Brainstem Gliosis Research Articles

Developmental neurotransmitter pathology in the brainstem of sudden infant death syndrome: a review and sleep position

Developmental studies on neurotransmitters and their receptors in sudden infant death syndrome (SIDS) infants and controls are reviewed, including comparison between the prone and supine positions at death. In SIDS infants, there are an increase of glial fibrillary acidic protein (GFAP)-positive astrocytes in the brainstem, an increase of substance P (SP) in the medulla and pons, a decrease of tyrosine hydroxylase (TH)-positive catecholaminergic neurons in the ventrolateral medulla (VLM), and vagal nuclei in the medulla oblongata and basal ganglia, a decrease of tryptophan hydroxylase (TrH)-positive serotonergic neurons in the periaqueductal gray matter (PAG), and decreases of 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A receptor immunoreactivities in the VLM and vagal nuclei in the medulla oblongata. These findings may be the result of chronic or repeated hypoxia and at the same time suggest hypofunction or immaturity of cardiorespiratory regulation. In contrast, 5-HT1A and 5-HT2A receptor immunoreactivities are increased in the PAG of SIDS infants. These increased immunoreactivities may reflect delayed neuronal maturation or a developmental abnormality of the nocicetive reaction of cardiorespiratory and arousal control in SIDS. Also, there are no differences of brainstem gliosis and catecholaminergic neuron changes between the prone and supine positions. Therefore, these changes may be predisposing factors for SIDS.

From epidemiology to physiology and pathology: apnea and arousal deficient theories in sudden infant death syndrome (SIDS)—with particular reference to hypoxic brainstem gliosis

Among 27,000 infants studied prospectively to characterize their sleep–wake behavior, 38 infants died under 6 months of age. They included 26 cases of sudden infant death syndrome (SIDS). Five infants who died from congenital cardiac abnormalities, two from infected pulmonary dysplasia, two from septic shock with multi-organ failure, one during a prolonged seizure, one from a prolonged neonatal hypoxemia, one from meningitis with brain infarction. All the infants had been recorded during one night in a pediatric sleep laboratory some 3–12 weeks before death. The frequency and duration of sleep apneas were analyzed. The infants’ brain stem material was collected and immunohistochemistry of glial fibrillary acidic protein (GFAP) was carried out. The density of GFAP-positive reactive astrocytes was measured in the cardiorespiratory and arousal pathway. Akaike information criterion statistics (AIC) were calculated to elucidate the relationship between the epidemiological data on sleep position, the physiological data and the pathological data in SIDS victims. The duration of obstructive apnea was the most significant variable to differentiate between SIDS victims and control infants. In conclusion, the present study sustains the possibility of an organic fragility within the arousal pathway in SIDS victims with repetitive sleep apneas.

Chapter 47 Reducing the risk of sudden infant death

Publisher Summary Prevention campaigns to avoid risk factors for the occurrence of sudden infant deaths (SID) during sleep have led to a significant decrease in the number of infants dying suddenly and unexpectedly during sleep. This chapter suggests a model for these underlying mechanisms responsible for SID and address the major challenges facing researchers in this field. During sleep SID has significantly more frequent obstructive apneas, less body movements, more sympathetic control of the heart rate, a desynchronized relation between sympathetic and vagal cardiac controls by the end of the night, and a decreased propensity to arouse from sleep. The respiratory and cardiac characteristics that would be found in the future SIDS victims could be related to an increased susceptibility to respiratory and cardiac dysregulations during sleep. These findings could represent a delay in maturation of vital control mechanisms in the infants at risk of SID. The decreased arousability could reveal a lesser propensity for these infants to arouse and autoresuscitate in the case of an acute respiratory or circulatory failure. These neurophysiological findings could result from postmortem findings within the victims' brain-stem, such as abnormally frequent occurrences of brain-stem gliosis, cellular apoptosis, or changes in receptor functions.

The amount of brainstem gliosis in sudden infant death syndrome (SIDS) victims correlates with maternal cigarette smoking during pregnancy

Brainstem gliosis is elevated in some SIDS victims and has been associated with hypoxic-ischaemic events. Factors which increase the risk of SIDS include possible risk factors for hypoxic-ischaemic events during foetal and perinatal life. In this study a scoring system was developed whereby possible risk factors for hypoxic-ischaemic events during pregnancy, birth and in the perinatal period were correlated with the level of gliosis in the nucleus olivaris inferior in SIDS victims (n = 19). The mothers' antenatal care and obstetric records and the SIDS infants' perinatal hospital records were investigated, and each possible risk factor for hypoxic-ischaemic events was given one point. The points were summarized for each infant, and this sum was correlated with the level of gliosis in the infant's nucleus olivaris inferior. The number of cigarettes the mothers smoked during pregnancy was also compared with the level of gliosis. Our results show that in SIDS victims there is 41% probability that the more the mothers smoked during pregnancy, the more gliosis in the nucleus olivaris inferior is found in their infants (p < 0.01). Gliosis in the nucleus olivaris inferior also correlated with the possible risk factors for hypoxic-ischaemic events during pregnancy, birth and the perinatal period (r2 = 0.28, p < 0.05). However, if cigarette smoking was excluded as a possible hypoxic-ischaemic risk factor, no correlation was found.

