Active Rehabilitation-a community peer-based approach for persons with spinal cord injury: international utilisation of key elements.

INTRODUCTION: Active Rehabilitation (AR) is a community peer-based approach that started in Sweden in 1976. As a key component of the approach, AR training camps provide intensive, goal-oriented, intentional, group-based, customised training and peer-support opportunities in a community environment for individuals with spinal cord injury. STUDY DESIGN: Prospective cross-sectional study. OBJECTIVES: To describe the profile of the organisations that use components of the AR approach, and to explore the characteristics and the international variations of the approach. SETTING: Twenty-two organisations from 21 countries from Europe, Asia and Africa reported using components of the AR approach during the past 10 years. METHODS: An electronic survey was developed and distributed through a personalised email. Sampling involved a prospective identification of organisations that met the inclusion criteria and snowball strategies. RESULTS: While there were many collaborating links between the organisations, RG Active Rehabilitation from Sweden and Motivation Charitable Trust from the United Kingdom were identified as key supporting organisations. The 10 key elements of the AR approach were found to be used uniformly across the participating organisations. Small variations were associated with variations in country income and key supporting organisation. CONCLUSIONS: This is the first study to describe the key elements and international variations of the AR approach. This will provide the basis for further studies exploring the effectiveness of the approach, it will likely facilitate international collaboration on research and operational aspects and it could potentially support higher integration in the health-care system and long-term funding of these programmes.

A prospective study of pain and psychological functioning following traumatic spinal cord injury.

STUDY DESIGN: Longitudinal study. OBJECTIVES: To study prospectively pain characteristics, change in pain over time and the associations between pain and psychological functioning in adults with traumatic spinal cord injury (SCI). SETTING: Neurosurgical departments, SCI rehabilitation centres and the community. METHODS: Adults with traumatic SCI admitted over a 3-year period to two neurosurgical departments underwent clinical examination and questionnaires within 3 months after injury (baseline) and at 6, 12 and 42 months following SCI. Pain intensity and interference within the last 7 days, a global quality of life (QoL) item, the 5-item Mental Health Index and the 6-item Catastrophizing scale were used. RESULTS: Ninety individuals were recruited, of which 81 completed a telephone interview on average 3.5 (s.d., 0.6) years after the SCI. Pain was present in 75% at 3.5 years. Baseline pain catastrophizing scores did not predict pain intensity at 3.5 years. Both psychological functioning and QoL increased over time. QoL scores increased less in participants who reported an increase in pain intensity from baseline to the 3.5-year follow-up, and the change in QoL score correlated with the change in pain interference. Neuropathic pain had an onset within the first 12 months and tended to become persistent, whereas musculoskeletal pain more often had a late onset or resolved in cases of early onset. CONCLUSIONS: A large proportion of SCI participants continue to experience pain many years after SCI. Teaching individuals with SCI skills to minimise pain's impact on function as soon as possible following injury may prove beneficial.

Neurophysiological evaluation of segmental motor neuron function of the thoracic cord in chronic SCI.

STUDY DESIGN: Pilot study. OBJECTIVES: The aim of the study was to develop a neurophysiological method to diagnose the cranial as well as the caudal level of a complete thoracic spinal cord injury (SCI) with higher precision than today's protocols. SETTING: SCI unit Karolinska University Hospital, Stockholm, Sweden. METHODS: Bipolar needle electromyography was recorded in intercostal spaces of five patients with chronic, complete thoracic SCI. Tests were performed during rest, during voluntary activation and during activation of lower body spasticity. Magnetic resonance imaging (MRI) was performed in each patient according to a protocol optimized for imaging near metal implants. RESULTS: Three distinct patterns were found in each patient. Above the lesion we found voluntary activated, normal motor unit potentials (MUPs). At the neurological level and a varying number of segments below, denervated intercostal segments with fibrillation potentials and positive sharp waves appeared. Below the neurological level, normal MUP activated in concert with lower body spasticity was found. The number of denervated segments showed a significant correlation to the length of spinal cord discontinuity on MRI (r=0.97, P<0.05). CONCLUSION: Intercostal neurophysiology in combination with MRI optimized for imaging near metal implants can be used to determine the extent of a chronic complete thoracic SCI, both anatomically and functionally. The described method increases the sensitivity to detect delicate neurological changes related to the dynamic of the pathology that follows SCI and may be useful in analyzing outcome in clinical trials.

Functional interactions between spinal cord grafts suggest asymmetries dictated by graft maturity.

