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In 1917, Austrian physician Constantin von Economo published his observations on a new disease that was making its way across Europe. The disease caused . Some patients presented with hypersomnia, spending all day asleep—they could be woken up but would return to sleep almost immediately. Others presented with hyperactivity and insomnia. Over 50% of cases resulted in death, and survivors were often left with permanent mental or physical disabilities. Von Economo labeled this new disease ‘encephalitis lethargica’ (EL). In the largest EL epidemic lasting from 1917-1930, more than 1 million individuals around the world were estimated to have been afflicted, and nearly 500,000 died from the disease.

Despite these numbers, EL all but disappeared from public consciousness after the epidemic, overshadowed by the much larger pandemic that took place during the same period—the 1918 Flu pandemic. With only a few sporadic cases diagnosed since the 1917-1930 epidemic, the causes of EL remain a medical mystery with very few clues.

What is Encephalitis Lethargica? Exploring the History and Presentation

Understanding the pathology of a disease only definitively described over 100 years ago in a single epidemic can be tricky. Symptomology based on historical descriptions can be vague, and while von Economo noted  of neurological diseases in Europe dating back to the 1500s, it is impossible to know if these diseases were EL or something else. Additionally, it is possible that some cases of diagnosed EL during the 1917-1930 epidemic were other diseases that were diagnosed as EL because it was a common or ‘popular’ diagnosis for medical practitioners at the time.

Despite these lingering questions, researchers can draw some general conclusions about EL based on the most recorded symptoms. EL can be characterized by 2 phases, acute and chronic. Acute EL could present with extreme sleepiness (somnolent-ophthalmoplegic); mania, involuntary twitching and insomnia (hyperkinetic); or rigidity and lack of movement (amyostatic-akinetic). A commonality between these acute presentations was the prodrome period, where patients would complain of ‘flu-like symptoms,’ such as headache, malaise and low-grade fever. The neurological symptoms would follow, often times very quickly.

The chronic phase of the disease could appear years after presentation of the acute phase. Parkinsonism was the typical presentation, and this would later become known as ‘post-encephalitic parkinsonism’ (PEP). Patients with PEP would effectively turn to statues, unable to initiate any movement on their own, but could be prompted into movement through reflexes. Chronic symptoms could also manifest as psychiatric conditions, in which patients would develop complete personality changes or psychosis. These mental changes were more common and pronounced in children with EL, and reports of  in young children were not unusual, an example of the extreme mental changes these patients could undergo.

What Causes EL? Unraveling a Medical Mystery

Over the years, scientists have explored potential microbiological, immunological and environmental causes of EL. While the exact etiology remains unknown, unpacking research surrounding these hypotheses may shed light on the mystery behind this historically devastating disease.

Influenza

During the 1917-1930 epidemic, the most  was that EL was linked to influenza, either as a neurological form of the disease, or the result of influenza coinfection with another unknown pathogen. The primary rationale behind this thinking was coincidence; influenza and EL outbreaks appeared to emerge in the same places at around the same time.

Additionally, previous epidemics of influenza that presented with neurological symptoms or other "sleepy sicknesses" occurred prior to 1917. For example, during  in Europe, there were

reports of a "post-influenzal encephalitis," referred to as "la nona," which presented with similar neurological symptoms to EL.

La nona encephalitis was noted to frequently occur in patients who had previously been afflicted by influenza, however,  of la nona fail to mention many of the more prominent acute symptoms associated with EL.

Furthermore, several epidemiological studies of EL and the 1918 influenza epidemics have found that there are inconsistent patterns of outbreaks. Edwin Oakes Jordan, an American epidemiologist, studied data of EL and influenza outbreaks in American cities between 1918 and 1923 and could find no . Outbreaks of EL and influenza simply did not always reach cities or settlements at the same time.

As influenza cases fell, and the EL epidemic continued through the 1920s, popularity of the influenza hypothesis declined. Modern attempts to find traces of influenza virus in  from the 1917-1930 EL epidemic have not yielded positive results. Though lack of evidence is not proof of absence, these findings suggest that influenza is not a likely cause of EL.

Enterovirus 

One of these more compelling hypotheses comes with stronger evidence. In 2012, a 

 examined preserved brain tissue samples from the 1917-1930 epidemic, as well as PEP cases and more recent EL cases. Using transmission electron microscopy and antibody staining, they found evidence of virus-like particles (VLP) in the EL and PEP samples. While the methods used in the 1920s for autopsy and tissue preservation have led to degradation of the overall cell structure, the presence of VLPs makes a compelling case that some kind of virus is a cause of EL. But what kind of virus?