The Amount of Brain Stem Gliosis in Sudden Infant Death Syndrome Correlates With the Number of Cigarettes the Mothers Smoked During Pregnancy

The Amount of Brain Stem Gliosis in Sudden Infant Death Syndrome Correlates With the Number of Cigarettes the Mothers Smoked During Pregnancy

Catecholamine neurons alteration in the brainstem of sudden infant death syndrome victims.

Sudden infant death syndrome (SIDS) is a leading cause of postneonatal infant death. The pathogenesis of sudden death is still unknown, but an abnormality in the central nervous regulation of breathing during sleep has been suggested. The aim of study is to confirm the brainstem disorder of SIDS victims. In order to do this, it is necessary to investigate the alterations of brain neurotransmitter systems thought to be involved in respiratory control. Neuropathologic study performed on the brainstem of SIDS victims. The disorders of catecholaminergic systems in 22 SIDS victims were examined on the substantia nigra in the midbrain, locus coeruleus in the pons, vagal nuclei, and area reticularis superficialis ventrolateralis with the immunohistochemical method. Immunoperoxidase staining was performed with the antityrosine hydroxylase (TH) and the glial fibrillary acidic protein antibodies. Immunoreactivity was compared with 13 age-matched control infants. For statistical analysis, the chi 2 test and the Student's t test were performed. The main finding was diminished TH immunoreactivity in the vagal nuclei and area reticularis superficialis ventrolateralis of SIDS victims, suggesting that adrenaline and noradrenaline neurons are altered in SIDS. In addition, this decrease in TH was closely correlated with brainstem gliosis. These catecholaminergic changes may be caused by chronic hypoxia or ischemia, and also may underlie alterations in respiratory and cardiovascular control in sleep.

Beta-endorphin immunoreactivity in spinal fluid and hypoxanthine in vitreous humour related to brain stem gliosis in sudden infant death victims.

Beta-endorphin may induce respiratory depression and bradycardia. Elevated levels of hypoxanthine (HX) in vitreous humour (VH) may possibly indicate hypoxia before death. Furthermore, gliosis in the brain stem may reflect a previous hypoxic/ischaemic injury in the brain. In the present study we relate beta-endorphin immunoreactivity (BENDI) in the CSF to the presence or absence of reactive astrocytosis in the nucleus olivae inferior (NOI). The relationship between the HX concentration in VH and the number of reactive astrocytes in sudden infant death (SID) cases (n = 17) and controls (n = 23) was also studied. The number of reactive astrocytes was examined in the NOI by immunohistochemical demonstration of glial fibrillary acidic protein (GFAP). The BENDI in CSF and the number of reactive astrocytes in the NOI divided the SID victims into two subpopulations (P < 0.01). One had a median of < 4 fmol/ml BENDI in CSF (range < 4) and 2 reactive astrocytes (range 0-15), and was similar to the controls that died from infections. The other subpopulation had a median of 260 fmol/ml BENDI in CSF (range 160-400) and 13 reactive astrocytes (range 7-33), similar to the control infants with previous hypoxia. In this latter SID subpopulation the number of reactive astrocytes correlated positively with BENDI in CSF (r = 0.7, P < 0.05). All the SID victims had elevated levels of HX in VH. In the SID subpopulation with high level of BENDI in CSF and increased number of activated astrocytes, the correlation factor between HX in VH and activated astrocytes was r = 0.7 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Developmental brain-stem pathology in sudden infant death syndrome.

The brain-stems of control and sudden infant death syndrome (SIDS) infants were examined developmentally with Golgi and immunohistochemical methods. The development of dendritic spines changed dramatically from the prenatal to postnatal period in the ventrolateral medulla as well as in the reticular formation and vagal nuclei in controls, but persisted in SIDS infants. These observations suggest a delay in maturation of the meduallary respiratory neurons and transneuronal connection between the central chemoreceptor and neural respiratory center in SIDS. In addition, substance P (SP)-positive nerve fibers were increased in the pons of SIDS infants. An increased activity in the afferent SP neurons in SIDS may be due to chronic hypoxia as in brain-stem gliosis, and may be involved in cardiorespiratory regulation.

