What is encephalitis lethargica
Encephalitis lethargica, also known as von Economo encephalitis, is a rare disease of unknown cause that affects the midbrain and basal ganglia that is characterized by high fever, headache, double vision, delayed physical and mental response, and extreme tiredness (lethargy). In acute encephalitis lethargica cases, patients may enter coma. Patients may also experience abnormal eye movements (oculogyric crises), upper body weakness, muscular pains, tremors, neck rigidity, extrapyramidal movements (parkinsonism and dyskinesias), and neuropsychiatric disturbance (psychosis, obsessive, compulsive disorder, catatonia, mutism, apathy and conduct disorders) and behavioral changes.
Whilst the exact frequency or incidence, presentation, disease course, treatment response and disease mechanisms are relatively undefined, there are some classic or typical presentations: encephalitis lethargica often presents as an acute illness in young adults (and sometimes children) with initial fever, headache, lethargy, visual symptoms, muscle weakness, neuropsychiatric features (e.g. confusion, hallucinations, behavioral changes), altered consciousness state (e.g. drowsiness) and sleep disorder (increased or decreased sleep). In addition, many patients develop a movement disorder, with either parkinsonism (reduction in movement) or abnormal increase in movements of various kinds, affecting limbs, trunk, face or eyes. This may sometimes develop many months after the onset of the initial illness. Typically behavioral and motor disturbances fluctuate over hours or days. Laboratory tests may show abnormalities of the cerebrospinal fluid (CSF – the fluid that the brain and spinal cord float in), abnormalities of brain imaging and negative tests for other known infectious and inflammatory cerebral disorders.
The cause of encephalitis lethargica is unknown, but a viral origin is suspected. Between 1917 to 1928, an epidemic of encephalitis lethargica spread throughout the world affecting half a million persons, but no recurrence of the epidemic has since been reported 1). The acute phase was lethal for many victims. Postencephalitic Parkinson’s disease may develop after a bout of encephalitis lethargica-sometimes as long as a year after the illness.
The course of encephalitis lethargica varies depending upon complications or accompanying disorders. Some people may make a full recovery, some patients die, and for others a Parkinsonian-type state may persist. Von Economo wrote “to look at these patients, one would suppose them to be in a state of profound secondary dementia. Emotions are scarcely noticeable in the face but they are mentally intact”.
Treatment for encephalitis lethargica is symptomatic. Levodopa and other antiparkinson drugs often produce dramatic responses. However, no specific treatment for the underlying encephalitis lethargica disorder is available at present.
Encephalitis lethargica epidemic
Encephalitis lethargica or Von Economo’s encephalitis was first recognized by von Economo in the wards of the Vienna Psychiatric Clinic in late 1916 2) although its initial appearance may have been in April and May 1915 in Rumania 3). By 1919, it had spread worldwide 4). During the course of the 1917–1926 epidemic, approximately half a million people world-wide were affected by encephalitis lethargica. About one-third of the patients died acutely, one-third developed postencephalitic Parkinson’s disease and the remainder recovered almost completely. Sporadic cases diagnosed as encephalitis lethargica have been reported up to the present time, but it has not been clear whether they share the same etiology as classical encephalitis lethargica 5).
Encephalitis lethargica manifested in a number of fashions, but typically included the triad of fever, somnolence, and oculomotor paresis. For unexplained reasons, the disease had a predilection for young adults. Nearly 50% of infected patients were between the ages of 10 and 30 years old 6). The etiology of the disorder has never been identified. In most circumstances, the disease predated the influenza pandemic 7) and modern studies have failed to amplify influenza DNA from the brain tissues of affected individuals 8).
The precipitating microorganism of epidemic encephalitis lethargica remains unknown. Unlike influenza, encephalitis lethargica was not very contagious and even intrafamilial spread was unusual. Further evidence against influenza being the cause of encephalitis lethargica was that von Economo had observed encephalitis lethargica for 3 years before the onset of the great influenza pandemic. In addition, patients with encephalitis lethargica rarely had influenza before neurological onset; in one early report of 76 encephalitis lethargica cases, only four had influenza in the preceding 6 months 9).
Recent PCR examination of five acute encephalitis lethargica brains from the 1920s epidemic revealed no influenza RNA. Unlike respiratory tissue from patients who died of the 1918 influenza viral pneumonia, brain tissue from encephalitis lethargica patients had no influenza RNA. The authors concluded that the 1918 influenza virus was unlikely to have been directly responsible for the outbreak of encephalitis lethargica 10). A separate recent study also demonstrated the lack of influenza genes in archived formalin‐fixed brain samples of encephalitis lethargica patients from 1916 to 1920 11).
