200667430ndash434

Spastic paraplegias (SPs) share the key symptom oflower extremity spasticity and weakness due to pro-gressive degeneration of the corticospinal tract1-3 Inpure SP symptoms are restricted to pyramidal mo-tor system malfunction In complicated SP the de-generative process affects multiple parts of thenervous system and presents clinically with addi-tional features like neuropathy ataxia cognitive im-pairment seizures optic atrophy amyotrophy orextrapyramidal involvement24

At present 29 genes or loci for SP termed SPG1ndash30 are known including 11 loci for autosomal domi-nant SP 14 loci for autosomal recessive disease and4 loci for X-linked forms56 Identification and firststeps in the functional characterization of 11 SPgenes over the last decade have shown similarities inthe pathophysiology of a number of clinically hetero-geneous genetic forms of SP Seven of the 11 SPgenes known so far are thought to impair axonaltransport processes Effective axonal transport of cel-

lular cargoes like mitochondria structural proteinsand neurotrophic factors is vital to neurons Motorneurons of the corticospinal tract that contain thelongest axonal processes of the whole nervous systemseem to be especially vulnerable to its disturbances7

At present no curative treatment is available forSP To evaluate potential new treatments clinicianswill critically depend on appropriate clinical mea-sures of disease severity However to date no ratingscale for SP is available

In 2003 the German Network for HereditaryMovement Disorders (GeNeMove) was founded to re-search rare genetic movement disorders in GermanyHere we report results of a multicenter trial per-formed by the GeNeMove SP task force to developand validate a clinical SP Rating Scale (SPRS)

Methods Development of SPRS SPRS was developed by atask force of GeNeMove consisting of movement disorder special-ists from six German universities The design of SPRS was basedon the following 1) SPRS should rate functional impairment andshould therefore not include neurologic signs without functionalimplications like presence of extensor plantar reflex or brisk ten-don reflexes 2) SPRS should focus on key features of pure SPcomplicating features should be recorded in an inventory of com-plicating signs and symptoms 3) SPRS should be practicable Nospecial equipment should be necessary to administer the scaleitems should be based on standard neurologic examination proce-

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the August 8 issue to find the title link for this article

From the Hertie Institute for Clinical Brain Research and Department of Neurology (RS LS) Eberhard Karls University Tubingen Department ofMedical Informatics Biometry and Epidemiology (TH-L) Ruhr University Bochum Department of Neurology (SK) Johannes Gutenberg UniversityMainz Department of Neurology (JK) University of Ulm Department of Neurology (TK) Ludwig Maximilians University Munich Department ofNeuropediatrics and Muscle Disorders (VM) University of Freiburg Department of Neurology (SO) Ruhr University Bochum and Department ofNeurology (BW) University of Regensburg GermanySupported by the German Bundesministerium fur Bildung und Forschung (grant 01GM0304 GeNeMove)Disclosure The authors report no conflicts of interestReceived October 21 2005 Accepted in final form April 3 2006Address correspondence and reprint requests to Dr L Schols Department of Neurology and Hertie Institute for Clinical Brain Research University ofTubingen Hoppe-Seyler-Str 3 D-72076 Tubingen Germany e-mail LudgerSchoelsuni-tuebingende

430 Copyright copy 2006 by AAN Enterprises Inc

dures Existing scales like the Ashworth Scale89 for rating of spas-ticity and the Medical Research Council Scale10 for musclestrength assessment were used4 Each scale item should discrimi-nate five grades (0 through 4) where 0 represents no affection and4 most severe affection The score result is calculated by addingsingle scores of each of the 13 items resulting in a maximum scoreof 52

Patients Sixty-three patients of 50 families were recruited inseven GeNeMove SP outpatient clinics based on the followingdiagnostic criteria411 1) pure SP or 2) spastic tetraparesis withearlier and more severe affection of lower limbs or 3) SP as anearly (first 3 years of the disease) and prominent sign of a degen-erative disease affecting several parts of the nervous system and4) other causes of the presenting symptoms excluded

Diagnosis of hereditary SP was considered definite in patientsthat reported a family history of spastic gait disturbances (3963patients) in addition to the above-mentioned criteria In subjectswith apparently sporadic disease (2463 patients) diagnosis wasconsidered probable Molecular diagnosis was available in 20 of 63patients 12 of them carried mutations in the spastin gene (SPG4)in 6 patients mutations in KIF5A (SPG10) were identified and 2sisters of a family with autosomal recessive SP showed linkage tothe SPG11 locus

The clinical characteristics of the sample are shown in table 1Only children above age 9 were included Patients were catego-rized as having pure or complicated SP according to presence ofadditional neurologic and nonneurologic features1213 as recorded inthe inventory of complicating signs and symptoms Only the fol-lowing additional features were considered consistent with diag-nosis of pure SP impaired vibration or joint position senseskeletal abnormalities (ie pes cavus) and urge incontinence

Patients were examined on their individual medication (ieoral antispastics botulinum toxin injections etc) Patients weregrouped by a simple 4-grade severity scale (landmarks of disabil-ity) based on their walking abilities taken by history

Landmarks of disability were as follows 1 able to walk 500meters without walking aid 2 able to walk 500 meters withwalking aid 3 able to walk 500 meters with walking aid 4 not able to walk

Additionally SPRS was performed in 10 healthy control sub-jects not aware of any neurologic diseases (table 1)

The study was approved by the ethics committees of the con-tributing centers Informed and written consent was obtainedfrom all study participants

Evaluation of SPRS SPRS was administered to patients bytwo experienced examiners Each patient was examined by thelocal investigator running the SP outpatient clinic and the studycoordinator who traveled to the GeNeMove centers Items 1through 6 were performed once and rated independently by bothinvestigators items 7 through 13 were administered and rated

independently by both investigators The inventory of complicat-ing signs and symptoms as well as Mini-Mental State Examina-tion (MMSE) International Cooperative Ataxia Rating Scale(ICARS)14 and Barthel Index15 were completed by the studycoordinator

SPRS was validated in a two-step procedure A preliminaryversion that was designed by the GeNeMove task force was ad-ministered to 21 patients Based on statistical pre-evaluation thepreliminary scale was modified The resulting final version wasadministered to 42 patients in a second validation step Finalstatistical evaluation relates to the second set of patients onlySubgroup analysis was done for patients with familial as opposedto sporadic disease and for patients with pure as opposed to com-plicated SP

Statistical analysis All statistical analyses were done usingSAS 802 Internal consistency of the various score componentswas investigated using Cronbach coefficient16 In addition afactor analysis was performed using principal componentanalysis17

Reliability of SPRS was assessed as interrater agreement cal-culating intraclass correlation coefficients (ICCs)18 These coeffi-cients calculate the ratio between interpatient variation and totalvariation (interpatient interrater) thus giving a measure ofwhat percentage of the score variation is real signal compared tonoise

To validate that increasing SPRS values reflect increasing dis-ease severity in terms of increasing impairment we used a simplefour-step severity scale (landmarks of disability) as an externalcriterion for validation Validity of the score was further investi-gated by correlating SPRS with ICARS MMSE scores and Bar-thel Index As the score seemed to show an approximately normaldistribution and all associations with other quantities seemed tobe nearly linear Pearson correlation coefficient and associatedtests were used

Results Evaluation of preliminary score version andscore modification A preliminary version of SPRS wasadministered to 21 patients The preliminary scale con-tained 17 items maximum score was 68 Mean SPRS was178 76 (5 to 34) As a measure of interrater agreementICC was acceptable (ICC 08) for all items with twoexceptions The ldquodorsal column sensationrdquo item (ICC 078) was subsequently removed from the score A detailedinstruction was added to the ldquocontracturesrdquo item (ICC 065) Two items concerning spasticity and weakness of theupper extremities were removed from the score as a fullscore in both items would imply complete paralysis and

Table 1 Characteristics of patient and control sample

Firstvalidation step

Secondvalidation step Total Controls

No 21 42 63 10

Gender MF 174 2220 3924 55

Age y

Mean SD 447 100 445 181 446 158 40 253

Range 24ndash63 9ndash80 9ndash80 11ndash82

Age at onset y

Mean SD 252 199 289 183 276 176

Range 0ndash54 0ndash66 0ndash66

Disease duration y

Mean SD 195 117 156 128 174 127

Range 3ndash44 2ndash53 2ndash53

Purecomplicated SP 156 1527 3033

Mode of inheritance ADFS 10110 23514 33624

Landmarks of disability 1234 10560 227112 3212172

See Methods

SP spastic paraplegia AD autosomal dominant F familial S sporadic

August (1 of 2) 2006 NEUROLOGY 67 431

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

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References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

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httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

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httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 4

Osredkar18 Massimo Pandolfo19 Joanna Pera20 Borut Peterlin18 Maria Salvadoacute5 Ludger Schoumlls14 Deborah Sival15 Matthis Synofzik14 Franco Taroni16 Sinem Tunc8 Bart van de Warrenburg21 Judith van Gaalen21 Martin Vyhnaacutelek9 Michegravel Willemsen21 Ginevra Zanni2 Judith Zima7 Alena Zumrovaacute9

Patient representatives Lori Renna Linton10 Cathalijne van Doorne10

1 Assistance Publique-Hocircpitaux de Paris Hocircpital Pitieacute-Salepeacutetriegravere France Reference Centre for Rare Diseases Neurogeneticsrsquo 2 Pediatric hospital Bambino Gesugrave Rome Italy 3 University Hospitals Leuven Belgium 4 AOU Siena Italy 5 Hospital Universitari Vall dHebron Spain 6 University College London Hospitals NHS Foundation Trust United Kingdom 7 University of Peacutecs Hungary 8 Semmelweis University Hungary8 Universitaumltsklinikum Schleswig-Holstein Germany 9 Motol University Hospital Czech Republic 10 Patient representative 11 General University Hospital in Prague Czech Republic 12 Universitaumltsklinikum Bonn Germany 13 Klinikum der Universitaumlt Muumlnchen Germany 14 Universitaumltsklinikum Tuumlbingen Germany 15 University Medical Center Groningen Netherlands 16 Foundation IRCCS neurological institute Carlo Besta ndash Milan Italy 17 Hospital Cliacutenic i Provincial de Barcelona y Hospital de Sant Joan de Deacuteu Spain 18 University Medical Centre Ljubljana Slovenia 19 Universiteacute libre de Bruxelles Belgium 20 University Hospital in Krakow Poland 21 Stichting Katholieke Universiteit doing business as Radboud University Medical Center Nijmegen Netherlands

Endorsement process

bull Mapping of used disease scales by disease group ndash June ndash December 2017 bull Proposal for endorsement of rating scale by ERN-RND disease group coordinators ndash

15052018 bull Discussion in ERN-RND disease group during annual meeting ndash 08062018 bull Consent on endorsement of disease scale during ERN-RND annual meeting 2018 ndash

08062018 bull Consent on endorsement by whole disease group ndash 13072018

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 5

SCALE

(1) Walking distance without pause Due to history walking aids allowed

0 Normal unlimited 1 Abnormal exhaustion due to spasticity after more than 500m 2 Walking distance less than 500m 3 Walking distance less than 10 m 4 Unable to walk

