Influenza caused epidemic encephalitis (encephalitis lethargica): the circumstantial evidence and a challenge to the nonbelievers.

Twenty years ago, circumstantial evidence was compiled to link the 1918 pandemic influenza virus to a CNS disorder called epidemic encephalitis or encephalitis lethargica. A challenge was issued to naysayers. During the past two decades, the knowledge about the influenza virus and the 1918 pandemic virus in particular has had dramatic advancement. The 1918 virus has been resurrected and reconstructed. Experimental studies of mice inoculated with a neurovirulent avian virus have delineated the neuropathology of influenza encephalitis. Review of autopsy cases of encephalitis lethargica revealed that the neuropathology during and shortly after the pandemic was unique. Surprisingly two different viruses were involved with the great pandemic. A single amino acid difference in the hemagglutinin of the two viruses changed the preferred receptor of the virus in the host cell. One virus has qualities that suggest that it is neurovirulent. Circumstantial evidence suggests that the cause of death in some influenza patients was neurogenic congestive heart failure with pulmonary edema. Theories about the pathophysiology of encephalitis lethargica and postencephalitic Parkinson's disease are offered.

The puzzle of where cerebrospinal fluid is absorbed: new pieces.

The widely held theory of cerebrospinal fluid (CSF) absorption by the arachnoid villus system cannot explain the movement of substances within the fluid, the deposition pattern of corpora amylacea on the surface of the brain, and pathological findings in neurological disorders. Experiments studying the movement of melatonin and inulin in the CSF compartment demonstrate that some CSF recycles into the ventricular system and CSF contacting tissue diffusely absorbs some. Photomicrographs of a suprapineal recess portal into the third ventricle are presented. A cycling theory of CSF assigns function to the structure of the choroid fissures and the suprapineal recess.

Postencephalitic Parkinson's disease, amyotrophic lateral sclerosis on Guam and influenza revisited: focusing on neurofibrillary tangles and the trail of tau.

Circumstantial evidence links neuropathological changes in postencephalitic Parkinson's disease and amyotrophic lateral sclerosis on Guam to the 1918 influenza pandemic. Postencephalitic Parkinson's disease and amyotrophic lateral sclerosis have neuronal neurofibrillary tangles that anatomically correlate with clinical signs and symptoms. Occurrences of the disorders peaked in the early 1950s and are now disappearing. Neurovirulent influenza associated with the lethal 1918 pandemic is suggested as the etiology of both diseases. Permissive tissue antigens are considered an important contributing factor. Neurofibrillary tangles also correlate with signs and symptoms in Alzheimer's disease. Oxidative stress may be the pathological process that induces neurofibrillary tangles. Tangles contain abnormally phosphorylated tau. In Alzheimer's disease, tau is present in cerebrospinal fluid and is deposited in corpora amylacea, demonstrating the direction of cerebrospinal fluid flow.

Alzheimer's disease: roles for mitochondrial damage, the hydroxyl radical, and cerebrospinal fluid deficiency of melatonin.

A deficiency of cerebrospinal fluid melatonin is postulated to be critical for the development of Alzheimer's disease. Some melatonin is normally secreted directly into the fluid inducing higher levels than in simultaneously sampled blood. Melatonin is carried into the ventricular system via choroid plexus portals. The neurohormone is a potent antioxidant that passes through cell membranes with ease and is concentrated in mitochondria. Neural tissue in contact with the ventricular system will have high levels of cellular melatonin. In Alzheimer's disease, inadequate melatonin allows hydroxyl radicals produced by mitochondrial complex IV to damage mitochondria and initiate a cascade of oxygen radicals that causes the neuropathological changes in Alzheimer's disease. Results from initial therapeutic trials of melatonin in Alzheimer's disease patients have demonstrated improved function, decreased 'sundowning', improved sleep, and a significant slowing of the progression of the disease.

A preliminary understanding of mania: roles for melatonin, vasotocin and rapid-eye-movement sleep.

