Von Economo Encephalitis

Etiology

The specific cause of von Economo encephalitis is unknown but is most likely related to an autoimmune reaction against neuronal proteins. The prevalence of encephalitis lethargica occurred during the Spanish influenza pandemic, and several reports attributed the etiology to the influenza virus.[7] However, recent studies using old brain samples do not confirm the association with the influenza virus.[8][9][10] 

Von Economo ruled out external sources such as sausage poisoning and gas poison. As there was no contact with another individual, meningitis, and polio were also ruled out. Discussions related to the etiology of influenza were still mentioned. However, his cases and a few other reports concluded that the encephalitis lethargica is a separate disorder than directly caused by the influenza infection. Still, influenza as a prodromal phase was not ruled out by von Economo.[11] 

The archival tissues of the encephalitis lethargica patients were RT-PCR tested in 2001 but failed to show evidence of the influenza virus. This disease was recently described as associated with streptococcal infection and included in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).[6]

Epidemiology

The spread of the disease is thought to have been facilitated by the military troops' movement during World War I across Europe. Although the exact amount of affected individuals was never recorded, it is estimated more than one million were affected.[7][12]

The condition was more prevalent in individuals between the ages of 10 and 45 without gender predominance. In the somnolent-ophthalmoplegic form, the mortality exceeded 50%.[12] Children, the elderly, and people with existing respiratory diseases are more susceptible.[13] No other epidemics have occurred after the epidemic of 1916, but occasional cases are still reported.

Pathophysiology

Von Economo encephalitis is a disorder of possible autoimmune origin that affects the midbrain, pons, basal ganglia, and substantial nigra. It is believed that this autoimmune reaction follows an initial viral (influenza) or bacterial (streptococcal) infection.[1] The damage to these areas manifests with a wide variety of symptoms, the most common of which are sleep disorders, abnormal movements (especially parkinsonism), and neuropsychiatric disorder.[13] The pathophysiology for hypersomnolence is attributed to inflammation of the reticular activating system, ophthalmoplegia to the involvement of cranial nerve nuclei and tracts, and parkinsonism-like features to basal ganglia involvement.[6]

Postencephalitic parkinsonism is based on the hypothesis that dopamine depletion and hypersensitive dopamine receptors result in dopamine neurotransmission imbalance.[5] In encephalitis lethargica, the parkinsonism syndrome affecting dopamine neurotransmission shows significant improvement with dopamine agonists.

Von Economo described three clinical forms of encephalitis lethargica:[1][4][6][11][13][14]

1. Somnolent-ophthalmologic form characterized by excessive sleepiness followed by progressive confusion, stupor, and coma. It was associated with internal ophthalmoplegia, oculogyric crisis, nystagmus, dyskinesia, pyramidal, and cerebellar signs.
2. Amyostatic-akinetic form characterized by acute parkinsonism, catatonia, or mutism.
3. The hyperkinetic form presented restlessness, mania, visual hallucination, chorea, hemichorea, myoclonic twitches, troublesome sleeplessness, and dyskinesia.

Histopathology

The pathology often shows changes in the upper midbrain, substantia nigra, basal ganglia, pons, thalamus, and medulla that correlate with the illness's clinical features. Perivascular lymphocyte infiltration, especially plasma cells, activated astrocytes, and macrophages were usually seen. No viral inclusion bodies, presence of amyloid or complement in basal ganglia were found.[14]

In a large percentage of patients, oligoclonal bands, and antibodies against the basal ganglia were detected. In 65% of patients, antibodies against beta-hemolytic streptococci were detected.[13] Autopsy findings revealed meningeal involvement with brain vessel engorgement. Red spots on the cerebral cortex, medulla oblongata, ventral and dorsal horns of the cervical spinal cord showed petechial hemorrhage.[1] Microscopic examination showed inflammation of the gray matter, especially at the midbrain.[2][11]