(2) Gait quality Patient is asked to walk as fast as possible a 10 meter distance including one turn

0 Normal 1 Mild stiffness running still possible 2 Clearly spastic gait interfering with running 3 Spastic gait requiring use of caneswalker 4 Unable to walk for a 10 meter distance even with maximal support

(3) Maximum gait speed Time for a 10 meter distance including one turn taken by stop watch

0 Normal 1 Slightly reduced (10m ge 5s) 2 Moderately reduced (10m ge 10s) 3 Severely reduced (10m ge 20s) 4 Unable to walk for a 10m distance or time ge 40s

(4) Climbing stairs 5 steps upstairs - turn - 5 steps downstairs

0 Normal needs no support of the banister 1 Mild impairment needs intermittent support of the banister 2 Moderate impairment needs permanent support of the banister 3 Severe impairment needs support of another person or additional walking aid to perform

task 4 Unable to climb stairs

(5) Speed of stair climbing Time for 5 steps upstairs - turn - 5 steps downstairs taken by stop-watch

0 Normal 1 Slightly reduced (ge 5s to perform task) 2 Moderately reduced (ge 10s to perform task) 3 Severely reduced (ge 20s to perform task) 4 Unable to climb stairs

(6) Arising from chair Patient attempts to arise from a straight-back wood or metal chair with arms folded across chest

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 6

0 Normal 1 Slow or may need more than one attempt 2 Pushes self up from arms of seat 3 Tends to fall back and may have to try more than one time but can get up without help 4 Unable to arise without help

(7) Spasticity -hip adductor muscles (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in adduction

(8) Spasticity -knee flexion (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in flexion or extension

(9) Weakness -hip abduction (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(10) Weakness -foot dorsiflexion (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(11) Contractures of lower limbs Score in supine position

minus Hip extension lumbar spine and thighs touch the underlay Hip abduction abduction up to an angle of gt60deg between the legs possible

minus Knee extension thigh and calf touch the underlay minus Ankle dorsal extension gt 10deg possible

Ankle pronation gt 10deg possible 0 No contractures 1 Mild not fixed abnormal position of one joint (unilaterally or bilaterally) 2 Fixed contracture of one joint (unilaterally or bilaterally) 3 Fixed contracture of two joints (unilaterally or bilaterally)

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 7

4 Fixed contracture of more than two joints (unilaterally or bilaterally)

(12) Pain due to SP related symptoms 0 None 1 le 50 of waking day present AND intensity 0 - 3 points on visual analogue scale 2 le 50 of waking day present AND intensity 4 - 10 points on visual analogue scale 3 gt 50 of waking day present AND intensity 0 - 3 on visual analogue scale 4 gt 50 of waking day present AND intensity 4 - 10 points on visual analogue scale

(13) Bladder and bowel function 0 Normal bladder and bowel function 1 Urinary or fecal urgency (difficulties to reach toilet in time) 2 Rare and mild urge incontinence (no nappy required) 3 Moderate urge incontinence (requires nappy or catheter when out of the house) 4 Permanent catheterization or permanent nappy

Annex - Original publication

The Spastic Paraplegia RatingScale (SPRS)

A reliable and valid measure of disease severityR Schule MD T Holland-Letz MSc S Klimpe MD J Kassubek MD T Klopstock MD V Mall MD

S Otto MD B Winner MD and L Schols MD

AbstractmdashObjective To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure diseaseseverity and progression Methods A 13-item scale was designed to rate functional impairment occurring in pure forms ofspastic paraplegia (SP) Additional symptoms constituting a complicated form of SP are recorded in an inventory Twoindependent patient cohorts were evaluated in a two-step validation procedure Results Application of SPRS requires lessthan 15 minutes and does not require any special equipment so it is suitable for an outpatient setting Interrateragreement of SPRS was high (intraclass correlation coefficient 099) Reliability was further supported by high internalconsistency (Cronbach 091) SPRS values were almost normally distributed without apparent floor or ceiling effectConstruct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative AtaxiaRating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity) Conclu-sion The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity

NEUROLOGY 200667430ndash434

Spastic paraplegias (SPs) share the key symptom oflower extremity spasticity and weakness due to pro-gressive degeneration of the corticospinal tract1-3 Inpure SP symptoms are restricted to pyramidal mo-tor system malfunction In complicated SP the de-generative process affects multiple parts of thenervous system and presents clinically with addi-tional features like neuropathy ataxia cognitive im-pairment seizures optic atrophy amyotrophy orextrapyramidal involvement24

At present 29 genes or loci for SP termed SPG1ndash30 are known including 11 loci for autosomal domi-nant SP 14 loci for autosomal recessive disease and4 loci for X-linked forms56 Identification and firststeps in the functional characterization of 11 SPgenes over the last decade have shown similarities inthe pathophysiology of a number of clinically hetero-geneous genetic forms of SP Seven of the 11 SPgenes known so far are thought to impair axonaltransport processes Effective axonal transport of cel-

lular cargoes like mitochondria structural proteinsand neurotrophic factors is vital to neurons Motorneurons of the corticospinal tract that contain thelongest axonal processes of the whole nervous systemseem to be especially vulnerable to its disturbances7

At present no curative treatment is available forSP To evaluate potential new treatments clinicianswill critically depend on appropriate clinical mea-sures of disease severity However to date no ratingscale for SP is available

In 2003 the German Network for HereditaryMovement Disorders (GeNeMove) was founded to re-search rare genetic movement disorders in GermanyHere we report results of a multicenter trial per-formed by the GeNeMove SP task force to developand validate a clinical SP Rating Scale (SPRS)

Methods Development of SPRS SPRS was developed by atask force of GeNeMove consisting of movement disorder special-ists from six German universities The design of SPRS was basedon the following 1) SPRS should rate functional impairment andshould therefore not include neurologic signs without functionalimplications like presence of extensor plantar reflex or brisk ten-don reflexes 2) SPRS should focus on key features of pure SPcomplicating features should be recorded in an inventory of com-plicating signs and symptoms 3) SPRS should be practicable Nospecial equipment should be necessary to administer the scaleitems should be based on standard neurologic examination proce-

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the August 8 issue to find the title link for this article

From the Hertie Institute for Clinical Brain Research and Department of Neurology (RS LS) Eberhard Karls University Tubingen Department ofMedical Informatics Biometry and Epidemiology (TH-L) Ruhr University Bochum Department of Neurology (SK) Johannes Gutenberg UniversityMainz Department of Neurology (JK) University of Ulm Department of Neurology (TK) Ludwig Maximilians University Munich Department ofNeuropediatrics and Muscle Disorders (VM) University of Freiburg Department of Neurology (SO) Ruhr University Bochum and Department ofNeurology (BW) University of Regensburg GermanySupported by the German Bundesministerium fur Bildung und Forschung (grant 01GM0304 GeNeMove)Disclosure The authors report no conflicts of interestReceived October 21 2005 Accepted in final form April 3 2006Address correspondence and reprint requests to Dr L Schols Department of Neurology and Hertie Institute for Clinical Brain Research University ofTubingen Hoppe-Seyler-Str 3 D-72076 Tubingen Germany e-mail LudgerSchoelsuni-tuebingende

430 Copyright copy 2006 by AAN Enterprises Inc

dures Existing scales like the Ashworth Scale89 for rating of spas-ticity and the Medical Research Council Scale10 for musclestrength assessment were used4 Each scale item should discrimi-nate five grades (0 through 4) where 0 represents no affection and4 most severe affection The score result is calculated by addingsingle scores of each of the 13 items resulting in a maximum scoreof 52

Patients Sixty-three patients of 50 families were recruited inseven GeNeMove SP outpatient clinics based on the followingdiagnostic criteria411 1) pure SP or 2) spastic tetraparesis withearlier and more severe affection of lower limbs or 3) SP as anearly (first 3 years of the disease) and prominent sign of a degen-erative disease affecting several parts of the nervous system and4) other causes of the presenting symptoms excluded

Diagnosis of hereditary SP was considered definite in patientsthat reported a family history of spastic gait disturbances (3963patients) in addition to the above-mentioned criteria In subjectswith apparently sporadic disease (2463 patients) diagnosis wasconsidered probable Molecular diagnosis was available in 20 of 63patients 12 of them carried mutations in the spastin gene (SPG4)in 6 patients mutations in KIF5A (SPG10) were identified and 2sisters of a family with autosomal recessive SP showed linkage tothe SPG11 locus

The clinical characteristics of the sample are shown in table 1Only children above age 9 were included Patients were catego-rized as having pure or complicated SP according to presence ofadditional neurologic and nonneurologic features1213 as recorded inthe inventory of complicating signs and symptoms Only the fol-lowing additional features were considered consistent with diag-nosis of pure SP impaired vibration or joint position senseskeletal abnormalities (ie pes cavus) and urge incontinence

Patients were examined on their individual medication (ieoral antispastics botulinum toxin injections etc) Patients weregrouped by a simple 4-grade severity scale (landmarks of disabil-ity) based on their walking abilities taken by history

Landmarks of disability were as follows 1 able to walk 500meters without walking aid 2 able to walk 500 meters withwalking aid 3 able to walk 500 meters with walking aid 4 not able to walk

Additionally SPRS was performed in 10 healthy control sub-jects not aware of any neurologic diseases (table 1)

The study was approved by the ethics committees of the con-tributing centers Informed and written consent was obtainedfrom all study participants

Evaluation of SPRS SPRS was administered to patients bytwo experienced examiners Each patient was examined by thelocal investigator running the SP outpatient clinic and the studycoordinator who traveled to the GeNeMove centers Items 1through 6 were performed once and rated independently by bothinvestigators items 7 through 13 were administered and rated

independently by both investigators The inventory of complicat-ing signs and symptoms as well as Mini-Mental State Examina-tion (MMSE) International Cooperative Ataxia Rating Scale(ICARS)14 and Barthel Index15 were completed by the studycoordinator

SPRS was validated in a two-step procedure A preliminaryversion that was designed by the GeNeMove task force was ad-ministered to 21 patients Based on statistical pre-evaluation thepreliminary scale was modified The resulting final version wasadministered to 42 patients in a second validation step Finalstatistical evaluation relates to the second set of patients onlySubgroup analysis was done for patients with familial as opposedto sporadic disease and for patients with pure as opposed to com-plicated SP

Statistical analysis All statistical analyses were done usingSAS 802 Internal consistency of the various score componentswas investigated using Cronbach coefficient16 In addition afactor analysis was performed using principal componentanalysis17

Reliability of SPRS was assessed as interrater agreement cal-culating intraclass correlation coefficients (ICCs)18 These coeffi-cients calculate the ratio between interpatient variation and totalvariation (interpatient interrater) thus giving a measure ofwhat percentage of the score variation is real signal compared tonoise

