Runfan Yang“Can you hear me?”, asked Dr. Sayer.
A patient arrived at a chronic hospital in the late 1960s. Almost half a century had passed since the influenza pandemic, and the world bore the scars of war and illness. Television had replaced radio as the primary broadcast medium, filling the airwaves with the overly excited sounds of commercials — sounds that were absent in the ears of the hospital’s patients. The hospital, established shortly after the First World War, was dedicated to caring for those with nervous system disorders. Its chronic facility hosted patients with various neurological dysfunctions: Tourette syndrome, multiple sclerosis, Parkinson’s disease, and other conditions yet unnamed by the medical society. Some orderlies referred to this facility as the “garden” because the patients received only food and water. Unlike plants in an outdoor garden, however, the patients neither grew nor changed. Day after day, year after year, they received food and water, but nothing changed except the window frames, which slowly rusted from disuse. The patients seemed trapped in an akinetic state, adrift in the wheel track of history. They were the forgotten ones.
Lucy was the new arrival, discovered days after the death of her last living relative. She had been catatonic for years and appeared unresponsive and incomprehensible when examined by Dr. Sayer. He cleaned the dust off her glasses and turned to fill out her paperwork. When he turned back, Lucy was frozen in the act of bending down to pick up her fallen glasses. It didn’t take long for Dr. Sayer to notice that Lucy seemed to respond to certain external stimuli, such as an object falling vertically in front of her, the visual rhythm of the floor pattern, or a baseball being thrown towards her. “It is as if, having lost all will of her own, she borrows the will of the ball,” Dr. Sayer explained to the other doctors, who dismissed Lucy’s reactions as mere reflexes rather than genuine responses.
Dr. Malcolm Sayer was different from his fellow medical doctors. Despite holding a medical degree, he had been engaged in research before becoming a clinical physician at the hospital. In fact, he preferred research to interacting with human subjects. His reluctance stemmed not from a lack of empathy but from an excess of it. He could endure five years of research proving a project ineffective, but how could he face patients in need with no answers? Working at the chronic hospital was an adjustment for Dr. Sayer. Confronted with countless patients in distress, he sometimes had to bang on the rusted windows just to breathe. But his keen attention to detail as a researcher led him to notice Lucy and the similarities among her and a few other patients who, while not fitting well into diagnostic categories, had been labeled merely as “atypical” on their charts. These patients had seen no changes in their symptoms or treatment recommendations, some for over two decades. Dr. Sayer, however, felt their breaths and heard their heartbeats. He knew that before being reduced to the state of human furniture, they were people. During the tests, each one reached out to catch the ball, their rigid responses silently screaming to the caretakers: “Look at me, look at me, I am right here.”
Dr. Sayer was determined to find a common thread among the patients trapped within themselves. He delved into their medical records and discovered that they all had suffered from encephalitis lethargica — the forgotten illness of the early 1900s. Encephalitis is the inflammation of the brain, primarily caused by viral infections or autoimmune disorders where the brain is mistakenly attacked. Symptoms of encephalitis vary among patients: some may experience problems with speech and vision, loss of consciousness, and disturbances of motor function while others may exhibit only flu-like symptoms. Encephalitis lethargica is a rare and atypical type of encephalitis that swept across the globe from around 1916 to the 1930s. It was first described contemporaneously by Austrian neurologist Constantin von Economo and French physician Jean-René Cruchet, who had been treating patients with various unusual neurological symptoms and found that many presented marked lethargy. Patients with encephalitis lethargica exhibited fever, impaired ocular motility, disordered movement, and, most importantly, excessive sleepiness. It was reported that patients would fall into a deep sleep lasting for weeks or months, sometimes striking so suddenly that they lost consciousness in the midst of actions such as writing or eating.
The epidemic of encephalitis lethargica affected an estimated one million people worldwide between 1916 and 1926. Approximately 9,000 research and medical papers were published discussing the cause and treatment of the disease. Yet, until it abruptly vanished at the beginning of the 1930s, scientists and doctors were left in the dark about its mysterious cause and elusive treatment. Encephalitis lethargica quickly receded from the forefront of medical attention as other illnesses emerged. Meanwhile, in a corner of the world that few noticed, patients who were considered to have awoken from encephalitis lethargica suffered chronic neurological sequelae that persisted for decades after the epidemic.
