Problem of diagnosis in postmortem brain studies of schizophrenia.

OBJECTIVE: The purpose of this study was to determine 1) the reliability of diagnoses of schizophrenia at coronal autopsy and 2) the degree to which the use of different diagnostic instruments for schizophrenia would affect postmortem brain research. METHOD: Eighty-three subjects, recorded at coronal autopsy as having had schizophrenia, were referred for neurochemistry studies. The diagnoses reported to the state coroner's office were reevaluated by a review of psychiatric case histories by clinicians using semistructured assessment and diagnostic criteria. RESULTS: The application of DSM-III-R, Research Diagnostic Criteria (RDC), ICD-10, Schneiderian, and Feighner criteria to the diagnosis of the 83 subjects revealed that 63.9%, 48.2%, 48,2%, 43.4%, and 42.2%, respectively, met the criteria for schizophrenia. Highest concordance was between the RDC and ICD-10 systems, while lowest concordance was between the RDC and Schneider systems. CONCLUSIONS: These data suggest that unless carefully reviewed, diagnosis may be a major confounding factor in postmortem studies of brain tissue from subjects with schizophrenia.

Mitochondrial respiratory chain activity in the human brain as a function of age.

Age-associated changes in mitochondrial respiratory chain activity were investigated in human brain tissue collected at autopsy. Four brain regions, the frontal cortex, superior temporal cortex, cerebellum and putamen, were studied to map any regional variation. A significant decrease in cytochrome c oxidase activity was seen in all regions studied with increasing age (P<0.05). Although a small decrease in succinate dehydrogenase-cytochrome c oxidoreductase and NADH: ubiquinone oxidoreductase activities was observed, this was not statistically significant. This study has shown that the age-related fall in cytochrome c oxidase activity affects the frontal cortex, superior temporal cortex, cerebellum and putamen. The variation in the extent of age-related oxidative phosphorylation decline was striking. We hypothesize that individuals with more severe age-related decline may be predisposed to neuronal dysfunction, whereas individuals with well preserved oxidative phosphorylation may enjoy some degree of neuronal protection.

Idiopathic generalized epilepsy: lack of significant microdysgenesis.

BACKGROUND: The idiopathic generalized epilepsies (IGE) are classically regarded as due to a functional abnormality. However, microscopic microdysgenetic changes have been reported in the majority of cases by one group. OBJECTIVE: To independently evaluate the microscopic microdysgenetic changes in a controlled, blinded study. METHODS: Five brains with IGE and five age-matched control brains were collected. Blocks were taken from nine standardized Brodmann areas, both hippocampi, and cerebellum. Slides were examined independently by two neuropathologists blinded to patient group, who qualitatively scored microdysgenetic features on standardized data sheets. The results were compared and any discrepancies were rescored by the pathologists together using a double-header microscope. Quantitative neuronal profile counts in the molecular layer in standardized Brodmann areas of frontal cortex and in deep frontal white matter were performed. RESULTS: Microdysgenetic features in nine Brodmann areas, hippocampi, and cerebellum were not increased in brains from subjects with IGE compared with control brains. Quantitative neuronal profile counts in the molecular layer of frontal cortex and deep frontal white matter were not increased in IGE compared with controls. CONCLUSIONS: This controlled, blinded study did not replicate the results of previous reports of microdysgenesis in IGE. Although factors such as syndrome heterogeneity and sample size may explain the discrepancy, technical factors could also play a role. The current ion channel hypothesis for the pathogenesis of IGE does not preclude microscopic or ultramicroscopic abnormalities and the search for these should continue.

[3H]raclopride binding to brain tissue from subjects with schizophrenia: methodological aspects.

The binding of [3H]raclopride to particulate membrane and frozen sections (with quantitative autoradiography) from the caudate-putamen, obtained at autopsy from schizophrenic and non-schizophrenic subjects, was measured. The affinity of [3H]raclopride to particulate membrane was significantly decreased in the schizophrenic compared to non-schizophrenic subjects. The density of [3H]raclopride binding to tissue from subjects with schizophrenia was increased, unchanged or decreased depending on the methodology used. Finally, there was an age-dependent decrease in [3H]raclopride binding in the frozen sections from the caudate-putamen of the non-schizophrenic subjects. This age-dependent decrease was not apparent using particulate membrane from schizophrenic or non-schizophrenic subjects or tissue sections from the schizophrenic subjects. We conclude that the binding of [3H]raclopride is dependent on methodology and therefore data from in vitro and in vivo studies using this drug should be interpreted with caution.