To validate that increasing SPRS values reflect increasing dis-ease severity in terms of increasing impairment we used a simplefour-step severity scale (landmarks of disability) as an externalcriterion for validation Validity of the score was further investi-gated by correlating SPRS with ICARS MMSE scores and Bar-thel Index As the score seemed to show an approximately normaldistribution and all associations with other quantities seemed tobe nearly linear Pearson correlation coefficient and associatedtests were used

Results Evaluation of preliminary score version andscore modification A preliminary version of SPRS wasadministered to 21 patients The preliminary scale con-tained 17 items maximum score was 68 Mean SPRS was178 76 (5 to 34) As a measure of interrater agreementICC was acceptable (ICC 08) for all items with twoexceptions The ldquodorsal column sensationrdquo item (ICC 078) was subsequently removed from the score A detailedinstruction was added to the ldquocontracturesrdquo item (ICC 065) Two items concerning spasticity and weakness of theupper extremities were removed from the score as a fullscore in both items would imply complete paralysis and

Table 1 Characteristics of patient and control sample

Firstvalidation step

Secondvalidation step Total Controls

No 21 42 63 10

Gender MF 174 2220 3924 55

Age y

Mean SD 447 100 445 181 446 158 40 253

Range 24ndash63 9ndash80 9ndash80 11ndash82

Age at onset y

Mean SD 252 199 289 183 276 176

Range 0ndash54 0ndash66 0ndash66

Disease duration y

Mean SD 195 117 156 128 174 127

Range 3ndash44 2ndash53 2ndash53

Purecomplicated SP 156 1527 3033

Mode of inheritance ADFS 10110 23514 33624

Landmarks of disability 1234 10560 227112 3212172

See Methods

SP spastic paraplegia AD autosomal dominant F familial S sporadic

August (1 of 2) 2006 NEUROLOGY 67 431

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

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This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 5

SCALE

(1) Walking distance without pause Due to history walking aids allowed

0 Normal unlimited 1 Abnormal exhaustion due to spasticity after more than 500m 2 Walking distance less than 500m 3 Walking distance less than 10 m 4 Unable to walk

(2) Gait quality Patient is asked to walk as fast as possible a 10 meter distance including one turn

0 Normal 1 Mild stiffness running still possible 2 Clearly spastic gait interfering with running 3 Spastic gait requiring use of caneswalker 4 Unable to walk for a 10 meter distance even with maximal support

(3) Maximum gait speed Time for a 10 meter distance including one turn taken by stop watch

0 Normal 1 Slightly reduced (10m ge 5s) 2 Moderately reduced (10m ge 10s) 3 Severely reduced (10m ge 20s) 4 Unable to walk for a 10m distance or time ge 40s

(4) Climbing stairs 5 steps upstairs - turn - 5 steps downstairs

0 Normal needs no support of the banister 1 Mild impairment needs intermittent support of the banister 2 Moderate impairment needs permanent support of the banister 3 Severe impairment needs support of another person or additional walking aid to perform

task 4 Unable to climb stairs

(5) Speed of stair climbing Time for 5 steps upstairs - turn - 5 steps downstairs taken by stop-watch

0 Normal 1 Slightly reduced (ge 5s to perform task) 2 Moderately reduced (ge 10s to perform task) 3 Severely reduced (ge 20s to perform task) 4 Unable to climb stairs

(6) Arising from chair Patient attempts to arise from a straight-back wood or metal chair with arms folded across chest

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 6

0 Normal 1 Slow or may need more than one attempt 2 Pushes self up from arms of seat 3 Tends to fall back and may have to try more than one time but can get up without help 4 Unable to arise without help

(7) Spasticity -hip adductor muscles (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in adduction

(8) Spasticity -knee flexion (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in flexion or extension

(9) Weakness -hip abduction (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(10) Weakness -foot dorsiflexion (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(11) Contractures of lower limbs Score in supine position

minus Hip extension lumbar spine and thighs touch the underlay Hip abduction abduction up to an angle of gt60deg between the legs possible

minus Knee extension thigh and calf touch the underlay minus Ankle dorsal extension gt 10deg possible

Ankle pronation gt 10deg possible 0 No contractures 1 Mild not fixed abnormal position of one joint (unilaterally or bilaterally) 2 Fixed contracture of one joint (unilaterally or bilaterally) 3 Fixed contracture of two joints (unilaterally or bilaterally)

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 7

4 Fixed contracture of more than two joints (unilaterally or bilaterally)

(12) Pain due to SP related symptoms 0 None 1 le 50 of waking day present AND intensity 0 - 3 points on visual analogue scale 2 le 50 of waking day present AND intensity 4 - 10 points on visual analogue scale 3 gt 50 of waking day present AND intensity 0 - 3 on visual analogue scale 4 gt 50 of waking day present AND intensity 4 - 10 points on visual analogue scale

(13) Bladder and bowel function 0 Normal bladder and bowel function 1 Urinary or fecal urgency (difficulties to reach toilet in time) 2 Rare and mild urge incontinence (no nappy required) 3 Moderate urge incontinence (requires nappy or catheter when out of the house) 4 Permanent catheterization or permanent nappy

Annex - Original publication

The Spastic Paraplegia RatingScale (SPRS)

A reliable and valid measure of disease severityR Schule MD T Holland-Letz MSc S Klimpe MD J Kassubek MD T Klopstock MD V Mall MD

S Otto MD B Winner MD and L Schols MD

AbstractmdashObjective To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure diseaseseverity and progression Methods A 13-item scale was designed to rate functional impairment occurring in pure forms ofspastic paraplegia (SP) Additional symptoms constituting a complicated form of SP are recorded in an inventory Twoindependent patient cohorts were evaluated in a two-step validation procedure Results Application of SPRS requires lessthan 15 minutes and does not require any special equipment so it is suitable for an outpatient setting Interrateragreement of SPRS was high (intraclass correlation coefficient 099) Reliability was further supported by high internalconsistency (Cronbach 091) SPRS values were almost normally distributed without apparent floor or ceiling effectConstruct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative AtaxiaRating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity) Conclu-sion The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity

NEUROLOGY 200667430ndash434

Spastic paraplegias (SPs) share the key symptom oflower extremity spasticity and weakness due to pro-gressive degeneration of the corticospinal tract1-3 Inpure SP symptoms are restricted to pyramidal mo-tor system malfunction In complicated SP the de-generative process affects multiple parts of thenervous system and presents clinically with addi-tional features like neuropathy ataxia cognitive im-pairment seizures optic atrophy amyotrophy orextrapyramidal involvement24

At present 29 genes or loci for SP termed SPG1ndash30 are known including 11 loci for autosomal domi-nant SP 14 loci for autosomal recessive disease and4 loci for X-linked forms56 Identification and firststeps in the functional characterization of 11 SPgenes over the last decade have shown similarities inthe pathophysiology of a number of clinically hetero-geneous genetic forms of SP Seven of the 11 SPgenes known so far are thought to impair axonaltransport processes Effective axonal transport of cel-

lular cargoes like mitochondria structural proteinsand neurotrophic factors is vital to neurons Motorneurons of the corticospinal tract that contain thelongest axonal processes of the whole nervous systemseem to be especially vulnerable to its disturbances7

At present no curative treatment is available forSP To evaluate potential new treatments clinicianswill critically depend on appropriate clinical mea-sures of disease severity However to date no ratingscale for SP is available

In 2003 the German Network for HereditaryMovement Disorders (GeNeMove) was founded to re-search rare genetic movement disorders in GermanyHere we report results of a multicenter trial per-formed by the GeNeMove SP task force to developand validate a clinical SP Rating Scale (SPRS)

Methods Development of SPRS SPRS was developed by atask force of GeNeMove consisting of movement disorder special-ists from six German universities The design of SPRS was basedon the following 1) SPRS should rate functional impairment andshould therefore not include neurologic signs without functionalimplications like presence of extensor plantar reflex or brisk ten-don reflexes 2) SPRS should focus on key features of pure SPcomplicating features should be recorded in an inventory of com-plicating signs and symptoms 3) SPRS should be practicable Nospecial equipment should be necessary to administer the scaleitems should be based on standard neurologic examination proce-

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the August 8 issue to find the title link for this article

From the Hertie Institute for Clinical Brain Research and Department of Neurology (RS LS) Eberhard Karls University Tubingen Department ofMedical Informatics Biometry and Epidemiology (TH-L) Ruhr University Bochum Department of Neurology (SK) Johannes Gutenberg UniversityMainz Department of Neurology (JK) University of Ulm Department of Neurology (TK) Ludwig Maximilians University Munich Department ofNeuropediatrics and Muscle Disorders (VM) University of Freiburg Department of Neurology (SO) Ruhr University Bochum and Department ofNeurology (BW) University of Regensburg GermanySupported by the German Bundesministerium fur Bildung und Forschung (grant 01GM0304 GeNeMove)Disclosure The authors report no conflicts of interestReceived October 21 2005 Accepted in final form April 3 2006Address correspondence and reprint requests to Dr L Schols Department of Neurology and Hertie Institute for Clinical Brain Research University ofTubingen Hoppe-Seyler-Str 3 D-72076 Tubingen Germany e-mail LudgerSchoelsuni-tuebingende

430 Copyright copy 2006 by AAN Enterprises Inc

dures Existing scales like the Ashworth Scale89 for rating of spas-ticity and the Medical Research Council Scale10 for musclestrength assessment were used4 Each scale item should discrimi-nate five grades (0 through 4) where 0 represents no affection and4 most severe affection The score result is calculated by addingsingle scores of each of the 13 items resulting in a maximum scoreof 52

Patients Sixty-three patients of 50 families were recruited inseven GeNeMove SP outpatient clinics based on the followingdiagnostic criteria411 1) pure SP or 2) spastic tetraparesis withearlier and more severe affection of lower limbs or 3) SP as anearly (first 3 years of the disease) and prominent sign of a degen-erative disease affecting several parts of the nervous system and4) other causes of the presenting symptoms excluded

Diagnosis of hereditary SP was considered definite in patientsthat reported a family history of spastic gait disturbances (3963patients) in addition to the above-mentioned criteria In subjectswith apparently sporadic disease (2463 patients) diagnosis wasconsidered probable Molecular diagnosis was available in 20 of 63patients 12 of them carried mutations in the spastin gene (SPG4)in 6 patients mutations in KIF5A (SPG10) were identified and 2sisters of a family with autosomal recessive SP showed linkage tothe SPG11 locus

The clinical characteristics of the sample are shown in table 1Only children above age 9 were included Patients were catego-rized as having pure or complicated SP according to presence ofadditional neurologic and nonneurologic features1213 as recorded inthe inventory of complicating signs and symptoms Only the fol-lowing additional features were considered consistent with diag-nosis of pure SP impaired vibration or joint position senseskeletal abnormalities (ie pes cavus) and urge incontinence

Patients were examined on their individual medication (ieoral antispastics botulinum toxin injections etc) Patients weregrouped by a simple 4-grade severity scale (landmarks of disabil-ity) based on their walking abilities taken by history

