Solving a medical mystery | Action Medical Research

Touching Lives - December 2004

Solving a medical mystery

Paediatric neurologist Dr Russell Dale was working at Great Ormond Street Hospital when he was struck by the terrifying and dramatic nature of the symptoms he was seeing in some of his patients. Previously healthy children would suddenly develop movement and psychiatric disorders, to the extent that their parents described them as having ‘changed personality overnight’.

Often these children required hospitalisation. Dr Dale started to research the area in his spare time, but what began almost as a hobby became more and more important to him, eventually leading to an application for an Action Medical Research grant. “Having seen the terrible effects on children, and their parents, I wanted to understand what causes these brain disorders and do my best to help,” says Dr Dale.

Three years on, Dr Dale’s research at the Neuroimmunology Unit in London’s Institute of Neurology has formed part of a great leap forward in the medical world’s understanding of this phenomenon. His work may lead to treatments for a wide range of physical and psychiatric disorders, from tics and obsessive behaviour to Tourette’s syndrome, Parkinson’s disease and encephalitis lethargica or ‘sleepy sickness’. And it is all due to a grant of £141,000 from Action Medical Research.

What’s the connection?

It seems incredible that something as banal as a sore throat might cause brain damage. Dr Dale explained to Touching Lives how this can happen: “When you get an infection of any sort, the body produces antibodies to try to fight it off. The antibody usually recognises which cell to attack by the kind of protein found on the cell’s surface.

“What we found in the laboratory stage of our research is that the proteins on the surface of streptococcus bacteria are very similar to those on the surface of brain cells. This means that antibodies produced when you get a streptococcal throat infection can ‘cross-react’ — the antibodies produced to fight the sore throat attack the brain as well. It’s basically the body making a mistake and overreacting. ^It thinks the brain cells are foreign, whereas in fact they’re not^.”

A wide range of symptoms

The particular range of symptoms is the result of damage to a part of the mid brain called the basal ganglia, which seems particularly vulnerable to the antibodies produced. “This part of the brain co-ordinates and sends out information,” says Dr Dale. “It acts as a modulator, regulating the quality of movements and emotions.”

So when this balancing system is damaged, both movements and emotions are unregulated and can become extreme or unpredictable. That’s why the physical symptoms of the disease include the body either making extra movements or moving too quickly, resulting in tics or similar repeated movements, or moving too slowly, resulting in the stiffness associated with, for example, Parkinson’s disease.

Alongside these physical changes are arguably more important psychiatric symptoms. Sufferers experience emotional changes, including extreme anxiety, obsessive behaviour and depression. And what makes these changes even more traumatic is the speed with which they come on. “There’s usually a lag of about two weeks between the infection and the onset of the symptoms. But when they arise, the onset is explosive — previously healthy children can suddenly become very ill. Some even have to be hospitalised. ^It’s extremely distressing both for children and parents. And that’s in part what motivated me to do this research^.”

Developing a test, minimising suffering

What’s so important about this new discovery is that bacterial infections, and the antibodies they produce, are relatively easy to treat. “The general aim of treatment is to remove the antibodies, which can be done in two ways,” says Dr Dale. “Steroids can be used to suppress the immune system generally, so that fewer antibodies are produced. But these are quite toxic drugs, with unpleasant side-effects.

“Alternatively, more specific treatments can be used to remove just the antibodies — that’s a ‘cleaner’ treatment with fewer side-effects. There is now a test which looks for these antibodies so that we can treat them directly, but it’s very complicated and expensive to administer, so we’re looking for one we could use on lots of patients. Ultimately an antibiotic could be developed to reduce the brain damage and improve the patients’ condition.”

Not everyone who suffers from these disorders will end up with permanent damage. The earlier they are treated, the less likely it is that permanent damage will occur — which is why a test of the kind Dr Dale is looking for is so important. And children are in fact more receptive to treatment than adults. This is because, up to the age of about 11, children’s brains are more ‘plastic’ than adults’ brains, which means that the brain is more able to take on different roles and so respond quickly to treatment.

An historic discovery

Dr Dale’s work forms part of a distinguished strand in the history of medical research. “The idea of infection leading to a brain disorder is very old,” explains Dr Dale. “It’s been known for over a hundred years that one particular brain disorder, called Sydenham’s Chorea, is linked to streptococcus. What wasn’t known before was how many other types of brain disorder might be triggered by this sort of infection.”

After clinical work with 60 children with a variety of brain disorders, together with his laboratory-based research, Dr Dale has established a connection between the antibodies produced after streptococcal infection and brain cell death in a much wider range of conditions than was previously recognised. “This wider recognition is very important for accurate diagnosis,” says Dr Dale. “Now, a child with any type of movement or psychiatric disorder after a streptococcal throat infection will be examined for these antibodies. And ^given how widespread some of these disorders are, this could be relevant for up to one per cent of the population^.”

What next?

This is only the beginning of the story for Dr Dale. There are still a number of questions to be asked — why, for example, is it only the streptococcal infection which causes sore throats that trigger this brain damage, and not the other common streptococcal infections? “We still don’t understand the brain very well,” says Dr Dale, “which is one of the reasons I chose to specialise in neurology — it’s a fascinating area, with lots of scope for work in the future. And I wanted to work in paediatrics in particular because working with children and their parents is so much fun! I’ve had very positive experiences as a paediatrician, and you feel you’re doing good.”

The importance of the Action Medical Research grant to Dr Dale’s work can’t be overestimated. “I’m overwhelmingly grateful to the Charity for supporting this project. Having seen the effects of this disorder on sufferers, I know how important it is to try to find a treatment. ^We simply wouldn’t have been able to do this without Action Medical Research^.”

Medical Mysteries

Dr Dale’s work was featured on the BBC documentary ‘Medical Mysteries’ earlier this year. The documentary explored a particular condition called encephalitis lethargica, or ‘sleepy sickness’, which causes a range of extreme symptoms, including paralysis, uncontrollable movements, and speech disorders.

Sleepy sickness was brought to popular attention by the Hollywood film ‘Awakenings’ starring Robert de Niro. It had been thought that the disease died out after the last major outbreak in the 1920s. But the BBC programme picked up on a number of cases which have suddenly appeared over the last few years, and explored the work being done to try to explain the condition.

The programme featured Dr Dale explaining his alarm at coming across patients with encephalitis lethargica — a disease he thought he would never see. And when he let the medical community know that he was interested in studying the disease, many more cases came to light. It had long been thought that, as with Sydenham’s Chorea, ^there was a link between encephalitis lethargica and some kind of infection — influenza was at one point the prime suspect^.

But when he looked for a common factor, Dr Dale found that half the patients with encephalitis lethargica had reported a sore throat before they developed the disease. It was this that triggered Dr Dale to consider streptococcus, the commonest cause of sore throats, as a possible cause. And sure enough, blood tests showed that every patient had been infected by a particular strain of streptococcus — an invaluable insight into the cause of this devastating disease.

The eminent neurologist Dr Oliver Sachs (author of ‘The Man Who Mistook His Wife for a Hat’) was featured talking about his life-long work with sufferers of encephalitis lethargica, and hailed Dr Dale’s work as “brilliant, and original, and maybe revolutionary.”

Thanks go to the Barnwood House Trust for their support of this grant.

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