Dietz, V.

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SCIENTIFIC COMMENTARYReady for human spinal cord repair?We are in an exciting time where, based on successfullyestablished animal models, a partial repair of the damagedhuman CNS appears to be feasible. A paper in the presentissue of Brain (Mackay-Sim et al., 2008) deals with theoutcome after transplantation of olfactory ensheathing cells(OEC) in subjects with chronic spinal cord injury. Anearlier report described the surgical and safety proceduresin this trial (Feron et al., 2005).Presently, rehabilitation of spinal cord injury is limitedto exploiting neuronal plasticity by functional training(Dietz, 2002). The combination of functional training andregenerative therapies, even if only limited structural repairis achieved, would certainly make an improved impact onoutcome. There is an impressive number of promisingapproaches for inducing regeneration or limiting neuronaldamage by neuroprotective treatments based on rodentexperiments (for review see Raineteau and Schwab, 2001;Deumens et al., 2005; Ramer et al., 2005; Dietz and Curt,2006). One is the application of regeneration-facilitatingOEC at the lesion site. Convincing evidence was found thatthis approach leads to some spinal cord repair in rodentspinal cord injury (Li et al., 1997; Ramon-Cueto et al.,2000; Barnett and Chang, 2004).The present article (Mackay-Sim et al., 2008) reports on theeffect of this approach in six chronic complete (ASIA A)spinal cord injury subjects (phase I/IIa design) with regularfollow-up using clinical, electrophysiological (MEP), imaging(MRI) and functional (Functional Independence Measure,FIM) examinations over 3 years. Thus, the present study, incontrast to other OEC trials (Huang et al., 2003; Lima et al.,2006), was carefully designed on the basis of standardsestablished during the past few years (Steeves et al., 2007).Such a study design is in line with the consensus that clinicalexaminations alone are insufficient reliably to monitor anytherapeutic effect of a new interventional therapy (Curt et al.,2004). Additional neurophysiological and functional exam-inations allow for some differentiation between compensa-tion, neuronal plasticity and regeneration as principal factorsunderlying an improvement of function after a spinal cordinjury (Curt et al., 2008). Meanwhile, the Spinal Cord Inde-pendence Measure (SCIM) has been established for func-tional testing in spinal cord injury subjects (Catz et al., 2001).The results described by Mackay et al. (2008) must beconsidered preliminary because of the small number ofspinal cord injury subjects included. In addition, the ther-apeutic effect of cell transplantation on outcome was notthe primary goal of this study, although a comparison wasmade with a control group of spinal cord injury subjects.Overall, there were no adverse findings 3 years afterautologous OEC transplantation. Only one spinal cordinjury subject showed some sensory gain, but no functionalrecovery; in all other treated subjects no change in clinicaland functional tests was detected. Also, the imaging andelectrophysiological examinations remained unchanged overthe course of the study. For this category of a completespinal cord injury (ASIA A) such an outcome correspondsto the natural history (Curt et al., 2008). The results appeardisappointing in view of the promising animal experiments.How can this be explained? During the last 10 years wehave become increasingly aware of the problems associatedwith such translational studies, due to the complexity ofthis field (Dietz and Curt, 2006). There are severalinterpretations that might be offered.First, the adequacy of the animal spinal cord injurymodel on which the clinical study is based has to beconsidered. There are some animal models that fit poorlywith the human condition. For example, the frequentlyused transection model (cf. Raineteau and Schwab, 2001;Bennett et al., 2004; Klapka et al., 2005) does not reflect thehuman condition, where the contusional lesion usuallyextends over several segments of the spinal cord. However,a contusion rat model shows similar electrophysiologicaland imaging results as well as outcome in function ashuman spinal cord injury (Metz et al., 2000). Similarly, thespastic movement disorder after spinal cord injury nevershows a motoneuronal hyperactivity (Dietz and Sinkjaer,2007) as described for the rat with a