Encephalitis Lethargica: Rediscovering a Forgotten Epidemic

“People have forgotten what life is. They have forgotten what it means to be alive,” says Leonard Lowe in the film Awakening, by Penny Marshall. Brought back to life after spending 30 years in a comatose state, this patient, played by actor Robert De Niro, believes that we should all remember “what we have, and what we risk losing.”

[Article issu de The Conversation, écrit par Jonathan Rogers, Clinical Lecturer in Psychiatry, UCL]

Inspired by a true story told by British doctor and neurologist Oliver Sacks in the book Awakeningsthe film details the experience of those affected by encephalitis lethargica, also known as epidemic von Economo-Cruchet encephalitis or “sleeping sickness.”

Far from being rare, this disease affected a million people worldwide, during and after the First World War. Then she disappeared. For a century, a question has remained unanswered: what could have been the cause of this condition which has claimed countless victims?

The ordeal of the survivors

Encephalitis lethargica was first described in 1917 in Vienna by the neurologist Constantin von Economo. If its first symptoms resemble those of the flu, the similarities end there. In the weeks following the onset of the illness, some victims found themselves unable to sleep. Others, conversely, were so sleepy that they could only be awakened for a few minutes in order to eat.

During this first phase, about half of those affected died. For those who survived, a confusing ordeal then began. After recovering and often returning to work, many convalescents began to notice that their movements were stiffer and slower than before the illness. In addition, sometimes their eyes would get stuck in certain positions, upwards or sideways, for a few seconds or a few hours (oculogyric crises).

Unfortunately for those affected, this new state, far from improving, progressed over time, and many of them ended up finding themselves completely frozen, unable to speak or move, like the character played by Robert De Niro.

But that wasn't all: many patients also developed language problems, with their speech becoming monotonous or unintelligible. Finally, some presented with mood, perception, or even personality disorders. Patients have seen their thoughts considerably slowed down. Others have had hallucinations or experienced strange delusions. Some seemed to lose all sense of right or wrong. As part of a study that my colleagues and I conducted, we met four patients who developed kleptomania (compulsive theft) following the illness.

What hypotheses would explain encephalitis lethargica?

Finding the origin of an illness is not always simple, as the history of the discovery of the human immunodeficiency virus (HIV, responsible for AIDS) or the discovery of the causal link reminds us. between human papillomavirus infection and cervical cancer. The same is true for encephalitis lethargica.

The sudden onset of the disease, then its equally abrupt disappearance, led some to speculate that it could have been linked to an infection. Remember that at that time, the Spanish flu epidemic had damaged populations. However, the first cases of encephalitis lethargica had predated its outbreak, and no influenza virus could be identified in the brains of people affected by encephalitis lethargica that we were able to autopsy.

To try to understand the origin of the disease, we spent many hours consulting the meticulously preserved archives of the National Hospital for Neurology and Neurosurgery and the Institute of Neurology at University College London. We were thus able to examine the cases of more than 600 patients suffering from encephalitis lethargica. This research told us that only 32% of them had been affected by something that vaguely resembled the flu in the year before the onset of encephalitis lethargica. In addition, the family circle was only affected in less than 1% of cases. Therefore, the hypothesis of influenza infection is not very convincing – at least if we consider said infection as the sole cause of encephalitis lethargica.

What about the patient environment? The least we can say is that 1917 was an eventful year, with the First World War leading to a considerable mobilization of personnel, weapons and equipment. One could imagine that in this exceptional context, part of the population could have been exposed to new substances. But our study did not highlight any link between the disease and the use of particular products.

More recently, a new theory involving autoimmune mechanisms has been proposed to explain the occurrence of encephalitis lethargica. According to this explanation, the patients' immune systems attacked their own brains.

We know that such a situation can occur in other contexts. Thus, it is an autoimmune reaction directed against the cells of the pancreas which is at the origin of type 1 diabetes. The production by the body of antibodies directed against the cells of the thyroid gland can also trigger the disease by Basedow. When such dysfunctions affect the brain, the results can be devastating, as in the case of multiple sclerosis, which also results from autoimmune problems.

Additionally, a condition called autoimmune encephalitis can also occur when antibodies attack nerve cells in the brain. Our work revealed that almost half of the patients diagnosed as suffering from encephalitis lethargica could in reality have been victims of autoimmune encephalitis, even if the form described then does not correspond to any of the forms of the disease that we know Today.

What could have been the connection with encephalitis lethargica and its many symptoms? This is where the hypothesis of collateral damage caused by infection (by the flu virus or another microorganism) could make sense.

We know that certain autoimmune diseases can be triggered by an infection. The molecular structures carried by certain pathogens can indeed present similarities with those which exist on the surface of our own cells. We understand the interest for the invaders: this disguise allows them to go relatively unnoticed. However, the immune system can still detect them. The problem is that it may then also turn against cells in the body that resemble said invaders…

To conclude, let us focus on one last question: why bother solving an enigma which concerns a pandemic whose last survivor died two decades ago? The answer, this time, is simple: encephalitis lethargica was not the first neurological epidemic of its kind. If we don't understand it, we won't be ready to face the next one.