Inštitut Republike Slovenije za rehabilitacijo CIP - Katalo,ni ,apis o puhlikaciji Narodna in unin:r,itetna knji,nica. Ljubljana 616.8-009.5(063) SYMPOSIUM on Amyotrophic Laterni Sclerosis (2008: Ljuhljana) Abstract = 17\ lečl-.i / Syrnposiurn on Amyotrophic Latcral Sclerosi, \\ith thc 24th Dr. Janez Faganel Memorial Lecture. Ljuhljana. 19-20 September 2(Xl8 = Simpo1ij o amiotrofični lateralni sklcro,i s 24. predm·anjem \ spomin dr. Jane,a Faganela. Ljuhljana. 19. in 20. ,eptemhcr 2008 : organiscd by Institute of Clinical Neurophysiolog). Uni\ersity Medica) Centre Ljuhljana [and I Society of Clinical europhysiology of thc Slm·enian Mcdical A,,ociation. and Dcpanment of Clinical Neuroscience. Institute of Psychiatry. King·, College London: [editor Bla, Koritnik[. - Ljuhljana: Inštitut Republike S)o\cnijc ,a rehabilitacijo. 2008. - (Rehabilitacija. ISSN 1580-9315. Suplemcnt: 4) ISBN 978-961-6060-74-5 l. Koritnil-.. Bla, 2. Dr. Janez Faganel Memorial Lecturc (24 : 2(Xl8 : Ljubljana) 3. UniYcr,itctni 1-.linični center (Ljubljana). Inštitut ,:a klinično ne\ rofi7iologijo 4. Slmensl-.o ,dravniško društ\O. Sekcija ,a klinično ncnofi,iologijo 5. King·s Collcgc (London). Institute of Psychiatr). Dcpartmcnt of Clinical Ncurmcicnce 24l030144 Rehabilitacija/ Rehabilitation Volume VII, Suppl. 4 / Letnik VII, supl. 4 Glavni urednik / Executive Editor: Symposium on Amyotrophic Lateral Sclerosis with the 24111 Dr. Janez Faganel Memorial Lecture / Simpozij Črt Marinček Odgovorna urednica / Managing Editor: o amiotrofični lateralni sklerozi s 24. predavanjem v spomin dr. Janeza FaganelaHelena Burger Lektorica / Reader for Slovenian: Ljubljana, Slovenia 19-20 September 2008 / Ljubljana. 19.-20. september 2008 Snežana Bitenc Kos Svetovalec za statistiko / Statistical Consultant: Gaj Vidmar Organised by / Organizatorji Izdajatelj in založnik / Published by Institute of Clinical Neurophysiology, University Inštitut Republike Slovenije za rehabilitacijo/ Institute for Rehabilitation, Republic of Slovenia, Linhartova 51, Ljubljana Medical Centre Ljubljana, Slovenia, Society of Clinical Neurophysiology of the Slovenian Medical Association, and Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, UK/ Inštitut za klinično nevrofiziologijo Univerzitetnega kliničnega centra Ljubljana, Sekcija za klinično ncvrofiziologijo Slovenskega zdravniškega društva in Oddelek za klinično nevrološko znanost Inštituta za psihiatrijo pri King's College iz Londona (Velika Britanija) Zanj/ Publisher Representative: Robert Cugelj Priprava in tisk/ Typeset and printed by: Birografika Bori d.o.o., Ljubljana Uredniški odbor/ Editorial Board: Helena Burger, Andrejka Fatur Videtič, Nika Goljar, Klemen Grabljevec, Črt Marinček, Zlatko Matjačic, Anton Zupan ISSN 1580-9315 TABLE OF CONTENTS FOREWORD Editor / Urednik: Blaž Koritnik Print run/ Naklada: 200 copics / izvodov B. Koritnik ........................................................................................................... ...... 4 SYMPOSIUM PROGRAMME ............................................................................. 5 THE 24111 DR. JANEZ FAGANEL MEMORIAL LECTURE ALS: ADVANCES IN THE LABORATORY AND IN THE CLINIC P.N. Leigh .................................................................................................................. 7 FUNCTIONAL MRI IN ALS: WHAT HAVE WE LEARNED? B. Stanton, V. Williams, A. Simmons, P.N. Leigh ...................................................... 10 PATHOPHYSIOLOGY OF ALS - INSIGHTS FROM DTI C. Blain, B. Stanton, V. Williams, D. Shinhma,; S. Brunton, A. Leemans, D. Jones, A. Si,nmons, P.N. Leigh ............................................................................................. II IS THE MOTOR CORTEX HYPEREXCITABLE IN MOTOR NEURON DISEASE? - A STUDY USING PHARMACOLOGICAL tMRI S. Azam, B. Koritnik, M. Mehta, S.C.R. Williams, P.N. Leigh ................................. 12 SENSORY NEUROPATHY IN ALS- SYNDROMIC OR CO-INCIDENTAL? J.D. lsaacs, A.F Dean, C.E. Shaw, A. AI-Chalabi, K.R. Mills, P.N. Leigh ............... 13 SILENT PERIOD AND MOTOR EVOKED POTENTIALS - FINDINGS IN ALS P. Ridzon, O. Ke/le,; R. Krejčf ................................................................................... 14 ■ - REPETITl\'E NER\'E STl\lllLATION I:'\ .\ P,\'I 11:YI' \\ ITII \I.S - \ C \SI•, REPO RT V. Marti{ ................................................................................................................... 15 C0(;\1 1 1\ 1-, CIL\ '\;(;E I'\ \LS S. Eer111e11tseli .......................................................................................................... 16 F\.H l 1 1\ E 1)\ SFl :\CTIO\ I\ .\I.S E. Ste_fa11ol'CI .............................................................................................................. 17 EXECl Tl\'I', ,\BILIT\' \NI> l> \1 L\' LI\ 1\(, l'EH.FOlnl \ \'('F 1:\ P \ 1'11· \TS \\ 1 II \ 1 V. Št11kol'llik. G. Repm·.{ J. Zidar ............................................................................. 18 \ S \ \1) I· ) ()( \ 1 \ 1 S \' C I· 1 1 ( \ \Rt· 1 "{S R.M. Li.vči{. V. Štukol'llik. D. Miick-Šeler. A. Bahic\ G. Nedic\ M. Mustapic�. J. Zidar...................................................................................................................... 19 \ "i"il· "iS \II· \'I 01 RESl'I K\TOR\' :\ ll SCLE STRE'\;( ;TI 1 J. Steie,; J. Mo.rha111 .... ......... .. ................ ................. ......... ........................ ...... .......... 20 ROLE 01· POL\ SO:\l:\O(;R,\1'11\' l:"I: \SSESS\IE,T OF \0\1\ \ \SI\ I• \ lc"-.TIL \ 110\ 1\ \I S P \TIE:\ 1 S L. Do/e11c-Grošelj, L. Leo11ardis. J. Zidar ................................................................. 21 S\'\IPTO:\IS OF RESl'IR,\TOR\' ITNCTIO:\ l'\Sl'FFKIE :\C\' AND ARTERli\L BLOOI> (;,\SES AN \L\'SIS ,\S PRO(;NOSTIC l:\DICATORS 1\ \LS L. Leonardis, L. Dolenc-Gro.fr/j. J. Zidar ................................................................. 22 SliPPORTI�(; \LS P,\TIE:\TS l'SI�(; \O�I:\ \,\Sl\'E \ E:'\iTIL.\TIO'I.; M.A. Ampong .......................................................................................................... 23 \1 \N \(;E'.\IEXI' OF RESPIR \TOR\ F.\IU RE ANI> DYSPIL\CL\ 1:\ \I S P\ l"IE�TS Z. Slel'i{ . . .. . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . .. . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 ELECTl{O'.\l\'O(;R1\l'II\' 01· THE DI.\PIIR,\(;'.\I ,\ "l;D l'IIRENIC \UH l. (0\Dl ( 110:\ STl I>IES 1:\ P.\TIE:\TS \\ ITII .\LS S. Podna,; l. Rigler .................................................................................................... 25 SNII• FIN(;-REL\TEI> COR l'ICAL \IOTOR POTE:\TL\LS I\' ALS - \ l'RFU\11\ \R\ IU POR 1 M. Korošec, l. Zidcu; D. Jeran. B. Koritnik. J. Zidar ................................................ 26 IN\'ESTl(;,\Tl:\G TIIE CE:\TR \L ('0\TROI. OF RESPIR ATIO\' I'\ \LS- \ PILOT l'\IRI S I l 1>\ B. Korit11ik, S. A-::.0111, C.M. Andre\\', J. Zidcu: S.C.R. Willia111s. PN. Leigh .............. 17 IR\ \SL \ 110:\,\L RESE,\RCII I'\ ,\LS A.C. L11do/p!, ............................................................................................................. 28 ll>P--B 1\ SPOR \1)1( \\OJ'\ \IIU \l. \LS B. Rogelj. J. Sreedharan. C. Vance, V. Tripathi. S. Ackerley. T Hor!Ohag_r. C. E. Shaw . . . . . . . . . . . . . . . . . . . ... . . . . . . .. . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 CI 1\1(' \l.<. \RE OF PATIE�TS \\'ITII ALS A. Rad1111m·i{ ............................................................................................................. 30 MULTIDISCIPLINARY APPROACH IN ALS E. Willey ................................................................................................................... 31 REHABILITATION MEDICINE IN ALS A. Pražnikar .............................................................................................................. 32 PALLIATIVE CARE IN ALS D. Ol iver.................................................................................................................... 33 HOSPICE ALS PATIENT - A CASE STUDY T. žargi ....................................................................................................................... 34 QUALITY OF LIFE ANO DEPRESSION IN THE PATIENT-CAREGJVER SCENARIO IN ALS A. Chio ...................................................................................................................... 35 DEMOGRAPHIC ANO PHENOTYPIC CHARACTERISATION OF OUR ALS PATIENTS V. Zgonc, L. D olenc-Grošelj, B. Koritnik, L. Le onardis, S. Rist ic-Kov ačič, V. Štukovnik, /. Zidat; l. Zidar .................................................................................. 36 ACKNOWLEDGEMENTS .................................................................................... 37 AUTHORS INDEX ................................................................................................. 38 DR. JANEZ FAGANEL MEMORIAL LECTURES ANO SYMPOSIA 1985-2008 ................................................................................................................. 39 INVITATION TO THE SYMPOSIUM 2009 ...................................................... 41 II Rchahilitac1p - Letnik VII. .11111/. -1 (!008) FOREWORD Dear Colleagues, /11 spite o.f rece111 ac/1'(111ces in both the research a11d clinical do11wi11s o.f C1111yotrophic late ral sclerosis (ALS), the disease re111ai11s CIII inrnrable.f atal condition. On the other hC111d it is a11 i11spiri11g challenge to researchers and clinicians olike. The Ljubljana ALS Team 11·as established in C111tu11111 2002 CII the Institute o.f Clinical Neurophysiology, University Medica/ Centre Ljubljana. The tew11, led by Professor Jane::, Zidar, li11ks together experts.from differentfields working in unison to provide care and support for patie11ts with ALS. A few reseC1rch projects have started in para/le/ making cli11icia11s C1nd researchers eve11 more co111111itted to this disease. ALS is tire topic of this year's Ljubljana au/1111111 clinicol 11e11roscie11ce 111eeti11g taking plC1ce at the Unil'ersity Meclical Centre, Ljubljana 011 19-20 September 2008. The Sy111posi11111 keynote speaker is Professor Nigel LeiglrJim11 Ki11g'.1· Col­ lege London prese11ti11g the 24'" D1: Jane::, Faganel Memorial Lecture entitled ''ALS: Admnces in the Laboratory a11d in the Clinic ". In two dC1ys the 111eeti11g wi/1 cover various C/.