sacral spinal cordinjury (Bennett et al., 2004).Second, thoracic lesions are usually studied in animalmodels (Gensel et al., 2006), whereas injury to the cervicalcord is most common in humans (Curt et al., 2008). Also, inthe trial discussed here (Mackay-Sim et al., 2008), spinal cordinjury subjects with thoracic lesions were included in order tominimize the risk of any additional loss of function as a resultof this procedure, with the consequence of recruitmentdifficulties. In the cervical lesion, every segment gained wouldhave a great impact on function, whereas in subjects withthoracic damage, improvement of locomotor function canonly be achieved if regenerating fibres make contact with thelong propriospinal neurons (Raineteau and Schwab, 2001).However, cervical and thoracolumbar spinal cord injuries arealways associated with damage to the peripheral nervoussystem (up to 40% of paresis might be due to a damage ofmotoneurons and roots; Collazos-Castro et al., 2005). Thisdeficit would possibly not be affected by an interventiondirected at spinal tract regeneration.doi:10.1093/brain/awn185 Brain (2008), 131, 2240^2242 The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.orgThird, new interventional therapies are frequently appliedin chronic spinal cord injury subjects aiming to achieveclinical stability (Mackay-Sim et al., 2008). However, recentstudies in chronic spinal cord injury describe demyelinationaround the injury cavities (Guest et al., 2005), scarformation (Klapka et al., 2005) and degradation of spinalneuronal function below the level of the lesion (Dietz andMuller, 2004). Thus, even if regeneration of tract fibres isachieved through intervention, this may not necessarily bematched by functional improvement. Therefore, for mostcurrent studies, early intervention is recommended (cf.Dietz and Curt, 2006).Fourth, no functional training was performed in thepresent trial (Mackay-Sim et al., 2008). In contrast tohumans, rodents train themselves automatically after spinalcord injury. There is evidence that functional training doesfacilitate appropriate re-connections by regenerating fibretracts after spinal cord injury (Edgerton et al., 1997; deLeon et al., 1999; Dietz and Harkema, 2004).Fifth, a number of mechanisms after spinal cord injuryprevent a spontaneous regeneration of fibre tracts (e.g. scarformation and expression of Nogo protein and chondroitinsulphate). This has prompted corresponding approaches toovercome these hurdles and to induce/facilitate regenera-tion of damaged fibres (for review see Raineteau andSchwab, 2001; Ramer et al., 2005; Dietz and Curt, 2006).Therefore, as exemplified in the rat, the use of comple-mentary approaches involving Schwann cell bridges, OECand chondroitinase might be applied to human subjects inthe future in order to enhance the number of regeneratingfibres and improve the prospects of functional recovery(Fouad et al., 2005).The last point concerns problems, which are welldiscussed in the paper of Mackay-Sim et al. (2008), ofachieving an optimal versus an ethically acceptable designincluding the issue of whether or how to include sham-surgical controls. With the availability of a detaileddescription of the natural history of spinal cord injury ina great number of subjects (Curt et al., 2008), the controlgroup in a trial can be kept relatively small.Based on the above points we can learn importantlessons from the work of Mackay-Sim et al. (2008) andhope to make such trials more successful in the future.AcknowledgementsThe author would like to thank Dr M. Schubert for helpfulcomments and R. Jurd for editorial assistance on the article.Volker DietzSpinal Cord Injury Centre, Balgrist University Hospital,Forchstr. 3408008 Zu¨rich,SwitzerlandE-mail: volker.dietz@balgrist.chReferencesBarnett SC, Chang L. Olfactory ensheathing cells and CNS repair: goingsolo or in need of a friend? Trends Neurosci 2004; 27: 54–60.Bennett DJ, Sanelli L, Cooke CL, Harvey PJ, Gorassini MA. Spastic long-lasting reflexes in the awake rat after sacral spinal cord injury.J Neurophysiol 2004; 91: 2247–58.Catz A, Itzkovich M, Agranov E, Ring H, Tamir A. The spinal cordindependence measure (SCIM): sensitivity to functional changes insubgroups of spinal cord lesion patients. Spinal Cord 2001; 39: 97–100.Collazos-Castro JE, Soto VM, Gutierrez-Davila M, Nieto-Sampedro M.Motoneuron loss associated with chronic locomotion impairments