Serotonin(2A) receptors are reduced in the planum temporale from subjects with schizophrenia.

[(3)H]ketanserin binding to 5HT(2A) receptors was measured in the left planum temporale (sensory speech cortex) from schizophrenic and non-schizophrenic (control) subjects using both particulate membranes and tissue sections. There was a significant decrease in the affinity of [(3)H]ketanserin binding to particulate membranes from schizophrenic subjects who were treated with phenothiazines up to death. Adding 2nM chlorpromazine to brain tissue from control subjects caused a similar decrease in the affinity of [(3)H]ketanserin binding to particulate membranes. This suggests that the decrease in affinity observed in the phenothiazine-treated subjects was due to residual drugs. In addition, there was a significant decrease in the density of [(3)H]ketanserin binding in both particulate membranes and tissue sections from schizophrenic subjects which did not appear to be due to residual antipsychotic drugs. Analysis of the laminar distribution of 5HT(2A) receptors showed that this decrease was greatest in cortical layer III. The decrease in the density of 5HT(2A) receptors was significant whether schizophrenic subjects were receiving phenothiazines or haloperidol at the time of death, and there was no correlation between the last recorded dose of antipsychotic drug and 5HT(2A) receptor density. These data suggest that a decrease in the density of 5HT(2A) receptors in the planum temporale may be associated with the pathology of schizophrenia.

Neither protein kinase C nor adenylate cyclase are altered in the striatum from subjects with schizophrenia.

Dopamine (DA) D2 receptors which act by modulating second messenger pathways that include protein kinase C (PKC) and adenylate cyclase (AC) have been repeatedly shown to be increased in striatum from subjects with schizophrenia. Therefore it seemed possible that chronic up-regulation of DA-D2 receptors in the schizophrenic brain could result in a change in either of these two proteins. Hence we measured PKC and AC in striatum from 20 schizophrenic subjects and 20 non-schizophrenic subjects by quantitative autoradiography and could show no difference in the density of either PKC (436 +/- 35 vs. 485 +/- 29 fmol/mg tissue equivalents (TE), mean +/- SEM) or AC (77 +/- 9 vs. 80 +/- 7 fmol/mg TE) in the tissue from schizophrenic compared to the non-schizophrenic subjects. Thus, these data do not support the hypothesis that PKC or AC are changed in the schizophrenic brain.

No change in the density of the serotonin1A receptor, the serotonin4 receptor or the serotonin transporter in the dorsolateral prefrontal cortex from subjects with schizophrenia.

Changes in serotonin receptors and the serotonin transporter have been reported in the dorsolateral prefrontal cortex from subjects with schizophrenia, an area of the brain thought to be important in the pathology of the illness. To further our understanding on how such changes could play a role in the pathology of the illness, in situ radioligand binding with autoradiography was used to measure the density of the serotonin1A receptor, the serotonin4 receptor and the serotonin transporter in the dorsolateral prefrontal cortex, obtained at autopsy, from 10 schizophrenic and 10 control subjects. The binding of [3H]8-OH-DPAT to serotonin1A receptor, [3H]GR113808 to the 5HT4 receptor and [3H]citalopram to serotonin transporter was not altered in subjects with schizophrenia. significantly, only in tissue from the control subjects was there a relationship between age and the density of the serotonin4 receptor in Brodmann's areas 8 (r = 0.71, P = 0.02) and 10 (r = -0.67, P = 0.03). Importantly, this confounding factor did not influence the comparison of the density of serotonin4 receptor in the tissue from the schizophrenic and control subjects. This study has failed to show a difference in the density of serotonin1A receptor, the serotonin4 receptor or the serotonin transporter in the dorsolateral prefrontal cortex (Brodmann's areas 8, 9 and 10) from subjects with schizophrenia. These data suggest that not all serotonergic markers are altered in the dorsolateral prefrontal cortex from schizophrenic subjects.

Serotonin2 receptors and the serotonin transporter in the schizophrenic brain.