\pects rlthe disease,from 11euroi111aging and 11europhysiology, to respiration, cognition, neurobiology, and- 111ost importantly - treat111ent and care o.f tire pC1tients. The meeting is 111C1i11/y a bi/(l{eral event bringing together two groups of hoth yow1g a11d also estClblished researchers • and clinicians: the Lj11hljC111a ALS Team and the MND Team from King 's Coli ege London. A.feir promi11e111 speakersfimn other part.1· of E11rope hm•e joi11ed the111 and it i.1· great to see that the participants are co111i11g not j11stfim11 Sl{ the hard l\'ork t�f CI group of dedicated co/leagues a11d good.fi-ie11dsJimn both SloFenia a11d the UK and 1 would like to tha11k the111 ali for their i11p11t. The orga11isatio11 oj the 111eeti11g ll'ould he i111pos­ sible without ge11ero11s s11pport .fimn the British Co1111cil (The Internat iona/ Networki11g Jor Young Scie111ists Pro­ gra111111e), the SlrJ\'enian Research Agency a11d also fimn 11wnero11s phar111aceutical co111pa11ies. /'111 deeply thankful to tlrem a/1. My hopes C1re that this 111eeti11g irill stre11gthe11 tire links betll'een the gro11ps a11d also create 11ei1· opportunities and ideas for reg iona/ collaboratio11. I C1!so hope tl1C1t 11w11y 11e1r.frie11dships will be 111ade. With this in 111i11d. I wish you an i11teresti11g and inspiring 111eeting, and a pleasant stay 11·ith /IS. We wish you a 1 1el)' 11·cir111 welcm11e to ½iublja11a, Bla: Koritnik Rchahilitacija - Letnik VII. .111p/. -1 (2008) PROGRAM ME FAIDAY, 19 SEPTEMBER 2008 08:00-09:00 Registration of Participants 09:00-09: 15 Opening of the Symposium 09:15-10:00 The 24 111 Dr. Janez Faganel Memorial Lecture 10:00-10:20 10:20-12:25 10:20-I0:45 l0:45-11: 10 ll:10-11:35 11 :35-11 :55 11 :55-12: 10 12: 10-12:25 12:25-13:25 13:25-15:05 13:25-13:50 13:50-14: 15 14: 15-14:40 14:40-15:05 15:05-16:20 15:05-15:30 15:30-15:55 15:55-16:20 16:20-16:40 16:40-18:15 16:40-17:05 16:40-17:05 17:05-17:30 17:30-17:55 17:55-18: 15 20:00 P.N. Leigh (King's Col/ege London): ALS - Advanccs in the Laboratory and in the Clinic Coffee Break Ncuroimaging and Ncurophysiology (Chair: P. Nigel Leigh) Biba Stanton (King's Col/ege London): Functional MRI in ALS: What Have We Learned? Camilla Blain (King's Col/ege London): Pathophysiology of ALS - Insights from DTI Sheba Azam (King's Col/ege London), Blaž Koritnik (University Meclical Centre Ljubljana): 1s the Motor Cortex Hyperexcitable in Motor Neuron Disease? A Study Using Pharmacological fMRI Jeremy D. Isaacs (King's Col/ege London): Sensory Neuropathy in ALS - Syndromic or Co-Incidental? Pctr Ridzoi\ (Thomayer's Teaching Hospital, Prague): Silent Period and Motor Evoked Potentials - Findings in ALS Vesna Martic (Military Medica! Academy, Belgrade): Repetitive Nerve Stimulation in a Patient with ALS - A Case Report Lunch Cognition and Dcmcntia (Chair: Adriano Chi6) Stella Tsermentseli (King's Col/ege London): Cognitive Change in ALS Elka Stefanova (Clinical Centre Serbia, Belgmde): Executive Dysfunction in ALS Vita Štukovnik (University Medica! Centre Ljubljana): Executive Ability and Daily Living Performancc in Patients with ALS Rajka M. Liščic (Institute Jor Medica! Research and Ocrnparional Health Zagreb): ALS and FTLD: Cognitive Changes and Gcnetic Markers Respiration I (Chair: Zorica Stevic) Jbrg Steier (King's Col/ege London): Assessment of Respiratory Muscle Strength Leja Dolenc-Grošelj ( University Medica! Centre Ljubljana): Role of Polysomnography in Assessment of' Noninvasive Ventilation in ALS Patients Lea Leonardis ( University Medica! Centre Ljubljana): Symptoms of Respiratory Function lnsufficiency and Arterial Blood Gases Analysis as Prognostic lndicators in ALS Coffee Break Respiration II (Chair: Janez Zidar) Mary Ann Ampong (King's Col/ege Hospital. London): Supporting ALS Patients Using Noninvasive Ventilation Zorica Stevic (Clinical Centre Serbia, Belgmde): Management of Respiratory Failure and Dysphagia in ALS Patients Simon Podnar, Igor Rigler ( Unil'ersity Meclical Centre Ljubljana): Electromyography of thc Diaphragm and Phrenic Nerve Conduction Studies in Patients with ALS Marko Korošec (University Medica! Centre Ljubljana): Sniffing-Related Cortical Motor Potentials in ALS - A Preliminary Report Blaž Koritnik (University Medica! Centre Ljubljana): lnvestigating the Central Control of Respiration in ALS - A Pilot fMRI Study Symposium Dinner (Ljubljana Castle) a RL'i1ahilit;1l·ij�1 l l·tnik \'II.,1111I.-11:!nnsi SATURDAY, 20 SEPTEMBER 2008 09:00-10:00 Basic Research (Clwir: Maja Bresjanac) 09:00-09:35 Albert C. Ludolph (Unil'ersity r!f U/111): Translational Research in ALS 09:35-10:00 Boris Rogelj (King's Col/ege London): TDP--l-3 in Sporadic and Familial ALS 10:00-11: 15 Treatment and Care 1 (C/wir: Bmno Cimnelfo) 10:00-10:25 Aleksandar Radunovic (Royol London Hospital. London): Clinical Care or Patients with ALS 10:25-10:50 Emma Willey (King's Col/ege London): Multidisciplinary Approach in ALS 10:50-11: 15 Aleš Pražnikar (Uni1•ersi1_,, Medica/ Centre Lj11bljana): Rehabilitation Medicine in ALS 11:15-11:35 Coffee Break 11:35-13:10 Treatmcnt and Carc II (C/wir: Albert C. Ludolph) 11 :35-12: 10 David Oliver (Uni1•ersity q(Kent. Canterh11ry): Palliative Care in ALS 12: 10-12:25 Tatjana Žargi (S!rJl'enian Hospice Association. '"jub/jww): Hospice ALS Patient -A Case Study 12:25-12:50 Adriano Chio (Uni1•ersity o(Torino): Quality of Life and Depression in the Patient-Caregiver Scenario in ALS I 2:50- I 3: I O Vid Zgonc ( Unil'ersity Medica/ Centre '"juhljana ): Demographic and Phenotypic Characterisation of Our ALS Patients 13:10-13:15 Closin� of the S� mposium 14:00-late Social Event (British Council Participants) d r Rehabilitacip - Letnil-. Vil. \1111! . ../ ( 2008) The 24th Dr. Janez Faganel Memorial Lecture ALS: ADVANCES IN THE LABORATORY ANO IN THE CLINIC P. N. Leigh MRC Centre far Neurodegeneration Research, King's College London and King's MND Care and Research Centre, Oepartment of Clinical Neuroscience, Institute of Psychiatry, London, UK ALS (MND) appears now a more complex disease than it did two or even one decade back, bul new insights have been plenti ful. From the perspecti ve of the cl inical scientist, some key (and inter-related) questions can be posed: l. What is the core definition of ALS and what does that teli us about pathogenesis? 2. What does the natura! history and epidemiology of ALS teli us about the biology of the disease? 3. What is selective vulnerability in relation to ALS, and is it a useful concept? 4. What insights have we gained from genetic studies and what have genetic studies told us about the causes of sporadic ALS? 5. What have we learnt from ALS trials and what might be key elements of a strategy to find effective therapies? There are some partial answers, many more questions, and a pressing need for ambitious, long-term collaborations between basic and clinical scientists. WHAT IS THE CORE OEFINITION OF ALS ANO WHAT OOES THAT TELL US ABOUT PATHOGENESIS? The molecular pathology of ALS indicates common path­ ways and generic mechanisms, despite a wide range of genotypes and phenotypes. According to the EI Escorial Criteria, 'Proven ALS' is defined by cellular pathology. This includes the presence of characteristic ubiquitin­ irnmunoreactive (Ub-IR) inclusions in lower motor neurons (LMNs), now widely accepted as the definitive hallmark. However, Ub-IRs are consistently associated with p62 (and now TDP43) across the spectrum of sporadic and familial ALS. Where there is ALS, we find typical Ub-IR inclu­ sions. Does this indicate that these protein aggregates are mechanistically involved? Is TDP43 telling us something fundamental about motor neuron degeneration? Both pro­ tein aggregation and disruption of splicing mechanisms are emerging as key themes in neurodegeneration, and targets for therapy. WHAT OOES THE NATURAL HISTORY ANO EPIOEMIOLOGY OF ALS TELL US ABOUT THE BIOLOGY OF THE OISEASE? Through the landmark epidemiological studies of ALS undertaken here in Scotland and other population-based cohorts we know that incidence and prevalence are rather sirnilar in Western countries. The only consistent risk factors are increasing age, male sex, and family history. Clearly, finding new ALS genes is of fundamental impor­ tance. But understanding the biological basi s of prog nosi s (survival) in terms of phenotype in sporadic and familial ALS is crucial. As we move into the era of large scale genome wide association studies, careful definition of these and other phenotypes will be of great interesi, and ali samples will require (verifiable!) data on onsct, survival and phenotype. WHAT IS SELECTIVE VULNERABILITY IN RELATION TO ALS ANO IS IT A USEFUL CONCEPT? Maybe, but the notion that ALS is a 'pure' degeneration of upper motor neurons (UMNs) and LMNs is not tenable, and arguably too much attention has focused on the sup­ posed 'Achilles heel' hypothesis. True, degcneration of LMNs is what shortens life, and anterior horn cells have some interesting susceptibilities to excitotoxin-mediated damage. But large neurons are easy to study compared to small neurons, and we found significant loss of GABAergic interneurons in extra-motor areas in ALS, and imaging and cognitive studies have amply confirmed that extra-motor involvement is the rule rather than exception, and not just as end-stage disease. In this context, the association between MND and dementia has becn 'rediscovered' and in some series cognitive abnormalities have been detected in > 50% of patients. More rigorous and conservative approaches to cognitive evaluation are needed but there is no doubt that frontotemporal pathology is more common - Rchahilitaci_ja Letni!-. VII. 11111I. --1 / 2/HJSJ --- than formerly appreciated. and thal we are beginning to understand the genetic. cellular. rnolecular and clinical implications of these phenotypes. Interestingly, SOD 1 Familial ALS (SOD 1-FALS) subjects may be less likely to have cognitive changes than non-SOD-FALS cases, sug­ gesting that the notion or a continuous spectrum of ALS through 'pure' motor neuron degeneration to frontotem­ poral !obar degeneration (FTLD) with ALS (FTLD-ALS) and FTLD without ALS. may be incorrect. Severa! gene loci are linked to ALS with FTLD but as yet the causative gene lesions are unknown. Almost always the underlying molecular palhology of frontotemporal involvemenl with MND is that of ubiquitin and TDP-43 immunoreactive ([R) intracytoplasmic (and in some familial forms. intra­ nuclear) inclusions. The role of tau remains enigmatic. Despite the likely importance or altered tau in the Guam form of ALS. such cases show Ub- and TDP-43-IR inclu­ sions in motor neurons, not Lau-positive inclusions. Motor neurones do not "do' abnorrnal tau, it seems. even in the rare cases of motor neurone degeneralion associated with tau gene mutations. WHAT INSIGHTS HAVE WE GAINEO FROM GENETIC STUOIES ANO WHAT HAVE GENETIC STUOIES TOLO US ABOUT THE CAUSES OF SPORAOIC ALS? Fourteen years has elapsed since the discovery of SOD 1 gene mutations that account for -20% of familial ALS cases. and 2-3% or apparently sporadic cases. Recently mutation in TDP43 have been identified in FALS and in some apparently sporadic cases. linking a striking patho­ logical hallmark wilh causative mulations. lntercslingly, TDP43-IR inclusions are absent or less common in SOD 1 familial ALS (FALS) than in sporadic ALS (SALS) or 11011-SOD 1-FALS. This (and the relative absence of cog­ nitive change in SOD 1-FALS compared to non-SOD 1- FALS) urges caution in equating SOD 1-ALS with SALS - although Don Cleveland has provided data irnplicating a common molecular signature for SOD 1-FALS and SALS. This issue is of key importance far translational rcsearch. as is the concept or non-cell autonomous mechanisms or celi death. Activation of the innate inflammatory system is present in MND and neurodegenerative disorders, ancl glial cells seem to contribute significantly to the neuro­ nal death process. Gene delects in other motor neuron disorders highlight altered transport or mitochondria as a possible mechanisrn underlying or contributing to axonal degcneration. Many other possible rnechanisrns are mooted but we may be moving closer to a consensus on the key mechanisms, although new genes. and new models, may upset Lhese notions. From the clinical viewpoint. finding generic mechanisms that might be susceptible to treatment must be the priority. At present the 'besi be1s· probably include neuroinflammation. axonal transport and energy II (mitochondrial) delects, protein aggregation, intracellular trallicking changes. and or course celi death mechanisms­ and ali are likely to be inler-related and inter-depenclent. Meanwhile, the 16q FALS gene has been identified but is not yel published. The major challenge. however. for the next decacle is to iclentify the cause(s) of