The killer with no name
New Scientist
By Duncan Graham-Rowe
In the organised chaos of Mary Sheppard’s offices she sees a small parcel has arrived on her desk. She doesn’t need to open it to know what’s inside – a human heart soaking in the preserving fluid formalin, and possibly some slides containing tissue samples neatly folded in bubble wrap. A specialist in heart and lung pathology at the Royal Brompton Hospital in London, Sheppard is the person to whom general pathologists round the country turn when they have no answers. This heart has been sent to her because nobody else can work out why it stopped beating.
Its owner, a 22-year-old man, died suddenly while swimming. The local pathologist determined that the man did not drown, yet could find no other cause of death. The man had no history of disease of illness, was fit and a strong swimmer, yet for no apparent reason had just died.
Such deaths are more common than you might think. Sheppard receives on average two hearts, or heart tissue samples, from cases like this each week. In fact, in the UK alone around 3,500 people, aged between 16 and 64, die in this way each year. Many of the deaths are left unexplained. Now, researchers are calling for these unexplained deaths to be recognised and named as Sudden Adult Death Syndrome, or SADS, and officially recorded as such by governments and the World Health Organisation. As well as helping bereaved relatives to grieve properly, such records would help scientists gather the data they need to uncover the causes of these deaths and learn how to prevent them.
But research is hampered by a lack of consistency among pathologists, in the UK and other European countries, in how sudden adult deaths are classified. Inaccurate or inadequate post-mortems often lead to these deaths being wrongly attributed to some other cause. Where there are no obvious physical abnormalities death may be put down as heart failure due to obstructed or reduced blood flow, because the pathologist can find no other reason why the heart could have stopped.
Some coroners may let a death be certified as “cause unascertained” but other prefer to record epilepsy or another plausible cause. “They think that they are doing the family a favour by giving them a cause of death,” says Ann Jolly, founder of the Sudden Adult Death Trust (SADS UK). But this inaccuracy can prove fatal. If the real cause was a genetic disease, other family members could miss out on potentially life-saving screening. “Families will sometimes suffer a second death because they weren’t given accurate information”, says Alison Cox, founder of the patients support charity Cardiac Risk in the Young.
Many experts now believe that like sudden infant death syndrome (SIDS), or cot death, sudden adult deaths should be given a new classification in the WHO’s International Classification of Diseases. The ICD is used by pathologists all over the world and scientists hope it would help them repeat the success they have had in preventing SIDS.
SIDS was first officially recognised in the 1970s. It was defined as the unexplained death of an infant under 12 months of age, and its classification led to better reporting and more consistency among coroners. With more accurate statistics on the number of cases it was possible to epidemiological studies and identify possible causes or factors that would reduce the risk, such as placing babies on their backs to sleep or reducing their exposure to cigarette smoke. According to the Foundation for Sudden Infant Deaths in London, when such advice was publicised in 1991, the number of SDS cases in the UK halved in the first year and since then has dropped to 25 per cent of 1991 levels. Other countries such as the US and Australia have had similarly dramatic reductions (see Graph). The aim is to repeat this success with SADS.
But the key is to identify cases correctly. The misreporting of SADS cases means that there are probably many more than we imagine. “It’s a much bigger problem than SIDS,” says John Camm a leading cardiologist at St George’s Hospital in London. In 2003, Time Bowker and his team at the National Heart and Lung Institute, University of London, published a study where they reviewed the post-mortems of British adults between 16 and 64 who had heart disease on their death certificates or causes unascertained (QMJ, vol 96, P 269.) The team confirmed or discovered a cause of death for most of these cases, leaving 4.1 per cent unexplained. From this figure they estimated that there are about 3,500 SADS cases in the UK per year – almost ten times the SIDS deaths.
Sheppard says that pathologists should not be afraid to admit they can find no cause of death. In about 40 per cent of cases referred to her, she can find the cause of death. Yet I n the remaining 60 per cent she too is stumped. But this is not say that no cause will ever be found. “The negative findings are just as important as the positive findings,” she says. The hallmark of certain diseases is that they leave no mark on the body, so listing a death as “cause unascertained” could actually point doctors and researchers in that direction.
A classic example of this is a sudden fatal “arrhythmia” or disturbance of the normal heart rhythm. Such arrhythmias are a common cause of sudden death and leave no traces in the heart and are indicative of conditions such as Long-QT syndrome or Brugada syndrome. In these diseases, called channelopathies, mutant genes can lead to the flow of ions across cell membranes in the heart being disrupted, producing sporadic arrhythmias. The heart can behave perfectly normally throughout a person’s life. But then without warning, its regular electrical activity can become chaotic, so that it stops pumping properly, resulting in fainting. If the heart does not recover its rhythm, the person will die.
What makes these kinds of disease so difficult to detect is that they are characterised by unusual electrical activity – which obviously ceases once the person is dead. But even when the heart appears completely normal at a post-mortem, there are still ways to find out if a channelopathy was responsible. The best way is to interview immediate relatives and see if there is any history of fainting, palpitations or sudden death in the family.
Last November, William McKenna of the Heart Hospital in London and his colleagues decided to take a closer look at the medical histories of the families of the 4.1 per cent of unexplained deaths highlighted in Bowker’s study. They were able to identify likely causes of death in many of the cases (The Lancet, vol 362, p 1457.) A quarter had an inherited heart disease, mostly Long-QT syndrome.