The binding of [3H]paroxetine and [3H]ketanserin to particulate membranes from frontal cortex of subjects who had or did not have schizophrenia was measured as was [3H]paroxetine binding to particulate membranes from the hippocampus and caudate nucleus. There was no change in either the affinity or density of [3H]ketanserin binding to membranes from the frontal cortex of subjects who had schizophrenia. Similarly, there was no difference in the density of [3H]paroxetine binding to membranes from subjects who had or did not have schizophrenia. The affinity of [3H]paroxetine binding in the frontal cortex and putamen did not differ in subjects who had schizophrenia. By contrast, there was a significant decrease in the affinity of [3H]paroxetine binding to the hippocampal membrane from subjects who had schizophrenia (0.40 +/- 0.06 nM vs 0.26 +/- 0.02 nM; p < 0.05). Furthermore, this difference was more apparent in the subjects who had schizophrenia and committed suicide (0.49 +/- 0.09 nM) than it was in those who had schizophrenia but did not commit suicide (0.32 +/- 0.09 nM). As [3H]ketanserin binds to the serotonin2 receptor our data suggest that this receptor is not changed in the Brodmann's area 9 of the frontal cortex. By contrast, [3H]paroxetine binds to the serotonin transporter and therefore our data suggest that the serotonin transporter is altered in the hippocampus of subjects with schizophrenia.

Does cardiac conduction pathology contribute to sudden unexpected death in epilepsy?

Heart weights have been reported to be increased in those dying suddenly and unexpectedly from epilepsy (SUDEP) and it has been suggested that cardiac pathology including cardiac conduction pathology and coronary artery atheroma may contribute to SUDEP. The purpose of this study was to perform a detailed controlled study of the microscopic pathology of the cardiac conduction system in SUDEP cases, in addition to assessing coronary artery atheroma and other cardiac pathology. The hearts of ten SUDEPs and ten control subjects (no history of epilepsy and a cause of death not primarily cardiac) were examined macroscopically and microscopically by two pathologists blinded to the patient group. Morphological abnormalities of the cardiac conduction system that could have possibly contributed to death were not increased in the SUDEP group (four cases showed such changes in the SUDEP group vs. six in the control). There was no significant difference between the maximal percentage coronary artery stenoses between the two groups and no increased prevalence of other cardiac pathology in the SUDEP group. However, since subtle abnormalities of the conduction system were identified in some of the epileptic deaths, it is still feasible that these may contribute to death by causing cardiac arrhythmia, when associated with apnoea, bradycardia or other cardiac arrhythmia related to an epileptic seizure.

A change in the density of [(3)H]flumazenil, but not [(3)H]muscimol binding, in Brodmann's Area 9 from subjects with bipolar disorder.

BACKGROUND: This study examines the hypothesis that there are changes in cortical serotonergic, GABAergic and glutamatergic systems in bipolar disorder and schizophrenia. METHODS: In situ radioligand binding and autoradiography were used to measure neurochemical markers in Brodmann's Area (BA) 9 from control subjects and subjects with bipolar disorder or schizophrenia (n=8 per group). RESULTS: Compared to tissue from schizophrenic (mean+/-S.E.M, 385+/-44 fmol/mg ETE) and control (383+/-44 fmol/mg ETE) subjects, there was an increase in the density of [(3)H]flumazenil binding to the benzodiazepine binding site on the GABA(A) receptor in subjects with bipolar disorder (451+/-17 fmol/mg ETE; P<0.05). There was no difference in the density of [(3)H]muscimol binding to the GABA(A) receptor or in the density of the serotonin(1A) receptor, serotonin(2A) receptor, ionotropic glutamate receptors or the serotonin transporter between the three cohorts. There was an age-related decrease in NMDA receptor density in control subjects that was absent in schizophrenia and bipolar disorder. An age-related increase in [(3)H]flumazenil binding in schizophrenia was absent in control and bipolar disorder subjects. LIMITATIONS: This study involved a relatively small number of individuals. CONCLUSIONS: An increase in the gamma2-receptor sub-unit in the GABA(A) receptor has been shown to increase benzodiazepine but not [(3)H]muscimol binding, this is the mismatch in binding we have shown in BA 9 from subjects with bipolar disorder. Thus, a change in the assembly of receptor subunits into GABA(A) receptors may be involved in the neuropathology of bipolar disorder. There may also be differences in age-related changes in cortical receptor density between bipolar disorder and schizophrenia.

Sudden death in pregnancy from congenital malformation of the coronary arteries.

