The Elusive Lessons of Encephalitis Lethargica

Submitted by Muhammed F. Aljerari and H. John Sharifi, PhD

Tags: autoimmune diseases clinical COVID-19 disease infection neurologist

The Elusive Lessons of Encephalitis Lethargica

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Author Summary

In this review we summarize the current understanding of Encephalitis Lethargica (EL). We focus on the history of the disease, the clinical manifestations, the current diagnostic and therapeutic strategies, potential links to preceding viral infections, and gaps in our knowledge of the disease.

Introduction

Encephalitis Lethargica (EL) was first described by the pathologist Jean-René Cruchet and subsequently characterized by Austrian neurologist Constantin Freiherr von Economo in the early 20th century (Di Vito et al., 2023). EL is a highly pathogenic illness with a mortality rate of 20-30 percent, with surviving patients often left with considerable neurological sequelae (Shorter, 2021). The etiology of EL remains unknown and is a source of debate. The pathogenesis of EL also remains poorly understood, making it difficult to treat patients with EL-like clinical presentations (Koning, 2009). EL presented as a global pandemic in the early 20th century, around the same time as the 1918 “Spanish” influenza pandemic. After the influenza pandemic ended, EL has since occurred sporadically around the world (Hoffman and Vilensky, 2017). The correlative timing of the EL and influenza pandemics of the early 20th century led many scientists and clinicians to speculate a connection between the influenza virus and EL. Several observers at the time attributed EL to a virus or a complication of influenza. Concordantly, EL’s epidemiology suggests an infective cause, such as a seasonal virus, with the ability to cause encephalitis and persistent neurological damage to the central nervous system. Links between influenza and EL are, however, hypothetical and etiological theories connecting the two have been postulated but not established. Many wonder if a widespread investigative effort could reveal a persistent low endemicity of EL and possibly identify its etiology (Mortimer, 2009).  More recently a connection between the Coronaviridae family of viruses and EL has been proposed. In 2020, Badrfam and Zandifar suggested that coronaviruses have the ability to produce persistent neurological lesions (Badrfam and Zandifar, 2020). For example, in 2006 a study conducted by Jacomy et al. demonstrated that intracerebral inoculation of the human coronavirus strain HCoV-OC43 caused acute encephalitis accompanied by neuronal cell death in animal models. Further, infected mice showed signs of neural degeneration, via reduced motor function and activity, months after infection (Jacomy et al., 2006). The findings support common pathology between coronavirus infection and EL as they can both target the central nervous system in a multitude of ways and can produce clinically similar forms of encephalitis. These data demonstrate that both coronaviruses and EL possess the ability to induce long lasting neurological damage. Understanding the possible connections between coronaviruses and EL may help scientists uncover the mechanisms of EL pathogenesis. A better understanding of EL would allow clinicians to treat the disease more effectively, thus improving patient outcomes (Badrfam and Zandifar, 2020).

Clinical Manifestations

Encephalitis Lethargica (EL) is difficult to detect and diagnose, primarily due to its non-specific symptoms that overlap with other conditions. Diagnosis relies on the presence of elevated white blood cell counts and protein levels in the cerebrospinal fluid (CSF) as well as oligoclonal bands, which are indicative of brain and central nervous system inflammation (Blunt et al., 1997; Carta et al., 2022). Patients with EL often exhibit psychiatric and neurological signs and symptoms such as psychosis, akinetic mutism, and severe dyskinesias. These signs and symptoms can be categorized into two main forms of EL: dyskinetic and Parkinsonian. The dyskinetic form, more common in children, shares clinical features with other forms of encephalitis and involves signs and symptoms like abnormal movements and behavioral changes. The Parkinsonian form, characterized by mutism, somnolence, and Parkinsonian rigidity, is more common in adults but has a particularly poor prognosis when occurring in pediatric patients (Mellon et al., 1991; Dale et al., 2009).

