Von Economo described encephalitis lethargica as an encephalitic epidemic that occurred between 1917 and 1925 (1). Encephalitis lethargica is a syndrome consisting of fever, headache, and nausea followed by hypersomnolence, oculomotor dysfunction, and ptosis (2). An estimated 100,000 to 160,000 cases of encephalitis lethargica occurred in Western Europe and North America, with a mortality rate of approximately 40% (3,4).

Since 1925, the number of new cases has dramatically decreased and there are only isolated sporadic cases reported. The neurological sequelae of encephalitis lethargica are referred to as postencephalitic parkinsonism (PEP) (4). The exact causative agent is unknown.

There is oligoclonal immunoglobulin G (IgG) banding in the cerebrospinal fluid (CSF) of patients during the acute phase of the illness (5). More recent cases of encephalitis lethargica have demonstrated magnetic resonance imaging (MRI) signal abnormality in the substantia nigra corresponding to autopsy findings initially reported by Von Economo in 1917 (6,7).

Encephalitis lethargica occurs in three clinical patterns: somnolent—ophthalmoplegic, hyperkinetic, and amyostatic-akinetic (4). The initial phase of the disorder includes nonspecific symptoms including fever, headache, and nausea. Somnolent—ophthalmoplegic (“sleepy sickness”) form of encephalitis lethargica was the most common of the three patterns and evolved into an increasing somnolent state. The patient could be easily aroused but would quickly lapse back into sleep if not continuously stimulated. The somnolence persisted for weeks to months, often progressing to stupor, coma, and death in nearly 50% of cases. Other symptoms included ptosis, ophthalmoplegia, nystagmus, oculogyric crisis, motor weakness, and rigidity.

The hyperkinetic form of encephalitis lethargica was characterized by an agitated, emotionally labile mental state mimicking catatonic schizophrenia in association with myoclonic jerks. Patients also developed neck and back pain, inversion of sleep patterns, and insomnia. Involuntary choreiform movements and dystonic posturing developed, as the condition progressed.

The amyostatic-akinetic form was the least common type of encephalitis lethargica. It was, however, associated with the highest percentage of neurologic sequelae. PEP represented a syndrome of delayed onset fatigue, weakness, rigidity, bent posture, and unsteady gait, which developed months to years after the acute phase of encephalitis lethargica. Although similar to Parkinson’s disease, several clinical differences distinguish PEP as a separate condition. The onset of symptoms in PEP could be at any age, including childhood, whereas idiopathic Parkinson’s disease typically occurs after 50 years of age. The characteristic
“pill rolling” tremor of idiopathic Parkinson’s disease was absent in cases of PEP. The progression of symptoms in PEP was rapid, often occurring in spurts versus the slowly insidious progression of idiopathic Parkinson’s disease.

Microscopic features of encephalitis lethargica included perivascular infiltration of lymphocytes in the Virchow-Robin spaces with small, perivascular ring hemorrhages (4). Cases of PEP demonstrated extensive severe degeneration and gliosis in the substantia nigra with intracytoplasmic globose neurofibrillary tangles (NFTs) in the remaining neurons. The presence of NFT and the absence of Lewy bodies distinguished PEP from idiopathic Parkinson’s disease (8,9 and 10). Reverse transcription-polymerase chain reaction for influenza RNA on archived tissue from patients who died during the original encephalitis lethargica epidemic did not yield any diagnostic findings (11).

In 1966, Oliver Sacks treated survivors of the 1917 epidemic with L-dopa (12). L-dopa and dopamine agonists (ropinirole) have been used to treat the extrapyramidal symptoms of PEP (7). Electroconvulsive therapy was beneficial in two cases of malignant catatonia secondary to encephalitis lethargica (13,14).

Fatal familial insomnia (FFI) typically begins between the ages of 36 and 62 years. Initially, there is impairment of attention and vigilance followed by an inability to initiate and maintain sleep. Autonomic dysfunction develops, manifested by hypertension, pyrexia in the evenings, and an increased tendency to perspire, tear, and salivate. As the condition worsens, the patient experiences hallucinations and possible acting out of dreams. The next phase includes the development of disturbances in gait, disequilibrium, dysmetria, signs of pyramidal tract involvement (hyperreflexia and presence of Babinski’s sign), and myoclonus. In the final stages, the patient suffers from increasing bouts of stupor, persistent drowsiness, myoclonus, inability to stand or walk, progressive dysarthria, dysphagia, and loss of sphincter control. Death occurs 8 to 72 months after the development of insomnia (mean duration of 18 months) (15).

A missense GAC—ACC mutation resulting in an asparagine-for-aspartic acid substitution at codon 178 of the PRNP gene (D178N) is the defining genetic marker for FFI (16,17). This same mutation is also seen in pedigrees of familial Creutzfeldt-Jakob disease (CJD). The phenotype expression of the D178N mutation (FFI vs. CJD) depends on a second polymorphism at codon 129. Homozygosity for methionine (Met/Met) at codon 129 results in FFI, whereas heterozygosity with alleles for methionine and valine (Met/Val) results in an FFI variant with longer symptom duration. Conversely, homozygosity for valine (Val/Val) results in familial CJD.