We report the case of a 40 yr old previously healthy woman who died suddenly during her second pregnancy from unusual coronary artery anomalies. The left anterior descending coronary artery arose from the above of the right sinus of Valsalva 1.1 cm above the ridge in the aorta and coursed behind the pulmonary valve before it dipped deeply into the myocardium of the interventricular septum. The left circumflex coronary artery was hypoplastic. The right coronary artery arose also from above the right sinus of Valsalva 1.1 cm above the ridge in the aorta but was otherwise normal. A fourth small coronary artery arose between the origins of the left anterior descending and right coronary artery and supplied the outflow tract of the right ventricle. Mild fibrosis was present in the interventricular septum. The rest of the autopsy examination was unremarkable. Such combination of coronary artery anomalies causing sudden unexpected death in a pregnant woman have not previously been reported.

Early onset of multiple sclerosis with autopsy confirmation.

A female had her first generalized epileptic seizure at age 11 yrs. Apart from intermittent seizures she remained well until 15 yrs of age when she developed double vision, unsteadiness and bilateral plantar responses which resolved spontaneously. Brain MRI scan at this stage revealed changes typical of multiple sclerosis. She died at 17 yrs of age from asthma and epilepsy. Autopsy confirmed the presence of multiple sclerosis and showed the disease to be very active. We consider it likely that multiple sclerosis was present at the age of 11 yrs when she had her first epileptic seizure. This case of multiple sclerosis is presented because of the rarity of the early age of onset, unusual presentation with epilepsy, marked activity of disease and early death. Also it is uncommon to have autopsy confirmation of such disease.

Primary meningeal glioma.

A 59 yr old man presented with headaches and was shown to have a posterior fossa tumor arising from the inferior surface of the tentorium cerebelli. At operation the tumor was discrete from the cerebellum and was thought to be a meningioma. Pathological examination showed the tumor had features similar to those of a meningioma. It consisted of interlacing bundles of spindle cells with a considerable amount of connective tissue. Some mitoses were present. The tumor cells, however, showed abundant staining for glial fibrillary acidic protein indicating their astrocytic nature. The tumor was diagnosed as astrocytoma Grade 2. The tumor 'recurred' 4 mths later and a second surgical removal was attempted. Pathological examination showed features similar to those in the first operative specimen but this time invasion of the cerebellum was present. Deep x-ray treatment (D.X.R.T.) did not alter the tumor growth which proved fatal 7 mths after presentation. The differential diagnosis of an apparently meningeal-based tumor includes the rare entity of primary meningeal glioma. The case is presented as an example of this rare entity which both clinically and pathologically may be mistaken for a meningioma. The prognosis of intracranial solitary primary leptomeningeal gliomas is variable with recurrence and survival being months to years.

The pathogenesis of Schmorl's nodes in relation to acute trauma. An autopsy study.

STUDY DESIGN: Seventy thoracolumbar spines from cadavers of individuals killed in motor vehicle accidents were examined pathologically and radiologically, particularly for the occurrence of acute Schmorl's nodes. OBJECTIVES: To document whether Schmorl's nodes occur acutely as a result of trauma. SUMMARY OF BACKGROUND DATA: Theories proposed to explain the pathogenesis of Schmorl's nodes include developmental, degenerative, traumatic, and disease influences. Few studies show a direct causal relation between a traumatic episode and acute Schmorl's node formation. METHODS: Thoracolumbar spines were removed at autopsy, underwent radiography in the anteroposterior and lateral planes, fixed, sagittally cut, and underwent radiography a second time. Pathologic and radiographic examinations were performed. RESULTS: Nine acute Schmorl's nodes were detected, most in association with other acute injuries to the spine. Most acute Schmorl's nodes were present in spines from individuals aged 11-30 years, with a male to female ratio of 9:1, and were localized to the T8-L1 region. Spines from motorcyclists showed the highest percentage of acute Schmorl's nodes. No acute Schmorl's nodes were detected radiologically. CONCLUSION: Schmorl's nodes do occur acutely as the result of a single traumatic episode, and are almost always associated with other acute spinal injury. The frequency and occurrence of acute Schmorl's nodes in motorcyclists suggest that axial loading is an important mechanism. Their predominance in the T8-L1 region suggests that this region is particularly susceptible to stress.

Death by greyhound.