sporadic ALS. A start has been made in Lhis direction with the firsl published genome wide association studies. At presen t. we cannol be sure that any of the published associations are definitely related to risk or causation. Hopefully we have learnl some lessons - chiefly the requirement far large well characterised samples with replication samples in-built. and stringent statistical analysis. WHAT HAVE WE LEARNT FROM ALS TRIALS ANO WHAT MIGHT BE KEY ELEMENTS OF A STRATEGY TO FINO EFFECTIVE THERAPIES? Only one phase 3 tria! (the riluzole study publishecl in 1996) has been convincingly positive, with only a small effecl on survival. Mcla-analyscs indicale tl1a1 the effect was real, and that there may have been a small effect on function. Yet we stili do not know how riluzole works. We do know through Lhe NNIPPS (Neuroprotection and Natural History in Parkinson Plus Syndrornes) tria! that the effecl on survival in ALS is not (alas) translatecl to PSP or MSA. So riluzole does not have a generic neuroprotective effect. We might conclude Lhat we would be unwise to abandon survival as an arbiter of efficacy. Paradoxically, we should beware of equating survival with funclion in trials. They are related. of course, bul the relationship is complex. ALS patienls (and thus functional rneasures of cleterioration) are very susceptible to adverse drug effects. A recent example may be the North American minocycline tria! - maximum tolerated dose may not be the best option for neuroprotection. The selcction of agenls for trials has been idiosyncratic, and (inevitably, given our ignorance of mechanisms) detcrminecl more by the enthusiasm or bias of particular investigators or cornpanies than rational processes. Perhaps more rigorous criteria for rnoving from cellular and animal model s to man might be agrecd to avoid Lime-wasting sLUclies. We urgently need a new approach to phase 2 stuclies that includes dose finding. Normally this relies on functional measures that have high variance and are relatively insensitive to change. ldeally. we need to identify biomarkers Lhat will inclicale whelher the sup­ posecl target has been modified. Examples would include inflammatory markers as indicators of the actions of minocycline and other pulative anti-inflammalory agenls, and proteomic or metabonomic markers of celi damage. Most likely, CSF analyses will be required. New imaging techniques may contribute. Rehabilitacija - Letni!,. VII. ,1111I. -1 (!008) I believe that we are on the threshold of new phase in ALS research. Understanding of the mechanisms of SODI ALS may at last be crystallising into more focused hypotheses, and treatments are being developed to modify this form of the disease. New ALS genes have been identified, and the prospects for success in sporadic ALS through genome wide association studies - although far from certain- are encour­ aging. Biomarker work is taking off, and even imaging may catch up with mechanisms in the next decade. We must have tools to study the human brain in life, and to develop an effective experimental medicine approach to neurodegenera­ tive disorders if we are to integrate laboratory science with clinical practice to find effectivc treatments. Acknowledgements The King's MND Care and Research Centre is supported by the MND Association and by King's College London and King's College Hospital NHS Foundation Trust. PNL has received research grant support from the MRC, Well­ come Trust, ALS Association (ALSA), UK Department of Health, MND Association, and Tim Perkins family (MND Research Fund). In the last 5 years PNL has hcld consultancies with and/or has reccived rcscarch grants in rclation to clinical trials from Sanofi-Avcntis. Glaxo­ SmithKline. ONO Pharma. Novartis. Exonhit. Tcva. Trophos. Oxford Biomcdica. and Evotcc. d Rehabilitacija - Letni!-. VII. 111p/ . ..J 12008! FUNCTIONAL MRI IN ALS: WHAT HAVE WELEARNED? 8. Stanton, V. Williams, A. Simmons, P. N. Leigh King's College London, Institute of Psychiatry, London, UK BACKGROUND Functional MRI has been widely used to study changes in motor and extra-motor pathways in ALS. lncreased activation during motor execution has been consistently demonstrated, and hypothesised to reflect adaptive changes or damage to inhibitory pathways. However, differences in task difficulty for patient and control groups confounds the interpretation of these findings. We have performed a series of fMRI studies of motor execution and motor imagery to test specific hypotheses about the observed changes in cortical function in ALS. HYPOTHESES l. Patient with ALS show increased cortical activation during a motor task compared to both healthy controls and patients with muscle weakness due to peripheral lesions. 2. Patients with ALS show increased cortical activation during motor imagery compared with healthy controls. 3. fMRI demonstrates altered function of cxtra-motor re­ gions in ALS. METHODS fMRI was used to measure activation during two block design paradigms contrasting execution and imagery of right hand movements against rest. Sixteen paticnts with ALS, seventccn healthy controls and nine patients with peripheral lesions took part in the study. The groups were matched for ii age and gender and the two patient groups were matchec for their degree of upper limb weakness. Analysis usec a non-parametric approach to perform hypothesis-driver comparisons betwcen the groups. RESULTS During the motor execution task, patients with ALS showec increased cortical activation bilaterally (extending frorr the sensorimotor cortcx posteriorly into the inferior pari­ etal !obule and inferiorly to the superior temporal gyrus; when compared to peripheral lesion patients and controls. In addition, ALS patients showed reduced activation in thc dorsolateral pre-frontal cortex (DLPFC) extcnding te anterior and medial fronta! cortex. Contrary to our hypothesis, patients with ALS showed reduced activation during the motor imagery task in the lefl inferior parietal !obule and in the anterior cingulate gyrm and mcdial pre-frontal cortex. CONCLUSIONS The findings of the motor cxecution study suggest that increased activation during motor tasks in ALS does not reflect confounding by task difficulty or a non-spccific adaptation to chronic wcakness, but is likely to be specifi­ cally related to upper motor neuron pathology in ALS. The contrasting reduction in cortical activation during motor imagery may reflect thc disruption of normal motor imagery networks by ALS pathology outside the primary motor cor­ tex. Our cxpcrience in ALS may have wider implications for the use of fMRI as a tool to study thc pathophysiology of neurodegenerative disorders. Rehabilitacija - Letnik VII. s1111I . ..f. (!OOSJ PATHOPHYS/OLOGY OF ALS INS/GHTS FROM OTI C. Blain1. B. Stanton1. V. Williams 1 . D. Shinhmar1 . S. Brunton1 . A. Leemans2, D. Jones2, A. Simmons1 . P. N. Leigh1 1 King's College London, Institute of Psychiatry, London, UK 2 CUBRIC School of Psychology, Cardiff University, Cardiff, UK BACKGROUND The majority of ALS cases are regarded as sporadic, although it is recognized that complex genetic factors may be involved. In sporadic ALS (sALS) there is heterogene­ ity in the distribution of motor and extra-motor damage within the brain and rate of disease progression. Patients homozygous for the D90A SOD-1 mutation (homD90A ALS) have a stereotyped phenotype, causing them to be uniquely suited to studying genotype/phenotype interac­ tions in ALS. Diffusion tensor MRI (OTI) allows quan­ tification of axonal damage within cerebral white matter tracts, providing a method of studying the pathophysiology of ALS in vivo. Using OTI we investigated differences in axonal damage between sALS and ALS patients with the homD90A mutation. HYPOTHESES l. On whole brain OTI analysis, sALS patients would show more widespread axonal damage (particularly extra mo­ tor), than homD90A ALS patients. 2. Oiffusion tensor tractography (DTT) would demonstrate more severe damage to the intracranial portion of the corticospinal tract in the sALS patients than the genetic group. 3. Correlations would be demonstrated between diffusion measures and clinical scores. METHODS Seven homO90A ALS patients, 21 sALS patients and 21 healthy controls underwent whole head OTI ( 1.5 Tesla). Yoxel based analyses were performed comparing FA across the whole brain between the three groups. Using OTI, the corticospinal tracts were dissected out bilaterally, allowing FA and MD to be calculated along their entire length. Dif­ fusion measures were related to disease duration and scores of disease severity. RESULTS In the whole brain analyses, homO90A ALS patients showed less widespread degeneration of both motor and extra-motor pathways than those with sALS, despite similar disease severity. In addition DTT revealed significantly greater damage to the intracranial portion of the corticospinal tract in sALS patients compared to HomD90A ALS patients. In both these studies, diffusion measures were correlated with the degree of upper motor neuron involvement assessed clinically and with overall disease severity. CONCLUSIONS OTI can be used to investigate and quantify in vivo differ­ ences in the patterns and extent of motor and extra-motor intracerebral axonal damage in sporadic and genetic forms of ALS. Our results indicate that genotype influences the distribution of cerebral pathology in ALS. II Rt:hahil itaci_ja Utnil-. VII. 11111/. --1 (2(HJ8J -- IS THE MOTOR CORTEX HYPEREXCITABLE IN MOTOR NEURON DISEASE - A STUDY USING PHARMACOLOGICAL fMRI S. Azam1 . B. Koritnik3, M. Mehta2, S. C. R. Williams2, P. N. Leigh1 1 MRC Centre for Neurodegeneration Research and 2 Centre far Neuroimaging Sciences, King's College London, Institute of Psychiatry, London, UK 3 Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia BACKGROUND In motor neuron disease (MNO) functional studies have shown altered intracortical inhibition and excitation. Excess glutamate induced corticomotor excitability has been proposed as a possible mechanism for this imbal­ ance. More recent anatomical studies showing a globa! loss of GABAergic interneurones and an altcration in the GABAA receptor mRNA expression pattern in pyramidal cells have highlighted that GABAergic mediated inhibition may also play an important role in the pathophysiology of MNO. Midazolam (MZ). a selective GABAA agonist allows us to probe the functional status of post-synaptic GABAA receptors, allowing us to investigate the role of Lhe GABAergic system in MNO. Increased motor effort in MNO patients, and subsequent cortical reorganisa­ tion as an adaptive phenomenon where greater effort is exerted in carrying out a motor task may explain some of the altered cortical activation. Therefore in this study we have examined the effects of MZ on motor task activation. controlling for effort. METHODS Using functional imaging (fMRJ) we studied 12 patients with MNO as defined by the EI-Escorial Criteria of defi­ nite, probable or possible MNO and two control groups: 12 healthy volunteers (HV), and 12 patients with multifocal motor neuropathy (MMN) matched for weakness with the MNO group. A visually paced motor task was performed, requiring responses of 5%, 10%, 20% and 30% of maxi­ mum grip strength thereby controlling for efforl. Subjects were scanned while they received an intravenous challenge of normal saline and on a separate vi sit an infusion of MZ. lmage pre-processing and s1a1is1ical analysis were carried oul using SPM5. Regions of interest (ROJ) were defined to extracl representative dara for the contralateral motor lil cortex, ipsilateral cerebellum and bilatcral subcortical areas. RESULTS BOLO signal changes in cortical and subcortical motor networks during motor task under control conditions were comparable between ali groups. In contrast 10 previous studies, we did not see a greater increase in BOLO signal in the cortex of MNO patients compared to HV. Following MZ, direct group comparisons revealed a decreased BOLO response in the contaralateral motor cortex (sensorimotor, premotor and supplementary motor areas) in HV, bul not MNO or MMN. In contrast, after MZ, the BOLO response was increased in the pulamen of ali groups. CONCLUSION The use of a graded motor task matchcd to individual maxi­ mum grip slrengths may be a more precise way of providing comparable dala on cortical activation between groups in whom motor effort can play an imponanl role in observed results. Suppression of BOLO signal in the motor cortex of HV is likely to be a direct result of post-synaptic GABAA receptor mediated inhibition or due to an indirect reduction of glutamatergic outpul from the motor cortex. The increase in BOLO signal in the subcortical areas following MZ in ali three groups may reflecl a compensatory response from parallel motor loops when the task is made more "difficult". The lack of conical BOLO signal suppression following MZ in the MNO group and in Lhe MMN group who have imponantly been matched for weakness, may reflecl further compensatory changes due 10 increased motor effort. In the MNO group this means tirni during a motor task GABAA receptor mediatcd effects seen are likely 10 be a compensa­ tory rcsponse to effort. R�hahilitacija - Letni!