While neuropathological studies have established the pathology of dementia pugilistica to be similar to that of Alzheimer's disease, there is little information about the early histological changes caused by the repetitive trauma that eventually produces dementia pugilistica. We have examined the brains of four young men and a frontal lobectomy specimen from a fifth, age range 23-28 years, all of whom suffered mild chronic head injury. There were two boxers, a footballer, a mentally subnormal man with a long history of head banging, and an epileptic patient who repeatedly hit his head during seizures. The four autopsy cases were widely sampled; the lobectomy specimen was serially sliced after fixation. Routine stains were performed; inmmunostaining included beta-amyloid precursor protein, amyloid beta-protein (Abeta), tau and apolipoprotein E (apoE). Pathological findings in all five cases were of neocortical neurofibrillary tangles (NFTs) and neuropil threads, with groups of tangles consistently situated around blood vessels in the worst affected regions. No Abeta immunoreactivity was detected. The amount of neuronal apoE expression varied widely between the cases with no clear relation to the NFTs. The apoE genotype was determined in only two cases (both epsilon3/epsilon3). It appears that repetitive head injury in young adults is initially associated with neocortical NFT formation in the absence of Abeta deposition. The distribution of the tau pathology suggests that the pathogenesis of cytoskeletal abnormalities may involve damage to blood vessels or perivascular elements.

Fifty-three cases of non-accidental head injury in children were subjected to detailed neuropathological study, which included immunocytochemistry for microscopic damage. Clinical details were available for all the cases. There were 37 infants, age at head injury ranging from 20 days to 9 months, and 16 children (range 13 months to 8 years). The most common injuries were skull fractures (36% of cases), acute subdural bleeding (72%) and retinal haemorrhages (71%); the most usual cause of death was raised intracranial pressure secondary to brain swelling (82%). On microscopy, severe hypoxic brain damage was present in 77% of cases. While vascular axonal damage was found in 21 out of 53 cases, diffuse traumatic axonal injury was present in only three. Eleven additional cases, all of them infants, showed evidence of localized axonal injury to the craniocervical junction or the cervical cord. When the data were analysed by median age at head injury, statistically significant patterns of age-related damage emerged. Our study shows that infants of 2-3 months typically present with a history of apnoea or other breathing abnormalities, show axonal damage at the craniocervical junction, and tend also to have a skull fracture, a thin film of subdural haemorrhage, but lack extracranial injury. Children over 1 year are more likely to suffer severe extracranial, particularly abdominal, injuries. They tend to have larger subdural haemorrhages, and where traumatic axonal injury is present, show patterns of hemispheric white matter damage more akin to those reported in adults. Diffuse axonal injury is an uncommon sequel of inflicted head injury in children.

The diagnosis of diffuse axonal injury (DAI), which may be of considerable importance in forensic medicine, necessitates widespread sampling of the brain for histology. Because a limited sampling method for screening brains for axonal damage would be of value for medico-legal work, the authors have tested the findings of an earlier study which suggested that a standard set of three blocks from above and below the tentorium could reliably be used in routine practice as a basis for the diagnosis of DAI. A series of 22 previously diagnosed cases of DAI, with a range of survival times, was studied using immunohistochemistry with antibodies to beta-amyloid precursor protein (beta APP), the microglial-associated antigen CD68 (PG-M1) and for GFAP. Strict histological criteria were used to assess traumatic damage, and the evolution of the histological changes with increasing survival is described. In four cases, the sampling scheme employed yielded evidence of axonal damage in only one block, and a diagnosis of DAI could have been made in only 13/22 cases. In six of the shortest surviving cases, beta APP positivity in the corpus callosum and brainstem outlined areas of early ischaemia, as well as of traumatic damage, so that interpretation of immunolabelling was not always clearcut The findings suggest that DAI cannot be reliably diagnosed on a restricted number of blocks from vulnerable areas, and that the use of beta APP and PG-M1 immunocytochemistry may bring interpretative problems that can only be resolved by taking a larger series of tissue samples for histology.

The chronic neurological sequelae of boxing are well described, but there have been few neuropathological studies of boxers dying early in their career. We report the case of a 23-year-old boxer, whose brain showed neurofibrillary tangles in all neocortical areas, but remarkable sparing of medial temporal lobe structures. These tangles, assumed to be the result of repetitive head injury, were the only detectable abnormality: none of the other changes previously described in the brains of retired boxers were seen. The distribution and features of the neuropathological findings in this case suggest that the mechanism of tangle formation induced by repetitive head trauma may be different from that in Alzheimer's disease.