With the help of the nursing staff, Dr. Sayer gathered a group of patients like Lucy. Using one triggering stimulus, the ball could be passed among these patients – carrying their will – going from one hand that throws the ball to the pairs of arms that had been transfixed for years. Dr. Sayer began to view the akinetic state of the patients as an extreme form of the tremor seen in patients with Parkinson’s disease. The accelerated bodily tremor and head bobbing, taken to its extreme, could turn people into stones.
At that time, levodopa had become the mainstay of Parkinson’s disease therapy. Levodopa is a metabolic precursor of dopamine that can cross the blood-brain barrier and get converted to dopamine. Postmortem exams had found that the striatum of patients with Parkinson’s disease was entirely depleted of dopamine. Recognizing this depletion, researchers introduced levodopa as an experimental drug in the therapy of Parkinson’s disease. In 1961, Drs. Oleh Hornykiewicz and Walter Birkmayer injected levodopa into 20 Parkinsonian patients and observed that, for a short while, their frozen limbs defrosted into motion. In 1968, Dr. George Cotzias and his team reported their revolutionary two-year clinical study on 28 patients with Parkinson’s disease using modified dosages and delivery of levodopa. Levodopa was later approved by the US Food and Drug Administration in 1970.
Influenced by Cotzias’s work, Dr. Sayer considered levodopa for treating the post-encephalitic symptoms of his patients. In the summer of 1969, the administration of levodopa miraculously melted the rigid bodies of patients who had been frozen for years. This story was told in the movie Awakenings, based on the clinical experience of Dr. Oliver Sacks (“Dr. Sayer” in the movie) with his post-encephalitic Parkinsonian patients. The film highlighted the infant-like contact of the newly awakened patients with the outer world. At the end of Awakenings, after a brief remission, Dr. Sayer’s patients fell back into their akinetic state. In the real world, Dr. Sacks and his colleagues witnessed the more complex and pessimistic side of levodopa therapy. In 1970, they reported that levodopa therapy severely affected the respiratory systems of post-encephalitic Parkinsonian patients. They also noted that patients with dementia were particularly susceptible to levodopa, which could worsen cognitive impairment. Additionally, they observed many adverse reactions associated with the use and withdrawal of levodopa, such as dyskinesia and the unsuppressed and sometimes worsened oculogyric crises. Following levodopa’s release for clinical use, physicians around the world reported on both its efficacy and the challenges it presented.
Up until today, levodopa remains the most efficacious drug for Parkinson’s disease therapy. Researchers have been striving to overcome the limitations in the pharmacokinetics of the drug. For example, levodopa is now delivered with carbidopa to extend its half-life in the blood for more efficient delivery. Furthermore, catechol-O-methyl-transferase (COMT) and monoamine oxidase (MAO) – inhibitors of enzymes that break down dopamine – are also added to the therapeutic mix to further extend the effects of levodopa. Unfortunately, more progress is needed at the biological level, as levodopa relieves the symptoms but does not slow the progression of Parkinson’s disease.
The abrupt occurrence of encephalitis lethargica and the attempts to optimize levodopa therapy are rare scientific phenomena. For patients who had been rigid and shut down for years, was it kind to bring them back to a world they no longer knew? Was it kind to give their families hope, only for them to witness their loved ones succumb back to rigidity? After 1972, Dr. Sacks reduced his research publications and adopted a more existential and philosophical approach to the neurological experience. His story reflected the latency of medical and scientific discovery. Armed with the power of knowledge from research, people stand a chance against diseases, fighting for more time under the sun. Science stands between desperation and love, yet it is running against time. The classification of an illness requires consistent evidence — evidence that takes time to observe and gather. Yet, during that same time, there are people struggling in the present who need answers. Sometimes, questions such as those posed by a cough or a cold have straightforward answers. In some cases, it takes much longer to find answers for complex questions, such as those posed by encephalitis lethargica and Parkinson’s disease. Ultimately, the story of the awakenings of post-encephalitic patients – filled with both hope and disappointment – underscores the complexity of scientific progress. It is a journey marked by both breakthroughs and setbacks, one where physicians and researchers persevere, driven by enduring hope, seeking those in need, and bringing them back.
Peer Editor: Fanting Kung