The hallmark of this prion disease is the deposition of the protein PrPSc, an aberrant isoform of PrP, which is resistant to proteases. The mediodorsal and anterior ventral thalamus, caudate nucleus, limbic areas, and the neocortex are the primary areas of deposition. The most consistent neuropathologic findings in patients with FFI are observed in the thalamus. Severe neuronal loss with reactive gliosis occurs in the anterior ventral and mediodorsal nuclei and in the inferior olives. In the later stages of the disease, there is spongy degeneration of cortical layers II to IV and loss of the cerebellar Purkinje and granule cells with reactive gliosis (17,18).

Neuroimaging with computed tomography (CT) and MRI reveals nonspecific findings of cortical and cerebellar atrophy with associated ventricular dilation. These findings become more prominent as the disease progresses (19).

Proton emission tomography (PET) imaging with fluorine-18-labeled 2-fluorodeoxy-D-glucose has demonstrated hypometabolism in the thalamus and cingulate cortex, the frontal and temporal cortices, caudate nucleus, and cerebellum in patients with prolonged disease. Hypometabolism of the thalamus and cingulate cortex is considered the PET hallmark of FFI (20).

There is progressive deterioration of normal sleep architecture and the development of aberrant behavior during rapid eye movement (REM) sleep. Electroencephalography (EEG) background activity progressively changes from an initial organized alpha rhythm to a slowed, flat, monomorphic activity with bursts of 1 — to 2-Hz periodic sharp waves associated with myoclonus. There is a reduction in total sleep time with a progressive loss of sleep spindles and K complexes. REM sleep can occur suddenly both with and without atonia. REM phases of longer duration were associated with complex behaviors of sitting up, looking around, speaking, and defensive posturing. All sleep stages are progressively lost (21).

No treatment exists for FFI; there is uniform progression to death.

Human African trypanosomiasis (HAT) is an endemic parasitic disease exclusively located in tropical Africa, reaching epidemic levels in Sudan, Uganda, the Democratic Republic of Congo, and Angola. Up to 500,000 individuals are infected with HAT (22,23,24 and 25). The trypanosome parasite is transmitted to man through the bite of the tsetse fly.

HAT is divided into two distinct forms: West African and East African trypanosomiasis (26). The West African form results from infection with Trypanosoma brucei gambiense, which is transmitted through the bite of the tsetse fly (Glossina palpalis) located in the rain forests of Central and West Africa. The East African form results from infection with T. brucei rhodesiense transmitted through the bite of the tsetse fly (G. morsitans) located in the savannahs of Central and East Africa.

HAT has two distinct successive phases: the hemolymphatic stage (stage I) and the meningoencephalitic stage (stage II) (27). An indurated, painful canker develops 1 to 2 weeks after a bite from an infected tsetse fly and then slowly resolves. Stage I begins with the development of intermittent bouts of high fever, lasting for days, alternating with extended periods of time without fever. Lymphadenopathy develops, which is particularly noticeable in the supraclavicular and cervical nodes. Specifically, enlargement of the lymph nodes in the posterior cervical triangle (Winterbottom’s sign) is a classic finding in T. brucei gambiense infection. Transient edema of the face, hands, and feet is also common. A pruritic rash composed of irregular, circular erythematous lesions with central clearing develops on the trunk, buttocks, and upper legs. In some cases, hepatosplenomegaly, tachycardia, malaise, headache, myalgias, arthralgias, irritability, and personality changes may occur.

Stage II is notable for its insidious development over the ensuing months. Apathy associated with daytime somnolence alternates with restlessness and insomnia at night. The severity and progression of the somnolence resulted in the colloquial name—sleeping sickness. Extrapyramidal signs, manifested by choreiform movements, tremors, fasciculations, and ataxia develop, resulting in some features of parkinsonism. Exaggerated deep tendon reflexes as well as presence of primitive reflexes (Babinski, sucking, palmomental) arise. Psychiatric symptoms range from indifference and mutism to agitation and confusion to aggression and in some cases, euphoria. The last stage is characterized by progressive neurologic deterioration, coma, and death.

Detection of the trypanosome is the key to diagnosis. A high index of suspicion is needed in patients who show signs of stage I infection. Fluid expressed from identified cankers or aspirated from affected lymph nodes should be fixed and stained with Giemsa. Wet preparations and Giemsa-stained thin and thick smears of peripheral blood are also useful for identifying African trypanosomes. CSF analysis is mandatory in all patients suspected of HAT. Pleocytosis (>5 cells/mm³) is typically the initial abnormality detected, followed by increased opening pressure, elevated IgM, and elevated total protein. Stage II of HAT is associated with the presence of trypanosomes in the CSF (28).

Polysomnographic studies revealed a loss of the normal sleep—wake cycle and significant disruption of sleep architecture during stage II of the disease (29). The sleep—wake cycles become shorter as the disease worsens. Frequent sleep-onset REM sleep periods occur in stage II as well. HAT is more of a circadian rhythm disorder than a hypersomnia. The sleep abnormalities can be reversed with treatment with melarsoprol (30).

Pentamidine (Pentacarinat) is the treatment of choice for stage I infections with T. brucei gambiense (44). Suramin (Germanin) is the preferred treatment of stage I T. brucei rhodesiense (31).