Landmarks of disability were as follows 1 able to walk 500meters without walking aid 2 able to walk 500 meters withwalking aid 3 able to walk 500 meters with walking aid 4 not able to walk

Additionally SPRS was performed in 10 healthy control sub-jects not aware of any neurologic diseases (table 1)

The study was approved by the ethics committees of the con-tributing centers Informed and written consent was obtainedfrom all study participants

Evaluation of SPRS SPRS was administered to patients bytwo experienced examiners Each patient was examined by thelocal investigator running the SP outpatient clinic and the studycoordinator who traveled to the GeNeMove centers Items 1through 6 were performed once and rated independently by bothinvestigators items 7 through 13 were administered and rated

independently by both investigators The inventory of complicat-ing signs and symptoms as well as Mini-Mental State Examina-tion (MMSE) International Cooperative Ataxia Rating Scale(ICARS)14 and Barthel Index15 were completed by the studycoordinator

SPRS was validated in a two-step procedure A preliminaryversion that was designed by the GeNeMove task force was ad-ministered to 21 patients Based on statistical pre-evaluation thepreliminary scale was modified The resulting final version wasadministered to 42 patients in a second validation step Finalstatistical evaluation relates to the second set of patients onlySubgroup analysis was done for patients with familial as opposedto sporadic disease and for patients with pure as opposed to com-plicated SP

Statistical analysis All statistical analyses were done usingSAS 802 Internal consistency of the various score componentswas investigated using Cronbach coefficient16 In addition afactor analysis was performed using principal componentanalysis17

Reliability of SPRS was assessed as interrater agreement cal-culating intraclass correlation coefficients (ICCs)18 These coeffi-cients calculate the ratio between interpatient variation and totalvariation (interpatient interrater) thus giving a measure ofwhat percentage of the score variation is real signal compared tonoise

To validate that increasing SPRS values reflect increasing dis-ease severity in terms of increasing impairment we used a simplefour-step severity scale (landmarks of disability) as an externalcriterion for validation Validity of the score was further investi-gated by correlating SPRS with ICARS MMSE scores and Bar-thel Index As the score seemed to show an approximately normaldistribution and all associations with other quantities seemed tobe nearly linear Pearson correlation coefficient and associatedtests were used

Results Evaluation of preliminary score version andscore modification A preliminary version of SPRS wasadministered to 21 patients The preliminary scale con-tained 17 items maximum score was 68 Mean SPRS was178 76 (5 to 34) As a measure of interrater agreementICC was acceptable (ICC 08) for all items with twoexceptions The ldquodorsal column sensationrdquo item (ICC 078) was subsequently removed from the score A detailedinstruction was added to the ldquocontracturesrdquo item (ICC 065) Two items concerning spasticity and weakness of theupper extremities were removed from the score as a fullscore in both items would imply complete paralysis and

Table 1 Characteristics of patient and control sample

Firstvalidation step

Secondvalidation step Total Controls

No 21 42 63 10

Gender MF 174 2220 3924 55

Age y

Mean SD 447 100 445 181 446 158 40 253

Range 24ndash63 9ndash80 9ndash80 11ndash82

Age at onset y

Mean SD 252 199 289 183 276 176

Range 0ndash54 0ndash66 0ndash66

Disease duration y

Mean SD 195 117 156 128 174 127

Range 3ndash44 2ndash53 2ndash53

Purecomplicated SP 156 1527 3033

Mode of inheritance ADFS 10110 23514 33624

Landmarks of disability 1234 10560 227112 3212172

See Methods

SP spastic paraplegia AD autosomal dominant F familial S sporadic

August (1 of 2) 2006 NEUROLOGY 67 431

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 6

0 Normal 1 Slow or may need more than one attempt 2 Pushes self up from arms of seat 3 Tends to fall back and may have to try more than one time but can get up without help 4 Unable to arise without help

(7) Spasticity -hip adductor muscles (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in adduction

(8) Spasticity -knee flexion (Modified Ashworth scale) Score more severely affected side

0 No increase in muscle tone 1 Slight increase in muscle tone manifested by a catch and release 2 More marked increase in muscle tone through most of the range of motion 3 Considerable increase in muscle tone - passive movement is difficult 4 Limb stiff in flexion or extension

(9) Weakness -hip abduction (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(10) Weakness -foot dorsiflexion (Medical Research Council 1976) 0 No weakness 1 Mild weakness (45) 2 Moderate weakness (35) 3 Severe weakness (1-25) 4 Plegia (05)

(11) Contractures of lower limbs Score in supine position

minus Hip extension lumbar spine and thighs touch the underlay Hip abduction abduction up to an angle of gt60deg between the legs possible

minus Knee extension thigh and calf touch the underlay minus Ankle dorsal extension gt 10deg possible

Ankle pronation gt 10deg possible 0 No contractures 1 Mild not fixed abnormal position of one joint (unilaterally or bilaterally) 2 Fixed contracture of one joint (unilaterally or bilaterally) 3 Fixed contracture of two joints (unilaterally or bilaterally)

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 7

4 Fixed contracture of more than two joints (unilaterally or bilaterally)

(12) Pain due to SP related symptoms 0 None 1 le 50 of waking day present AND intensity 0 - 3 points on visual analogue scale 2 le 50 of waking day present AND intensity 4 - 10 points on visual analogue scale 3 gt 50 of waking day present AND intensity 0 - 3 on visual analogue scale 4 gt 50 of waking day present AND intensity 4 - 10 points on visual analogue scale

(13) Bladder and bowel function 0 Normal bladder and bowel function 1 Urinary or fecal urgency (difficulties to reach toilet in time) 2 Rare and mild urge incontinence (no nappy required) 3 Moderate urge incontinence (requires nappy or catheter when out of the house) 4 Permanent catheterization or permanent nappy

Annex - Original publication

The Spastic Paraplegia RatingScale (SPRS)

A reliable and valid measure of disease severityR Schule MD T Holland-Letz MSc S Klimpe MD J Kassubek MD T Klopstock MD V Mall MD

S Otto MD B Winner MD and L Schols MD

AbstractmdashObjective To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure diseaseseverity and progression Methods A 13-item scale was designed to rate functional impairment occurring in pure forms ofspastic paraplegia (SP) Additional symptoms constituting a complicated form of SP are recorded in an inventory Twoindependent patient cohorts were evaluated in a two-step validation procedure Results Application of SPRS requires lessthan 15 minutes and does not require any special equipment so it is suitable for an outpatient setting Interrateragreement of SPRS was high (intraclass correlation coefficient 099) Reliability was further supported by high internalconsistency (Cronbach 091) SPRS values were almost normally distributed without apparent floor or ceiling effectConstruct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative AtaxiaRating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity) Conclu-sion The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity

NEUROLOGY 200667430ndash434

Spastic paraplegias (SPs) share the key symptom oflower extremity spasticity and weakness due to pro-gressive degeneration of the corticospinal tract1-3 Inpure SP symptoms are restricted to pyramidal mo-tor system malfunction In complicated SP the de-generative process affects multiple parts of thenervous system and presents clinically with addi-tional features like neuropathy ataxia cognitive im-pairment seizures optic atrophy amyotrophy orextrapyramidal involvement24

At present 29 genes or loci for SP termed SPG1ndash30 are known including 11 loci for autosomal domi-nant SP 14 loci for autosomal recessive disease and4 loci for X-linked forms56 Identification and firststeps in the functional characterization of 11 SPgenes over the last decade have shown similarities inthe pathophysiology of a number of clinically hetero-geneous genetic forms of SP Seven of the 11 SPgenes known so far are thought to impair axonaltransport processes Effective axonal transport of cel-

lular cargoes like mitochondria structural proteinsand neurotrophic factors is vital to neurons Motorneurons of the corticospinal tract that contain thelongest axonal processes of the whole nervous systemseem to be especially vulnerable to its disturbances7

At present no curative treatment is available forSP To evaluate potential new treatments clinicianswill critically depend on appropriate clinical mea-sures of disease severity However to date no ratingscale for SP is available

In 2003 the German Network for HereditaryMovement Disorders (GeNeMove) was founded to re-search rare genetic movement disorders in GermanyHere we report results of a multicenter trial per-formed by the GeNeMove SP task force to developand validate a clinical SP Rating Scale (SPRS)

Methods Development of SPRS SPRS was developed by atask force of GeNeMove consisting of movement disorder special-ists from six German universities The design of SPRS was basedon the following 1) SPRS should rate functional impairment andshould therefore not include neurologic signs without functionalimplications like presence of extensor plantar reflex or brisk ten-don reflexes 2) SPRS should focus on key features of pure SPcomplicating features should be recorded in an inventory of com-plicating signs and symptoms 3) SPRS should be practicable Nospecial equipment should be necessary to administer the scaleitems should be based on standard neurologic examination proce-

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the August 8 issue to find the title link for this article

From the Hertie Institute for Clinical Brain Research and Department of Neurology (RS LS) Eberhard Karls University Tubingen Department ofMedical Informatics Biometry and Epidemiology (TH-L) Ruhr University Bochum Department of Neurology (SK) Johannes Gutenberg UniversityMainz Department of Neurology (JK) University of Ulm Department of Neurology (TK) Ludwig Maximilians University Munich Department ofNeuropediatrics and Muscle Disorders (VM) University of Freiburg Department of Neurology (SO) Ruhr University Bochum and Department ofNeurology (BW) University of Regensburg GermanySupported by the German Bundesministerium fur Bildung und Forschung (grant 01GM0304 GeNeMove)Disclosure The authors report no conflicts of interestReceived October 21 2005 Accepted in final form April 3 2006Address correspondence and reprint requests to Dr L Schols Department of Neurology and Hertie Institute for Clinical Brain Research University ofTubingen Hoppe-Seyler-Str 3 D-72076 Tubingen Germany e-mail LudgerSchoelsuni-tuebingende

430 Copyright copy 2006 by AAN Enterprises Inc

dures Existing scales like the Ashworth Scale89 for rating of spas-ticity and the Medical Research Council Scale10 for musclestrength assessment were used4 Each scale item should discrimi-nate five grades (0 through 4) where 0 represents no affection and4 most severe affection The score result is calculated by addingsingle scores of each of the 13 items resulting in a maximum scoreof 52

Patients Sixty-three patients of 50 families were recruited inseven GeNeMove SP outpatient clinics based on the followingdiagnostic criteria411 1) pure SP or 2) spastic tetraparesis withearlier and more severe affection of lower limbs or 3) SP as anearly (first 3 years of the disease) and prominent sign of a degen-erative disease affecting several parts of the nervous system and4) other causes of the presenting symptoms excluded

Diagnosis of hereditary SP was considered definite in patientsthat reported a family history of spastic gait disturbances (3963patients) in addition to the above-mentioned criteria In subjectswith apparently sporadic disease (2463 patients) diagnosis wasconsidered probable Molecular diagnosis was available in 20 of 63patients 12 of them carried mutations in the spastin gene (SPG4)in 6 patients mutations in KIF5A (SPG10) were identified and 2sisters of a family with autosomal recessive SP showed linkage tothe SPG11 locus