Speculation about mania links melatonin, vasotocin and rapid-eye-movement (REM) sleep. Normal REM sleep can have the loss of reality testing and this feature intruding into the wake period could be the cause of the distorted reality present in manic delusions. REM sleep has a role in memory formation. Abnormal levels and/or rhythms of melatonin are thought to be involved in mania. Decreased melatonin production with malfunction of REM sleep is proposed to be a cause of sudden infant death syndrome and Alzheimer's disease, because the loss of the antioxidant function of melatonin allows brain injury to occur.

A cycle of cerebrospinal fluid: supporting evidence and theoretical considerations.

An entrenched theory of cerebrospinal fluid (CSF) absorption by the arachnoid villi fails to explain observations regarding the movement of substances in the fluid. Experiments that demonstrated the arachnoid villi as the site of absorption were based on non-physiologic methods. CSF does not flow through the arachnoid villi, because villi require bulk flow and bulk flow of CSF does not exist. CSF is transported through the choroid fissure and recycled through the tela choroidae by the choroid plexus, with reentry into the ventricular system. Observed failures of the effete arachnoid villus theory can be readily explained by the cycling theory. A complete cycle of CSF is suggested to pace the 90 to 100-minute ultradian rhythms found in human physiology.

Could antioxidant therapy reduce the incidence of deafness following bacterial meningitis?

Sensorineural hearing loss following acute bacterial meningitis could be caused by hydroxyl radicals generated by the inflammatory response. Obstruction of cerebrospinal fluid circulation through the tela choroidae of the choroid plexuses, with subsequent rupture of the tela choroidae, would expose the auditory nerve to selective radical damage. Acute administration of lipophilic antioxidants might provide the auditory nerve with increased protection.

Short note: The fetal origins hypothesis: linking pineal gland hypoplasia with coronary heart disease and stroke.

Pineal gland hypoplasia secondary to intrauterine malnutrition is suggested as a fetal contribution to sudden infant death syndrome, coronary artery disease and ischemic stroke. The loss of melatonin's antioxidant activity is proposed as an additional factor to consider in atherosclerotic vascular disease.

Loss of intraventricular fluid melatonin can explain the neuropathology of Alzheimer's disease.

Loss of intraventricular fluid melatonin explains why Alzheimer's disease neuropathology has a laminar, regional and neural-system-specific pattern, which includes the entorhinal cortex, CA1 of the hippocampus, the dorsal raphe nucleus and the locus ceruleus. High metabolic activity may be part of the neuronal vulnerability. Without elevated levels of ventricular fluid melatonin, the hydroxyl radical damages the mitochondria of the most active neurons, causing apoptosis, with resultant failure of the memory system. General brain atrophy follows in the absence of new memory formation.

Could exogenous melatonin prevent sudden infant death syndrome?

Hypoplastic pineal glands and decreased melatonin levels are found in sudden infant death syndrome. Excess oxygen radical production and inadequate radical quenching is suggested to cause oxidative stress in the brain of sudden infant death syndrome victims. Loss of intraventricular cerebrospinal fluid melatonin could play an important role in the disease process. Infants at risk might be protected by exogenous melatonin.

Superficial siderosis of the brain: roles for cerebrospinal fluid circulation, iron and the hydroxyl radical.

Superficial siderosis is associated with chronic blood loss into the cerebrospinal fluid. The pattern of hemosiderin deposition and clinical signs in superficial siderosis suggest that cerebrospinal fluid is recirculated into the ventricular system. Patterns of deposition of corpora amylacea and findings in normopressure communicating hydrocephalus also support the recirculation theory. 'Free' iron with excess production of hydroxyl radicals is the probable mechanism of tissue damage. The arachnoid villus-superior saggital sinus theory of cerebrospinal fluid circulation should be abandoned.

The mystery of Alzheimer's disease and its prevention by melatonin.

Preliminary observation suggested that a melatonin deficiency could cause Alzheimer's disease. New evidence reveals that: 1) a significant melatonin deficiency is common in the disease, 2) melatonin acts as a hydroxyl radical scavenger and 3) brain tissue mitochondria from Alzheimer's patients have damage consistent with hydroxyl radical injury.

