The forgotten case of the sleepy virus

I spent last night rewatching the Steven Soderbergh classic “Contagion“. Halfway through I realized that a story of an unidentified, mind-bending infectious brain disease would make the perfect neuroscience halloween tale. This is not “based” on a true story. It IS a true story.

The year is 1917. Dr. Constantin Economo sat deep in thought, staring through the pages of his half-finished manuscript as he remembered his last patient of the day. She was a young woman, no more than 30, sitting immobile in an armchair lids-half closed, indifferent to the surrounding like a wax doll. Her face masked all expression, moulded into an eternal state of apathy.

“Please get up.” He had asked her. Following a brief pause, she complied; her movements were slow and depressed; her gait tilted. She often paused, holding a position as if frozen in time. Soon, without further probing, she fell back into a stupor. All the while, she was aware of her surroundings.

In stark contrast, the doctor recalled solemnly, was that 15-year-old boy with paranoia. His mother took him in due to sleep complaints – his sleep pattern had completely inverted. 3 days later, his gaze became permanently slanted; his tongue and limbs contorted into uncomfortable positions. An equally macabre shift occurred in his mind: he became increasingly paranoid and anxious, mixed with bouts of agitation. He developed a vocal tick and an obsession with compulsively touching his body. 8 months later, he showed no signs of remission.

The two patients share one thing in common. Von Economo thought as he wrote down the title of his manuscript, “Die Encephalitis lethargica”. An infection by an unidentified virus, transmitting in an unknown manner across continental Europe.

Little did he know that by the end of the epidemic in 1927, the virus would had spread across the globe, taking the lives of at least half a million people. Those spared from death were left in broken bodies, trapped in their shattered minds.

The disease stages of a “sleepy” brain

Encephalitis lethargica (EL) literally translates to “brain inflammation with lethargy”. Reports of the virus can be dated back to the age of Aristotle; however, the virus’ most ferocious rampage occurred between 1917-1926.

The disease is commonly known as “sleepy sickness”. Don’t be fooled by the innocent sounding name: one-thirds of those infected die, another third develop Parkinson’s-like symptoms that haunt them for life. Only one third may recover relatively unscarred.

The initial stages of EL infection seem like that of any other nasty bug: fever, sour throat, headache and general lethargy. The infected, unaware of the pathogen’s true nature, battles flu symptoms with bed rest and water, thus giving EL virus ample time to spread across the brain.

Autopsies have confirmed that the virus first and foremost causes infection in the hypothalamus, a small region at the base of the brain. This region controls our vital functions, including breathing, body temperature, hunger and sleep. Viral multiplication causes severe inflammation in the hypothalamus leading to its dysfunction. The EL virus then jumps to other areas of the brain, including the thalamus, cortex, and midbrain (striatum and substantia nigra), which play a role in reward, addiction and movement.

encephalitis-rmn

MRI of a patient with EL. Arrows point to areas of inflammation. Source: Ref 3

Infected adults quickly develop extreme daytime lethargy, unwilling to move for even basic bodily needs such as bathroom runs. To the observer, they seem either completely asleep or caught in the “twilight” zone between sleep and wakefulness. The chilling truth is that they’re completely aware of their surroundings – it just takes them incredible effort to talk or to move, perhaps due to the destruction of their basal ganglia. Most never survive this stage of acute infection – when the hypothalamus shuts down, so do basic survival functions. Unable to breathe, victims suffocate in a mockery of “peaceful sleep”.

Those who survive the initial attack are changed for life. Victims often seem like a shadow of their former selves, unable to concentrate and uninterested in life. Then, years or even decades later, they’re barraged by an onslaught of motor problems. Patients are unable to freely initiate movement; when they do its painfully slow. They’re plagued by tremors, speech and vision problems and abnormal limb movements. The most unfortunate victims managed to retain their hearing, cognition and reasoning but are left in a state of constant stupor. This untreatable, irreversible parkinsonism condemned younger survivors to decades of disability.

40 years after the discovery of post-encephalitic parkinsonism, neurologist Dr. Oliver Sacks famously tried to treat these motor symptoms with L-dopa (used for Parkinson’s Disease). At first it worked, but tolerance grew fast and soon the required dosage exceeded what the body could process. When drug treatment stopped due to toxicity, most patients soon slipped back into a catatonic state. Only a lucky few remained awake.