The clinical characteristics of the sample are shown in table 1Only children above age 9 were included Patients were catego-rized as having pure or complicated SP according to presence ofadditional neurologic and nonneurologic features1213 as recorded inthe inventory of complicating signs and symptoms Only the fol-lowing additional features were considered consistent with diag-nosis of pure SP impaired vibration or joint position senseskeletal abnormalities (ie pes cavus) and urge incontinence

Patients were examined on their individual medication (ieoral antispastics botulinum toxin injections etc) Patients weregrouped by a simple 4-grade severity scale (landmarks of disabil-ity) based on their walking abilities taken by history

Landmarks of disability were as follows 1 able to walk 500meters without walking aid 2 able to walk 500 meters withwalking aid 3 able to walk 500 meters with walking aid 4 not able to walk

Additionally SPRS was performed in 10 healthy control sub-jects not aware of any neurologic diseases (table 1)

The study was approved by the ethics committees of the con-tributing centers Informed and written consent was obtainedfrom all study participants

Evaluation of SPRS SPRS was administered to patients bytwo experienced examiners Each patient was examined by thelocal investigator running the SP outpatient clinic and the studycoordinator who traveled to the GeNeMove centers Items 1through 6 were performed once and rated independently by bothinvestigators items 7 through 13 were administered and rated

independently by both investigators The inventory of complicat-ing signs and symptoms as well as Mini-Mental State Examina-tion (MMSE) International Cooperative Ataxia Rating Scale(ICARS)14 and Barthel Index15 were completed by the studycoordinator

SPRS was validated in a two-step procedure A preliminaryversion that was designed by the GeNeMove task force was ad-ministered to 21 patients Based on statistical pre-evaluation thepreliminary scale was modified The resulting final version wasadministered to 42 patients in a second validation step Finalstatistical evaluation relates to the second set of patients onlySubgroup analysis was done for patients with familial as opposedto sporadic disease and for patients with pure as opposed to com-plicated SP

Statistical analysis All statistical analyses were done usingSAS 802 Internal consistency of the various score componentswas investigated using Cronbach coefficient16 In addition afactor analysis was performed using principal componentanalysis17

Reliability of SPRS was assessed as interrater agreement cal-culating intraclass correlation coefficients (ICCs)18 These coeffi-cients calculate the ratio between interpatient variation and totalvariation (interpatient interrater) thus giving a measure ofwhat percentage of the score variation is real signal compared tonoise

To validate that increasing SPRS values reflect increasing dis-ease severity in terms of increasing impairment we used a simplefour-step severity scale (landmarks of disability) as an externalcriterion for validation Validity of the score was further investi-gated by correlating SPRS with ICARS MMSE scores and Bar-thel Index As the score seemed to show an approximately normaldistribution and all associations with other quantities seemed tobe nearly linear Pearson correlation coefficient and associatedtests were used

Results Evaluation of preliminary score version andscore modification A preliminary version of SPRS wasadministered to 21 patients The preliminary scale con-tained 17 items maximum score was 68 Mean SPRS was178 76 (5 to 34) As a measure of interrater agreementICC was acceptable (ICC 08) for all items with twoexceptions The ldquodorsal column sensationrdquo item (ICC 078) was subsequently removed from the score A detailedinstruction was added to the ldquocontracturesrdquo item (ICC 065) Two items concerning spasticity and weakness of theupper extremities were removed from the score as a fullscore in both items would imply complete paralysis and

Table 1 Characteristics of patient and control sample

Firstvalidation step

Secondvalidation step Total Controls

No 21 42 63 10

Gender MF 174 2220 3924 55

Age y

Mean SD 447 100 445 181 446 158 40 253

Range 24ndash63 9ndash80 9ndash80 11ndash82

Age at onset y

Mean SD 252 199 289 183 276 176

Range 0ndash54 0ndash66 0ndash66

Disease duration y

Mean SD 195 117 156 128 174 127

Range 3ndash44 2ndash53 2ndash53

Purecomplicated SP 156 1527 3033

Mode of inheritance ADFS 10110 23514 33624

Landmarks of disability 1234 10560 227112 3212172

See Methods

SP spastic paraplegia AD autosomal dominant F familial S sporadic

August (1 of 2) 2006 NEUROLOGY 67 431

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

This document was supported by and done in the framework of the European Reference Network for Rare Neurological Diseases (ERN-RND) ERN-RND is one of the 24 European Reference Networks (ERNs) approved by the ERN Board of Member States The ERNs are co-funded by the European Commission (ERN-RND 3HP 767231)

Page | 7

4 Fixed contracture of more than two joints (unilaterally or bilaterally)

(12) Pain due to SP related symptoms 0 None 1 le 50 of waking day present AND intensity 0 - 3 points on visual analogue scale 2 le 50 of waking day present AND intensity 4 - 10 points on visual analogue scale 3 gt 50 of waking day present AND intensity 0 - 3 on visual analogue scale 4 gt 50 of waking day present AND intensity 4 - 10 points on visual analogue scale

(13) Bladder and bowel function 0 Normal bladder and bowel function 1 Urinary or fecal urgency (difficulties to reach toilet in time) 2 Rare and mild urge incontinence (no nappy required) 3 Moderate urge incontinence (requires nappy or catheter when out of the house) 4 Permanent catheterization or permanent nappy

Annex - Original publication

The Spastic Paraplegia RatingScale (SPRS)

A reliable and valid measure of disease severityR Schule MD T Holland-Letz MSc S Klimpe MD J Kassubek MD T Klopstock MD V Mall MD

S Otto MD B Winner MD and L Schols MD

AbstractmdashObjective To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure diseaseseverity and progression Methods A 13-item scale was designed to rate functional impairment occurring in pure forms ofspastic paraplegia (SP) Additional symptoms constituting a complicated form of SP are recorded in an inventory Twoindependent patient cohorts were evaluated in a two-step validation procedure Results Application of SPRS requires lessthan 15 minutes and does not require any special equipment so it is suitable for an outpatient setting Interrateragreement of SPRS was high (intraclass correlation coefficient 099) Reliability was further supported by high internalconsistency (Cronbach 091) SPRS values were almost normally distributed without apparent floor or ceiling effectConstruct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative AtaxiaRating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity) Conclu-sion The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity

NEUROLOGY 200667430ndash434

Spastic paraplegias (SPs) share the key symptom oflower extremity spasticity and weakness due to pro-gressive degeneration of the corticospinal tract1-3 Inpure SP symptoms are restricted to pyramidal mo-tor system malfunction In complicated SP the de-generative process affects multiple parts of thenervous system and presents clinically with addi-tional features like neuropathy ataxia cognitive im-pairment seizures optic atrophy amyotrophy orextrapyramidal involvement24

At present 29 genes or loci for SP termed SPG1ndash30 are known including 11 loci for autosomal domi-nant SP 14 loci for autosomal recessive disease and4 loci for X-linked forms56 Identification and firststeps in the functional characterization of 11 SPgenes over the last decade have shown similarities inthe pathophysiology of a number of clinically hetero-geneous genetic forms of SP Seven of the 11 SPgenes known so far are thought to impair axonaltransport processes Effective axonal transport of cel-

lular cargoes like mitochondria structural proteinsand neurotrophic factors is vital to neurons Motorneurons of the corticospinal tract that contain thelongest axonal processes of the whole nervous systemseem to be especially vulnerable to its disturbances7

At present no curative treatment is available forSP To evaluate potential new treatments clinicianswill critically depend on appropriate clinical mea-sures of disease severity However to date no ratingscale for SP is available

In 2003 the German Network for HereditaryMovement Disorders (GeNeMove) was founded to re-search rare genetic movement disorders in GermanyHere we report results of a multicenter trial per-formed by the GeNeMove SP task force to developand validate a clinical SP Rating Scale (SPRS)

Methods Development of SPRS SPRS was developed by atask force of GeNeMove consisting of movement disorder special-ists from six German universities The design of SPRS was basedon the following 1) SPRS should rate functional impairment andshould therefore not include neurologic signs without functionalimplications like presence of extensor plantar reflex or brisk ten-don reflexes 2) SPRS should focus on key features of pure SPcomplicating features should be recorded in an inventory of com-plicating signs and symptoms 3) SPRS should be practicable Nospecial equipment should be necessary to administer the scaleitems should be based on standard neurologic examination proce-

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the August 8 issue to find the title link for this article

From the Hertie Institute for Clinical Brain Research and Department of Neurology (RS LS) Eberhard Karls University Tubingen Department ofMedical Informatics Biometry and Epidemiology (TH-L) Ruhr University Bochum Department of Neurology (SK) Johannes Gutenberg UniversityMainz Department of Neurology (JK) University of Ulm Department of Neurology (TK) Ludwig Maximilians University Munich Department ofNeuropediatrics and Muscle Disorders (VM) University of Freiburg Department of Neurology (SO) Ruhr University Bochum and Department ofNeurology (BW) University of Regensburg GermanySupported by the German Bundesministerium fur Bildung und Forschung (grant 01GM0304 GeNeMove)Disclosure The authors report no conflicts of interestReceived October 21 2005 Accepted in final form April 3 2006Address correspondence and reprint requests to Dr L Schols Department of Neurology and Hertie Institute for Clinical Brain Research University ofTubingen Hoppe-Seyler-Str 3 D-72076 Tubingen Germany e-mail LudgerSchoelsuni-tuebingende

430 Copyright copy 2006 by AAN Enterprises Inc

dures Existing scales like the Ashworth Scale89 for rating of spas-ticity and the Medical Research Council Scale10 for musclestrength assessment were used4 Each scale item should discrimi-nate five grades (0 through 4) where 0 represents no affection and4 most severe affection The score result is calculated by addingsingle scores of each of the 13 items resulting in a maximum scoreof 52

Patients Sixty-three patients of 50 families were recruited inseven GeNeMove SP outpatient clinics based on the followingdiagnostic criteria411 1) pure SP or 2) spastic tetraparesis withearlier and more severe affection of lower limbs or 3) SP as anearly (first 3 years of the disease) and prominent sign of a degen-erative disease affecting several parts of the nervous system and4) other causes of the presenting symptoms excluded

Diagnosis of hereditary SP was considered definite in patientsthat reported a family history of spastic gait disturbances (3963patients) in addition to the above-mentioned criteria In subjectswith apparently sporadic disease (2463 patients) diagnosis wasconsidered probable Molecular diagnosis was available in 20 of 63patients 12 of them carried mutations in the spastin gene (SPG4)in 6 patients mutations in KIF5A (SPG10) were identified and 2sisters of a family with autosomal recessive SP showed linkage tothe SPG11 locus

The clinical characteristics of the sample are shown in table 1Only children above age 9 were included Patients were catego-rized as having pure or complicated SP according to presence ofadditional neurologic and nonneurologic features1213 as recorded inthe inventory of complicating signs and symptoms Only the fol-lowing additional features were considered consistent with diag-nosis of pure SP impaired vibration or joint position senseskeletal abnormalities (ie pes cavus) and urge incontinence