Postencephalitic Parkinson’s disease was a frequent sequelae of this disorder. Parkinsonism could develop acutely or after more than a decade. A hiatus of 45 years from the time of encephalitis lethargica to parkinsonism has been reported 12). In contrast to idiopathic Parkinson’s disease, these patients often demonstrated oculogyric crises, catatonia, cataplexy, paradoxical movements, and unique speech and respiratory problems 13). Examination might reveal pupillary changes, torsion spasms, and corticospinal tract abnormalities 14). In 1961, Poskanzer and Schwab proposed that nearly all cases of idiopathic Parkinson’s disease were the consequence of clinical or subclinical encephalitis lethargica 15). Subsequent population-based studies, failed to confirm that hypothesis 16).
Encephalitis lethargica cause
So far, the exact cause is unknown, but there is lymphocyte infiltration of the midbrain and basal ganglia. It is thought that there may be an autoimmune component, possibly triggered after a viral infection. Autoantibodies reactive against human basal ganglia antigens present in the majority of encephalitis lethargica patients.
Several opinions argued that encephalitis lethargica started from the 1919 influenza epidemic as either an acute viral, or a post viral syndrome. More recent work linking encephalitis lethargica to a streptococcal infection may prove more compelling than the influenza theory. Although the last epidemic of encephalitis lethargica occurred nearly a century ago, the cause was never scientifically established, and remains a matter of controversy today. This makes diagnosis difficult, and is one of the reasons why scientists and doctors do not know how many cases of encephalitis lethargica there have been in recent times. Doctors still see seeing sporadic cases of encephalitis lethargica today. Some suspected encephalitis lethargica may actually be N-methyl-D-aspartate (NMDA) receptor encephalitis and therefore all suspected cases of encephalitis lethargica should be tested for N-methyl-D-aspartate (NMDA) receptor encephalitis.
Postencephalitic Parkinson’s disease was a well recognized consequence of encephalitis lethargica, typically developing 1 to 5 years after the acute illness 17). This illness differed from idiopathic Parkinson’s disease in several respects as patients often displayed paradoxical movements, oculogyric crises, catatonia, and unusual speech and respiratory problems 18). Dale and colleagues have recently reported 20 cases of encephalitis lethargica and maintain that the illness persists in the modern population 19). Occasional cases of selective involvement of the substantia nigra and parkinsonism following an acute encephalitic illness from identified viruses are recognized as well. Among these viruses are coxsackie B4 20), Epstein-Barr virus 21), and Japanese B encephalitis 22). HIV may also cause a clinical picture that masquerades as Parkinson’s disease 23) and the basal ganglia appears to be a selective target for HIV with greater rates of viral replication, associated with loss of dopaminergic neurons, decrease CSF dopamine, central atrophy exceeding cortical atrophy 24). Parkinsonism may also follow other infectious illnesses including gram negative sepsis 25), and cryptococcal meningoencephalitis 26).
Encephalitis lethargica symptoms
The term ‘sleeping sickness’, where people seem to fall asleep or freeze whilst eating or working was first used to describe two cases in Vienna. However, the disease can present a wide and sometimes confusing range of symptoms, often with unusual and bizarre behavior. There are indications that the majority of cases were referred to psychiatrists before being admitted to hospital if the symptoms progressed. It is often mistaken for epilepsy, hysteria, intoxication or a reaction to drugs.
Proposed diagnostic criteria for encephalitis lethargica which has been widely accepted includes an acute or subacute encephalitic illness where all other known causes of encephalitis have been excluded. More recently it has been suggested that the diagnosis of encephalitis lethargica may be considered if the patient’s condition cannot be attributed to any other known neurological condition and that they show the following signs: influenza-like signs; hypersomnolence (hypersomnia), wakeability, opthalmoplegia (paralysis of the muscles that control the movement of the eye), and psychiatric changes.
The following symptoms are based on 20 new cases of encephalitis lethargica from 1999-2002 who were referred to tertiary neurology centers with a new‐onset CNS dysfunction resulting in an encephalitis lethargica‐like syndrome (sleep disorder and associated lethargy, parkinsonism and neuropsychiatric disorders) 27).
Eleven patients (55%) had an infection shortly before disease onset. The infections were described as upper respiratory tract infection (n = 6) and tonsillitis (n = 5). Presentation was described as acute, subacute and insidious in 35, 50 and 15% of patients respectively. In this study, one of the patients died and five had a reduced consciousness level and required ventilation. It is probable that these ventilated patients would have died were it not for contemporary intensive care. Complete recovery occurred in a minority of patients in this series; the majority are still suffering continued psychiatric and movement disorders. The course of disease was monophasic or fluctuating, unlike the progressive course characteristic of the metabolic, biochemical or inherited causes of Parkinson’s disease.