History and Physical

Von Economo encephalitis involves acute and chronic phases.[12] The acute phase can have flu-like prodromal symptoms followed later by neurological sequelae, including hemiplegia and death in several cases. There is an initial manic phase in the hyperkinetic form, followed by chorea, vocalization, myorhythmia of ocular and masticatory muscles, and myoclonic twitches. In the amyostatic-akinetic form, rigidity and lack of movements may be observed, without noticeable weakness. In the somnolent ophthalmoplegic form, patients exhibit meningeal irritation with cranial nerve III, IV, and VI palsies leading to ophthalmoplegia. Amblyopia due to the oculomotor nerve was most common but paresis related to trigeminal, abducens, and facial nerves were also noted. Most patients experience an overwhelming desire to sleep and sleep for abnormally long hours; however, they were easily awakened.[2][3] 

Parkinsonism with extrapyramidal signs due to basal ganglia involvement can be seen as an early or late complication. Patients will present stiffness and bradykinesia involving the upper extremities more than the lower. They can also show chorea, myoclonus, torsion spasms, and facial tics, including the tongue and palate.[1] Von Economo encephalitis can present with high fever, headache, double vision, vertigo, vomiting, catatonia, confusion, and increased tone in all four extremities. Catatonia presents with immobility, staring, negativism, stupor, and echolalia. Characteristic symptoms of hypersomnolence, easy arousable, ophthalmoplegia, and extrapyramidal signs following a recent upper respiratory tract infection suggest the development of autoimmune encephalitis.[3][12]

The chronic phase of encephalitis lethargica can immediately follow the acute phase; however, it usually starts one to five years later. This phase was typified by parkinsonism. Several other symptoms occurred concomitantly, including oculomotor abnormalities, sleep disturbances, psychiatric disorders, and involuntary movements. Psychiatric manifestations consisted of mood changes, euphoria, increased sexual drive, and hallucinations. Post paresis phase had presentations of increased reflexes, including positive Babinski’s signs and spasms for a prolonged time even after the recovery from ocular muscle paralysis and somnolence.[1][3]

Evaluation

Brain magnetic resonance imaging will reveal hyperintense lesions in the midbrain tegmentum, thalamus, and basal ganglia. The changes resolve when recovery from the disease is complete.[14]

Cerebrospinal fluid (CSF) analysis:[1][2][3][15]

• sometimes show increased CSF protein
• negative for bacteria or virus
• oligoclonal IgG bands present
• mild/moderate lymphocytic pleocytosis
• normal glucose

Electroencephalography and evoked potentials: may present diffuse unilateral or bilateral slowing, with occasional focal sharp waves and altered evoked potential.[1][4][13]

Treatment / Management

Treatment for encephalitis is supportive. Methylprednisolone 1 gram intravenously daily for three days produces significant improvement. The first-line treatment for catatonia is benzodiazepines, followed by electroconvulsive therapy. In treatment-resistant cases, bromocriptine, memantine, zolpidem, and valproate can also be used.[5] However, in encephalitis with parkinsonism, dopamine agonists played a pivotal role. Few reports showed that simultaneous administration of levodopa and carbidopa has a better outcome than levodopa alone.[5][16] The use of immunoglobulin and plasmapheresis has not been well established yet.[14] Acyclovir has not proven any benefits.(B3)

Differential Diagnosis

• Parkinson disease
• Psychiatric illness
• Limbic encephalitis
• Herpes simplex encephalitis
• Bickerstaff brainstem encephalitis
• Rasmussen encephalitis
• Hashimoto encephalopathy
• Anti-N-methyl-D-aspartate receptor encephalitis

Prognosis

One-third of the patients died during the acute phase, while another third recovered without sequelae and another third suffered chronic neurological sequelae.[1][14]

Complications

• Hemiplegia
• Stupor
• Coma
• Ophthalmoplegia
• Oculogyric crisis 
• Chorea
• Hemichorea
• Dyskinesia
• Acute parkinsonism
• Mood changes
• Catatonia
• Mutism
• Visual hallucination
• Mania
• Euphoria
• Troublesome sleepiness