Patients were examined on their individual medication (ieoral antispastics botulinum toxin injections etc) Patients weregrouped by a simple 4-grade severity scale (landmarks of disabil-ity) based on their walking abilities taken by history

Landmarks of disability were as follows 1 able to walk 500meters without walking aid 2 able to walk 500 meters withwalking aid 3 able to walk 500 meters with walking aid 4 not able to walk

Additionally SPRS was performed in 10 healthy control sub-jects not aware of any neurologic diseases (table 1)

The study was approved by the ethics committees of the con-tributing centers Informed and written consent was obtainedfrom all study participants

Evaluation of SPRS SPRS was administered to patients bytwo experienced examiners Each patient was examined by thelocal investigator running the SP outpatient clinic and the studycoordinator who traveled to the GeNeMove centers Items 1through 6 were performed once and rated independently by bothinvestigators items 7 through 13 were administered and rated

independently by both investigators The inventory of complicat-ing signs and symptoms as well as Mini-Mental State Examina-tion (MMSE) International Cooperative Ataxia Rating Scale(ICARS)14 and Barthel Index15 were completed by the studycoordinator

SPRS was validated in a two-step procedure A preliminaryversion that was designed by the GeNeMove task force was ad-ministered to 21 patients Based on statistical pre-evaluation thepreliminary scale was modified The resulting final version wasadministered to 42 patients in a second validation step Finalstatistical evaluation relates to the second set of patients onlySubgroup analysis was done for patients with familial as opposedto sporadic disease and for patients with pure as opposed to com-plicated SP

Statistical analysis All statistical analyses were done usingSAS 802 Internal consistency of the various score componentswas investigated using Cronbach coefficient16 In addition afactor analysis was performed using principal componentanalysis17

Reliability of SPRS was assessed as interrater agreement cal-culating intraclass correlation coefficients (ICCs)18 These coeffi-cients calculate the ratio between interpatient variation and totalvariation (interpatient interrater) thus giving a measure ofwhat percentage of the score variation is real signal compared tonoise

To validate that increasing SPRS values reflect increasing dis-ease severity in terms of increasing impairment we used a simplefour-step severity scale (landmarks of disability) as an externalcriterion for validation Validity of the score was further investi-gated by correlating SPRS with ICARS MMSE scores and Bar-thel Index As the score seemed to show an approximately normaldistribution and all associations with other quantities seemed tobe nearly linear Pearson correlation coefficient and associatedtests were used

Results Evaluation of preliminary score version andscore modification A preliminary version of SPRS wasadministered to 21 patients The preliminary scale con-tained 17 items maximum score was 68 Mean SPRS was178 76 (5 to 34) As a measure of interrater agreementICC was acceptable (ICC 08) for all items with twoexceptions The ldquodorsal column sensationrdquo item (ICC 078) was subsequently removed from the score A detailedinstruction was added to the ldquocontracturesrdquo item (ICC 065) Two items concerning spasticity and weakness of theupper extremities were removed from the score as a fullscore in both items would imply complete paralysis and

Table 1 Characteristics of patient and control sample

Firstvalidation step

Secondvalidation step Total Controls

No 21 42 63 10

Gender MF 174 2220 3924 55

Age y

Mean SD 447 100 445 181 446 158 40 253

Range 24ndash63 9ndash80 9ndash80 11ndash82

Age at onset y

Mean SD 252 199 289 183 276 176

Range 0ndash54 0ndash66 0ndash66

Disease duration y

Mean SD 195 117 156 128 174 127

Range 3ndash44 2ndash53 2ndash53

Purecomplicated SP 156 1527 3033

Mode of inheritance ADFS 10110 23514 33624

Landmarks of disability 1234 10560 227112 3212172

See Methods

SP spastic paraplegia AD autosomal dominant F familial S sporadic

August (1 of 2) 2006 NEUROLOGY 67 431

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

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reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

The Spastic Paraplegia RatingScale (SPRS)

A reliable and valid measure of disease severityR Schule MD T Holland-Letz MSc S Klimpe MD J Kassubek MD T Klopstock MD V Mall MD

S Otto MD B Winner MD and L Schols MD

AbstractmdashObjective To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure diseaseseverity and progression Methods A 13-item scale was designed to rate functional impairment occurring in pure forms ofspastic paraplegia (SP) Additional symptoms constituting a complicated form of SP are recorded in an inventory Twoindependent patient cohorts were evaluated in a two-step validation procedure Results Application of SPRS requires lessthan 15 minutes and does not require any special equipment so it is suitable for an outpatient setting Interrateragreement of SPRS was high (intraclass correlation coefficient 099) Reliability was further supported by high internalconsistency (Cronbach 091) SPRS values were almost normally distributed without apparent floor or ceiling effectConstruct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative AtaxiaRating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity) Conclu-sion The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity

NEUROLOGY 200667430ndash434

Spastic paraplegias (SPs) share the key symptom oflower extremity spasticity and weakness due to pro-gressive degeneration of the corticospinal tract1-3 Inpure SP symptoms are restricted to pyramidal mo-tor system malfunction In complicated SP the de-generative process affects multiple parts of thenervous system and presents clinically with addi-tional features like neuropathy ataxia cognitive im-pairment seizures optic atrophy amyotrophy orextrapyramidal involvement24

At present 29 genes or loci for SP termed SPG1ndash30 are known including 11 loci for autosomal domi-nant SP 14 loci for autosomal recessive disease and4 loci for X-linked forms56 Identification and firststeps in the functional characterization of 11 SPgenes over the last decade have shown similarities inthe pathophysiology of a number of clinically hetero-geneous genetic forms of SP Seven of the 11 SPgenes known so far are thought to impair axonaltransport processes Effective axonal transport of cel-

lular cargoes like mitochondria structural proteinsand neurotrophic factors is vital to neurons Motorneurons of the corticospinal tract that contain thelongest axonal processes of the whole nervous systemseem to be especially vulnerable to its disturbances7

At present no curative treatment is available forSP To evaluate potential new treatments clinicianswill critically depend on appropriate clinical mea-sures of disease severity However to date no ratingscale for SP is available

In 2003 the German Network for HereditaryMovement Disorders (GeNeMove) was founded to re-search rare genetic movement disorders in GermanyHere we report results of a multicenter trial per-formed by the GeNeMove SP task force to developand validate a clinical SP Rating Scale (SPRS)

Methods Development of SPRS SPRS was developed by atask force of GeNeMove consisting of movement disorder special-ists from six German universities The design of SPRS was basedon the following 1) SPRS should rate functional impairment andshould therefore not include neurologic signs without functionalimplications like presence of extensor plantar reflex or brisk ten-don reflexes 2) SPRS should focus on key features of pure SPcomplicating features should be recorded in an inventory of com-plicating signs and symptoms 3) SPRS should be practicable Nospecial equipment should be necessary to administer the scaleitems should be based on standard neurologic examination proce-

Additional material related to this article can be found on the NeurologyWeb site Go to wwwneurologyorg and scroll down the Table of Con-tents for the August 8 issue to find the title link for this article

From the Hertie Institute for Clinical Brain Research and Department of Neurology (RS LS) Eberhard Karls University Tubingen Department ofMedical Informatics Biometry and Epidemiology (TH-L) Ruhr University Bochum Department of Neurology (SK) Johannes Gutenberg UniversityMainz Department of Neurology (JK) University of Ulm Department of Neurology (TK) Ludwig Maximilians University Munich Department ofNeuropediatrics and Muscle Disorders (VM) University of Freiburg Department of Neurology (SO) Ruhr University Bochum and Department ofNeurology (BW) University of Regensburg GermanySupported by the German Bundesministerium fur Bildung und Forschung (grant 01GM0304 GeNeMove)Disclosure The authors report no conflicts of interestReceived October 21 2005 Accepted in final form April 3 2006Address correspondence and reprint requests to Dr L Schols Department of Neurology and Hertie Institute for Clinical Brain Research University ofTubingen Hoppe-Seyler-Str 3 D-72076 Tubingen Germany e-mail LudgerSchoelsuni-tuebingende

430 Copyright copy 2006 by AAN Enterprises Inc

dures Existing scales like the Ashworth Scale89 for rating of spas-ticity and the Medical Research Council Scale10 for musclestrength assessment were used4 Each scale item should discrimi-nate five grades (0 through 4) where 0 represents no affection and4 most severe affection The score result is calculated by addingsingle scores of each of the 13 items resulting in a maximum scoreof 52

Patients Sixty-three patients of 50 families were recruited inseven GeNeMove SP outpatient clinics based on the followingdiagnostic criteria411 1) pure SP or 2) spastic tetraparesis withearlier and more severe affection of lower limbs or 3) SP as anearly (first 3 years of the disease) and prominent sign of a degen-erative disease affecting several parts of the nervous system and4) other causes of the presenting symptoms excluded

Diagnosis of hereditary SP was considered definite in patientsthat reported a family history of spastic gait disturbances (3963patients) in addition to the above-mentioned criteria In subjectswith apparently sporadic disease (2463 patients) diagnosis wasconsidered probable Molecular diagnosis was available in 20 of 63patients 12 of them carried mutations in the spastin gene (SPG4)in 6 patients mutations in KIF5A (SPG10) were identified and 2sisters of a family with autosomal recessive SP showed linkage tothe SPG11 locus

The clinical characteristics of the sample are shown in table 1Only children above age 9 were included Patients were catego-rized as having pure or complicated SP according to presence ofadditional neurologic and nonneurologic features1213 as recorded inthe inventory of complicating signs and symptoms Only the fol-lowing additional features were considered consistent with diag-nosis of pure SP impaired vibration or joint position senseskeletal abnormalities (ie pes cavus) and urge incontinence

Patients were examined on their individual medication (ieoral antispastics botulinum toxin injections etc) Patients weregrouped by a simple 4-grade severity scale (landmarks of disabil-ity) based on their walking abilities taken by history

Landmarks of disability were as follows 1 able to walk 500meters without walking aid 2 able to walk 500 meters withwalking aid 3 able to walk 500 meters with walking aid 4 not able to walk

Additionally SPRS was performed in 10 healthy control sub-jects not aware of any neurologic diseases (table 1)

The study was approved by the ethics committees of the con-tributing centers Informed and written consent was obtainedfrom all study participants

Evaluation of SPRS SPRS was administered to patients bytwo experienced examiners Each patient was examined by thelocal investigator running the SP outpatient clinic and the studycoordinator who traveled to the GeNeMove centers Items 1through 6 were performed once and rated independently by bothinvestigators items 7 through 13 were administered and rated

independently by both investigators The inventory of complicat-ing signs and symptoms as well as Mini-Mental State Examina-tion (MMSE) International Cooperative Ataxia Rating Scale(ICARS)14 and Barthel Index15 were completed by the studycoordinator

SPRS was validated in a two-step procedure A preliminaryversion that was designed by the GeNeMove task force was ad-ministered to 21 patients Based on statistical pre-evaluation thepreliminary scale was modified The resulting final version wasadministered to 42 patients in a second validation step Finalstatistical evaluation relates to the second set of patients onlySubgroup analysis was done for patients with familial as opposedto sporadic disease and for patients with pure as opposed to com-plicated SP

