Medical writing owes a debt to Oliver Sacks, whose books bring readers nose to nose with great neurological puzzles. The British physician is best known for capturing detailed, narrative case histories that convey a human experience of disease. And while Sacks has more than 40 years of published work, he may be best remembered for his first successful book, which chronicled an enigma he encountered as a neurologist at Beth Abraham hospital in the Bronx: encephalitis lethargica.

{% video Ulp-lVnXrz0 %}

Nearly forgotten today, encephalitis lethargica infected nearly five million people between 1915 and 1927, and killed roughly a third of this population quickly. At first, a patient might simply feel unwell, and perhaps experience a sore throat. Then the characteristic symptoms would appear: lethargy and deep slumber. Roughly one-third of patients died during this phase of the illness, typically of respiratory failure. Those who survived often felt apathetic, detached and had trouble concentrating.

Some would recover, but the majority of survivors would face the disease’s final phase, where movement became stiff and slow, as it does in those with Parkinson’s disease. Some slowed to the pace of sleepwalkers, others became motionless, living statues for years. Although their minds appeared to remain clear during their brief interludes of lucidity, those who suffered the “sleepy sickness” lacked all sense of the passing of time.

The French pathologist Jean-René Cruchet first witnessed cases of the disease on the battlefields of World War I. By 1917, Baron Constantin von Economo, a Vienna-based psychiatrist and neurologist, had described the illness in an article titled “Die encephalitis lethargica,” and would later find that these patients had damage in the mid-brain, in a structure called the substantia nigra.

Patients immobilized by encephalitis lethargica were sent to institutions, which is where Oliver Sacks encountered them. In the late 1960s, the experimental drug L-DOPA was first given to Parkinson’s patients, with encouraging results. (Patients with Parkinson’s disease also show damage within the substantia nigra.) Sacks eventually decided to treat a group of these patients at Beth Abraham with L-DOPA.

To Sacks’s great surprise, his patients awakened from their frozen states to act and move normally. Tragically, after a period of time L-DOPA’s effects began to wear off and the patients no longer responded to the drug, leaving them just as frozen inside their bodies as they had been before. In many cases, the drug not only wore off, but the patients began to show “strange, unstable states,” as Sacks put it. This story would become the basis of Sacks’s 1973 book, Awakenings, which was later made into a movie.

The cause of encephalitis lethargica was never found, but studies of its victims have revealed swelling of the midbrain and basal ganglia and evidence of an autoimmune reaction to the tissue there. Although the epidemic occurred at the same time as the 1918 influenza pandemic and many speculated a connection, no genetic material from the flu strain has been found in victims’ brain tissue.

Although the original epidemic ended abruptly in 1927, as mysteriously as it came, the disease never completely disappeared. In 2003, Russell Dale, a pediatric neurologist working in the United Kingdom, found that in a new group of 20 patients who seemed to have encephalitis lethargica, more than half had suffered a sore throat caused by a rare form of strep before the illness struck. Antibodies mobilized by the immune system to fight the strep bacterium were elevated in more than half of patients with the condition. Dale hypothesized that an autoimmune process sparked by the body’s reaction to strep might be to blame, with the antibodies mistakenly attacking the basal ganglia neurons. What’s still completely unknown is why the disease would suddenly become epidemic, an ignorance that leaves open the possibility that the disease might one day reemerge.

The mystery continues, and Sacks has yet to see it unraveled. But he spent his career chronicling new mysteries of the mind, from Tourette syndrome to musical hallucination, via compelling and detailed case histories. If the mechanisms behind encephalitis lethargica are ever finally brought to light, Sacks’s legacy will surely remain part of the story.