Fetal spinal cord tissue grafts have been advocated as a possible repair strategy for spinal cord injury. In the present study, we used intraocular spinal cord grafts to model the interactions which may occur between fetal and adult spinal cord after making such a graft and to study to which extent functional connections can be expected to occur between the host and graft tissue. We first grafted fetal spinal cord to the anterior chamber of the eye where it was allowed to mature. A second piece of fetal spinal cord was then sequentially grafted in contact with the first graft. Electrophysiological recordings made from the older graft while electrically stimulating the younger graft provided evidence for an excitatory innervation from the younger spinal cord graft to the mature spinal cord which appeared to be glutamatergic. However, we only rarely found excitatory inputs from the first, mature spinal cord graft to the younger graft. Fiber connections between the two spinal cord grafts were verified by retrograde tracing and neurofilament immunohistochemistry. In no case was a trophic influence on graft volume observed between spinal cord grafts regardless of whether the transplantations were performed sequentially or at the same time. Even the introduction of a second graft to immature spinal cord tissue was ineffective. In contrast, we found a marked trophic, neuron-rescuing effect of spinal cord grafts upon cografts of fetal dorsal root ganglia. This latter observation is consistent with the hypothesis that spinal cord tissue can exert a trophic effect on developing sensory ganglia and demonstrates that many sensory neurons can survive in the presence of a central target and in the absence of the appropriate peripheral target. These intraocular experiments predict that fetal spinal cord grafted to the injured adult spinal cord may develop effective excitatory inputs with the host, while host-to-graft inputs may develop to a considerably smaller extent. Our results also suggest that the adult spinal cord does not exert marked trophic effects on growth of fetal spinal cord, while it does exert a trophic influence on central projections of dorsal root ganglia.

A comparison of the effects of glial cell line-derived neurotrophic factor on spinal cord and cortex cerebri grafts.

Glial cell line-derived neurotrophic factor (GDNF) has trophic effects on developing dopamine neurons, enhances survival of embryonic motoneurons in vitro and prevents axotomy-induced motoneuron atrophy in vivo. Here we investigate effects of GDNF on grafts of cortex cerebri tissue from E18, P1 and P8 donors and on spinal cord tissue for P8 and adult animals transplanted to the anterior chamber of the eye of host rats. Grafts were treated with GDNF or cytochrome C on days 0, 5, 10, 15, 20 and 25 (total amounts 0.5 microgram GDNF/eye/injection). Spinal cord grafts from P8 donors treated with GDNF grew to sizes larger than controls, had higher numbers of neuron-like cells and showed increased areas of neurofilament immunoreactivity and decreased glial fibrillary acidic protein immunoreactivity. In contrast to the P8 spinal cord grafts, there were no such effects observed in adult spinal cord grafts or in E18, P1 or P8 cerebral cortex grafts. To determine if an endogenous source of GDNF might exert similar effects on spinal cord grafts, we transplanted spinal cord tissue from P1 together with pieces of developing kidney, known to express high levels of GDNF mRNA. Spinal cord cografted with kidney tissue grew to a slightly larger extent then controls. We conclude that GDNF exerts a powerful trophic effect on P8 spinal cord grafts, although GDNF appears unable to support survival of grafted adult spinal cord tissue. Grafts of cortex cerebri from several different stages of development were not affected.

Differential immune responses to fetal intracameral spinal cord and cortex cerebri grafts.

While the central nervous system (CNS) has been characterized as an immunologically privileged site, there are also several reports describing immunological reactions within the CNS. A certain degree of immunological privilege has also been ascribed to the anterior chamber of the eye. We have used the intraocular transplantation model to study immunological reactions in transplants of embryonic neural tissue. Outbred Sprague-Dawley rats and inbred Fisher rats were used. Pieces of rat parietal cortex or the cervical spinal cord were prepared from embryonic day 14 and implanted into the eye chambers of adult rats of the same strain. Following intraocular maturation, grafts were analysed using antibodies against: major histocompatibility complex (MHC) class I, MHC class II; rat antigens CD4, CD8, CD11b; T-cell receptor; rat antigen ED1; and glial fibrillary acidic protein. Using this set of markers for immunological reactions, transplants were scored on a blind basis. We found no significant differences in immunological scores between transplants obtained from different litters of fetuses of the outbred animals. Grafting in the outbred strain led to increased numbers of immunologically reactive cells in the grafts. This was not seen in grafts in the inbred strain. Spinal cord transplants led to a significantly higher degree of cytotoxic immunity-related cells expressing MHC class II as well as CD4-positive cells. There was a positive correlation between ED1 negativity and well-developed ramified microglia. From these results we conclude also that well-developed intraocular CNS tissue grafts do contain cellular evidence of immunological events and that different areas of the CNS may provoke different degrees of response. Reactive microglial proliferation appears to be one of the most sensitive ways to monitor the immunological condition of grafted CNS tissue.

Glial cell line-derived neurotrophic factor enhances survival and growth of prenatal and postnatal spinal cord transplants.

