The applied neuropathology of human spinal cord injury

Kakulas, Byron

doi:10.1038/sj.sc.3100807

Cited by 109 publications

(72 citation statements)

References 56 publications

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“…2,5 In one 'incomplete' patient with retained motor function of the ankle there was only 1.17 mm 2 of retained white matter at the level of the lesion, whereas in complete SCI patients there may be as much as 3.89 mm 2 spared. Clearly, there is no direct correlation with function, which is not unexpected as the site and quality of preserved white matter would be quite variable.…”

Section: Clinicopathological Correlationmentioning

confidence: 98%

“…Thus by quantifying the number of axons that traversed the lesion, it was possible to estimate the minimum number of axons needed to restore function in regeneration experiments. 2,9 Although approximate due to the limitations of the methodology, these results provide a useful indication of the number of axons required to restore voluntary motor activity and conscious sensation within the framework of planning a curative treatment.…”

Section: Clinicopathological Correlationmentioning

confidence: 99%

“…It was not so long ago that a spinal injury was a virtual death sentence little different to the historical reference that it was 'a condition not to be treated'. 1,2 This terrible prognosis no longer applies as a result of the magnificent work of Sir Ludwig Guttmann in the UK followed by Sir George Bedbrook in Australia, both of whom revolutionized the treatment of SCI. These men are recognized internationally as the pioneers of the new era and we pay special tribute to Sir Ludwig in whose memory this Lecture is named and which I am honored to give.…”

Section: Introductionmentioning

confidence: 99%

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Neuropathology: the foundation for new treatments in spinal cord injury

2004

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The first step essential in the search for a cure of human spinal cord injury (SCI) is to appreciate the complexity of the disorder. In this regard, it is not only the loss of ambulation but the sensory and autonomic changes that are equally important in recovery. In addition, there are the serious social emotional psychological and lifestyle effects of SCI which should also be taken into account. It is also true that no two SCI lesions are alike as each is the result of a SCI unique to that individual. Clinically of utmost importance is the segmental level of injury and whether it is complete, incomplete or discomplete (loss of all neurological functions below the injury but with physiological or anatomical continuity of Central nervous system tracts across the lesion). We are not concerned here with primary and secondary prevention or methods designed to limit the severity of the lesion after the event, important as they are, but with the requirements for a cure. Clearly, the greater the number of nerve fibers that can be preserved in the acute stage, the better will be the end result. Our focus at present is on the end-stage lesion with the aim of showing that a cure for SCI will depend upon establishing functionally useful central axonal regeneration and reestablishing physiological reconnections. Existing experimental methods are based on stimulating axonal regeneration by neutralizing inhibitory factors, adding positive trophisms and creating a permissive environment. Better results are obtained by bridging the gap with grafts of peripheral nerves or transplants of Schwann cells and genetically engineered fibroblasts. Recently, the potential for stem cells to enhance this process has created great interest. This is because of the ability of pluripotential cells to differentiate into neural tissue. A cure based on the physiopathology of SCI requires pyramidal, extrapyramidal, sensory, cerebellar and autonomic pathways to be regenerated with their appropriate neurotransmitters restored and reflexes integrated physiologically and in synchrony. In human SCI, there is a very long distance anatomically for axonal regrowth to occur in order to reach their relevant nuclei. This is because of continuing Wallerian degeneration. It also presumes that the target neurons are intact and that there has been no transneuronal degeneration above or below the lesion. Alternatively, in place of regenerated long axons, a multisynaptic pathway may be constructed from stem cells that have developed into neurons. Whether such a pathway would restore useful neurological functions is unknown. At present, the transplant and grafting research teams are exploring these possibilities in experimental animals. Moderate success in gaining axonal regeneration has been reported; however, it must be appreciated that the human lesion differs considerably from that of the experimental animal. In order to be successful, the neuropathology and neurophysiology of human SCI must be taken into account. The purpose of this review is to place the req...