Diagnostic and Therapeutic Strategies

Diagnosis of Encephalitis Lethargica (EL) remains challenging due to the lack of specific tests and the overlap of symptoms with other encephalitic conditions. The presence of diffuse slow wave activity in an electroencephalogram, as observed in patients, indicates dysfunctional cerebral activity, though this is not exclusive to EL (Blunt et al., 1997). Therapeutically, treatment options for EL are limited and primarily focus on managing symptoms rather than addressing the underlying cause. Dopaminergic medications, such as apomorphine and Levodopa, have been used to treat both the acute stage of EL and the delayed post-encephalitic Parkinson's (PEP) phase. The later phase being characterized by degeneration in the substantia nigra leading to clinical Parkinsonism. However, the effectiveness of these treatments varies, and some patients experience severe side effects (McAuley, Shahmanesh and Swash, 1999; Das et al., 2014). Other treatment options, such as Electroconvulsive Therapy (ECT), have been explored with positive outcomes (Kapadia and Grant, 1990; Dekleva and Husain, 1995).

Viral Infection

The potential link between Encephalitis Lethargica (EL) and viral infections, particularly influenza, has been a topic of debate for decades. Some researchers suggest that the co-occurrence of EL and influenza pandemics in the 20th century indicates a possible connection, while others argue that the relationship is coincidental (Vilensky, Foley and Gilman, 2007). Studies on archived brain samples have failed to conclusively establish a link between the two diseases, leaving the etiology of EL uncertain (Lo et al., 2003; McCall et al., 2008). Recent cases of autoimmune encephalitis triggered by COVID-19 in young patients have further complicated the understanding of EL's origins (Derakhshani, Ghazavi and Hosseini, 2023). The presence of anti-NMDAR antibodies in such cases highlights the potential for respiratory viruses like SARS-CoV-2 to induce encephalitic conditions that mimic EL as anti-NMDAR antibodies have been correlated with the dyskinetic form of EL (Dale et al., 2009). Still other work has implicated autoimmune dysregulation following bacterial infections, such as with Streptococcus pyogenes, to the development of EL-like disease (Dale et al., 2004).

Gaps in Current Knowledge

Despite some level of ongoing research, the etiology and pathogenesis of Encephalitis Lethargica (EL) remain elusive. The lack of conclusive evidence connecting EL to influenza, or other microbial diseases, puts into question the validity of earlier theories. Additionally, molecular diagnostic criteria for EL are limited and there are no standardized treatments for the disease.

Discussion

The origins of Encephalitis Lethargica (EL) are currently unknown. This is problematic as this disease is associated with a high mortality rate and only a fraction of surviving patients making a full recovery. Like the influenza virus strain responsible for the 1918 pandemic, EL can target young, seemingly able-bodied people. Further, EL is both difficult to diagnose and to treat, with no standardized process for either diagnosis or treatment. Currently, diagnosis and treatment of EL is experimental and differs from one case to another. Oftentimes healthcare providers diagnose a patient with EL when they present with an encephalitis of unknown origin with similar clinical manifestations to EL. EL has few potentially effective forms of treatment with Levodopa, ECT and, less commonly, apomorphine having shown some promise. While it is fortuitous that the medical field had progressed sufficiently to recognize the EL pandemic of the early 20th century, many of the resources we have today were non-existent at that time. Thus, as the EL pandemic waned, the opportunity to acquire critical data about the disease has been lost to time. This, in combination with subsequent cases of EL occurring only sporadically, makes the search for information regarding this disease convoluted and tedious. The pursuit of such inquiries on EL frequently results in dead ends and much of the information available stems from the same small number of dated sources. Further, as EL is currently considered a rare disease, the scientific community lacks a large enough sample size to conduct the studies needed to obtain appropriate statistical significance. Though the rare instance of a patient suffering from EL is not trivial, the greater concern remains our ignorance of the disease enabling its return in epidemic or pandemic proportions. Therefore, a global concerted effort to learn about EL is necessary. This may be best accomplished through the establishment of a global registry as has been done for other rare diseases (Hageman et al., 2023).

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Use of Artificial Intelligence (AI)

The authors declare that ChatGPT was used in a non-generative manner to optimize organizational structure of the manuscript using the authors’ own words.

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