-.. VII. 111f1/. -1 (!008! SENSORYNEUROPATHYINALS­ SYNDROM/C OR CO-INCIDENTAL? J. D. lsaacs1.4, A. F. Dean2, C. E. Shaw1. A. AI-Chalabi1, K R. Mills3, P. N. Leigh 1 1 King's College London MRC Centre far Neurodegeneration Research, Department of Neurology, Institute of Psychiatry, London, UK 2 Oepartment of Histopathology, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK 3 Oepartment of Clinical Neurophysiology, King's College Hospital, London, UK 4 National Hospital far Neurology and Neurosurgery, London, UK Although an increasing body of evidence suggest that ALS is a multi-system neurodegcnerative disorder, sen­ sory involvement is stili thought not to be a significant feature of the discase. In our cohort of over 1000 patients with ALS we have identified five who had clinical and/ or neurophysiological evidence of sensory neuropathy. Sensory nerve biopsy of three cases demonstrated mild or moderate loss of larger myelinated fibres, some reduction in myelin and in two cases, regeneration clusters. These findings are in accord with clinical, neurophysiological, pathological and animal studics suggesting that peripheral sensory neuronopathy and/or axonopathy can occur in ALS and may be relatively common. Wider knowledge of this association might help avoid diagnostic delay or unneces­ sary treatment in a minority or ALS patients who present with sensory features. II RL'hahilitaci_ja IL'llliJ.- \ II. ,1111I -11 :!IH/SJ S/LENT PERIOD ANO MOTOR EVOKED POTENTIALS - FINDINGS IN ALS P Ridzor\ O. Keller. R. Krejčf Neurological clinic of Institute far Postgraduate Education in Medicine and Thomayer's Teaching Hospital, Prague, Czech Republic Amyotrophic laterni sclcrosis (ALS) is degenerative dis­ ease involving in various forms central and peripheral motoneurons. Pyramidal tracl - or otherwise les ion of cen­ tral motoneuron, ean be investigated using Motor cvoked potentials (MEP). Silen! period (SP) in MEP represenls function of desccndcnt inhibitory spina! tract and cortical inhibitory intcrneurons. In our ALS group we noticed variability of thresholds for corlical stimulation. sometimes absence of evoked corti­ cal potentials. Si lent period were absent in 21 % of ALS patients on upper extremities and in 36% patients on lower extrcmities. Acknowledgement In our group of 46 patients with ALS we investigated MEP and SP in upper and lower extremities in the time of assess- This study was supported by grant IGA MZ CR NR/8491-4. meni of diagnosis. We used machines Magstim 200 and Medelec Synergy. Id Rehabilitacija - Li:tnil-.. VII. rn11I . ..f. (!.008/ REPETITIVE NERVE STIMULATION IN A PATIENT WITH ALS - A CASE REPORT v. Martic Glinic far Neurology, Military Medica! Academy, Beograd, Serbia Lower content of acetylcholine in reinnervated nerve end­ ings is a possible reason for decremental responses to repeti­ tive nerve stimulation in patients with amyotrophic laterni sclerosis. Electrophysiological features suggesting other disease processes should be considered when the decre­ ment on repetitive stimulation exceeds 20% on repetitive stimulation. We present a patient with fluctuating muscle weakness increased by exertion of facial muscles, in which maximal decremenl on repetitive nerve stimulation was 45%. By pharmacological and immunological testing, myasthenia gravis was not confirmed. At the beginning, after detailed clinical investigations and neurophysiological testing, multifocal motor neuropathy was suspected, and because of that the patient was treated by humane immunoglobulins. Clinical deterioration after lhe treatment and appearing of pathological reflexes reflecting corticospinal tract degeneration suggested the diagnosis of amyotrophic lateral sclerosis. II Rchahilitaci_1a I L'tnil-.. VII. 111,,/ . ./ rl!HJSJ COGNITIVE CHANGE IN ALS S. Tsermentseli Institute of Psychiatry, King's College London, UK Amyotrophic laterni sclerosis (ALS) was traditionally believed to spare cognitive functions. but is now known to involve a range of cognitivc impairmcnls suggcsting Lhat ALS is a mulLisysLem neurodegcnerative disordcr. Cognitivc and behavioural symptoms have becn describecl for ovcr a ccntury, and there is evidence that ALS and fronLoLcmporal dcmcntia (FTD) overlap. Although Lhere is a clear link betwccn some forms of ALS and FTD. the prevalence and characterization of mild cogniLive dysfunction in classic ALS stili remain unclcar. Cogni­ tivc impairment occurs in sporadic and ramilial forms of ALS; Paticnts may presen! with cognitive deficits beforc. aftcr, or at the onscl of motor neuron disease. The most II consisLcntly reported cognitivc changcs in ALS relate to dysfunction in components of thc cxccutivc system whereas abnormalities in languagc ancl mcmory are rare bul increasingly reported. Neuroimaging studies havc also shown extra-motor cortical degeneration cor­ rcsponding to lcvcls of fronta! executive impairment on neuropsychological tcsting. Thc purposc of this talk is to review the evidence on cognitivc clcficits in ALS. The potential clinical and theoretical implications of cognitive impairment in non-demented ALS patients will be also discussed. Understanding of this condition will lead to bcttcr carc for patients and provide valuable insights into thc pathogcncsis of ncurodcgcncration. Rehah1litacqa - Letnik VII. 111pl. -f. 12008! EXECUTIVE DYSFUNCTION IN ALS E. Stefanova Institute of Neurology, Clinical Centre Serbia, Belgrade, Serbia BACKGROUND Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that has sporadic and inherited forms. Cognitive and behavioural symptoms have been described for over a century. Cognitive decline in ALS is characterised by per­ sonality change, irritability, obsessions, poor insight, and pervasive deficits in fronta! executive tests. OBJECTIVE To investigate the profile of cognitive impairment in patients with ALS. METHODS Forty-nine ALS patients and 25 healthy controls underwent a comprehensive neuropsychological assessment including: Mini Mental State test; Raven Progressive Matrices Letter Fluency Test; Category Fluency Test (Animal Naming Test); Boston Naming Test; Cambridge Automated Neuropsy­ chological Battery (CANTAB). The affective status was estimated with Apathy scale and Hamilton Rating Scale For Depression (HDRS). RESULTS The most striking impairment was found on tests of verbal fluency- indicating executive dysfunction. Also, the signifi­ cant difference was shown on Boston Naming Test, as sign of deficit in spontaneous confrontation naming. The difference among groups found on tests of Spatial Work Memory (strat­ egy score) (p < 0.05) and on Stockings of Cambridge (initial thinking tirne) (p < 0.01) indicates deficits in planning, allen­ tion and working memory. Behavioural changes, especially on apathy scale was found (p < 0.01 ). There was significant difference on HDRS, but according to DSM IV criteria, none of the patients fulfilled the diagnosis of depression. CONCLUSIONS Understanding of cognitive impainnent in ALS will improve care for patients and their families and provide valuable insights into the pathogenesis of neurodegeneration. II Rehabilitacija - Letnik VII. 11111!. -1- (2008/ EXECUTIVE ABILITY ANO DAILY LIVING PERFORMANCE IN PATIENTS WITH ALS V štukovnik1. G. Repovš2 , J. Zidar1 1 Institute of Clinical Neurophysiology, University Medica! Centre Ljubljana, Ljubljana, Slovenia 2 Department of Psychology, Washington University in Saint Louis, USA Amyotrophic lateral sclerosis (ALS) was traditionally thought to affect solely the lower and upper motor neurons. Recent studies suggest that the pathogenic processes of ALS are more extensive, involving a wider dysfunction of cortical grey and white matter with clinical correlates in the impairment of cognitive abilities. Cognitive deterioration has until recently been associated almost exclusively with a subgroup of 3-5% of ALS patients with frontotemporal dementia. However, a number of latest neuropsychologi­ cal investigations demonstrated selective impairments of the executive and memory functions in nondemented ALS patients (25-75% ). The relevance of these results for every­ day life, however, stili remains in question, thus demonstrat­ ing the need for the development and use of an ecologically valid test ( 1 ). The purpose of this preliminary study was to assess the prevalence of cognitive dysfunction in ALS and also dys­ function 's impact on patients' daily activities. Wc evaluated 16 patients with ALS, according to EI-Escorial Criteria of "possible", "probablc" or "definite" ALS, and with a mean age of M = 59.6 (SO = 7.3) on a battery of standardized neuropsychological tests as well as a specially designed and ecologically valid test of executive functions called Medi­ cation Scheduling task - MST (2). With MST, paticnts are asked to coordinate multiple rules in order to create a safe daily schedule of medications. Both, standardized neuropsychological measures as well as the ecologically valid measure of executive functions, revealed important deficits in cognitive performancc of ALS patients. Using the cut-off value of the 15'" percen­ tile to mark the deficient activity (3), wc found tliat most II patients demonstrated the same kind of impaired activity. i.e. placing incorrectly the pills to the medica! schedule and neglecting to follow the rules while executing the MS1 task. The MST task's high demand for cognitive controL including the ability to coordinate multiple tasks and/01 multiple sources of information, the application of strate­ gies to a novel problem and the ability to monitor incom­ ing information for relevance to the task at hand, seems to presen! great difficulties to patients with ALS and could possibly interfere with the planning and executing of their daily activities. Further explorations of patients' daily liv­ ing performance are necded. Knowing whether or not an ALS patient has cognitive impairment brings up important considerations regarding the management of the patients, including a higher degree of involvement and supervision on the part of their caretakers. References: l. Chaytor N, Schmitter-Edgecombe M, Burr R. Improving the ecological validity of cxecutive functioning asscss­ mcnt. Arch Ciin Neuropsychol. 