Glial cell line-derived neurotrophic factor was first described as a trophic factor for developing dopamine neurons. However, it has been shown that glial cell line-derived neurotrophic factor messenger RNA is also expressed in several areas of the developing brain and spinal cord, suggesting that it may have additional roles in the nervous system. Intraocular transplantation of neural tissue provides a unique method to examine in vivo effects of trophic factors. We have therefore studied the effects of glial cell line-derived neurotrophic factor on spinal cord survival and development following grafting to the anterior chamber of the eye of adult rats. We used spinal cord tissue from fetal stages (embryonic days 14 and 18) and postnatal days 1 and 14 as donors. The spinal cord tissue was allotransplanted to the anterior eye chamber of Sprague-Dawley host rats after incubation in buffered saline containing 100 micrograms glial cell line-derived neurotrophic factor/ml or 100 micrograms cytochrome C/ml. One group of postnatal day 1 spinal cord grafts was also treated with concentrations of 20 and 10 micrograms glial cell line-derived neurotrophic factor/ml. In all cases, 5 microliters of the same solution was injected into the anterior eye chamber on postgrafting days 5, 10, 15 and 20 (total amounts 0.5, 0.1 and 0.05 microgram/eye/injection, respectively). We found that all glial cell line-derived neurotrophic factor-treated spinal cord grafts grew more than controls. The effect of glial cell line-derived neurotrophic factor was most prominent in grafts from newborn rats. In these grafts we found a dose-dependent effect of glial cell line-derived neurotrophic factor on growth. Moreover, grafts treated with the highest dose (0.5 microgram) grew to sizes exceeding the initial size at transplantation. In these transplants we also found greater numbers of large neurons compared to controls. Glial fibrillary acidic protein immunoreactivity, in contrast, showed increased gliosis in controls. Similar results were found with syngeneic spinal cord postnatal day 1 grafts in Fisher hosts. Spinal cord tissue grafts from two-week-old rats treated with the highest glial cell line-derived neurotrophic factor dose every fifth day, through day 35 postgrafting, responded with increased growth and less necrotic tissue compared with controls; however, we could not detect neurofilament immunoreactivity in these transplants. Taken together, these results suggest that glial cell line-derived neurotrophic factor may be a potent trophic factor for neurons in the spinal cord and in spinal cord transplants. Of particular importance is that glial cell line-derived neurotrophic factor treatment can be used to obtain survival of postnatal spinal cord tissue, that would otherwise show minimal or no survival. Thus, glial cell line-derived neurotrophic factor allows successful transplantation of more mature spinal cord tissue, which may have important implications for both basic and clinical neuroscience.

Spinal cord-skeletal muscle cografts: trophic and functional interactions.

Skeletal muscle from embryonic day 20 (E20) was combined with E15 rat spinal cord in the anterior chamber of the eye of adult albino rats. The two grafts were either transplanted concomitantly or sequentially, in which case muscle tissue was added 4 months after the spinal cord. Control groups received a single graft of either spinal cord or skeletal muscle. Survival and intraocular growth were observed through the cornea. After maturation in oculo, the double grafts were examined immunohistologically utilizing antisera to neurofilament (NF) and acetylcholinesterase (AChE). The grafts were also evaluated using electrical stimulation to determine functional connectivity. The spinal cord and skeletal muscle grafts were found to exert reciprocal trophic effects on each other, evidenced as a larger muscle mass in skeletal muscle grafts allowed to develop in the presence of spinal cord tissue, and a larger volume of spinal cord grafts allowed to develop together with a skeletal muscle graft, respectively. Immunohistochemistry revealed NF-positive nerve fibers leaving the spinal cord graft and entering the muscle tissue. AChE-positive endplates developed in the muscle grafts. Electrical stimulation of the spinal cord part of double-graft combinations generally elicited contractile responses in specific areas of the muscle cograft. These results demonstrate both structural and functional connections between grafts of spinal cord and skeletal muscle tissue in vivo. The fact that such connections were also established between a mature (adult) spinal cord graft and fetal skeletal muscle tissue suggests that some alpha-motoneurons are able to survive for many months in the intraocular grafts without an appropriate target, and that they are able to subsequently innervate skeletal muscle targets.

Functional innervation of spinal cord tissue by fetal neocortical grafts in oculo: an electrophysiological study.

The ability of fetal neocortex transplants, to functionally innervate maturated cervical spinal cord grafts in oculo, was investigated in rats. We found that a neocortex co-graft will grow and develop in contact with a spinal cord graft, and will generate a functional input to maturated spinal cord tissue which can be activated by electrical stimulation of the neocortex graft. Our data suggest that orthodromic stimulation of this pathway causes short latency, transient excitations of spinal graft neurons. These appear to be mediated by an excitatory amino acid receptor since the response was noncompetitively antagonized by kynurenic acid. Kynurenic acid also noncompetitively antagonized the excitatory effects of glutamate superfused over single spinal cord grafts. The mechanism of the excitation probably does not involve an NMDA (N-methyl-D-aspartate) receptor since APV (2-amino-5-phosphonovalerate) did not alter the spinal graft neuronal responses to neocortical co-graft stimulation. These data suggest that fetal neocortex can functionally innervate maturated cervical spinal cord in the in oculo graft preparation. The in oculo spinal cord graft model may thus provide a unique test system for studies of the influence of drugs and other manipulations that might alter cortico-spinal pathway development as well as influence reestablishment of neuronal pathways after spinal cord injury.