Sleep disturbance and lethargy
Nineteen of 20 (95%) patients had sleep disturbance, hypersomnolence (n = 12), insomnia (n = 2) or sleep inversion (n = 5). It was usually possible to rouse the somnolent patients without difficulty, but they would fall asleep if not stimulated. Other sleep abnormalities included vivid nightmares (n = 2) and sleep‐walking (n = 1). Ten patients had lethargy, which was in excess of what would be expected for the degree of motor weakness.
All patients had signs consistent with parkinsonism. Twelve of 20 patients had a Parkinson’s syndrome according to United Kingdom Parkinson’s Disease Society Brain Bank criteria: six had all three cardinal features (bradykinesia, rigidity and rest tremor), two had bradykinesia with postural instability, two had bradykinesia with rigidity, and two had bradykinesia with rest tremor. The other eight patients had isolated features of the parkinsonian phenotype: bradykinesia/akinesia (n = 6), rest tremor (n = 1) or rigidity with rest tremor (n = 1).
In addition to parkinsonism, 11 patients had evidence of dyskinetic movement disorders: dystonia (n = 6, of whom five had generalized dystonia); chorea/hemiballismus (n = 2); motor tics (n = 2); stereotypies (n = 2); facial grimacing and blepharospasm (n = 1 each). Three patients had oculogyric crises.
The psychiatric manifestations are described in Table 3. Seventeen of 20 patients had psychiatric disturbance. Mutism occurred in ten patients. Emotional disorders were also common and included depression (n = 6), obsessive–compulsive disorder (n = 3) and anxiety (n = 2). Apathy and catatonia occurred in four and three patients respectively.
Five patients had profound reduction in consciousness and required ventilation. Eight patients had ocular abnormalities [four ophthalmoplegia, three pupillary disturbance (one with ophthalmoplegia), one ptosis, one optic neuritis]. Hyper ventilation and nocturnal bradycardia were also observed. Seizures and memory loss occurred in three patients each. Symptoms of intracranial pathology were common, including headache (n = 6), photophobia (n = 3) and meningism (n = 2). Other features included incontinence (n = 3) and limb pains (n = 2).
Table 1. Patient demographics and clinical characteristics
|Diagnosis||Primary management option||Alternate option|
|Inflammatory and papulosquamous lesions|
|Angiokeratoma||Observation||Surgery, cryoablation, electrocautery, laser ablation|
|Lichen nitidus||Observation||Topical corticosteroids, vitamin A analogues, cyclosporine (Sandimmune), itraconazole (Sporanox), phototherapy|
|Lichen planus||Topical corticosteroids||Circumcision for isolated prepuce lichen planus|
|Lichen sclerosus||Topical corticosteroids||Circumcision for isolated prepuce lichen sclerosus|
|Psoriasis||Topical corticosteroids||Vitamin D3 analogues, tacrolimus (Protopic), or pimecrolimus (Elidel)|
|Carcinoma in situ||Circumcision for isolated prepuce lesions||Mohs micrographic surgery Topical imiquimod (Aldara)|
|Invasive squamous||Circumcision for isolated prepuce lesions Mohs micrographic surgery for nonisolated lesions||Partial or radical penectomy Laser therapy, radiation, and brachytherapy have been attempted as alternatives|
Note: M = male; F = female; OCD = obsessive–compulsive disorder.[Source 28)]
Encephalitis lethargica treatment
There is no known cure and no clearly effective treatment. Treatment for encephalitis lethargica is symptomatic. Historically, success has been claimed for immunomodulating therapies and steroids (anti-inflammatory drugs), anti-parkinson drugs (levodopa and other antiparkinson drugs often produce dramatic responses) and electroconvulsive therapy (ECT). During the initial stages of the illness, bodily functions need to be maintained, often involving intensive care therapy. As the condition settles it is a matter of maintaining and hopefully improving function by good physiotherapy, speech therapy and nutrition, as well as providing emotional support.