2006; 21 (3): 217-27. 2. Schefman J, Foster ER, Lim A, Perantie O. Repovš G, Baum C, Hearshey T. The medication Scheduling Task: The development of a naturalistic executive function­ ing task. Presented at the 2006 American Occupational Therapy Association Meeting: Charlottc, NC. 3. Ocutsch Lezak M, Howieson OB, Loring OW. Ncuropsy­ chological assessment. 4'" ed. Oxford University press: Oxford, New York etc.; 2004. Rchahilitaci_ja - Lct11i1' VII. .,1111! . ./ 1 J()(J8/ ALS ANO FTLO: COGNITIVE CHANGES ANO GENET/C MARKERS R. M. Lišči61 , V. Štukovnik2, D. Muck-Šeler3, A. Babi63, G. Nedi63, M. Mustapi63, J. Zidar2 1 Institute far Medica! Research and Occupational Health, Zagreb, Croatia 2 Institute of Clinical Neurophysiology, University Medica! Centre Ljubljana, Ljubljana, Slovenia 3 Division of Molecular Medicine, Ruder Boškovic Institute, Zagreb, Croatia BACKGROUND Amyotrophic laterni sclerosis (ALS) may be accompanied by cognitive impairment; when present, it is mainly in the form of frontotemporal impairment. Frontotemporal lobar degeneration (FfLD) is a focal, non-Alzheimer form of dementia, clinically characterized as either behavioral or aphasic variants ( I ). The overlap between dementia and ALS is demonstrated by the presence of cognitive, behavioural, executive dysfunction and change of personality in up to 50% of ALS patients (2). Behavioural features are mostly due to changes in serotoninergic and catecholaminergic system (3). OBJECTIVE To identify genetic correlates of cognitive changes with the emphasis on executive function in ALS patients. and 6% for CC, CT and TI genotype, respectively. The frc­ quency of CC, CT, TI genotype for 5-HT2A gene polymor­ phism was 30%, 60% and 10%, respectively. 57% of patients showed deficient word generation capability. 21 % of patients were impaired on TOL Total move score and 33% of patients on TOL Tota! rules violation score. 40% of patients were impaired at DRS II Conceptualization subtest and 20% of patients on DRS-11 Memory subtest. No significant (p>0.05) relationship between genes polymorphism and variables of executive functional tests was found (4). CONCLUSIONS The preliminary findings reveal a tendency for executive deficit in ALS. There is a potential genotype-specific influence in ALS for executive functions. Further stud­ ies on a larger sample, however, are needed in order to confirm it. MATERIALS ANO METHODS References: In a prospective study, two tests of executive functions (Con­ trolled oral word association - FAS test; Tower of London (TOL)), were applied on 16 ALS patients ( 10 male, 60.5 ± 5.8 years), as defined by EI Escorial Criteria. Ali subjects also completed the Dementia Rating Scale II (DRS-11). 1021 C/T polymorphism of DBH gene, 102 C/T polymorphism of 5-HT2A receptor gene, val66met polymorphism of COMT gene and val 158/ 108met polymorphism of BDNF gene were correlated with a cognitive tests. RESULTS ALS patients carrying GG, GA and AA genotype of the BDNF gene polymorphism were 73%, 20% and 7%, respec­ tively. The frequency of GG, GA, AA genotype for COMT gene polymorphism was 33%, 53% and 14%, respectively. The DBH gene polymorphism distribution was 47%, 47% 1. McKhann GM, Albert MS, Grossman M, Miller B, Dick­ son D, Trojanowski JQ. Work Group on Frontotemporal Dementia and Pick's Disease. Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease. Arch Neurol 2001; 58 ( 11 ): 1803-9. 2. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic laterni sclerosis and frontotemporal demen­ tia. Neurology 2002; 59 (7): 1077-9. 3. Huey ED, et al. A systematic review of neurotransmit­ ter deficits and treatments in frontotemporal dementia. Neurology 2006; 66: 17-22 4. Liščic RM, et al. Cognitive changes and genetic mark­ ers in amyotrophic laterni sclerosis: Preliminary results of a prospective study. 6'h International Conference on Frontotemporal Dementias, Rotterdam 2008 (P-097). - { IJ 1 11 \ 1 ,, ASSESSMENT OF RESPIRATORY MUSCLE STRENGTH J. Steier. J. Moxham King's College London School of Medicine, London, UK The respiratory musclcs are an important pari or the res­ piratory system. Normal respiratory musclc runetion is necded for suffieient ventilation. Weakness or the respira­ tory musclcs eventually results in respiratory failure. Tests or respiratory muscle strength. in particular thc diaphragm. are therefore an integral pari of the approach towards patients with motor neuron disease. There are various tests or respiratory muscle strength tirni havc dirtcrenl advantages. The most uscful assessment start s with noninvasive cstimations. Tests or general inspiratory muscle strength are maximum inspiratory pressures ( Plmax ). measured with a mouth-occlusion technique. and sniff nasal pressure (Sniff Pnasal). Such tests are ea:-.y to per­ rorm and high results exclude severe inspiratnry weakness. 1 lowevcr. low results in volitional tcsts do not nccessarily coni"irm weakness. hut might be causcd by poor cffort. Thc mcasurement or sniff oesophageal pressure (Sniff Poes) is more invasive and is measured with an oesophageal balloon catheter. It is more precise than Sniff Pnasal measurements. Usually Snill Pnasal should be within 90-1000'< or Sniff Poes. but. ii" the nose is blockecl. the pressures are lower. More specific ror diaphragmatic strength evaluation is the measurcment or transdiaphragmatic pressurc (Sniff Pdil. For such measurement. a gastric balloon cathcter is needed in addition to an oesophageal balloon catheter. Sniff Pdi is the di llerence bet ween gastric and oesophageal pressure and therefore exelusively measures the gradient across the diaphragm. However. ali these manoeuvres are volitional and only high values can exclude weakness. low values do not neccssarily conrirm it. Out or a group or 39 patients with a clinical diagnosis or unilateral diaphragm paralysis ( UDP) we found that only 17 had the diagnosis conf"irmed by spe­ cif"ic diaphragm tests while the 22 had either no weakness at ali or bilateral diaphragmatic inrnlvement ( 1 ). Nonvolitional tests or diaphragm strength are thererore uscful. Magnetic stimulation or the phrenic nerves \\'ith the simultaneous measurement or transdiaphragmatic pressure ( Pdi) allm\s m the function or each hemidiaphragm to be tested independ­ entl) or patient efli.m. The phrenic nerve can be stimulated (twitch Pdi ). using anterolatcral (bilatcral or unilatcral), ccr\'ical ( bi late ral) or antcrior ( bi late ral) apprnachcs. Such tcchniqucs are hclpful in the diagnosis or unilateral or bi lat­ erni diaphragm weakncss in sedatcd or ventilated patients on the intensive care unit. However. the measurement of twitch Pdi requires expensi ve equipment and appropriatc expertise. A combination of test s to increase diagnostic precision can hclp to support or revisc a diagnosis or musclc weakness. For examplc thc comhination or the two noninva:-.ivc tests Plmax and Sniff Pna:-.al increases the accuracy or diagnosing inspiratory muscle weakness (2). Which test should be used dcpend:-. on clinical circum­ stances. Re:-.piratory musclc strength in paticnts with motor neuron diseasc (}) is an important predictor or vcntilatory f'ailure and should theref orc be an integral pari or the clini­ cal assessment. l. Stcicr .l. Jollc) C. Scymour .l. Kaul S. Luo Y. Raflcrty G. Hart N. Polkey Ml. Moxharn J. Slccp-disordcrcd brcathing in unilateral diaphragm paralysis or severe weaJ..ness. Eur Respir J 2008: epub dni: I0.l 183/090W->36.00018808. .., Stcier J. Kaul S. Scymour J. Jolley C. Man WD. Roughton S. Polkey Ml. Moxham J. The ,·alue or rnultiple tests or rcspirat(>r) muscle strength. Thorax 2007: 62 ( 11 ): 975-80. 3. Lyall RA. Donaldson N. Polke) Ml. Lcigh PN. Moxham J. Respiratory muscle strength and ,·entilatory failure in arnyotrophic lateral sclernsi:-.. Brain 2001: 12-+ ( 10): 2000-13. Rehabilitacija - Letni!-- VI . ,1111I . ./ / 2008) ROLE OF POLYSOMNOGRAPHY IN ASSESSMENT OF NONINVASIVE VENTILATION IN ALS PATIENTS L Dolenc-Grošelj, L Le onardis, J. Zidar Institute of Clinical Neurophys iology, University Medical Centre Ljubljana, Ljubljana, Slovenia INTRODUCTION Respiratory weakness in patients with ALS causes dyspnoea and orthopnea, but can also present only with symptoms of nocturnal hypoventilation ( 1, 2, 3). Clinical symptoms and signs along with pulmonary function tests may not be sensitive enough (forced vita! capacity) or not in routine assessment (sniff nasal pressure) to recommend starting noninvasive ventilation ( 1 ). As sleep disturbance may be one of the earliest signs of respiratory insufficiency in ALS patients the aim of our study was to perform the whole-night polysornnographic (PSG) recording to objectively asses the effectiveness of noninvasive ventilation on sleep. METHODS One hundred and twenty-four (n = 124) patients with ALS were followed in our ALS Center frorn October 2002 to July 2008. They were seen at regular 3 rnonths intervals when syrnptorns and signs of respiratory insufficiency were searched for and forced vita! capacity and/or arterial blood gases were measured. When the first symptoms or signs of respiratory insufficiency appeared the noninvasive respira­ tion was discussed and PSG was recornrnended. RESULTS In 34 (27%) of our patients (38% with bulbar onset, 2 pts with farnily history of ALS) overnight PSG was performed. In 20 patients sleep architecture was disrupted together with night hypoventilation and the use of noninvasive ven ti lation was indicated. 19 patients accepted BiPAP and underwent the second overnight PSG using the noninvasive ven ti lati on (rnean tirne from diagnosis to noninvasive ventilation was 32 months in pts with spina! and 28 months in pts with bulbar form). Howeveronly 7 patients (5.6% (5 pts with bul bar and 2 pts with spina! form)) tolerated the BiPAP well and used it on a regular basis (more than 4 hours per night). In these patients (n = 7) better sleep architecture with more slow wave sleep (27 ± 0.02 min/52 ± 0.02 min (p = 0.07)) and longer REM sleep ( 10 ± 0.00 min /33 ± 0.01 min (p = 0.002)) with less night oxygen desaturation (mean SaO 0 (91 ± 0.03%/94 ± 0.01 % (p = 0.02)) were found. Patients �sing BiPAP also reported better sleep quality and less daytime sleepiness. CONCLUSION PSG objectively shows disruption of slecp architecture as one of the earliest signs of respiratory insufficiency in ALS patients. It may help in identification of early respiratory impairment and assess effectiveness of noninvasive ventila­ tion therapy. References: l. Radunovic A, Mitsumoto H, Leigh PN. Clinical care of patients with amyotrophic laterni sclerosis. Lancet Neurol 2007; 6: 913-25. 2. Jennurn P, Santamaria J, Mernbers of the Task Force. Report of an EFNS task force on rnanagernent of sleep disorders in neurologic disease (degenerative neuro­ logic disorders and stroke). Eur J Neurol 2007; 14 ( 11 ): 1189-200. 