Severe Axonal Injury Research Articles

Head injury.

Head injury.

Damage to intracranial optic pathways in fatal closed head injury in man

Head injury is a leading cause of visual impairment. This is partly due to direct trauma to the eye and optic nerve but much of the damage involves the intracranial optic pathways. We have studied the frequency, distribution and nature of the intracranial lesions of the optic pathways at autopsy in 45 cases of severe closed head injury, and examined the correlation between these post-mortem lesions and the ante-mortem clinical findings. Twenty-four of the patients had been involved in road traffic accidents. The ages ranged from 9 to 88 years (mean 46.4), the Glasgow Coma Score (GCS) on admission ranged from 3 to 15 (mean 5), and the survival time after injury from 2.5 h to15 days (mean 3.3 days). Skull fractures were present in 75.6% of the cases. Histological assessment included the use of immunohistochemistry for β-amyloid precursor protein (β-APP) and the microglial marker CD68. Axonal injury of varying severity was demonstrable in all cases, and in 39 (87%) the optic chiasm, tracts or radiations were involved, usually in more than one region. The severity of axonal injury was mild in 11 (24%), moderate in 9 (20%) and severe in 19 (42%) cases. The optic radiation at the level of the trigone of the lateral ventricle was particularly frequently and severely affected. The least affected parts of the intracranial optic pathways were the optic chiasm and the posterior segment of the optic nerve. The severity of injury to the optic pathways did not always reflect severity of axonal injury elsewhere in the brain and correlated poorly with the type of trauma (high- or low-velocity), presence of skull fractures or evidence of raised intracranial pressure (ICP). Of the 39 patients who survived more than 6 h, histological evidence of ischaemic injury to the primary optic cortex was present in 26 (67%) and was severe in 12. We conclude that the visual pathways are affected in a high proportion of patients with fatal closed head injury, nerve fibres in the optic radiations being particularly vulnerable. The findings suggest that damage to the posterior parts of the optic pathways may be under-diagnosed among patients with head injury.

Topography and severity of axonal injury in human spinal cord trauma using amyloid precursor protein as a marker of axonal injury.

Axonal injury was examined in 18 human cases of acute spinal cord compression using amyloid precursor protein as a marker of AI. To topographically map and semiquantitate axonal injury in spinal cord compression of sufficient severity to produce para- or quadriplegia. Amyloid precursor protein is carried along the axon by fast axoplasmic transport and has been extensively used as a marker of traumatic axonal injury. The study group comprised 18 cases of spinal cord compression (17 due to fracture dislocation of the vertebral column and 1 iatrogenic compression from Harrington rods) and two normal control. All the cords were examined according to a standard protocol, and at least 10 segmental levels were immunostained using a monoclonal antibody to amyloid precursor protein and immunopositive AI was semiquantitated using a grading system to provide the axonal injury severity score (AISS). The focal injury at the site of cord compression (haemorrhage, haemorrhagic necrosis, ischaemic necrosis) was also semiquantitated to provide the focal injury area score (FIAS). AI occurring around the site of focal compression (focal axonal injury severity score or FAISS) was distinguished from AI distant to the focal injury (nonfocal axonal injury severity score or NFAISS). All 18 cases showed widespread amyloid precursor protein immunoreactive axonal injury and the AISS ranged from 28 to 60%. In all cases, the FAISS was greater than the NFAISS and there was a statistically significant relationship between the AISS and the FIAS. Acute spinal cord compression of sufficient severity to produce permanent paralysis causes widespread axonal damage that is maximal at the site of compression but also present throughout the length of the cord in segments far distant from the site of the focal injury.

Enhanced Axonal Regeneration Following Combined Demyelination plus Schwann Cell Transplantation Therapy in the Injured Adult Spinal Cord