afterspinal cord contusion in the rat. J Neurotrauma 2005; 22: 544–58.Curt A, Schwab ME, Dietz V. Providing the clinical basis for newinterventional therapies: refined diagnosis and assessment of recoveryafter spinal cord injury. Spinal Cord 2004; 42: 1–6.Curt A, Van Hedel HJ, Klaus D, Dietz V. Recovery from a spinal cordInjury: significance of compensation, neural plasticity, and repair.J Neurotrauma 2008; 25: 677–85.De Leon RD, Hodgson JA, Roy RR, Edgerton VR. Retention of hindlimbstepping ability in adult spinal cats after the cessation of step training.J Neurophysiol 1999; 81: 85–94.Deumens R, Koopmans GC, Joosten EA. Regeneration of descending axontracts after spinal cord injury. Prog Neurobiol 2005; 77: 57–89.Dietz V. Proprioception and locomotor disorders. Nat Rev Neurosci 2002;3: 781–90.Dietz V, Curt A. Neurological aspects of spinal-cord repair: promises andchallenges. Lancet Neurol 2006; 5: 688–94.Dietz V, Harkema SJ. Locomotor activity in spinal cord-injured persons.J Appl Physiol 2004; 96: 1954–60.Dietz V, Muller R. Degradation of neuronal function following a spinalcord injury: mechanisms and countermeasures. Brain 2004; 127:2221–31.Dietz V, Sinkjaer T. Spastic movement disorder: impaired reflex functionand altered muscle mechanics. Lancet Neurol 2007; 6: 725–33.Edgerton VR, de Leon RD, Tillakaratne N, Recktenwald MR, Hodgson JA,Roy RR. Use-dependent plasticity in spinal stepping and standing. AdvNeurol 1997; 72: 233–47.Feron F, Perry C, Cochrane J, Licina P, Nowitzke A, Urquhart S, et al.Autologous olfactory ensheathing cell transplantation in human spinalcord injury. Brain 2005; 128: 2951–60.Fouad K, Schnell L, Bunge MB, Schwab ME, Liebscher T, Pearse DD.Combining Schwann cell bridges and olfactory-ensheathing glia graftswith chondroitinase promotes locomotor recovery after completetransection of the spinal cord. J Neurosci 2005; 25: 1169–78.Gensel JC, Tovar CA, Hamers FP, Deibert RJ, Beattie MS, Bresnahan JC.Behavioral and histological characterization of unilateral cervical spinalcord contusion injury in rats. J Neurotrauma 2006; 23: 36–54.Guest JD, Hiester ED, Bunge RP. Demyelination and Schwann cellresponses adjacent to injury epicenter cavities following chronic humanspinal cord injury. Exp Neurol 2005; 192: 384–93.Huang H, Chen L, Wang H, Xiu B, Li B, Wang R, et al. Influence ofpatients’ age on functional recovery after transplantation of olfactoryensheathing cells into injured spinal cord injury. Chin Med J 2003; 116:1488–91.Klapka N, Hermanns S, Straten G, Masanneck C, Duis S, Hamers FP, et al.Suppression of fibrous scarring in spinal cord injury of rat promoteslong-distance regeneration of corticospinal tract axons, rescue ofprimary motoneurons in somatosensory cortex and significant func-tional recovery. Eur J Neurosci 2005; 22: 3047–58.Li Y, Field PM, Raisman G. Repair of adult rat corticospinal tract bytransplants of olfactory ensheathing cells. Science 1997; 277: 2000–2.Lima C, Pratas-Vital J, Escada P, Hasse-Ferreira A, Capucho C,Peduzzi JD. Olfactory mucosa autografts in human spinal cordinjury: a pilot clinical study. J Spinal Cord Med 2006; 29: 191–203;Discussion, 4–6.Scientific Commentary Brain (2008), 131, 2240^2242 2241Mackay-Sim A, Feron F, Cochrane J, Bassingthwaighte L, Bayliss C,Davies W, et al. Autologous olfactory ensheating cell transplantation inhuman paraplegia: a 3 year clinical trial. Brain 2008; 131: 2376–86.Metz GA, Curt A, van de Meent H, Klusman I, Schwab ME, Dietz V.Validation of the weight-drop contusion model in rats: acomparative study of human spinal cord injury. J Neurotrauma 2000;17: 1–17.Raineteau O, Schwab ME. Plasticity of motor systems after incompletespinal cord injury. Nat Rev Neurosci 2001; 2: 263–73.Ramer LM, Ramer MS, Steeves JD. Setting the stage for functional repair ofspinal cord injuries: a cast of thousands. Spinal Cord 2005; 43: 134–61.Ramon-Cueto A, Cordero MI, Santos-Benito FF, Avila J. Functionalrecovery of paraplegic rats and motor axon regeneration in their spinalcords by olfactory ensheathing glia. Neuron 2000; 25: 425–35.Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH, Ditunno JF,et al. Guidelines for the conduct of clinical trials for spinal cord injury(SCI) as developed by the ICCP panel: clinical trial outcome measures.Spinal Cord 2007; 45: 206–21.2242 Brain (2008), 131, 2240^2242 Scientific Commentary

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