3. Bourke SC, Bullock RE, Williams TL. Shaw PJ, Gibson GJ. Noninvasive ventilation in ALS: indications and ef­ fect on quality of life. Neurology 2003; 61 (2): 171-7. EI Rehabilitacija - Letnik VII. rnp/. -1 ( 2008/ SYMPTOMS OF RESP/RATORY FUNCTION INSUFFICIENCY AND ARTERIAL BLOOD GASES ANALYSIS AS PROGNOST/C INDICATORS IN ALS L. Leonardis, L. Dolenc-Grošelj, J. Zidar Institute of Clinical Neurophysiology, University Medica! Centre Ljubljana, Ljubljana, Slovenia INTRODUCTION Many patients with amyotrophic lateral sclerosis (ALS) develop symptoms of respiratory insufficiency during the time of the disease and for the majority respiratory failure is the cause of the death ( 1 ). We were interested in usefulness of symptoms of respiratory insufficiency and/or abnormal results of the daytime arterial gas analyses as indicators (AGA) for initiation of non-invasive mechanical ventilation (NIV) and if they are predictive for survival. METHODS Clinical and laboratory data of 82 patients with ALS, who were followed by our ALS clinic since October 2002 and died before July 2008, were analyzed retrospectively. Patients were regularly followed at 3-month intervals. We questioned them about the symptoms of respiratory insufficiency (dyspnoea. orthopnoea, morning headaches, nightmares, disturbed sleep), and performed arterial gases analyses. The last AGA was on average performed 65 days before death (range: 1-702 days, SO 130). Patients with respiratory infections or lung disease were cxcluded from study. RESULTS Mean age at the disease onset was on average 70 years (SO 11 ). Fifty-three patients reported symptoms of respiratory insufficiency which started 23 months after the disease onset (range 0-108 months, SO 22) and died on average 9 months later (SO 9). These patients had slightly longer survival (29 months from the disease onsct (SO 21 )) compared to those without respiratory problems (mean 25 months, SO 14), but the difference was not significant (t = 0.89, p = 0.38). Thir- lil teen symptomatic patients and/or those with increased p co2 saturation underwent a NIV llial but only seven of them used it for at least 4 hours per night (good compliance). They, on average, survived for 312 days (range 52-485 days, SO 150) after the onset of respiratory insufficiency. Those who did not comply with NIV, survived for 258 days (range 3-1347, SO 279). The difference was not significant (t = 0.50, p = 0.62). At least two arterial gas analyses were performed in 48 patients. Only 48%, 67% and 27% of patients had abnormal Pco 2 , p 02 and oxygen saturation, respectively, at any tirne of the disease course. Symptoms of respiratory insufficiency most commonly preceded AGA abnormalities and much less frequently occurred concurrcntly or afterwards. AGA abnonnalities could even not be detected at ali. First abnor­ malities in Pcm' p 02 and oxygen saturation were found 160, 297 and 108 days before death, respectively. NIV tolerant and intolerant patients had similar survival ( 143 compared to 150 days on average) when measured from the first abnormal Pcm result. Similar 11011-significant differences were found also, when low p 02 values and oxygen desaturation were used as starting point of survival measurements. Mean age at the discase onset was at 70 years (SO 11 ). CONCLUSION In our small group of paticnts, the occurrence of symptoms of respiratory i nsufficiency and arterial gases abnormal ities did not aflect survival and are thercforc unlikely to be useful as only indicators for NIV initiation. Reference: l. Borasio GO, Gelinas OF, Yanagisawa N. Mechanical ven­ tilation in amyotrophic laterni sclerosis: a cross-cultural perspective. J Neurol 1998; 245 (Suppl 2): 7-12. Rchahilitaci_Ft - Letnik VII. rn11!.-112008) SUPPORTING ALS PATIENTS USING NONINVASIVE VENTILATION M. A. Ampong King's College Hospital, London, UK For patients with ALS who develop breathing difficulties the decision to consider noninvasive ventilation can pose additional difficulties and dilemmas. There has been an increase in the numbers of patients wishing to consider ventilatory support. Evidence that it improves quality of life and in some cases prolongs survival is growing. Improvements in technology, and a greater awareness of the benefits of noninvasive ventilation, have increased the nmnber of patients wishing to access ventilatory support. As the symptoms of ALS progress, complex symptom manage­ ment is essential alongside ventilatory support in order to maximise the quality of life for the patient. This session is based on my experience in support­ ing patients, their carers and the professionals involved throughout the course of the disease, including monitoring for breathing difficulties, information giving, helping with decision making, symptom management and supporting patients until the end of life. m Rehabilitacija - l.L'lnil-- VI l. .11111I. -1 ( 2008) MANAGEMENT OF RESPIRATORY FAILURE ANO DYSPHAGIA IN ALS PATIENTS z. Stevic Institute of Neurology, Clinical Centre Serbia, Belgrade, Serbia INTRODUCTION Symptomatic treatment primarily based on noninvasivc ventilation (NIV) and percutaneous endoscopic gastrostomy (PEG) provides longer survival and better quality of life of ALS patients. AIM To detcrmine frcquency or PEG placemcnt and/or NIY in ALS patients and their influence on duration of ALS. METHODS A total of 242 (91 femalc and 151 male) ALS paticnts wcrc initially diagnosed between 2003 and 2007 at the Institute of Ncurology in Bclgrade, Scrbia. Sixty fivc had a bulbar and 177 had a spinal onset of the discase. Among them, a group of 31 ( 16 female and 15 male) patients, 16 with spinal and 15 with bul bar onset, was formcd cither with placed PEG or used NIY, due to dysphagia and/or respiratory insufficiency (FYC bclow 65%, Pacm > 6.0 kPa). II RESULTS Fram the group of 211 ALS patients 136 (64.5%) died during the period from 2003 till the cnd of 2007. In the same period, 21 (67.7%) died in the group or 31 patients with PEG and/or NIV Therc was no statistically signifi­ cant difference betwcen thcse two groups in the mean duration of thc discase. We also did not register the statistically significant diffcrence in the mcan duration of thc diseasc betwccn the group of ALS patients with PEG (3.25 ± 0.52 ycars) and the group without PEG (3.71 ± 0.55 years). The mean duration of the disease was longer in the group of patients with PEG and/or NIV (4.2 ± O.S ycars) which was statistically significant in comparison with the group without PEG and/or NIV (3.0 ± 0.1 years, p < O.OS). CONCLUSIONS Only a small number or ALS patients in Serbia ( 12.8%) wcrc with PEG and/or they used NIY. The rcsults of this study show that much has to be done to prolong the lile of our ALS paticnts improve thcir quality of lifc. Rchahilitacija - Letnik VII. .111p/.-/ ! 2008) ELECTROMYOGRAPHY OF THE DIAPHRAGM ANO PHRENIC NERVE CONDUCTION STUD/ES IN PATIENTS WITHALS S. Podnar. l. Rigler Institute of Clinical Neurophysiology. University Medical Centre Ljubljana. Ljubljana. Slovenia In patients with restrictive ventilation failure of unknown aetiology neuromuscular disorders always need to be con­ sidered. In suspected lesions to the phrenic anterior horn neurons or motor axons or to the diaphragm electrodiag­ nostic investigation, including phrenic nerve conduction studies and needle examination of the diaphragm muscle, can be useful. Phrenic nerve conduction studies are usually done using a supramaximal (80-100 mA, 0.1-0.2 ms long) electrical stimulation applied by a surface electrodes in the supraclavicular fossa (just above the clavicle, between both heads of the sternocleidomastoid (SCM) muscle) ( 1 ), and with a pair of self adhesive recording electrodes on the thorax (the active electrode (G 1 ): 5 cm above the xiphoid process, the reference electrode (G2): 16 cm from G 1, on the chest margin (2)). Phrenic nerve M-wave parameters describing axonal loss (amplitude (mY), and area (mYms)), or demy­ elination (latency and duration and (ms)) can be measured. Needle examination of the diaphragm muscle is usually done by a standard concentric EMG needle inserted into thc mcdial recess of the 7 th, 8th or 9th intercostal space (3). During slow advancement of the needle electrode through the tissue EMG signal is carefully observed and listened. Rhythmic bursts of low amplitude MUPs during inspirations disclose that tip of the electrode reached the diaphragm (3). At that point EMG activity during normal breathing is obscrved. In addition, motor unit potential (MUP) parameters can be measured (quantitative MUP analysis), and compared to normative limits ( 1 ). Respiratory electrodiagnostic studies are valuable also in paticnts with suspected ALS, because some of these patients present with respiratory insufficiency. Furthermore, respira­ tory failure limits the life span of these patients. However, in this population apart from lower motor neuron (at high cervical or thoracic levels) upper motor neuron involvement may cause of respiratory failure. Phrenic nerve conduction studies and needle examination of the diaphragm muscle, however, evaluate mainly only the lower motor neuron func­ tion. Low amplitude or area of the phrenic nerve M-wave point to few remaining functional diaphragm muscle fibres, and therefore to a advanced stage of the disease in the res­ piratory domain. The needle EMG studies may be of some prognostic value and aid in long-term planning of respiratory management in patients with ALS. Abundant spontaneous denervation activity with a decreased number of relatively normal-sized MUPs points to acute denervation and rapidly developing disease with poor reinnervation. In contrast, little spontaneous denervation activity with a decreased number of large MUPs indicates a more slowly progressive denerva­ tion and better reinervation. Respiratory electrodiagnostic findings need to be combined with electrodiagnostic find­ ings obtained in other trunk and limb nerves and muscles to diagnose ALS. References: l. Resman-Gaspcršič A, Podnar S. Phrenic ncrve con­ duction studies: technical aspects and normative data. Muscle Nerve 2008; 37: 36-41. 2. Chen R, Collins S, Remtulla H, Parkes A, Bolton CF. Phrenic nerve conduction study in normal subjects. Muscle Nerve 1995; 18: 330-5. 3. Bolton CF, Grand'Maison F, Parkes A, Shkrum M. Ncc­ dle electromyography of the diaphragm. Musclc Nerve 1992; 15: 678-81. m RL'iiahilitacija IL·tnil-. VII. 11111I ../ / :!IHJSJ SNIFF/NG-RELATED CORTICAL MOTOR POTENTIALS IN ALS - A PRELIMINARYI REPORT M. Korošec, l. Zidar, D. Jeran, 8. Koritnik, J. Zidar Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia BACKGROUND Respiratory insufficiency is by far the most frequent cause of death in amyotrophic laterni sclerosis (ALS). Neural control of breathing depends on a central drive to the respiratory muscles. Affection of the latter, which is in clinical set­ ting most difficult to assess in isolation, may contribute to respiratory deficiency in ALS. A possible way to study the central mechanisms for the control of voluntary breathing is through different respiratory manoeuvres, e.g. sniffing and coughing. Movement-related cortical potentials (MRCPs) mainly reflect functioning of the supplementary, premotor and primary motor areas that are involved in sniffing as well. OBJECTIVE To determine whether MRCPs evoked by sniffing (sniffing­ related cortical potentials - SRCPs) can serve as a use­ ful marker of cortical respiratory drive dysfunction. We hypothesised that SRCP amplitude is reduced in ALS due to neuronal loss. We were also interested if sizes of SRCPs correlate with overall and specific respiratory functional scores and results of pulmonary function tests. METHODS Eight patients (48-75 years; 4 with definite and 4 with probable ALS according to El-Escorial criteria) and 10 healthy control subjects (21-26 years) were studied. None of the patients had symptoms or clinical signs of respiratory insufficiency. Both groups performed self-pacecl sniffing manoeuvre every 5-10 