The majority of deaths in the study, however, remain a mystery. How can we begin to account for these and other unexplained deaths? Some may be down to other known electrical heart conditions that were missed, says Bowker. Still others may be caused by inherited heart conditions that scientists have yet to discover.
Other prime suspects are anaphylactic shock, a potentially fatal allergic reaction, and epilepsy. Both can strike without warning. Again, however, although both of these conditions can be diagnosed after death, they are often confused with other diseases. Epilepsy, for example, can leave damage in the heart that can be mistaken for heart disease, says Marjory Black, a forensic pathologist and expert in sudden epilepsy deaths at the University of Glasgow in Scotland.
The same can be said of anaphylaxis. In extreme cases anaphylaxis can kill in a matter of seconds, says Richard Pumphrey, an immunologist at St Mary’s Hospital in Manchester. Anaphylaxis could be ruled out if the blood test run by pathologist included a test for mast cell tryptase, a protein associated with allergies that remains stable after death. However, UK pathologists do not routinely screen for it.
A key problem in the UK is that once foul play has been ruled out and the coroner is satisfied, there is no legal obligation to conduct the kind of extended investigation that would include tests for things such as mast cell tryptase. “(Pathologist) either don’t have the expertise, or they don’t have the time or inclination,” says Sheppard.
Another reason is cost. A coroner has a budget of only £250 for each case, of which £87 is spent on a single post-mortem. Under such financial constraints even carrying out a second post-mortem can stretch the budget. So pathologists usually only look for common causes of death, which is appropriate in the majority of cases.
One of the reasons British pathologists miss clues that could lead to an accurate diagnosis is that many are now reluctant to do histology. This follows the fallout from the Alder Hey scandal in 2000, in which doctors from the Liverpool hospital had been taking organs from dead children without parental consent. “Suddenly, pathologists were called necrophilic, body-snatching psychopaths,” says Sheppard. As a result they are oversensitive about asking relatives if they can keep organs for research, she says.
James Underwood, president of the Royal College of Pathologists in London, agrees that Alder Hey has left pathologists feeling very nervous. “I know that many pathologists are reluctant to retain such tissue and organs even thought they have a bearing on the death,” he says. Another problem is that coroners can only ask for consent when the person has died under suspicious circumstances, and that means the added cost of holding an inquest.
But even in Europe, beyond the shadow of Alder Hey, professional pride means pathologists are misdiagnosing deaths, says Peter Schwartz, a cardiologist who runs the European register of Long-QT at the University of Pavia in Italy. “Pathologists don’t like to admit that they can’t find a cause,” he says.
In the US, investigators are prepared to go further, says Michael Vincent, a cardiologist and expert in Long-QT at the University of Utah in Salt Lake City. “Here there’s more of an intellectual curiosity and desire to find the cause, and not just rule out foul play,” he says. Pathologists routinely keep tissue samples for genetic examination and are often aware of the risks of inherited diseases and so frequently work with the families to find the cause.
What is needed in many countries is a set of guidelines on what to do with SADS cases. Tissue samples and organs need to be retained where possible and referred to the relevant specialist. At the moment, even if a pathologist wishes to investigate further it is not clear whether they should send the heart to someone like Sheppard or send the brain to a neuropathologist, who may easily be able to rule out epilepsy. The quality of information collected by coroners has been pretty poor in general, says Camm. “There should be major changes to post-mortems; they should involve taking genetic material,” he says.
Fortunately, there has been some progress. After rejecting a private members bill earlier this year which aimed to make it a legal requirement to follow up SADS cases, the UK government has now set up a national standard of care strategy, called a National Service Framework, to work out guidelines for pathologists in such cases. A report is due in the new years.
At the moment, Sheppard says she has to push to get the hearts she need to investigate, push to get family screening and push to get accurate diagnoses. “My hope is that the National Service Framework will revolutionise this,” she says. The aim is to get funding to set up protocols for consulting specialists and procedures for investigating family medical histories, giving families the option of being screened where possible.
But there has been little movement on creating a new ICD classification for SADS. According to the UK office of National Statistics, the best we can hope for is that the word “sudden” will be included on death certificates. But this isn’t good enough, says Camm. At the moment there are three nondescript classifications for unexplained death (see “Defining a death”) making it very confusing for coroners and pathologists.
Still, epidemiological studies based on what data we do have are already under way in the UK. The Drug-induced Arrhythmia Risk Evaluation Study is being carried out at St George’s Hospital in London and the University of Southampton to try and determine the role that commonly prescribed drugs such as antibiotics play in sudden deaths. The belief is that some people with diseases like Long-QT may be genetically predisposed to fatal arrhythmias triggered by some of these drugs.
Back in her lab, Sheppard examines the heart carefully for clues. The overall structure appears to be normal and there is no sign of damage that could hint at any disease. She turns to her microscope to scrutinise the underlying cell structure, looking for abnormalities that could reveal a genetic condition. She also examines the heart valves for signs of infection. All appears normal. In her report to the pathologist she puts it down as suspected Long-QT and recommends a family follow-up. But for now there is no way to ensure this will actually happen.