We present the case of a man who was last seen leaving to feed his greyhound dogs. He was found dead lying in a yard just outside the gate to one of the dog pens. Holes were present in the fence on both sides of the gate. The holes were of sufficient size to allow the passage of the head and neck of a greyhound to the shoulders. To open the gate one had to bend down to unfasten a latch 45 cm above ground level. Leaning down to unfasten the latch brought one into close proximity to the holes on either side of the gate. The scene and clothing appeared undisturbed. Autopsy (K.A.L.) revealed the cause of death to be blunt throat trauma. The throat trauma was of marked degree and consistent with at least a single heavy crushing injury directed from the front and somewhat below. In addition there were a series of almost vertical light abrasions on one side of the neck. There were minimal injuries to the rest of the body. There were no injuries specific for assault. In an attempt to explain the almost vertical abrasions on the side of the neck, the scene was re-examined by the pathologist. This revealed loose wire strands on the gate post. It is consistent that a fall against this area could account for the almost vertical abrasions on one side of the neck.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal alkali burns.

A case is reported of a worker in an aluminium plant who was found lying in a shallow pool of concentrated caustic solution, which had been heated to approximately 95 degrees C. He had been employed to operate a pump draining a sump. A pressurised ruptured airline lay nearby, this being the likely precipitating cause of an alkaline spray. The spray led to the deceased running towards the nearest safety shower, at the base of which he was subsequently found. This is a relatively uncommon form of death, resulting from contact with a hot concentrated alkali solution. Subsequent experimentation indicated that the deceased had been in contact with the fluid for a period of approximately 13 min.

Gunshot suicide with nasal entry.

A man with a long history of depression had recently borrowed a rifle. His body was found on its back in bed in his caravan. A rifle lay over the body with the muzzle pointing towards the head. A suicide note was found at the scene. Autopsy revealed entry via the nose with the track passing through the base of the skull to the right parietal region where the main bullet fragments were located beneath the scalp. The history, scene and autopsy findings were consistent with the gunshot wound being suicidal. We can find only one mention of a suicidal gunshot wound with nasal entry in the English-language literature, although a personal communication informed us of a similar case in the Republic of Ireland within the past two years. We report this case because of its unusual nature.

A device for cutting brain slices.

A device for cutting brain slices is described as an alternative to cutting angle guides and the "brain macrotome." With this new device, slices of uniform thickness optimal for assessing morphological detail and photography can be produced. A similar but smaller device for cutting pieces of tissue for paraffin embedding is also presented. These devices should be useful in either the histopathology laboratory or mortuary.

False positive diagnosis of subarachnoid haemorrhage on computed tomography scan.

Five cases are presented in which subarachnoid haemorrhage (SAH) was diagnosed by clinicians and/or radiologists on computed tomography (CT) scan. No macroscopic SAH was present on neuropathologic examination. In retrospect it was considered that the neurologic signs and the neuropathologic features close to the time of CT scan were in keeping with the patients being brain dead, i.e. had no cerebral blood flow at the time of the scans. On review of the CT scans it was considered the hyperdense material seen in the subarachnoid space must have been blood in congested subarachnoid blood vessels. The cases demonstrate that if a patient presents comatose and CT scan shows cerebral oedema then the presence of high attenuation material in the subarachnoid space should not necessarily be considered to represent SAH. The value of seeking radiological opinion is highlighted but even then diagnosis may be difficult.

Suspected MPTP-induced parkinsonism.

The case of an intravenous heroin user who developed parkinsonian symptoms from the age of 28 years is presented. Neuropathologic examination revealed a marked loss of neurons and gliosis with the presence of Lewy bodies in the substantia nigra and locus ceruleus; they stained variably with antibody to ubiquitin and negatively with antibodies to tau and neurofibrillary tangles. Pseudo-Lewy bodies were also seen. Electron microscopy showed features in keeping with other electron microscopic studies of Lewy bodies in idiopathic Parkinson's disease and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced inclusion bodies in monkeys. Given that the deceased was a known heroin user, the rarity of the early age of onset, that MPTP is a recognized cause of parkinsonism in the drug abusing population, the absence of history of exposure to neuroleptics and the neuropathologic features, the parkinsonism was considered to be due to MPTP contamination of heroin. However, given the onset of parkinsonism 11 years prior to death it was not possible to obtain samples of the heroin injected to test for the presence of MPTP. Therefore it could not be absolutely excluded that this was a case of idiopathic Parkinson's disease occurring at a very young age in a heroin abuser. The immunohistochemical and electron microscopic features of Lewy bodies in such a case have not been previously described. The similarity of the neuropathological features to those of idiopathic Parkinson's disease and MPTP-induced parkinsonism further strengthens the hypothesis of MPTP or an MPTP-like agent being a cause of idiopathic Parkinson's disease.