A dreadful challenge

these young cases. Despite the many uncertainties, prion diseases are among the best understood of the neurodegenerative disorders, and rapid advances in the fundamental biology open realistic therapeutic strategies.

transmissible cannot

Collinge, Martin Rossor

Prion Disease

Group, Department of Biochemistry and

Molecular

Genetics, Imperial College School of Medicine at St Mary’s; Department of Neurology, St Mary’s Hospital Trust; and Dementia Research National Hospital for Neurology and Neurosurgery, London, UK

Group,

1 Smith PEM, Zeidler M, Ironside JW, Estibeiro P, Moss TH. Creutzfeldt-Jakob disease in a dairy farmer. Lancet 1995; 346: 898. 2 Britton TC,

Al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK. Lancet 1995;

346: 1155. 3 Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet 1995; 346: 1155-56. 4 Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991; 352: 340-42. 5 Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet 1991; 337: 1441-42. 6 Zeidler M, Will RG, and Ironside JW. Magnetic resonance imaging is not a sensitive test for Creutzfeldt-Jakob disease. BMJ 1996; 312: 844. 7 Bruce M, Chree A, McConnell I, Foster JP, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice—strain variation and the species barrier. Philos Trans R Soc Lond B Biol Sci 1994; 343: 405-11.

A dreadful challenge See pages 921, 945 In this week’s issue, Will and colleagues report the clinical and neuropathological features of a new human spongiform encephalopathy similar to Creutzfeldt-Jakob disease (CJD) with a possible link to bovine spongiform encephalopathy (BSE). The challenge now is to develop a theory to account for the possible infectivity of the BSE agent for man. First, we know that prompt action was taken to ensure the safety of implanted materials of bovine origin (eg, non-synthetic surgical sutures) or injected preparations associated at some time during synthesis with calf serum or bovine serum albumin (eg, viral vaccines). Let us concentrate, therefore, on the possibility of infection by the oral route. Several key questions follow from this (panel). An oral dose of about a teaspoonful of highly infective cattle feed concentrate (meat and bone meal prepared from unusually high-titre raw material) is thought to be enough to cause BSE in a cow. Prions are sticky and tend to aggregate. For cattle, the risk of a significant challenge of this sort might be likened to encountering a small Panel: Key

questions

Was the disease in the ten route?

.

cases

What host cell-type is initially involved in prion uptake? Might factors influencing gut permeability be important? Could coinfections

w

acquired by the oral

compromise early defences? Might local mucosal immunity merit more study? What are the respective roles of the lymphoreticular system and the nervous system in prion transport and replication? Is spinal cord function spared? What triggers disease onset? Will the human-adapted prion have its own strain-typing

profile, or will

it conform to BSE?

a

to

can be considered.’ At some time in the midthe early 1990s, before successive control measures in the UK became effective, many foods contained bovine brain and other offal. The ingestion of infected bovine brain or a product containing this as a major constituent could have delivered BSE prions into the human alimentary tract. The pronounced heatresistance of prions would protect against cooking temperatures and even normal domestic pressurecooking;2,3 the chemical resistance of the prions and the accompanying protein in the meal would protect against the defence mechanisms of the stomach; and the relative proteinase resistance of the prions4 would allow substantial amounts to be available for uptake by the lymphoreticular system in Peyer’s patches throughout the intestine. We do not know whether factors influencing the permeability of the gut epithelium (alcohol, non-steroidal anti-inflammatory drugs, local inflammation) might influence uptake at this stage. Nor do we know the cell types that might be initially involved in the pathogenesis. Host clearance mechanisms in the gut might be compromised, on occasion, by another infecting agent such as that of infectious mononucleosis, measles, or influenza, thereby temporarily upsetting effective macrophage function. The infecting prions do not seem to generate a host-antibody response. In these circumstances, and as happens at some stage in AIDS, the prions might even find a macrophage response advantageous, offering a protected niche and perhaps allowing transport to other organs such as the spleen. It seems that prions reproduce by inducing abnormal structural changes in host prion protein (PrP), which is present in many cells and is particularly associated with neurons. The invaders might begin to transform PrP in the local cells and boost their numbers within the local lymphatic system. With protected transport in macrophages, the ultimate delivery of the challenge could not be assured since the prions would be largely trapped in the immune system and would not have free access to the brain. The model of poliomyelitis allows us then to envisage neurotropic tracking of the invading prions via the local nerve supply into the spinal cord and upwards to the brain. The general lack of early localising signs in the new disease suggests that lesions are not produced in the peripheral nervous system or in the spinal cord but that abnormal PrP is generated in excessive amounts in essentially silent areas of the brain and in the cerebellum (if kuru is a valid parallel). As in kuru, with an incubation period that ranges from 4 years to more than 30 years,5 the extended time-course is presumably necessary for the slow penetration of prions into the brain and their replication there until frank cerebral signs develop. In scrapie, the dynamics of agent replication within the nervous system and lymphoreticular system have been comparedand discussed.’ The new spongiform encephalopathy presents with a