Statistical analysis All statistical analyses were done usingSAS 802 Internal consistency of the various score componentswas investigated using Cronbach coefficient16 In addition afactor analysis was performed using principal componentanalysis17

Reliability of SPRS was assessed as interrater agreement cal-culating intraclass correlation coefficients (ICCs)18 These coeffi-cients calculate the ratio between interpatient variation and totalvariation (interpatient interrater) thus giving a measure ofwhat percentage of the score variation is real signal compared tonoise

To validate that increasing SPRS values reflect increasing dis-ease severity in terms of increasing impairment we used a simplefour-step severity scale (landmarks of disability) as an externalcriterion for validation Validity of the score was further investi-gated by correlating SPRS with ICARS MMSE scores and Bar-thel Index As the score seemed to show an approximately normaldistribution and all associations with other quantities seemed tobe nearly linear Pearson correlation coefficient and associatedtests were used

Results Evaluation of preliminary score version andscore modification A preliminary version of SPRS wasadministered to 21 patients The preliminary scale con-tained 17 items maximum score was 68 Mean SPRS was178 76 (5 to 34) As a measure of interrater agreementICC was acceptable (ICC 08) for all items with twoexceptions The ldquodorsal column sensationrdquo item (ICC 078) was subsequently removed from the score A detailedinstruction was added to the ldquocontracturesrdquo item (ICC 065) Two items concerning spasticity and weakness of theupper extremities were removed from the score as a fullscore in both items would imply complete paralysis and

Table 1 Characteristics of patient and control sample

Firstvalidation step

Secondvalidation step Total Controls

No 21 42 63 10

Gender MF 174 2220 3924 55

Age y

Mean SD 447 100 445 181 446 158 40 253

Range 24ndash63 9ndash80 9ndash80 11ndash82

Age at onset y

Mean SD 252 199 289 183 276 176

Range 0ndash54 0ndash66 0ndash66

Disease duration y

Mean SD 195 117 156 128 174 127

Range 3ndash44 2ndash53 2ndash53

Purecomplicated SP 156 1527 3033

Mode of inheritance ADFS 10110 23514 33624

Landmarks of disability 1234 10560 227112 3212172

See Methods

SP spastic paraplegia AD autosomal dominant F familial S sporadic

August (1 of 2) 2006 NEUROLOGY 67 431

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

dures Existing scales like the Ashworth Scale89 for rating of spas-ticity and the Medical Research Council Scale10 for musclestrength assessment were used4 Each scale item should discrimi-nate five grades (0 through 4) where 0 represents no affection and4 most severe affection The score result is calculated by addingsingle scores of each of the 13 items resulting in a maximum scoreof 52

Patients Sixty-three patients of 50 families were recruited inseven GeNeMove SP outpatient clinics based on the followingdiagnostic criteria411 1) pure SP or 2) spastic tetraparesis withearlier and more severe affection of lower limbs or 3) SP as anearly (first 3 years of the disease) and prominent sign of a degen-erative disease affecting several parts of the nervous system and4) other causes of the presenting symptoms excluded

Diagnosis of hereditary SP was considered definite in patientsthat reported a family history of spastic gait disturbances (3963patients) in addition to the above-mentioned criteria In subjectswith apparently sporadic disease (2463 patients) diagnosis wasconsidered probable Molecular diagnosis was available in 20 of 63patients 12 of them carried mutations in the spastin gene (SPG4)in 6 patients mutations in KIF5A (SPG10) were identified and 2sisters of a family with autosomal recessive SP showed linkage tothe SPG11 locus

The clinical characteristics of the sample are shown in table 1Only children above age 9 were included Patients were catego-rized as having pure or complicated SP according to presence ofadditional neurologic and nonneurologic features1213 as recorded inthe inventory of complicating signs and symptoms Only the fol-lowing additional features were considered consistent with diag-nosis of pure SP impaired vibration or joint position senseskeletal abnormalities (ie pes cavus) and urge incontinence

Patients were examined on their individual medication (ieoral antispastics botulinum toxin injections etc) Patients weregrouped by a simple 4-grade severity scale (landmarks of disabil-ity) based on their walking abilities taken by history

Landmarks of disability were as follows 1 able to walk 500meters without walking aid 2 able to walk 500 meters withwalking aid 3 able to walk 500 meters with walking aid 4 not able to walk

Additionally SPRS was performed in 10 healthy control sub-jects not aware of any neurologic diseases (table 1)

The study was approved by the ethics committees of the con-tributing centers Informed and written consent was obtainedfrom all study participants

Evaluation of SPRS SPRS was administered to patients bytwo experienced examiners Each patient was examined by thelocal investigator running the SP outpatient clinic and the studycoordinator who traveled to the GeNeMove centers Items 1through 6 were performed once and rated independently by bothinvestigators items 7 through 13 were administered and rated

independently by both investigators The inventory of complicat-ing signs and symptoms as well as Mini-Mental State Examina-tion (MMSE) International Cooperative Ataxia Rating Scale(ICARS)14 and Barthel Index15 were completed by the studycoordinator

SPRS was validated in a two-step procedure A preliminaryversion that was designed by the GeNeMove task force was ad-ministered to 21 patients Based on statistical pre-evaluation thepreliminary scale was modified The resulting final version wasadministered to 42 patients in a second validation step Finalstatistical evaluation relates to the second set of patients onlySubgroup analysis was done for patients with familial as opposedto sporadic disease and for patients with pure as opposed to com-plicated SP

Statistical analysis All statistical analyses were done usingSAS 802 Internal consistency of the various score componentswas investigated using Cronbach coefficient16 In addition afactor analysis was performed using principal componentanalysis17

Reliability of SPRS was assessed as interrater agreement cal-culating intraclass correlation coefficients (ICCs)18 These coeffi-cients calculate the ratio between interpatient variation and totalvariation (interpatient interrater) thus giving a measure ofwhat percentage of the score variation is real signal compared tonoise

To validate that increasing SPRS values reflect increasing dis-ease severity in terms of increasing impairment we used a simplefour-step severity scale (landmarks of disability) as an externalcriterion for validation Validity of the score was further investi-gated by correlating SPRS with ICARS MMSE scores and Bar-thel Index As the score seemed to show an approximately normaldistribution and all associations with other quantities seemed tobe nearly linear Pearson correlation coefficient and associatedtests were used

Results Evaluation of preliminary score version andscore modification A preliminary version of SPRS wasadministered to 21 patients The preliminary scale con-tained 17 items maximum score was 68 Mean SPRS was178 76 (5 to 34) As a measure of interrater agreementICC was acceptable (ICC 08) for all items with twoexceptions The ldquodorsal column sensationrdquo item (ICC 078) was subsequently removed from the score A detailedinstruction was added to the ldquocontracturesrdquo item (ICC 065) Two items concerning spasticity and weakness of theupper extremities were removed from the score as a fullscore in both items would imply complete paralysis and

Table 1 Characteristics of patient and control sample

Firstvalidation step

Secondvalidation step Total Controls

No 21 42 63 10

Gender MF 174 2220 3924 55

Age y

Mean SD 447 100 445 181 446 158 40 253

Range 24ndash63 9ndash80 9ndash80 11ndash82

Age at onset y

Mean SD 252 199 289 183 276 176

Range 0ndash54 0ndash66 0ndash66

Disease duration y

Mean SD 195 117 156 128 174 127

Range 3ndash44 2ndash53 2ndash53

Purecomplicated SP 156 1527 3033

Mode of inheritance ADFS 10110 23514 33624

Landmarks of disability 1234 10560 227112 3212172

See Methods

SP spastic paraplegia AD autosomal dominant F familial S sporadic

August (1 of 2) 2006 NEUROLOGY 67 431

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

stiffness of the upper extremities and would therefore con-tradict diagnosis of SP Two items evaluating pain inten-sity and duration were condensed into one single item

The final version of SPRS is provided in appendix E-1on the Neurology Web site (go to wwwneurologyorg)

Description of the sample Final version of SPRS wasadministered to 42 patients and 10 healthy control sub-jects In healthy control subjects SPRS scores ranged from0 to 2 points All but the three eldest control individualshad a score of 0 Controls received pathologic ratings forslow walking (item 3) stair climbing (item 5) and arisingfrom chair (item 6)

Mean SPRS in patients was 200 102 (1 to 43) Dis-tribution of SPRS is presented in figure 1 SPRS shows anonly slightly skewed and approximately normal distribu-tion in our sample

SPRS showed moderate correlation with disease dura-tion (correlation coefficient 044 p 0004 figure 2)

Reliability To assess internal consistency Cronbach (average correlation between all items in the score ) wascalculated and found to be 091 for the total score indicat-ing that the score components do measure a common con-cept (though with some redundancy) To furtherinvestigate this a factor analysis was performed and re-sulted in one main factor representing items 1 to 10 whichexplained 54 of the variation in the data (Eigenvalue 71) and two barely relevant factors which covered items12 and 13 (10 of variation Eigenvalue 14) and item 11(9 of variation Eigenvalue 11) Thus items 1 to 10can be said to represent closely related aspects of the main

concept whereas items 11 to 13 describe two somewhatdistinct additional areas

Interrater agreement based on results obtained in 42patients assessed by two investigators was high with anICC of 099 Detailed ICCs for single items are given intable 2 ICC was excellent (ICC 090) for 10 of 13 itemsand acceptable (ICC 080) for the remaining three items

Validity Criterion-related validity To examinecriterion-related validity we chose landmarks of disabilitya simple four-step severity scale based on walking abili-ties as main external criterion SPRS increased (p 0001) with the disease stage Correlation of SPRS totalscore with landmarks of disability was 083 (p 0001)

Figure 3 gives details on SPRS score in dependence onlandmarks of disability

Construct validity To prove construct validity dis-criminant and convergent validity were calculated Corre-lation of SPRS total score to MMSE was low as expecteddemonstrating discriminant validity (004 ns) Conver-gent validity was demonstrated by a correlation betweenSPRS and Barthel Index (073 p 0001) as well asSPRS and ICARS (081 p 0001) a motor scale devel-oped for rating of ataxia

Subgroup analyses To confirm feasibility of SPRS for

Figure 1 Distribution of Spastic Paraplegia Rating Scale(SPRS) scores SPRS scores were grouped in bins of fivefor clarity reasons SPRS scores show an approximatelynormal distribution in our sample

Figure 2 Correlation between disease duration and Spas-tic Paraplegia Rating Scale (SPRS) scores SPRS corre-lates moderately with disease duration

