How Knut’s disease is leading to medical breakthroughs
Abandoned by his mother, and reared by a zookeeper, Knut was Berlin Zoo’s adorable polar bear. Cameras captured his every fluffy white move – even documenting his sudden death in 2011. Footage shows the bear shaking uncontrollably before howling and collapsing into the enclosure’s pool. Hundreds of visitors stood by, confused and shocked, as the world’s favourite polar bear had a seizure and drowned.
Dr Alex Greenwood at the Leibniz Institute for Zoo and Wildlife Research in Berlin was called to conduct the autopsy and uncover what killed Knut. “The zoo was under pressure to show that they weren’t responsible. The media was hounding us, and the public was so upset,” he says. “It was like trying to solve a gigantic jigsaw puzzle with a gun to your head.” But, after an exceptionally extensive investigation, what killed Knut remained a mystery.
The autopsy revealed that the polar bear suffered from encephalitis – inflammation of nervous tissue in the brain. This caused the seizure. But encephalitis is usually triggered by an infectious agent, such as bacteria, viruses or parasites. No such thing was found in Knut. It would take four years until the puzzle was complete.
In August this year, Knut was found to have died from a rare autoimmune disease that was attacking his brain and causing the inflammation. The disease, dubbed anti-NMDA receptor encephalitis, has only recently been described in humans and never before seen in any other species.
International headlines reported “death riddle solved”, but the story of Knut’s unusual condition is more profound than a cute bear. Hundreds of human lives may have been saved in its discovery and some even say our growing understanding of “Knut’s disease” has revolutionised the field of clinical neurology.
A few years before Knut was born, four women were admitted to the psychiatric unit at the Hospital of the University of Pennsylvania. Inexplicably, these women had become psychotic. Some were hallucinating and delusional. One vacillated between inappropriate giggling, paranoia and aggression. She hadn’t slept for weeks. All the women experienced seizures.
Other than the bizarre symptoms, Dr Josep Dalmau at the University of Pennsylvania noticed that each patient had an ovarian teratoma, a benign tumour that develops from follicles in ovaries. These curious tumours tend to have a throng of human cells within them – some contain teeth, hair and nervous tissue. Dalmau had a hunch that the tumours were playing a role in the women’s psychiatric state. He thought, perhaps, part of the immune system was attempting to kill the nervous tissue within the tumour but had started to inappropriately attack the women’s brains.
To test his theory, Dalmau and his team soaked slices of rat brains in samples of the patients’ blood and cerebrospinal fluid, the wash of liquid that snakes through the brain. As suspected, proteins in the samples grasped onto the rodent’s brain in a pattern suggesting these women suffered from an autoimmune disease.
Dalmau joined forces with David Lynch, now a professor of neurology at the Children’s Hospital of Philadelphia, and together they revealed that defunct immune proteins were going after a specific protein in the brain called N-methyl-D-aspartate (NMDA) receptors. Normally found on the outside of neurons, these receptors “are crucial for learning and memory”, says Lynch. It’s believed they are responsible for inhibiting redundant information from our potentially overwhelming environment. For affected patients, however, the dysfunctional immune proteins were pushing the receptors inside cells, rendering them largely useless. In 2007, Lynch and Dalmau published their work, and anti-NMDA receptor encephalitis became a recognised syndrome.
“At the time, we thought it was very exciting, but very rare,” says Dr Maarten Titulaer, a neurologist at Erasmus Medical Centre in the Netherlands. “But then it exploded.” Soon, it was no longer just women with teratomas who were diagnosed, but adults and children with no underlying tumours. While still an extremely rare disease – Titulaer estimates two in every million people are affected each year – within the world of clinical neurology the finding was big.
When a team at the Children’s Hospital at Westmead, in Sydney, reanalysed the blood of their cases of kids with encephalitis they found 6 per cent had the anti-NMDA receptor variety, making it the hospital’s fourth most common cause of encephalitis. In Berlin, Dr Harald Prüß at the German Centre for Neurodegenerative Diseases recently reported that six out of his seven patients with a hitherto unknown cause of encephalitis, that is no obvious viruses or bacteria, were later found to have Knut’s disease.
Susannah Cahalan was terrified when she heard her father attempt to murder her stepmother. She almost jumped out of a window, three storeys high, to escape. It was only when a small statue of Buddha in her dad’s apartment smiled at her that she stopped. “I had a lot of auditory hallucinations,” says Cahalan. “It was really scary and very intense.” In 2012, Cahalan published her memoir, Brain on Fire, in which she recounted living through anti-NMDA receptor encephalitis. She describes a quick descent from being a healthy 24-year-old journalist living in New York City to experiencing extreme paranoia, hallucinations, seizures and, later, bouts of catatonia. She spent a month in hospital, where she ripped off her electrodes and ran through the hallways. “I was violent and aggressive,” she says, an experience pieced together from medical records and interviews. Cahalan hardly remembers the worst of this disease as her NMDA receptors, critical for memory formation, were under attack. “Her experience is quite typical of this encephalitis,” says Titulaer.
Before the discovery of anti-NMDA receptor encephalitis many patients manifesting its symptoms were admitted to psychiatric centres, and according to Titulaer, would have “ended up in nursing homes”. Now, patients are given immunosuppressants, such as steroids, to dampen their autoimmune response. If an underlying tumour inspiring defective proteins is found, it’s removed. Other medications are used to wipe the attacking proteins from the body. About 80 per cent of patients, such as Cahalan, recover. This is particularly meaningful as roughly 40 per cent of those diagnosed with this form of encephalitis are under 18. “Instead of going to a nursing home for 50 years, they will go to school,” says Titulaer.
Where the treatment is unsuccessful, patients often become severely disabled. A small proportion die. Titulaer says this may happen because immune cells have entered the brain and set up “factories”, which continue to pump out dangerous proteins that attack the critical receptors.
While questions surrounding this illness remain – perhaps most crucially why it develops in some people, and not others – neurologists are hailing its discovery as a watershed moment. “It has changed the way neurologists look at encephalitis as a whole,” says Dr James Nicholas Brenton at the University of Virginia Health System. For example, it has given this community a “better appreciation of how autoimmune disease can lead to neurologic and psychiatric manifestations”. The discovery has also launched a hunt for other aggressive immune proteins that could be attacking the brain. Already scores of these entities have been found, and Brenton anticipates still more will be uncovered.
From this story there was also hope that many psychiatric disorders, and even cases of schizophrenia, might have an underlying, and therefore treatable, autoimmune cause. But Lynch and Titulaer say that the search for dysfunctional autoimmune proteins in more common mental illnesses have largely come up empty. While open to the possibility of future discoveries in this area, they both said that the current evidence does not warrant treating psychiatric patients en masse with immunosuppressive drugs.
It was after diagnosing a handful of patients with this new disease that Dr Harald Prüß phoned Dr Alex Greenwood at the Institute for Zoo and Wildlife Research. Soon the pair were slicing Knut’s brain and testing it for the characteristic pathological proteins. There they were. “It was really exciting,” says Prüß. “You look through the microscope and see something no other scientist has experienced before.”
The team hope Knut’s diagnosis will increase awareness for this disease. Greenwood says that perhaps, “patients that have been misdiagnosed could be properly diagnosed because doctors think of Knut disease”.
This article was first published in the print edition of The Saturday Paper on Oct 24, 2015 as "Disease laid bear". Subscribe here.