References [ + ]
|1.||↵||Dourmashkin RR, Dunn G, Castano V, McCall SA. Evidence for an enterovirus as the cause of encephalitis lethargica. BMC Infectious Diseases. 2012;12:136. doi:10.1186/1471-2334-12-136. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448500/|
|2.||↵||von Economo C. Encephalitis lethargica: Its sequelae and treatment. London: Oxford University Press; 1931.|
|3.||↵||Urechia CL. Dix cas d’encephalite epidemique avec autopsie. Arch Inter Neurol. 1921;2:65–78.|
|4, 13, 14, 17, 18.||↵||Berger JR, Glitza IC. Von Economo’s Encephalitis. In: Nath A, Berger JR, editors. Clinical Neurovirology. New York: Marcel Dekker, Inc; 2003. pp. 523–42.|
|5.||↵||Lopez-Alberola R, Georgiou M, Sfakianakis GN, Singer C, Papapetropoulos S. Contemporary encephalitis lethargica: phenotype, laboratory findings and treatment outcomes. J Neurol. 2009;256:396–404. doi: 10.1007/s00415-009-0074-4. https://www.ncbi.nlm.nih.gov/pubmed/19412724|
|6.||↵||Wilson SAK. Epidemic encephalitis. Neurology. 1940;1:99–144.|
|7, 12.||↵||Berger JR, Glitza I. Von Economo’s encephalitis. In: Nath A, Berger JR, editors. Clinical Neurovirology. New York, NY: Marcel Dekker; 2003. pp. 523–42.|
|8.||↵||McCall S, Henry JM, Reid AH, Taubenberger JK. Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases. J Neuropathol Exp Neurol. 2001 Jul;60(7):696–704. https://www.ncbi.nlm.nih.gov/pubmed/11444798|
|9.||↵||Stallybrass CO. Encephalitis lethargica. Lancet 1923; 2: 922–5.|
|10.||↵||McCall S, Henry JM, Reid AH, Taubenberger JK. Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases. J Clin Neuropathol Exp Neurol 2001; 60: 696–704.|
|11.||↵||Lo KC, Geddes JF, Daniels RS, Oxford JS. Lack of detection of influenza genes in archived formalin‐fixed, paraffin wax‐embedded brain samples of encephalitis lethargica patients from 1916 to 1920. Virchows Arch 2003; 442: 591–6.|
|15.||↵||Poskanzer DC, Schwab RS. Studies in the epidemiology of Parkinson’s disease predicting its disappearance as a major clinical entity by 1980. Trans Am Neurol Assoc. 1961;86:234–5 https://www.ncbi.nlm.nih.gov/pubmed/14488169|
|16.||↵||Lipczynska-Lojkowska W. Etiology of parkinsonism. A verification of Poskanzer’s and Schwab’s hypothesis. Neurol Neurochir Pol. 1979 Nov-Dec;13(6):593–9 https://www.ncbi.nlm.nih.gov/pubmed/514436|
|19.||↵||Dale RC, Church AJ, Surtees RA, et al. Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain. 2004 Jan;127(Pt 1):21–33 https://www.ncbi.nlm.nih.gov/pubmed/14570817|
|20.||↵||Cree BC, Bernardini GL, Hays AP, Lowe G. A fatal case of coxsackievirus B4 meningoencephalitis. Arch Neurol. 2003 Jan;60(1):107–12. https://www.ncbi.nlm.nih.gov/pubmed/12533096|
|21.||↵||Roselli F, Russo I, Fraddosio A, et al. Reversible Parkinsonian syndrome associated with anti-neuronal antibodies in acute EBV encephalitis: a case report. Parkinsonism Relat Disord. 2006 May;12(4):257–60. https://www.ncbi.nlm.nih.gov/pubmed/16459123|
|22.||↵||Murgod UA, Muthane UB, Ravi V, Radhesh S, Desai A. Persistent movement disorders following Japanese encephalitis. Neurology. 2001 Dec 26;57(12):2313–5 https://www.ncbi.nlm.nih.gov/pubmed/11756619|
|23.||↵||Mattos JP, Rosso AL, Correa RB, Novis SA. Movement disorders in 28 HIV-infected patients. Arq Neuropsiquiatr. 2002 Sep;60(3-A):525–30. https://www.ncbi.nlm.nih.gov/pubmed/12244384|
|24.||↵||Berger JR, Arendt G. HIV dementia: the role of the basal ganglia and dopaminergic systems. J Psychopharmacol. 2000;14(3):214–21 https://www.ncbi.nlm.nih.gov/pubmed/11106299|
|25.||↵||Alasia DD, Asekomeh GA, Unachuku CN. Parkinsonism induced by sepsis: a case report. Niger J Med. 2006 Jul-Sep;15(3):333–6. https://www.ncbi.nlm.nih.gov/pubmed/17111773|
|26.||↵||Wszolek Z, Monsour H, Smith P, Pfeiffer R. Cryptococcal meningoencephalitis with parkinsonian features. Mov Disord. 1988;3(3):271–3 https://www.ncbi.nlm.nih.gov/pubmed/3193965|
|27, 28.||↵||Russell C. Dale, Andrew J. Church, Robert A. H. Surtees, Andrew J. Lees, Jane E. Adcock, Brian Harding, Brian G. R. Neville, Gavin Giovannoni; Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity, Brain, Volume 127, Issue 1, 1 January 2004, Pages 21–33, https://doi.org/10.1093/brain/awh008|