The pathogenesis of retinal and subdural haemorrhage in non-accidental head injury in infancy: assessment using Bradford Hill criteria.

Fatal non-accidental head injury (NAHI) in infancy is characterised by severe bilateral retinal haemorrhage (sbRH), thin film diffuse bilateral subdural haemorrhage (dbSDH) and severe fatal hypoxic ischaemic encephalopathy (sfHIE). The Geddes hypothesis is that sfHIE is the direct cause of sbRH and dbSDH. The conventional hypothesis (post-Geddes) is that trauma precipitates hypoxia to cause sfHIE and independently tears veins to cause sbRH and dbSDH. These hypotheses are assessed using Bradford Hill criteria of causation. The triad (sbRH, dbSDH and sfHIE) is a strong, specific and consistent association which suggests a causative link. Furthermore sbRH and dbSDH are positively correlated with severity of HIE but negatively correlated with objective evidence of trauma. The conventional hypothesis (post-Geddes) fails the test of biological plausibility because trauma causes asymmetrical and focal bleeding not diffuse bilateral capillary and venular oozing. The conventional hypothesis lacks coherence since it was shown that the encephalopathy of the triad is not traumatic. Arguments by analogy also support the Geddes hypothesis. There is a paucity of experimental evidence for either hypothesis but this is likely to be rectified as molecular methods (genomics and proteomics) are used in the infant autopsy.

Anorexia nervosa, autoimmunity and the hygiene hypothesis.

The hypothesis proposed is that anorexia nervosa (AN) is an autoimmune disease caused by delayed exposure to common micro-organisms in which auto-antibodies to regulatory peptides and hypothalamic neurons, which cross react with microbial antigens, disturb appetite and lead to decreased intake of food. IgG, IgA and IgM auto-antibodies to a range of regulatory peptides concerned with appetite and mood are found in patients with AN. The regulatory peptides show sequence homology with common micro-organisms of the microbial flora. Auto-antibodies to α melanocyte stimulating hormone (αMSH) are positively correlated with AN psychopathology. But patients with bulimia nervosa (BN) and normal healthy controls also have a similar range of auto-antibodies at comparable levels. The incidence of AN is rising in developed countries, the disease is more common in females than in males, the peak incidence is in the teenage years, there is seasonal variation in the month of birth and the disease is more common in higher socio-economic groups. These are all features which are consistent with the hygiene hypothesis. But there is no evidence that the disease is more common in first born than in later born children. There is a paucity of data on early life events such as attendance at nursery and exposure to pets. Genetic factors are important but the data on major histocompatibility complex (MHC) gene polymorphisms are contradictory. The epidemiological and serological data are consistent with the hypothesis under investigation but key questions in relation to the hygiene hypothesis have not been posed. A large case control study of AN epidemiology is indicated. MHC gene polymorphisms should be assessed. There is, however, sufficient evidence to justify a trial of pooled immunoglobulin therapy in patients with life threatening AN.