seconds, patients with 20% and controls with 30% of maximal sniff nasal inspiratory pres- lil sure. Onset of sniff nasal inspiratory pressure was used for back-averaging of electroencephalogram ( 10-10 system, 32 electrodes). MRCPs on right index finger flexion was used as a comparison. The maximum amplitudes of SRCPs and MRCPs as well as amplitudes at 500 ms and 100 ms before and at the time of sniff/finger flexion (O ms) were measured. Grand average was calculated for each task. A three-way mixed ANOVA and Pearson 's correlation coefficient were used for statistical analysis. RESULTS On grand average, MRCPs and SRCPs of ALS patients were larger compared to controls, but the differences wcre not statistically significant. No correlation was found between sizes of individual SRCP components' and age, overall and specific respiratory and upper limb subdivisions of Norris and ALS FSRr scores, and results of pulmonary function tests. CONCLUSIONS The findings are in contrast with our hypothesis. A tendency toward increased SRCPs and MRCPs may suggest that degeneration of upper and lower motor neurons in ALS is parallelecl by processes that compensate for such loss. Plastic changes possibly involve recruitment into the response of additional generator cells within and adjacent to the motor cortical areas that are not called upon in physiologic cir­ cumstances (e.g. by reduction of neuronal celi inhibition). The drawbacks of our study are small number of patients that do not include those with clinically overt respiratory dysfunction, large interindividual variability ofSRCPs, and non-matched control group. Rehabilitacija - Letnih. VII. 11111/. -1 (2008) INVESTIGATING THE CENTRAL CONTROL OF RESPIRATION IN ALS - A PILOT fMRI STUDY B. Koritnik1 , S. Azam2, C. M. Andrew2, J. Zidar1 , S. C. R. Willams2, P. N. Leigh2 1 Institute of Clinical Neurophysiology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Deparment of Clinical Neuroscience, Institute of Psychiatry, King's College London, London, UK BACKGROUND How the brain controls breathing is stili not completely understood ( 1 ). In recent years, functional magnetic resonance imaging (fMR1) has been used to study voluntary brealhing in healthy subjects (2). Respiratory failure due to progressive respiratory muscle weakness is lhe usual cause of death in ALS. Maximal sniff nasal pressure measurement was the single respiratory test combining linear decline, sensitivity in mild disease, and feasibility in advanced disease. Therefore it appears well suited to assess the decline of respiralory muscle strength, the risk of respiratory failure and to provide prognoslic information in ALS palients (3). Upper motor neuron abnor­ malities could add to the respiratory dysfunclion in ALS. HYPOTHESES We hypothesised thal fMRI during sniffing would reveal sniffing-associated brain activation palterns both in healthy Compared to healthy subjects, ALS paticnts showed reduced activation bilaterally in lhe prefrontal corlex, and to a lesser extent also in temporal and occipilal lobes and cerebellum. lncreased activation in ALS patients was found in left tem­ poral lobe only. CONCLUSIONS Using fMRI during sniffing, it is possible to visualise the cortical sensorimotor network associated with voluntary control of breathing both in healthy subjecls and in ALS patients. The reduced prefrontal activation suggesls lhat a central neural component to the respiratory dysfunction could exisl in ALS. Some clinical observalions support this hypothesis (4). Reduced prefrontal activation was also described in ALS patients using fMRI during hand move­ ments (5). subjecls and in ALS patients, and that ALS patients would show References: reduced cortical activation compared to healthy subjects. METHODS Six ALS patients and five healthy subjects were studied. Static inspiratory and expiratory mouth pressure and maximal sniff nasal pressure were measured. lmaging was performed on a 3T Siemens Trio scanner. In each subject, 221 functional seans were acquired. Nasal pressure and chest movements were rneasured during scanning. An event-related experimental design was used. A submaximal sniff manocuvre was per­ formed every 20 s. Image pre-processing and stalistical analy­ sis werc done using the SPM5 software. A random effects group analysis was performed (p < O.OJ uncorrected). l. Guz A. Brain, breathing and breathlessness. Respir Physiol 1997; 109: 197-204. 2. McKay LC. Evans KC, Frackowiak RS, Corfield DR. Neural corrclatcs of voluntary breathing in humans. J Appl Physiol 2003; 95: 1170-8. 3. Lyall RA, Donaldson N, Polkey MI, Leigh PN, Moxham J. Respiratory muscle strength and ventilatory failure in amyotrophic laterni sclcrosis. Brain 2001; 124: 2000- 13. 4. Pinto S, Pinto A, Atalaia A, Peralla R, de Carvalho M. Respiratory apraxia in amyotrophic lateral sclcrosis. Amyotroph Laterni Scler 2007; 8: 180-4. RESULTS 5. Stanton B, Williams V, Leigh P, Williams S, Blain C, Jarosz J, Simmons A. Allered cortical activation during A bilateral cortical and subcortical sensorimotor network a motor task in ALS. J Neurol 2007; 254: 1260-7. was found to be activated during sniffing in both groups. rli Ludolph / Rchahilitaci_ja - kt11. VII.,1111I.-112008/ TRANSLATIONAL RESEARCH IN ALS A. C. Ludolph University of Ulm, Ulm, Germany The need for new therapeutic, including pharmacological approaches for ALS/MND is undebated. However, in the past 10 years a number of experimentally promising therapeutics and candidate drugs met with failure in cost-intensive human clinical trials. On First sight this experience is surprising since the ficld of ALS/MND seems to be well-prepared for translational research because a number of in vitro models and in vivo rodent models exist for anterior horn celi disease. Also, a priori, since the field of ALS/MND pioneers the field of neurodegenerative diseases with regard to translational medicine a number of new and uncxpected experiences werc unavoidablc. Today, we have identified some major reasons which obviously played a negative rale for the success of translational medicine in ALS/MND in the past decade. lf these problems are resolved, the path to more effective therapeutics seems to be more clearly defined than ever. Which are the major insights which need to be given atten­ tion in the future? l. Like the majority of neurodcgenerative diseascs ALS/ MND was defined as a clinical-neuropathological syn­ drome by our forefathcrs. It is gctting increasingly clear m that this syndrome has multiple aetiologies, potentiall� not only genetic ones. Therefore, there is an urgent need for validation of the common aspects of the pathogenesis of selective motor neuron degeneration, independent from the various etiological factors ("'target val ida­ tion"). 2. There is an urgent need to clarify reccnt results which seem to suggest that intervention could be stage-specific, in other words drugs for prevention of disease might diffcr from those influencing the course of the disease i tself. 3. Preclinical experimental animal - in particular rodent­ studies need rigorous methodological standardization, approaching the standards of human clinical trials. 4. The step from in vitro to in vivo studies is a major hurdle and far from being understood and standardized. 5. The step from experimental rodcnt studies to human can­ didate drugs requires additional expertise, in particular with regard to the development of biomarkcrs, mirroring the specific effect of the drug and the natura! history of anterior horn celi disease. To avoid major financial loss for the field, these issues need to be resolved in the forthcoming ycars to build the basis for successful translational research, including drug develop­ ment in ALS/MND. Rehahi litacija - Letnik V 11. 111f1/. -1 ( 2008/ TDP-43 IN SPORADIC ANO FAMILIAL ALS B. Rogelj, J. Sreedharan, C. Vance, V. Tripathi, S. Ackerley, T. Horto�agy, C. E. Sh_aw MRC Centre far Neurodegeneration Research, Department of Cl1nical Neurosc1ence, Institute of Psychiatry, King's College London, London, UK For nearly 20 years the neuropathological hallmark of ALS has been polyubiquitinated skein-like and globu­ lar inclusions in the perikaryon and proximal axon of motor neurons in the brain stem and spina] cord. These have recently been shown to colocalise with a 25kDa, C-terminal, detergent-resistant fragment of TAR DNA binding protein TDP-43. These inclusions are present in -90% of ALS cases and a subset of frontotemporal ]obar degeneration cases now termed the "TDP-43 pro­ teinopathies" ( 1-3). TDP-43 is predominantly a nuclear protein but in those neurons with the most �tri�ing cyto­ plasmic inclusions there is a marked reduct1on 111 n�1clear TDP-43, suggesting that it has been sequestered 111 the cytoplasm and that miss-localisation may play a role in pathogenesis. We have recently identified a TARDBP mutation (the gene encoding TDP-43) in a single familial ALS kindred (4). The mutation is predicted to result in a single amino­ acid substitution of methionine for vali ne at rcsidue 337. We also identified two sporadic MND missense mutations (Q331 K and G293A) in neighbouring amino acids. The only two mutations studied showed increased tendency to protein cleavage and were toxic to the embryonic chick spina! cord neurons causing apoptosis and developmental delay. Fourteen missense mutations have now been reported in familial and sporadic MND (3, 5-7). Ali but one of the mutations. reside in the C-terminal domain. The findino of rare mutations in TARDBP in familial and b sporadic ALS does implicate a mechanistic role for TDP-43 cleavage, mislocalisation and aggregation in ALS and FfD. These pathogenic mutations should provide important bio­ logical tools that will enable us to develop more informativc cellular and animal models of ALS. References: l. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TI, et al. Ubiquitinated TDP-43 in frontotemporal !obar degeneration and amyotrophic lateral sclerosis. Science 2006; 314 (5796): 130-3. 2. Arai T, Hasegawa M, Akiyama H, lkeda K, Nonaka T, Mori H, et al„ TDP-43 is a component of ubiquitin­ positive tau-negative inclusions in frontotempornl !obar degenerntion and amyotrophic laterni sclerosis. Biochem Biophys Res Commun 2006: 351 (3): 602-11. 3. Gitcho MA, Baloh RH, Chakrnverty S, Mayo K, Norton JB, Levitch D, ct al. TDP-43 A315T mutation in familial motor neuron clisease. Ann Neurol 2008; 63 (4): 535-8. 4. Sreeclharan J, Blair IP, Tripathi YB, Hu X, Yance C, Rogelj B, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008; 319 (5870): 1668-72. 5. Van Deerlin YM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, et al. TARDBP mutations in amyo­ trophic laterni sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 2008; 7 (5): 409-16. 6. Kwong LK, Neumann M, Sampathu DM. Lee YM. Tro­ janowski JQ. TDP-43 proteinopathy: The neuropathology underlying major forms of sporadic and familial fronto­ tcmporal !obar degencration and motor neuron diseasc. Acta Ncuropathol 2007; 1 14 ( 1 ): 63-70. 