We have treated spinal cord injured rats with demyelination plus Schwann cell transplantation and assessed neurite outgrowth in a quantifiable model of axonal regeneration. Axonal injuries of differing severity were induced in the dorsal funiculus of adult rats using a micromanipulator-controlled Scouten knife. Demyelinated regions were produced so as to overlap with the injury site by the injection of galactocerebroside antibodies plus complement one segment cranial to the axonal injury site. Schwann cells were isolated from the sciatic nerve, expanded in vitro, and transplanted into the injury site 1 day later. Animals were killed after an additional 7 days. Schwann cells were evenly distributed throughout the region of demyelination, which extended 6–7 mm cranial to the axonal injury site. The severity of axonal injury was quantified by counting degenerate axons in transverse resin sections. The degree of axonal regeneration was assessed by an electron microscopic analysis of growth cone frequency and distribution relative to the site of axonal injury. Quantification of growth cones at a distance from the site of axonal injury indicated a strong linear relationship (P < 0.001) between the number of growth cones and the number of severed axons; the ratio of growth cones to severed axons was increased by 26.5% in demyelinated plus transplanted animals compared to demyelinated animals without a transplant. Furthermore, only the demyelinated plus transplanted animals contained growth cones associated with myelin in white matter immediately outside of the region of complete demyelination. Growth cones were absent in transplanted-only animals at a distance from the site of axonal injury. These findings indicate that combined demyelination plus Schwann cell transplantation therapy enhances axonal regeneration following injury and suggests that growth cones are able to overcome myelin-associated inhibitors of neurite outgrowth in the presence of trophic support.

A Quantifiable Model of Axonal Regeneration in the Demyelinated Adult Rat Spinal Cord

Strategies to increase the extent of axonal regeneration in the adult CNS must address an array of intrinsic and environmental factors which influence neuritic outgrowth. In order to develop anin vivomodel of axonal regeneration in which potential therapies may be assessed, we have quantified growth cones within demyelinated regions in the dorsal funiculus of the spinal cord, following a discrete axotomy. Demyelinated lesions were produced by the intraspinal injection of galactocerebroside antibodies plus serum complement proteins. Axonal integrity was not compromised by the demyelination protocol. Axonal injury was induced at the caudal extent of the demyelinated region using a micromanipulator-controlled Scouten knife. The severity of axonal injury was varied in different animals at the time of surgery and was quantified 8 days later by counting degenerate axons in transverse 1-μm resin sections. Evidence of axonal regeneration within these animals was assessed by an electron microscopic analysis of growth cone frequency and position relative to the site of axotomy. Growth cones were identified within the region of demyelination only; no growth cones were identified within the dorsal column white matter adjacent to the demyelinated region, or rostral or caudal to the region of demyelination, or in animals with an injury but no demyelination. Quantification of growth cones within regions of demyelination indicated a strong linear relationship (P< 0.001) between the number of growth cones and the number of axons severed. These findings indicate that demyelination facilitates axonal regeneration in the adult rat CNS and illustrate a quantifiable method of assessing axonal regeneration.

Axonal injury in falls.

Amyloid precursor protein (APP) immunocytochemistry was used as a marker for axonal injury (AI) in a series of 16 cases of head trauma associated with fatal falls. Nine cases were falls from not more than the person's own height (falls from < or = own height) and seven cases were falls from a distance greater than the person's own height (falls from > own height). AI was recorded on a series of line diagrams of standard brain sections divided into 116 sectors. AI around focal lesions (infarcts, hemorrhages, contusions) was distinguished from nonfocal axonal injury that was distant from any focal area of damage. The percentage of sectors showing focal AI provided the Focal Axonal Injury Score (FAIS) and the percentage showing nonfocal AI the Non-Focal Axonal Injury Score (NFAIS). The FAIS is a measure of secondary AI and the NFAIS of diffuse axonal injury (DAI). The percentage of sectors involved with AI (focal and nonfocal) provided the cumulative Axonal Injury Score (AIS). A semiquantitative grading system was also used to assess the severity of axonal injury in each sector and the sum of the grades from all sectors was expressed as a percentage to provide the Axonal Injury Severity Score (AISS). Widespread AI was present in all cases irrespective of the height of the fall. AI was present in the midbrain (94%), pons (94%), corpus callosum (100%), central grey matter (100%), and cerebral hemispheric white matter (94%). AIS ranged from 10 to 94 in falls from < or = own height (mean 73) and from 38 to 92 in falls from > own height (mean 82). AISS ranged from 6 to 95 in falls from < or = own height (mean 65) and 28 to 95 in falls from > own height (mean 72). There was no statistically significant difference in AIS or AISS between the two groups. The extent and severity of AI cannot be predicted from biomechanical data, such as the height of the fall, as the total AI in a given case is a variable mixture of Nonfocal AI (DAI) and Focal AI arising by secondary mechanisms, and APP immunostaining is unable to distinguish primary from secondary AI. However, the combination of the Hypoxic-Ischemic Score (HIS) defined as the percentage of sectors showing any hypoxic-ischemic damage ranging from neuronal "red cell change" to infarction in conjunction with the FAIS and NFAIS provided a measure of the relative contribution of primary and secondary AI in a given brain.