Beta-endorphin immunoreactivity in spinal fluid and hypoxanthine in vitreous humour related to brain stem gliosis in sudden infant death victims

Beta-endorphin immunoreactivity in spinal fluid and hypoxanthine in vitreous humour related to brain stem gliosis in sudden infant death victims

BETA-ENDORPHIN IMMUNOREACTIVITY (BEI) IN CSF CORRELATED WITH BRAINSTEM GLIOSIS AND WITH HYPOXANTHINE (HX) IN CORPUS VITREUM LIQUOR IN VICTIMS OF SUDDEN INFANT DEATH SYNDROME (SIDS)

Beta-endorphin is released during stress and activates receptors in ncl. tractus solitarius and induces bradycardia and respiratory depression.We measured BEI in CSF. in caudal area of ncl. tractus solitarius, brainstem gliosis by immunohistochemistry and HX in corpus vitreum liquor in SIDS victims (n=27). The levels were compared with control infants dying from other causes than SIDS (n=12).BEI measurements in CSF revealed two distinct subpopulations of SIDS, P<0.01, (G1 and G2). In approximately half of the SIDS victims (G1) there was a high level of BEI in CSF (160-400 fmol/ml CSF) and a non detectable level of BEI in ncl. tractus solitarius area (<4.3 fmol/mg tissue), p<0.05, G1 compared to G2. G1 cases had a higher level of astrogliosis in ncl. Oliva inf., p<0.01, than G2 patients. The BEI level in CSF of G1 correlated with HX concentrations in corpus vitreum liquor, r=0.92, p<0.001. The other half of SIDS cases (G2) had non delectable level of BEI in CSF (<4.3 fmol/ml) and high level of BEI in ncl. tractus solitarius area, (<4.3-17.1 fmol/mg tissue). The controls with high beta-endorphin level in CSF died under stressfull circumstances as heart operation and the controls dying from infection had low BEI in CSF.Conclusion; SIDS is characterized by 2 groups. G1: High BEI level in CSF, low level BEI in ncl. tractus solitarius area, increased level of brainstem gliosis and a correlation between BEI level in CSF and HX level in corpus vitreum liquor. Group 2: Low BEI in CSF, high level BEI in ncl tractus solitarius area and low level of brainstem gliosis.

The cause of death in patients with glioblastoma is multifactorial: clinical factors and autopsy findings in 117 cases of supratentorial glioblastoma in adults.

To delineate the causes of death (COD) in adults with supratentorial glioblastoma multiforme (GM) we reviewed 117 consecutive cases examined at autopsy over a nineteen year period at the University of Washington. Twenty cases (17%) had expired unexpectedly without ante mortem diagnosis, 5 patients (4%) had been diagnosed as having lower grade astrocytomas prior to death. Other than the 20 patients without ante mortem diagnosis, all patients had a surgical procedure for treatment and/or diagnosis (biopsy 10%, craniotomy 90%). Postsurgical therapy varied, but there was no significant difference in median length of survival among the different treatment groups. Factors considered as potential COD were: herniation (axial, transtentorial, subfalcine, tonsillar), surgical complications (death within thirty days of surgery secondary to cerebral hemorrhage and/or edema), severe systemic illness, brainstem invasion by tumor, and neutron-induced cerebral injury (cerebral and brainstem gliosis were evident in these cases). A potential COD could be identified in 93% of patients. Patients with no ante mortem diagnosis were likely to have herniated (p = 0.01), whereas patients who underwent neutron irradiation were unlikely to have herniated (p = 0.001). No other variables were statistically significant predictors of herniation, including multifocal tumors (20 patients), and brainstem invasion by tumor (18 patients). No patients died as a result of treatment except those who underwent neutron radiotherapy and those who died postoperatively. Although significant mass effect, as evidenced by herniation, was apparent in 61% of patients, most of these patients had an additional identifiable COD. We conclude that the COD in patients with GM varies and is multifactorial.

Post Concussion Syndrome: Brainstem Seizures, a Case Report

Following head injury and associated unconsciousness, a 19 year old woman developed chronic intractable headaches, absence attacks and a cluster of other symptoms which did not respond to conventional medical therapy. During the course of implanting a brain stimulation electrode for the treatment of chronic and recurring incapacitating headaches, diagnostic electrographic recordings revealed focal abnormal discharges in the mesothalamus. Electrical stimulation attenuated the discharges and alleviated the headaches and associated symptoms. A retrospective analysis of this case suggested that a head injury-induced brain stem gliosis was the source of the brainstem abnormal discharges. It is speculated that various biologic systems represented within the brainstem were implicated by the reticular formation generated discharges. Symptoms making up the chronic pain syndrome were thus thought to emanate from the electric malfunctioning of those biologic systems.