7. Yokoseki A. Shiga A, Tan CF, Tagawa A. Kaneko H. Koyama A, et al. TDP-43 mutation in familial amyotroph­ ic laterni sclerosis. Ann Neurol 2008: 63 ( 4 ): 538-42. ii Rd1ahilitacij.1 - l.ctnik VII. 11111I. -1 (:!.OOSJ CLINICAL CARE OF PATIENTS WITH ALS A. Radunovi6 MND Care Centre, Royal London Hospital, London, UK Amyolrophic lateral sclerosis (ALS; motor ncuron diseasc) is a well-delinealed bul nonctheless clinically and patho­ genically heterogeneous syndrome. In most cases, ALS and its variants are casily recogniscd by ncurologists but diagnostic errors occur in about 10 percent or paticnls and delays in the diagnostic proccss are common. Accuratc and prompt diagnosis, sensitive communication of thc diagnosis, close involvement of lhe palient and family, and an aclive, positivc care plan are prerequisites of good management. A mul1idisciplinary approach to care may prolong survival and probably improves quality of life. Riluzole improvcs survival by a few months bul has a mar­ ginal effect on the rale of functional deterioration whercas noninvasive vcntilation bolh prolongs survival (oflen by many months) and improves or maintains quality of life.Thc Ei role of palliativc care. broadly dcfined, is likcly to cxpan bul the evidence for the cffectivcness of some intervcntior (e.g., gastrostomy) is weak. The diagnosis, managemen and coping with impaircd function and cnd-of-life will t discussed in the light of our own expcrience, expert opir ion, existing guidelines, and clinical trials. The prcscnt, 1ion also highlights the need for research into the efficac of gastrostomy, faclors influcncing access to noninvasiv ventilation and pallialive care. as wcll as communicatio in patients unable to speak or on long-term venlilatior and the impacl of cognilive impairment on qualily of lil of patients and care-givcrs. Finally, it also suggests th, thc plethora of cxisting cvidencc-bascd guidclines shoul bc distillcd into a single internationally agrccd guidelin of besi practice. �chahilitaci_ja - Letni!,.. VII. ,1111I . ./ I l008/ MULTIDISCIPLINARY APPROACH IN ALS E. Willey King's MNO Care & Research Centre, Institute of Psychiatry, London, UK Although Amyotrophic Laterni Sclerosis (ALS) is currenlly incurable, it is not untreatablc, and multi-disciplinary care has become an accepted cornerstone of management ( 1 ). Correct early diagnosis and introduction of pall iative care and specific therapy can have a profound influence on the care and quality of life of the patient and may increase survival tirne (2). This is in contrast to the common mis­ conception that in the absence of a cure 'nothing can be done'. Involvement of the multi-disciplinary team in supporting patients diagnosed with ALS allows greater flexibility of response to patient needs and promotes individualised care, essential in a disease characterised by uncertain patterns of progression and deteriorating function. lnterventions such as gastrostomy and noninvasive ventilation are used to palliate symptoms and require a network of healthcare professionals, social care and support groups, working in co-ordination to support clinical, educational and psy­ chosocial needs of patients and carers (3). Timeliness of intervention can raise difficult practical and ethical ques­ tions about individual choice, quality of life and end of life decisions. In the UK, MND care centres supported by the MND Association and a network of regional of multidisciplinary teams are established and work to promote and support the development of local care. Their effectiveness depends on excellent channels of communication, and a coherent philosophy of care ( 1 ). Health profcssionals in hospital and community settings face different challenges, and multi disciplinary team input may be identified as both a help and as a hindrance, depending on effective communication and acceptance of overlapping roles (4). This talk will define the essential elements of multi-dis­ ciplinary care; discuss organisation and effective delivery drawing on experience from the model of care developed at King's MND Care & Research Centre. There are various models of care in existence depending on local history of service organisation, funding and patient population/ geog­ raphy. Commitment to communication, collaboration and the nomination of a single point of contact or key worker is recommended good practice. References: l. Leigh PN, Abrahams S, AI-Chalabi A, Ampong MA, Goldstein LH, Johnson J, et al. King's MND Care and Research Team. The management of motor neurone disease. J Neurol Neurosurg Psychiatry2003; 74 (Suppl 4): iv32-47. 2. Andersen PM, Borasio GD, Denglcr R, Hardiman O, Kollewe K, Leigh PN, et al. EFNS Task Force on Diag­ nosis and Management of Amyotrophic Laterni Sclerosis. EFNS task force on management of amyotrophie laterni sclerosis: Guidelines for diagnosing and clinical care of patients and relatives. Eur J Neurol 2005; 12 (12): 921-38. 3. Brotherton A, Abbott J, Aggett P. The impact of percu­ taneous endoscopic gastrostomy feeding upon daily life in adults. J Hum Nutr Diet 2006; 19 (5): 355-67. 4. Carter H, McKenna C, MacLeod R, Green R. Health professionals' responses to multiple sclerosis and motor neurone disease. Palliat Med 1998; 12 (5): 383-94. il REHABILITATIDN MEDICINE IN ALS A. Pražnikar Oepartment of Neurology, University Medical Centre Ljubljana, Ljubljana, Slovenia Amyotrophic latcral sclcrm,is (ALS) is a progrcssivc ncu­ rodcgencrative clisorder that poses a myriad or clinical. personal and social proble1m. ALS is clinically manifcsted predominantly by upper motor neuron signs and symptoms in limb and trunk musculature like spasticity. central paresis. loss or clexterity. desinhibition of pathological reflexes: lower motor ncuron signs ancl symptoms like atrophy. wcakncss. loss of tendon reflexes. Iowe red musclc tone. rascicu lation: ancl bulbar signs and symptoms like dysarthria. dysphagia. siallorhoe. emotional lability .... Fatigue. demcntia. pain. slecp disorclers. depression or cachexia could contribute to severity of clinical picture in some patients with ALS. At the moment therc is no causal treatment tliat would significantly change the prognosis or the paticnts with ALS. The disease course relentlessly progresses to respiratory compromisc. Rehabilitation medicine (also in neurology) bascs its inter­ vcntions on clisordcrcd function ( .. lack or activity .. ) in order to lessen the clisability of thc individual paticnt c·lack or participation .. ). According to lntcrnational Classification or Functioning. Disability ancl Hcalth (ICF. WHO) functioning Ed and disability are vicwed as a complex intcraction bctween thc health condition of the individual and thc contextuat factors of the environmcnt as wel I as pcrsonal factors - "the pcrson in his or her world". Rchabilitation principlc trcats thcse dimensions of hcalth as interactive and dynamic in each patient with ALS. By doing so. rchabilitation tcam that consists or rehabilitation specialist or ncurologist. physical and occupational therapists. specch language pathologists, dietitians. psychologists. social workers. rehabilitation nurses and casc managers eval uates ancl treats loss of func­ tion due to motor. psychological and/or social consequences of ALS. The need for anticipation and for a quick response of thc health system makes rehabilitation of patients with ALS specific. The main goals are to prolong indcpendence, prevcnt complications ancl improvc quality or lile. Thcreli.)re, rehabilitation medicine olkrs activc approach in adclressing the discase. improves the quality of lile and prolongs the survival in paticnts with ALS as pari or complex multidis­ ciplinary team management as a gold standard of today's managemcnt of patients with ALS. Rdiahilitaci_1a - Letnik Vil. ,11,,/. -1 (2(HJ8J PALLIATIVE CARE IN ALS D. Oliver Wisdom Hospice, Rochester, and University of Kent, Canterbury, UK As there is at present no curc for ALS the treatment of the patient should be palliative care from the tirne of diagnosis (l ). There is the need for a co-ordinated multidisciplinary approach. The various aspects of care should be consid­ ere-W 1- o:: en WI- u C, w � z :l!: o:: z W :l!: - <( o:: :l!: 1- u :l!: ::::>U �� <( o:: u -wen w uu z o LL. <( C, o C, en - 1-w C, Q - o<(W <( � Q. <( o z 1-z :C z :l!: z :l!: o<(U <( w 1 O limes ULN), myoglobinaemia and myoglobonuria wh,ch may lead ta ,enal failure. INTERACTION WITH OTHER MEOICINAL PRODUCTS AND OTHER FORMS OF INTERACTION: The risk of myopothy during treotmenl wilh HMG-CoA reductose inhibitors is increosed with concurrenl odministrotion of ciclosporin, fibric ocid derivatives, mocrolide onti­ b1otics including erythromycir,, ozole anflfungoh, or niocin ond on rore occosions hos resulted in rhabdomyo1ysis with renol dysfunction secondory to myoglobinurio. Other interodions: nefozodone, HIV protease inhibitors, inducers of cyfochrome P450 3A4 (e.g. rifompicin ar phenytoin) , digoxin, oral controceptives, colestipol, ontocid , worforin, phenozone, cimetidine. UNDESIRABLE EFF ECTS: The most commonly expected odverse events are moinly gostrointesrinal, including constipation, flotulence, dyspepsio, obdominol poin ond usually ome1iorole on continued treolment. Most common are: conslipotion, flatulence, dyspepsio, nouseo, diorrheo, allergic readions, insomnio, heodoche, dizziness, poroesthoesio, hypoeslhesio, skin rosh, pruritus, myolgio, orthmlgio, osthenio, chesl pain, back pain, peripheral oedema. NATURE AND CONTENTS OF CONTAINER: Blister packs conta,ning 30 and 90 film-caated tablets canta,rnng I O. 20 or 40 mg af atarvastatin. MARKETING AUTHORISATION HOLDER: Lek farmacevtska družba d. d .• Verovškova 57, Ljubljana, Slavenia. DATE OF REVISION OF THE TEXT: March 2007. full summory of product choracterishcs 1s ovoiloble from Lek d. d. (@lek a Sandoz company Lek Pharmaceuticals d.d., Verovškova 57, 1526 Ljubljana, Slovenia • www.lek.si Early diagnosis of Pompe disease leads to better management DO YOU RECOGNIZE SYMPTOMS OF POMPE DISEASE? A progressive, multisystem, debilitating and often fatal muscular disease Lisosomal enzyme deficiency (acid alpha-glucosidase) results in progressive glycogen accumulation that eventually may lead to irreversible muscle damage and ultimatery death SYMPTOMS OF POMPE DISEASE lnfantile onset • Profound and rapidly progressive muscle weakness • Hypotonia • Floppy baby • Head lag • Delayed motor milestones • Frequent respiratory infections • Progression to respiratory insufficiency • Marked cardiomegaly/cardiomyopathy • Death due to cardiorespiralory Late onset • Progressive proximal muscle weakness (esp. trunk and lower limbs) • Muscle pain • Gait abnormalities • Difficulty climbing stairs • Frequent falls • Scapular winging • Respiratory failure/insufficiency • Respiratory infections .. failure , .. .. ......_ ____________ � ........ .._ ____________ � 'f(Myozyme· (alglucos1dase alfa) FIRST ANO ONLY SPECIFIC TREATMENT FOR POMPE DISEASE Pompe disease - the only congenital neuromuscular disease with available treatment Re resentative Office of Genz me Euro e B.V. Hektoroviceva 2NI Grand Centre. 10 000 Za reb, Croatia Torrex ____ PHARMA Chiesi People and ideas for innovation in healthcare ATIMOS - formoterol BUDIAIR - budezonid CITALOPRAM TORREX - citalopram CUROSURF - naravni fosfolipidi - poraktant a FENTANYL TORREX - fentanil FOSTER - beklometazon/formoterol GABITRIL - tiagabin 1 NOTO P - dobutamin ISOFLURAN - izofluran MIDAZOLAM TORREX - midazolam MOCLOBEMID TORREX - moklobemid PAM ITO R - pamidronska kislina REVIA - naltrekson SUFENTANIL TORREX - sufentanil Torrex Chiesi Slovenija, d.o.o. Trdinova 4 1000 Ljubljana T (01) 43 00 901 F (01) 43 00 900 E info@torrex-chiesi.com Ugled je povezan z zaupanjem Sledimo poslanstvu Creda in ustvarjamo inovativno prihodnost. Iz Credn. Johnson & Johnson, 1943: ''Menimn, dn. smo najprej odgovorni zdravnikom, sestram in bolnikom, materam in očetom ter vsem drugim, ki uporabljajo naše izdelke in storitve. Ko poskušamo zadostiti njihovim potrebam, mora biti zelo kakovostno vse, kar naredinw ... 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