Table 2 Spastic Paraplegia Rating Scale interrater agreement

Item ICC

1 Walking distance without pause 095

2 Gait quality 097

3 Maximum gait speed 100

4 Climbing stairs 100

5 Speed of stair climbing 100

6 Arising from chair 097

7 Spasticity hip adductor muscles 087

8 Spasticity knee extension 083

9 Weakness hip abduction 093

10 Weakness foot dorsiflexion 090

11 Contractures of lower limbs 087

12 Pain due to SP-related symptoms 097

13 Bladder and bowel function 095

ICC intraclass correlation coefficient SP spastic paraplegia

Figure 3 Spastic Paraplegia Rating Scale (SPRS) in de-pendence of landmarks of disability as defined in Methods(mean whiskers indicate standard deviation) SPRS totalscore increases with disease stage (p 0001)

432 NEUROLOGY 67 August (1 of 2) 2006

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

the whole spectrum of SP we performed subgroup analy-ses for pure and complicated forms as well as hereditaryand apparently sporadic variants of SP Reliability andvalidity of SPRS was quite similar for all subgroups (table 3)

Inventory of complicating signs and symptoms Skel-etal abnormalities were present in 21 of 63 patients mostcommonly lumbar hyperlordosis and pes cavus Sensorydeficits were present in 38 of 63 (603) patients In 24 ofthose patients sensory deficits were restricted to reductionof vibration or joint position sense the remaining 14 pa-tients showed affection of additional sensory qualities liketouch sense or temperature discrimination Only the latterled to classification of SP as complicated (see Methods fordetails) Signs and symptoms of cerebellar involvementwere present in 14 of 63 patients the most common signsand symptoms in this subgroup were gaze-evoked nystag-mus (814) and dysarthria (714)

The inventory of complicating signs and symptoms isprovided in appendix E-1 on the Neurology Web site

Discussion The lack of validated measures fordisease severity is a barrier to therapeutic trials inorphan diseases Scientifically rigorous and clinicallymeaningful rating scales are essential to measuretreatment impact especially in diseases in whichconventional laboratory markers of disease activityare missing Recently effort has been undertaken todevelop new rating scales like the Unified MultipleSystem Atrophy Rating Scale19 and evaluate widelyused scores like the ICARS retrospectively20-22

To the best of our knowledge SPRS is the firstscore evaluated for SP SPRS is suitable for all sub-types of SP including familial and sporadic forms aswell as pure and complicated phenotypes As SPRSuses standard neurologic examination procedures inmost of its items instructions for test performanceand scoring could be kept short for most items with-out endangering interrater reliability Completion ofSPRS required less than 15 minutes and did notdepend on any special equipment The variety ofsigns and symptoms that accounts for clinical vari-ability in complicated forms of SP is listed in aninventory This inventory thus provides a standard-

ized tool to document multisystem involvement ofthe disease The inventory is adapted to a routineneurologic examination and avoids additional time-consuming tests Taken together these characteris-tics make SPRS particularly suitable for anoutpatient setting

We excluded infants from the SPRS evaluationprocess Milestones of motor development takingplace in the first decade of life are inseparably inter-woven with a possible disease progression in affectedchildren a differentiated depiction of these complexinterrelations in a score not specialized for this pur-pose seems impossible Consequently SPRS is notsuitable to differentiate between developmental andage-related changes of the motor system and changesdue to disease progression When applying SPRS infuture studies it will be necessary to carefully com-pare age-matched groups

We evaluated SPRS in a two-step validation pro-cedure with independent cohorts of patients Thisapproach enabled us to optimize several items ac-cording to the results of the preliminary analysisAdjustment of several items after the first validationstep might have led to unintended adaptation of thescale to our special patient sample therefore wevalidated the final scale version in a second inde-pendent patient cohort This procedure resulted in ascale with high reliability and validity An interrateragreement of 099 for the total score proves SPRS asa robust measure for disease severity We recom-mend SPRS for upcoming interventional studies asits high reproducibility will substantially help to re-duce patient numbers required to prove therapeuticeffects Validity of SPRS has been shown in concor-dant and discriminant direction Comparison ofSPRS with 1) landmarks of disability 2) ICARS as awell established rating scale for another movementdisorder (ataxia) and 3) Barthel Index as a measureof impairment in activities of daily living revealedhigh correlations and supports the relevance ofSPRS to monitor functional impairment in SP Con-struct validity is further supported by poor correla-tion to MMSE as a test for cognitive function that isnot usually impaired at least in pure forms of SPdemonstrating discriminant validity

For every single item full score has been reachedby individual patients However no patient reachedthe maximum sum score of 52 points This designhelps to prevent that patients receive maximal SPRSscore before the final stage of the disease is reached(ceiling effect) as SPRS should be able to depict pro-gression even in very late disease stages SPRS sep-arates almost perfectly between SP patients andhealthy controls Only the mildest affected patient(9-year-old girl) had a score value lower than thehighest scoring control subject (82-year-old woman)SPRS is able to detect SP symptoms even in earlydisease stages None of our patients received a 0score value Together with an almost normal distri-bution of SPRS values in our sample this arguesstrongly against a significant floor effect

Table 3 Reliability and validity of Spastic Paraplegia RatingScale in subgroups of SP patients

ICC Cronbach

Correlation to landmarksof disabilityBarthelIndexICARSMMSE

Pure SP n 15 099 086 072074080003

Complicated SP n 27 099 089 084071076009

Positive family historyn 28

099 091 084081084003

Negative family historyn 14

098 090 085048077008

All n 42 099 091 083073081004

p 005

SP spastic paraplegia ICC intraclass correlation coefficient ICARS

International Cooperative Ataxia Rating Scale14 MMSE Mini-MentalStatus Examination

August (1 of 2) 2006 NEUROLOGY 67 433

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

SPRS correlated only moderately with disease du-ration This result was expected as a broad spectrumof SP subtypes has been included in this cross-sectional analysis Variability in disease progressionbetween subtypes results in variable impairment af-ter a fixed duration of the disease and reduces corre-lation of disease severity and durationClinicogenetic studies comparing SPRS in differentgenotypes and prospective longitudinal analyses willhelp to identify specific progression profiles in SPsubtypes

Longitudinal studies are necessary to analyze thesensitivity of SPRS to depict changes in disease se-verity and to monitor progression of the disease Anatural history study is ongoing by GeNeMove thatwill use SPRS to provide data for progression of SPand power calculations concerning patient numbersand study duration in forthcoming therapeutic trials

AcknowledgmentThe authors thank Tom-Wahlig Stiftung and HSP Selbsthilfe-gruppe Deutschland for help recruiting patients They also thankDr Stephan Schule for critical review of the manuscript

References1 Strumpell A Beitrage zur Pathologie des Ruckenmarks I Spastische

Spinalparalysen Arch Psychiatr Nerv 1880676ndash7172 Harding AE Hereditary ldquopurerdquo spastic paraplegia a clinical and ge-

netic study of 22 families J Neurol Neurosurg Psychiatry 198144871ndash883

3 Durr A Brice A Serdaru M et al The phenotype of ldquopurerdquo autosomaldominant spastic paraplegia Neurology 1994441274ndash1277

4 Harding AE Classification of the hereditary ataxias and paraplegiasLancet 198311151ndash1155

5 Fink JK The hereditary spastic paraplegias nine genes and countingArch Neurol 2003601045ndash1049

6 Klebe S Azzedine H Durr A et al Autosomal recessive spastic para-plegia (SPG30) with mild ataxia and sensory neuropathy maps to chro-mosome 2q373 Brain 20061251456ndash1462

7 Crosby AH Proukakis C Is the transportation highway the right roadfor hereditary spastic paraplegia Am J Hum Genet 2002711009ndash1016

8 Ashworth B Preliminary trial of carisoprodol in multiple sclerosisPractitioner 1964192540ndash542

9 Bohannon RW Smith MB Interrater reliability of a modified Ashworthscale of muscle spasticity Phys Ther 198767206ndash207

10 British Medical Research Council Aids to the investigation of the pe-ripheral nervous system 1976

11 Fink JK Heiman-Patterson T Bird T et al Hereditary spastic paraple-gia advances in genetic research Hereditary Spastic Paraplegia Work-ing Group Neurology 1996461507ndash1514

12 Harding AE Hereditary spastic paraplegias Semin Neurol 199313333ndash336

13 Valente EM Seri M Hereditary spastic paraplegias Orphanet Encyclo-pedia 2004

14 Trouillas P Takayanagi T Hallett M et al International CooperativeAtaxia Rating Scale for pharmacological assessment of the cerebellarsyndrome The Ataxia Neuropharmacology Committee of the WorldFederation of Neurology J Neurol Sci 1997145205ndash211

15 Mahoney FI Barthel DW Functional evaluation the Barthel IndexMd State Med J 19651461ndash65

16 Cronbach LJ Course improvement through evaluation Teachers Col-lege Record 196364

17 Jolliffe IT Principal component analysis Heidelberg Springer 198618 Shrout PE Fleiss JL Intraclass correlations uses in assessing rater

reliability Psychol Bull 197986420ndash42819 Wenning GK Tison F Seppi K et al Development and validation of

the Unified Multiple System Atrophy Rating Scale (UMSARS) MovDisord 2004191391ndash1402

20 Cano SJ Hobart JC Hart PE et al International Cooperative AtaxiaRating Scale (ICARS) appropriate for studies of Friedreichrsquos ataxiaMov Disord 2005201585ndash1591

21 Schmitz-Hubsch T Tezenas du Montcel S Baliko L et al Reliabilityand validity of the International Cooperative Ataxia Rating Scale astudy in 156 spinocerebellar ataxia patients Mov Disord 200621655ndash704

22 Storey E Tuck K Hester R Hughes A Churchyard A Inter-raterreliability of the International Cooperative Ataxia Rating Scale (IC-ARS) Mov Disord 200419190ndash192

RESIDENT AND FELLOW PAGECall for teaching videos

The Neurology Resident section is featured online at wwwneurologyorg The Editorial Team of this section is seekingteaching videos that will illustrate classic or uncommon findings on movement disorders Such videos will aid in therecognition of such disorders Instructions for formatting videos can be found in the Information for Authors atwwwneurologyorg

434 NEUROLOGY 67 August (1 of 2) 2006

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

httpnneurologyorgcontent673430fullincluding high resolution figures can be found at

Supplementary Material httpnneurologyorgcontentsuppl20060801673430DC1

Supplementary material can be found at

References httpnneurologyorgcontent673430fullref-list-1

This article cites 17 articles 4 of which you can access for free at

Citations httpnneurologyorgcontent673430fullotherarticles

This article has been cited by 6 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionspastic_paraplegiaSpastic paraplegia

_design_httpnneurologyorgcgicollectionclinical_trials_methodology_studyClinical trials Methodologystudy designfollowing collection(s) This article along with others on similar topics appears in the

Permissions amp Licensing

httpwwwneurologyorgaboutabout_the_journalpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnneurologyorgsubscribersadvertiseInformation about ordering reprints can be found online

Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright All rights reserved Print ISSN 0028-3878

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

DOI 10121201wnl00002282425333690200667430-434 Neurology

R Schuumlle T Holland-Letz S Klimpe et al severity

The Spastic Paraplegia Rating Scale (SPRS) A reliable and valid measure of disease

This information is current as of August 7 2006

ServicesUpdated Information amp

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