BSE agent 1980s

John

in

haystack of mixed meal. If BSE is man, the possibly infective oral dose really be estimated, but human exposure to the

packet of needles

or

moderately rapid and inexorable progression to death. The reason is, presumably, because the production of abnormal PrP is increased, because a threshold amount of 917

abnormal PrP is reached, system that has held for threshold notion does not

host control long gradually fails. The seem to fit, because the new spongiform encephalopathy shows so much more abnormal PrP and yet progresses more slowly than CJD after clinical onset. However, the variant has struck a much younger age group. How might one of the other mechanisms be triggered? We are driven by this logic again into the realm of coinfection, cofactors, or antiprion mechanisms that influence our normal defences or clearance systems. An essential step is to check whether the causal prion of this spongiform encephalopathy has (or lacks) the BSE profile that can be determined by strain-typing studies in mice.8 Would a human-adapted strain now have its own or

because

some

so

profile? J Gerald Collee c/o Department of Medical Microbiology, University

of

Edinburgh,

UK

Dealler SF, Lacey RW. Transmissible spongiform encephalopathies: the threat of BSE to man. Food Microbiol 1990; 7: 253-79. 2 Taylor DM. Inactivation of SE agents. Br Med Bull 1993; 49: 810-21. 3 Taylor DM. Deactivation of BSE and scrapie agents: rendering and other UK studies. In: Bradley R, Marchant B, eds. Transmissible spongiform encephalopathies. Brussels: C.E.C., 1995. 4 Prusiner SB. Prion diseases of humans and animals. J R Coll Physicians Lond 1994; 28 (suppl): 1-30. 5 Gajdusek DC, Zigas V. Degenerative disease of the central nervous system in New Guinea: the endemic occurrence of "kuru" in the native population. N Engl J Med 1957; 257: 974-78. 6 Kimberlin RH, Walker CA. Incubation periods in six models of intraperitoneally injected scrapie depend mainly on the dynamics of agent replication within the nervous system and not the lymphoreticular system. J Gen Virol 1988; 69: 2953-60. 7 Kimberlin RH. Unconventional "slow" viruses. In: Collier LH, Timbury MC, eds. Topley and Wilson’s principles of bacteriology, virology and immunity. Vol 4. 8th ed. London: Edward Arnold, 1990: 671-93. 8 Bruce M, Chree A, McConnell I, Foster JP, Pearson G, Fraser H. Transmission of bovine spongiform encephalopathy and scrapie to mice—strain variation and the species barrier. Philos Trans R Soc Lond B Biol Sci 1994; 343: 405-11. 1

Oestrogen

and

postnatal depression

See page 930 Like most psychiatric conditions in ICD-10,’ postnatal affective disorders are classified syndromally rather than to be clinically identical aetiologically. They are to affective disorders in general, and are coded as such. A second code can be added to indicate a complication of childbearing but does not distinguish between pregnancy, childbirth, and the puerperium. Clinicians and researchers divide postnatal psychological disturbances into the blues, puerperal psychosis, and postnatal depression.2 The blues, which are common (50-80%), mild, and transient, are judged to be a normal experience and require no intervention apart from explanation and reassurance. Puerperal psychoses are rare (0-2%), severe, and mostly manic depressive in nature. They usually begin within 30 days of childbirth, a period during which the relative risk for psychiatric admission is as high as 22.3 Postnatal depression is the subject of the oestrogen treatment trial of Gregoire and colleagues in this issue. Despite its aetiological overtones, the diagnostic term postnatal depression is still a syndromal one. It refers to nonpsychotic (neurotic) depression occurring in 10% of women in the first 6-12 weeks after delivery. This

thought

918

condition is not as florid as puerperal psychosis and usually does not require psychiatric admission. Postnatal depression often goes untreated,’ even though it can be severe, persistent, and disabling, with adverse consequences for the mother, infant, and family as a whale.2,5 These are compelling reasons for clinical and research activity in this area. The oestrogen trial of Gregoire et al reported in this issue is especially interesting because it tests a treatment that may have specific aetiological relevance to postnatal depression. Patients were selected as having severe postnatal depression with an onset in the first 12 weeks after delivery, since depression during that period is most likely to be hormonally influenced. The active treatment and placebo groups were well matched. Several outcome measures were used to ensure validity, and the results on clinical interview and self-report scales were consistent. However, the dropout rate in the placebo group after the third month of treatment was ten of 27 compared with only six of 34 in the active treatment group. For the nonattenders, only self-report scale measures were available as a measure of depression, and these may give spuriously high readings in premenstrual syndrome.6 Nonetheless, the result that oestrogen is effective in treating depression is convincing, and certainly impressive enough to warrant replication. Further research should address the questions raised by Gregoire et al: (a) are patients’ anecdotal accounts of a quick response to oestrogen true? (b) what the minimum effective dose and duration of are treatment? (c) is oestrogen effective in those who do not respond to conventional antidepressants? and (d) does oestrogen have more general antidepressant properties? The last question raises a broader issue-depression is twice as common in women as in men, most noticeably in the 20-40-year age group, the childbearing era. This observation is not fully explained but multiple factors are probably at work in the same direction.’ From a biological perspective, oestrogen has been suggested as having a role, a possibility that is now certainly worth further study. There will be many other research ideas generated by this report, but from a clinical perspective what is the role of oestrogen? Currently, prevention and treatment require a broad range of measures, including psychiatric, psychological, and social interventions. For now, use of conventional antidepressants will continue. In patients who do not respond, lithium augmentation or possibly electroconvulsive therapy will be used as appropriate. In severe cases resistant to such measures, the results of the oestrogen trial add a treatment possibility. No more substantial change in clinical practice is warranted from a single controlled trial. However, since half the active treatment group had had no apparent benefit from 6 weeks’ antidepressant treatment, the portents for a useful role for oestrogen in resistant cases are hopeful. It will be important to evaluate very carefully the research on oestrogen and depression as it emerges, and to base changes in practice on evidence. Other hormonal treatments for postnatal depression-eg, progesteronehave been used widely without controlled trials. The positive results of Gregoire et al may create a perception that we can now treat the "cause" of postnatal depression. Doctors may be asked by patients to prescribe oestrogen as a first-line treatment. It is much too early for