Tuesday, June 23, 2020

The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?


One hundred years ago the world experienced a mysterious epidemic - no, not the 1918 pandemic - but a devastating neurological disease that appeared about the time the influenza pandemic began, and continued for a full decade.

There are some scientists who believe this disease - called Encephalitis Lethargica (EL) -  to be a rare sequelae of the 1918 pandemic virus, but the evidence for this remains scant.

More recently, a 2012 study presented a case for the EL epidemic having been caused by an enterovirus (see Evidence for an enterovirus as the cause of encephalitis lethargica). But the cause remains unknown.
Encephalitis lethargica is a disease characterized by high fever, headache, double vision, delayed physical and mental response, and lethargy. In acute cases, patients may enter coma. Patients may also experience abnormal eye movements, upper body weakness, muscular pains, tremors, neck rigidity, and behavioral changes including psychosis. The cause of encephalitis lethargica is unknown.
Between 1917 to 1928, an epidemic of encephalitis lethargica spread throughout the world, but no recurrence of the epidemic has since been reported. Postencephalitic Parkinson's disease may develop after a bout of encephalitis-sometimes as long as a year after the illness.
It has been estimated that between 1 and 5 million people were afflicted with EL between 1917 and 1927 -  and while roughly 1/3rd died during the acute phase of the illness - many of the survivors would go on to develop Parkinsonian features and other profound neurological sequelae, often years later. 

EL is truly one of the great medical mysteries of the 20th century. 

Its aftermath was depicted in the 1990 fictionalized movie Awakenings, which was based on Oliver Sacks' 1973 memoir. In it, he described patients who had been comatose for 40 years who were treated with L-DOPA in the 1960s, and briefly recovered, only to slip back into a catatonic state. 

Throughout history, there have been reports of similar outbreaks, resulting in severe neurological disease, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in 1890 in Italy, in the wake of the 1889–1890 influenza pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.

Among those who survived, Parkinsonism and other neurological sequelae was common.

While the exact cause of these epidemics remain unknown, a virus - or perhaps  an autoimmune response to a viral infection - are both plausible suspects.  

Over the past dozen years or so, we've seen ample evidence of neurological involvement from a variety of viral infections, including West Nile Virus (WNV), EV-D68, Zika Virus, and even seasonal influenza.

Two years ago, in Neuroinfluenza: A Review Of Recently Published Studies, we looked at rare instances or neurological manifestations associated with with seasonal (and avian) influenza infection.
Credit CDC 2018 COCA Call On Severe Influenza
The exact mechanisms behind these neurological symptoms are unknown, as seasonal flu viruses are generally not regarded as being neurotropic. But some researchers have suggested that these neurological symptoms may be due to neuroinflammation induced by the host's immune response.

Also in 2017, in Nature Comms: Revisiting The Influenza-Parkinson's Link, we looked at new, and past research,  on the link between influenza infection and neurological disorders. 

In the short history of our COVID-19 pandemic, we've already seen a number of worrisome reports linking neurological manifestations to the disease.  A few recent blogs include:

PrePrint: Cytokine Release Syndrome-Associated Encephalopathy in Patients with COVID-19

CDC HAN: Multisystem Inflammatory Syndrome In Children (MIS-C)

JAMA: Neurologic Manifestations Of Patients With Severe Coronavirus Disease

While there have been anecdotal reports of COVID-19 patients with neurological impacts, the JAMA Neurology study above found more than 1/3rd of a study group of 214 patients hospitalized in Wuhan, China showed signs of neurological involvement.
Neurological manifestations ranged from relatively mild (headaches, dizziness, anosmia, mild confusion, etc.) to more profound (seizures, stupor, loss of consciousness, etc.) to potentially fatal (ischemic stroke, cerebral hemorrhage, muscle injury (rhabdomyolysis), etc.).
As a result, the question is increasingly being asked: Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms  by  Emily A. Troyer,  Jordan N. Kohn, and Suzi Hong.

COVID-19 is projected to affect a remarkably high proportion of the global population, which is unprecedented for a virus with such case fatality and infection rates in modern medicine. Nevertheless, the neuropsychiatric burden of this pandemic is currently unknown, but likely to be significant.
Past pandemics of this magnitude occurred tens to hundreds of years ago; therefore, epidemiologic associations between viral infection and neuropsychiatric symptoms were noted, but causality and etiopathogenic mechanisms were not well elucidated. In more recent CoV outbreaks, neuropsychiatric symptoms have generally been underexplored relative to respiratory and other symptoms. The breadth of the current SARS-CoV-2 pandemic will likely require closer examination of the mechanisms underlying, and the interventions for, post-viral neuropsychiatric sequelae, which will likely be heterogeneous and extensive.
(Continue . . . )
Adding to this concern, The Lancet has published a very brief  (1-page) focal point opinion, which reminds us of the EL epidemic of 100 years, points out the unusual incidence of neurological manifestations reported with COVID-19 patients, and warns that we should not underestimate the potential long-term sequelae from this pandemic virus. 

Follow the link below to read the opinion. 
COVID-19: can we learn from encephalitis lethargica?
Antonino GiordanoGhil SchwarzLaura CacciaguerraFederica EspositoMassimo Filippi
Published:July, 2020
While it is far from certain that there will be significant long-lasting neurological sequelae from COVID-19, and another EL epidemic would seem highly unlikely, our tendency as a society is always to minimize the risks. 

We tell ourselves that `it's only a flu', or that kids are `immune', and it `mostly only kills those over 80'.  

Yet, we continue to see evidence that COVID-19 is more than just another `respiratory' virus, and that more than just the elderly are at risk.  COVID-19 can, and occasionally does, present in unusual ways. 
Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young
All are reminders that five months into our battle with COVID-19, there is still a lot we don't know about this new virus, and our body's response to it.  

And that it is far too soon to assume we know all of the risks going forward.