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Section: Clinicopathological Correlationmentioning

confidence: 98%

Section: Clinicopathological Correlationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neuropathology: the foundation for new treatments in spinal cord injury

2004

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“…This is consistent with previous reports that Wallerian degeneration in human SCI is a prolonged process that may last up to several months. [13][14][15] Focal regions of white matter near the center of the contusion appear to be not only demyelinated but also show an absence of CD68, GFAP, 4-hydroxynonenal or nitrotyrosine labeling in the lateral and anterior columns (Figure 2e-i). These regions may correspond to demyelinated but viable axons as reported in previous SCI studies 16,17 and could be potential therapeutic targets.…”

Section: Autopsy Findingsmentioning

confidence: 99%

Subacute human spinal cord contusion: few lymphocytes and many macrophages

Chang

2006

Spinal Cord

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Study design: Clinicopathological correlation of three cases of subacute cervical spinal cord contusions. Objective: To correlate the pathology of subacute cervical spinal cord injury (SCI) with imaging and clinical-functional studies, and to compare with findings from previous human SCI studies and animal models of SCI. Setting: Department of Pathology, SUNY-Upstate Medical University, Syracuse, NY, USA. Method: Post mortem pathology report. Case report/Results: The clinical, radiological, and pathological findings of three cases of subacute spinal cord contusions are described in detail. The postinjury survival periods were 15, 20, and 60 days, respectively. Extensive microglia/macrophage infiltrations without significant lymphocytes are seen in all cases. Free radical injury as assessed by immunocytochemistry for 4-hydroxynonenal and nitrotyrosine showed a labeling pattern parallel to that of the macrophage distribution at 15 days, but no significant labeling in the injury sites at 20 and 60 days. Conclusion: The present report, though limited in sample size, shows plenty of activated microglia/macrophages in human SCI up to 60 days postinjury. This observation not only confirms similar findings in previous studies, but also raises an intriguing question of potential interactions between these activated microglia/macrophages and the experimental therapy, proposed by some authors, of injecting exogenously activated macrophages to promote SCI repair. The small number of human SCI cases (in this as well as in most other single medical centers) available for detailed study illustrates the need for the establishment of a consortium of human SCI tissue banks.

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“…Closed contusion injuries spare axons in the subpial white matter in the vicinity of the impact site (Bunge et al, 1993;Kakulas, 1999), and some of these spared axons lose their myelin sheaths as a result of the death of oligodendrocytes (Kakulas, 1999). As a result, action potential propagation is disrupted because of the exposure of voltage-gated potassium channels at the internodes (Nashmi and Fehlings, 2001).…”

Section: Introductionmentioning

confidence: 99%

Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Transplants Remyelinate and Restore Locomotion after Spinal Cord Injury

Keirstead

Nistor²,

Bernal³

et al. 2005

J. Neurosci.

1,120

861

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Demyelination contributes to loss of function after spinal cord injury, and thus a potential therapeutic strategy involves replacing myelin-forming cells. Here, we show that transplantation of human embryonic stem cell (hESC)-derived oligodendrocyte progenitor cells (OPCs) into adult rat spinal cord injuries enhances remyelination and promotes improvement of motor function. OPCs were injected 7 d or 10 months after injury. In both cases, transplanted cells survived, redistributed over short distances, and differentiated into oligodendrocytes. Animals that received OPCs 7 d after injury exhibited enhanced remyelination and substantially improved locomotor ability. In contrast, when OPCs were transplanted 10 months after injury, there was no enhanced remyelination or locomotor recovery. These studies document the feasibility of predifferentiating hESCs into functional OPCs and demonstrate their therapeutic potential at early time points after spinal cord injury.

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The applied neuropathology of human spinal cord injury

Cited by 109 publications

References 56 publications

Neuropathology: the foundation for new treatments in spinal cord injury

Neuropathology: the foundation for new treatments in spinal cord injury

Subacute human spinal cord contusion: few lymphocytes and many macrophages

Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitor Cell Transplants Remyelinate and Restore Locomotion after Spinal Cord Injury

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