Infected young children fared even worse. Following a brief stint of lethargy, the virus quickly took over the developing brain, causing rapid changes in personality. At first the child may seem irritable or anxious, often unable to concentrate. As they grew, approximately one third become explosively violent; they “annoy strangers on the street… abuse them; they tramp, beg, lie, steal… indulge in sexual misbehaviour of every kind (at a young age) and make other dangerous acts.” In extreme cases, children self-mutilate to the point of extracting their own teeth; some display malicious cruelty toward others, coupled with feigned friendliness in a psychopathic manner. Their memory and intelligence remained intact; the virus just ate away any sense of morality.

Not much could be done. Many children were arrested or placed into mental institutions; some were subjected to frontal leucotomy. The procedure did not alleviate their destructiveness.

How did EL cause these changes in personality and behaviour? Some doctors propose it stems from direct lesions to the cortex and striatum, resulting in lowered cortical inhibition and skewed motivation. Others believe that dysfunction in the sensorimotor system in turn disrupted the thalamus and emotion-related circuits, increasing a child’s mental and physical sensitivity to any external stimuli. A few doctors opted for a psychoanalytic explanation, in which delinquent behaviours “represented a deep wounding of the ego.”

We still don’t know.

The face of an enigmatic killer virus

What is the true identity of Encephalitis lethargica? Von Economo famously proposed the cause to be a virus, much to the chagrin of Freudian scholars who preferred a psychoanalytical explanation.

Early on, scientists noticed something peculiar: EL almost always trailed behind flu outbreaks; the 1920 epidemic, for example, partially overlapped with the Spanish Flu pandemic, which took more than 20million lives. This overlap in time has led to scientists to speculate that the flu virus may directly be responsible for EL. Although some clinicians and epidemiologists rejected the idea from the get-go, they could not directly study the virus due to its rapid disappearance in the late 1920s.

Almost a century later, in 2001, scientists reopened the case. They obtained brain samples collected from victims of the epidemic and meticulously analyzed them with modern molecular biology techniques. The samples were well preserved, yet scientists could not find any traces of the flu’s genetic material. This may indicate that the flu operated in a “hit-and-run” manner, lingering in the body just long enough to lower its immune defences, allowing EL to “swoop in”. On the contrary, the flu may have triggered the body to produce autoantibodies, which viciously attacked the brain during subsequent EL infection. Or it could mean the two viruses were completely unrelated; a horrendous coincidence.

A study from 2012 further unmasked the EL virus. Scientists obtained brain samples of EL victims from both the epidemic age and from several modern cases. Studies using electron microscopy found virus-like particles in brain cells of EL victims (below).

1471-2334-12-136-3

Endoplasmic Reticulum membrane (normal cell protein factory) embedded in viral particles. Electron microscopy. Source: Ref 3

Surprisingly, these particles also appeared in the cell nucleus, where genomic DNA is stored. Hunkering down in the nucleus is a trait of the Enterovirus – the most notorious of which causes polio – leading scientists to suspect that EL may belong to the genus. Using fluorescent-tagged protein probes specific for poliovirus protein, researchers found proteins similar to that of poliovirus; genetic studies also found ~93% similarity in the genes of EL virus and various Enteroviruses. Unless samples were contaminated, these data strongly suggest that EL is a type of Enterovirus.

Encephalitis lethargica: the case continues

As quickly as it came, the EL virus vanished in 1927, leaving behind hundreds of thousands with broken bodies and shattered minds. Why are scientists interested in a seemingly obsolete virus, quarantined between the pages of history long gone?

The truth is that EL is far from eradicated. Like the boogyman, the virus occasionally rears its ugly head, infecting both adults and children alike. Modern case studies show that EL virus often shadows common “sore throat” bacterium* like Strep or Diplococcus, taking a second, brutal swing at already-infected patients. We still don’t know where it comes from, how it transmits or who is most vulnerable.

Scattered outbreaks are occurring to this day. As of now there is no cure.

* Edit: Thanks @aetiolgy for pointing out that I called Strep a “virus”. It’s a bacterium.

Case descriptions at the beginning of the article are based on Von Economo’s description of patients – nothing made up.

Final word: So…research is “non-essential”, huh?

ResearchBlogging.org

Vilensky JA, Foley P, & Gilman S (2007). Children and encephalitis lethargica: a historical review. Pediatric neurology, 37 (2), 79-84 PMID: 17675021

Dourmashkin RR, Dunn G, Castano V, & McCall SA (2012). Evidence for an enterovirus as the cause of encephalitis lethargica. BMC infectious diseases, 12 PMID: 22715890

Dale RC, Church AJ, Surtees RA, Lees AJ, Adcock JE, Harding B, Neville BG, & Giovannoni G (2004). Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain : a journal of neurology, 127 (Pt 1), 21-33 PMID: 14570817

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