To answer this, the researchers examined brain tissue from the patients of modern viral diseases and compared the results to the VLPs found in the EL samples. They were able to identify influenza viral particles in the brain tissue sample from an influenza case, but those particles did not visually match the VLPs identified in EL samples. The EL VLPs did resemble VLPs that were found in the tissue from a case of infection with coxsackie B4 virus—a type of enterovirus. Based on antibody staining and knowledge of viral replication, the researchers suggested that a small RNA virus, such as enterovirus, could be a probable cause of EL.

Many  are known to cause diseases with neurological symptoms, the most infamous being poliovirus.  can cause a condition called acute flaccid myelitis (AFM), a neurological condition that causes muscles and reflexes to weaken, which can, in turn, cause respiratory failure. Meanwhile, a  found that chronic enterovirus infections contribute to the chronic illness myalgic encephalomyelitis, or chronic fatigue syndrome. These known associations strengthen the plausibility that EL could be caused by an enterovirus similar to these examples.

Autoimmune

Unsatisfied with viral hypothesis, scientists have also investigated the possibility of EL being an autoimmune disorder. In 2004, a  had elevated levels of anti-streptolysin-O antibodies, indicating a recent infection of Streptococcus bacteria, while 11 patients reported a sore throat—potentially caused by strep—prior to the onset of EL. The researchers proposed that EL could be a post-strep disorder involving mechanisms of  an autoimmune response induced when antigen(s) produced by a pathogen closely resemble molecule(s) produced by the host and resulting in cross-activation of autoreactive T or B cells that can mistakenly attack host cells.

Another possibility is , an autoimmune disorder where antibodies attack the NMDA receptor in the brain. NMDA is an important neurotransmitter receptor involved in memory formation. Anti-NMDA-receptor encephalitis patients experience behavioral changes such as paranoia and hallucinations, memory deficiencies, movement disorders and seizures. Some modern cases initially diagnosed with EL were  for NDMAR antibodies. It’s not currently known what triggers anti-NMDA encephalitis, but like many autoimmune conditions, a combination of genetic and environmental factors are speculated to be involved.

While these case studies are interesting, it is difficult to imagine an autoimmune disorder causing an epidemic at the scale documented in the early 1900s. However, it’s not unheard of for autoimmune conditions to be linked to viral infections— is closely tied to the  and   can be caused by several different infections. This leaves the possibility that EL was an autoimmune condition caused by an unknown pathogen open for further research.

Fading Into Obscurity

Encephalitis lethargica is not a disease that springs to mind when discussing epidemics of the past. Why has a disease that claimed hundreds of thousands of lives and caused significant neurological debilitation to patients been largely forgotten? 

Historically, the survivors that continued to suffer from chronic EL were often housed in asylums and care facilities, where they remained for the rest of their lives. It was simply easier to forget when the afflicted individuals were unable to advocate for themselves or a cure. At first, hopes for a vaccine held strong. Founded by , the Matheson Commission attempted to find the cause of EL and develop a vaccine. However, Matheson died in 1930, and funding for the commission soon died too. Since then, EL research has remained sparse.

The last known survivor of the 1917-1930 epidemic, , died at the age of 82 in 2002. He was first diagnosed with EL at the age of 11 when he was admitted to a mental hospital where he remained until he died, watching the world pass around him while mostly unable to move.

There has been little interest in EL since the epidemic. The Oscar-award winning movie Awakenings, based on neurologist Oliver Sack’s 1973 book of the same name, brought EL into the public briefly. The movie featured Sack’s experience with PEP patients and their responses to the Parkinson’s drug L-DOPA.

In recent decades, there have simply been very few cases of EL. Only about 80 reports of EL have been published in the last 85 years, and even these diagnoses are not definitive.  to clarify the diagnostic criteria have been contradictory with one another and include symptoms that were either not noted, barely appeared or were only common in cases of PEP. Ultimately, a diagnosis of EL relies primarily on elimination of other disorders, as there is still no pathogen to identify, no antibodies to test for and no genetic markers or any other lab test to use for diagnosis.

Will EL remain a disease of the past, or could it reemerge and cause additional devastation? Without a known cause and a lack of cases to motivate funding to search for a cause or cure, it is impossible to answer this question. Still, the sufferers of this disease deserve to be remembered. If EL ever does cause another epidemic, remembering its history could be the key to finally finding an answer.

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Learn more about acute flaccid myelitis and the evidence linking it to Enterovirus D68 (EV-D68).