Recirculation of cerebrospinal fluid through the tela choroidae is why high levels of melatonin can be found in the lateral ventricles.

Evidence is presented to support the hypothesis that cerebrospinal fluid (CSF) is transported through the tela choroidae and recirculated in the ventricular system. The concept that the CSF is resorbed by the arachnoid villus-superior sagittal sinus system is accepted as fact. The experimental studies on which the currently accepted theory is based were published in 1914 by Dr Lewis Weed. Weed used a low pressure (near physiologic) method and a high pressure (non-physiologic) method. His observations with the high pressure method are a basis for the theory of arachnoid villus absorption. On the other hand, his low pressure method provides evidence that CSF is absorbed in the area of the basilar cisternae. Studies of communicating hydrocephalus and chemical analysis of ventricular melatonin give evidence that CSF recirculates through the tela choroidae back into the ventricles.

The therapeutic potential for tryptophan and melatonin: possible roles in depression, sleep, Alzheimer's disease and abnormal aging.

Evidence suggests that stress and/or a dietary lack of tryptophan may make deficiencies of serotonin and melatonin common. In addition, older animals and human beings have a reduced ability to synthesize melatonin. Disorders of melatonin levels and rhythms are suggested to be a cause of affective disease, abnormal sleep, Alzheimer's disease, and some age related disorders. If these ideas prove to be true, then preventive measures are possible.

Influenza caused epidemic encephalitis (encephalitis lethargica): the circumstantial evidence and a challenge to the naysayers.

Circumstantial evidence implicates the influenza virus as the cause of epidemic encephalitis. Arguments used to refute influenza as the causative agent are examined and a challenge is made to naysayers to implicate a viral agent other than influenza.

Why not treat melancholia with melatonin and tryptophan and treat seasonal affective disorders with bright light?

Symptoms, signs, and biologic markers in melancholia are suggested to be secondary to a deficiency of melatonin, with the resultant increase of monoamine oxidase activity, increase in plasma cortisol, and alteration of sleep physiology. Tryptophan and melatonin, given shortly before bedtime, seem to be rational treatment for melancholia. Bright light may be effective in seasonal affective disorder because it markedly strengthens the zeitgeber that controls biologic rhythms in human beings.

Dementia--the failure of hippocampal plasticity and dreams. Is there a preventative role for melatonin?

Anatomic, chemical, physiologic, pathologic and clinical evidence suggests that senile dementia (Alzheimer's disease) is a dysfunction of the hippocampus. Failure of hippocampal plasticity could be secondary to loss of input from the medial septal nucleus and/or locus ceruleus or due to a functional abnormality. When compared to age-matched controls, demented patients have decreased hippocampal norepinephrine and serotonin, increased hippocampal monoamine oxidase, and decreased REM sleep. These observations could be explained by a melatonin deficiency. A chronic melatonin deficiency, with loss of dreams, could cause dementia.

The function of dreams (REM sleep): roles for the hippocampus, melatonin, monoamines, and vasotocin.

Rapid eye movement (REM) sleep is suggested to play a role in the storage of memory, resolution of emotional experiences, and erasure of memory (forgetting). Plasticity of hippocampal physiology, morphology, and chemistry seems to be evidence for new memory formation. REM sleep, melatonin, and monoamines may be involved in the transfer of memory from the intermediate-term high-capacity buffer in the hippocampus into long-term memory storage in the neocortex. Vasotocin, which is released by melatonin, could be an amnestic agent that erases recent memory from the hippocampal-entorhinal complex during dreams.

The pathophysiology of enlarged ventricles in normal pressure communicating hydrocephalus and schizophrenia: a possible therapeutic role for melatonin.

A dysfunction of the choroid plexus or the tela choroidae is suggested as the cause of ventricular enlargement in normal pressure communicating hydrocephalus and in some schizophrenic syndromes. In communicating hydrocephalus, the function of the tela choroidae could be impaired by infectious or inflammatory processes; while in schizophrenia a physiologic disorder of cerebrospinal fluid production due to a melatonin deficiency may result in dilated ventricles. Paradoxically, in both disorders, there is decreased production of cerebrospinal fluid.