SUMMARY Diffuse axonal injury typified by retraction balls and axonal swellings was identified in the brains of a series of infants, 5 months old and younger, who had suffered closed head injuries.These axonal discontinuities were shown by using Nauomenko and Feigin's silver method, which is particularly useful for showing fine axons such as those found in the developing brain.Diffuse axonal injury in early infancy may occur in the same way as that described in adults. The low incidence of intracerebral haematomata suggests that recurrent trauma to the head from a combination of direct contact and shaking results in axonal damage to the poorly myelinated axons and that blood vessels are rarely damaged.Closed head injury in early infancy (5 months of age and younger) produces focal lesions, contusional tears, and diffuse astrocytic reaction.1 2 Contusions, typical of adult closed head injuries, are not seen because of the smooth inner surface of the infant skull. The diffuse degeneration of the white matter first defined by Strich3 is now commonly known as diffuse axonal injury and is a recognised distinct clinicopathological entity in adult closed head injury.4 Diffuse axonal injury has not been described in infants under 5 months of age.We describe diffuse axonal injury in a series of infants 5 months old and younger who had suffered serious closed head injuries. Intracerebral haemorrhages are rarely seen in abused infants, indicating that small blood vessels are not commonly torn at the time of trauma. Material and methodsThe brains of nine infants (cases 1-9 from Calder et al, 1984) and one additional case (10), all of which had been subject to non-accidental injury and had died of head injury, were studied.

SUMMARY The spinal cords of 10 cases of motor neuron disease were compared with those of six age-matched controls using myelin and silver impregnation methods, and the Marchi reaction for myelin degradation products. These studies revealed striking asymmetry in involvement of the lateral and anterior corticospinal tracts, without concordance in the pattern of involvement of these crossed and uncrossed corticospinal pathways. In addition there was prominent involvement of the posterior and anterior spinocerebellar tracts, but less marked abnormality was seen in the reticulospinal pathways. These findings highlight the asymmetrical involvement of the upper and lower motor neuron components of the motor system that is a characteristic feature of the disease, and demonstrate that involvement of the spinocerebellar system is a frequent finding.Motor neuron disease is a progressive and fatal disorder of the motor system, characterised by clinical and pathological features of coexistent upper and lower niotor neuron degeneration.1-4 Involvement of the motor system may be strikingly asymmetrical.5 Sensory involvement is not evident to ordinary clinical examination but, in some cases, paraesthesiae have been noted,6 ' and subclinical abnormalities have been found in teased fibre preparations of sensory peripheral nerves.8 In the spinal cord the major abnormalities comprise loss of anterior horn cells and degeneration of the crossed and uncrossed corticospinal tracts.9'-1 Degeneration of the spinocerebellar tracts has been described in familial cases'2 but is thought to be infrequent in the more common sporadic form of the disease.2 3 13 However, no systematic pathological study has been made of noncorticospinal pathways in the spinal cord in sporadic motor neuron disease.In a previous study we showed that

Ubiquinated cytoplasmic inclusions are a characteristic feature of the anterior horn cell pathology of amyotrophic lateral sclerosis. The underlying abnormality leading to the production of these inclusions in this neurodegenerative motor system disease is unknown. Despite the application of a wide range of histochemical and immunocytochemical techniques we have been unable to identify a core constituent protein in these intraneuronal inclusions. A novel approach to this problem is required.

The development of the glial reaction in human closed head injury has been investigated using morphometry and statistical analysis. The brains of eight individuals that survived less than 48 h following closed head injury were analysed using immunoperoxidase for glial fibrillary acidic protein (GFAP). Controls were eight patients without neurological disease. The density of reactive astrocytes was estimated in 25 fields in each of 10 different areas sampled bilaterally avoiding the subpial and subependymal zones, and the perivascular white matter. There was great variation between the zones within and between groups, and considerable variation between individuals. The raw data were expressed as logarithms averaged and analysed using the median and non-parametric statistics. The corpus callosum in the head injury group showed the highest densities of reactive astrocytes, particularly in the splenium which achieved statistical significance using the non-parametric tests. This pattern was not reproduced in the control group. Although there was overlap between the head injured and control individuals, the head injury group had relatively higher densities in all zones, and showed an overall increase in the density of reactive astrocytes. This achieved statistical significance in the corpus callosum, the occipital subcortical white matter, and the cerebellum. This study has shown that the glial reaction is often prominent in the corpus callosum irrespective of the presence of a primary lesion although the pattern varies from case to case.