Brain morphology in Duchenne muscular dystrophy: A Golgi study

Intellectual impairment associated with Duchenne muscular dystrophy is well recognized, although no consistent anatomic central nervous system lesions have been reported. The autopsy findings of 13 patients, ages 13–18 years, were reviewed. Intelligence quotients, ascertained in 5 patients, ranged from 46–79. Gross and microscopic examinations of brain and spinal cord revealed no consistent pattern of abnormalities. Neuropathology included neuronal loss and gliosis in spinal gray matter and tegmental brainstem, extensive Purkinje cell loss, mononuclear perivascular cuffing with cortical and subcortical gliosis, and cerebral heterotopia. Quantitative analysis of rapid Golgi impregnations of the visual cortex revealed significantly reduced dendritic length and branching of apical and basal dendrites from pyramidal neurons in 1 patient and less striking attenuation of dendritic arborization in 2 others. The literature suggests that the intellectual deficit in Duchenne muscular dystrophy is nonprogressive and unrelated to age or severity of muscle disease, although performance intelligence quotient may deteriorate with progressive muscle weakness. Golgi analysis suggested that abnormal dendritic development and arborization may underlie intellectual impairment. Although the pathogenesis of the cellular defect is not fully known, the coexistence of central nervous system and muscle pathology raises the possibility of a common molecular mechanism.

577 DECREASED FETAL ACTIVITY: A POSSIBLE INDICATION OF SUSCEPTIBILITY TO SIDS

Over the past decade, obstetricians have begun to utilize maternal perception of fetal movements in utero as a measurement of fetal well-being. Some have speculated that fetal movements may be a qualitative measure of placental perfusion. Recent findings of brainstem gliosis in victims of Sudden Infant Death Syndrome (SIDS) and other indicators of deficient brainstem function have led Naeye and others to postulate that intrauterine hypoxemia may be an important prenatal factor in such children. The possible correlation between decreased fetal movements and intrauterine hypoxemia led us to question mothers of infants who died of SIDS, as well as mothers of infants with observed apnea and cyanosis, about the movements of their children prior to delivery. A significant decrease in fetal activity was recorded only if there was a total absence of activity for 24 consecutive hours or longer during the pregnancy. Forty percent (8/20) of SIDS victims were retrospectively recalled by their mothers to have decreased intrauterine activity. Similar questioning of mothers of “near miss” infants led to a 43% (59/137) response indicative of an absence of fetal activity for at least 24 hours. Clearly this represents a very significant minority of the SIDS population. A prospective study of infants exhibiting decreased fetal activity is being designed to test this hypothesis. Identification of such previously unrecognized “at risk” infants may be effective in helping to prevent SIDS deaths.

Chronic hypoventilation and development of brain stem gliosis.

Chronic hypoventilation is important in the pathogenesis of congenital hypoventilation syndromes and sudden infant death syndrome. Cases of hypoventilation can be divided clinically into those with a defective respiratory drive and those with mechanical impairment of either the lungs or the chest wall. To determine the relationship between chronic hypoventilation and brain stem gliosis, the development of astrocytes in the brain stem of normal and abnormal cases with either type of chronic hypoventilation was studied morphometrically. The glial fibrillary acidic protein immunoperoxidase method of staining astrocytes showed a transient increase of astrocytes in some parts of the brain stem during early infancy in thirty-five normal cases. The astrocytosis was even greater in both types of chronic hypoventilation including subjects with myopathy, Ondine's curse, and sudden infant death syndrome. Gliosis in these subjects may have resulted from "asphyxia" of the brain stem, as seen in cases with myopathies involving respiratory muscles. However, the involvement of brain stem respiratory centers may suggest a failure of neural respiratory control that further compromises respiratory function.

Cerebral hypoperfusion in the sudden infant death syndrome? Brainstem gliosis and vasculature.

Gliosis is increased in the respiratory control area of the brainstem in victims of sudden infant death syndrome (SIDS), as it is in infants who have died of congenital heart disease. In the latter, the lesions appear to result from hypoxia or ischemia, and studies of the brainstem microvasculature of SIDS victims indicated a close relationship between the gliosis and adjacent vasculature. It is postulated that cerebral hypoperfusion may play a role in SIDS.

Brain stem gliosis in a case with clinical manifestations of amyotrophic lateral sclerosis.

Summary A 32-year-old male with typical clinical course of progressive bulbar paresis was investigated histopathologically. The main pathological change was prominent fibrous gliosis in the brain stem and cervical cord without remarkable nerve cell loss in the same area. Concerning the pathogenesis of this case, the significance of primary role of fibrous gliosis was discussed.