Post-mortem confirmation of fetal brain abnormalities: challenges highlighted by the MERIDIAN cohort study.

OBJECTIVES: To assess and analyse the concordance between post-mortem findings and in utero magnetic resonance imaging (iuMRI) in the MERIDIAN (MRI to enhance the diagnosis of fetal developmental brain abnormalities in utero) cohort. DESIGN: Prospective cohort study. SETTING: Fetal medicine units in the UK. POPULATION: Pregnant women with a diagnosis of fetal brain abnormality identified on ultrasound at 18 weeks of gestation or later. METHODS: All pregnancies from the MERIDIAN study that resulted in a abortion were included and the rate of uptake and success of post-mortem examinations were calculated. In the cases in which diagnostic information about the fetal brain was obtained by post-mortem, the results were compared with the diagnoses from iuMRI. MAIN OUTCOME MEASURE: Outcome reference diagnosis from post-mortem examination. RESULTS: A total of 155 from 823 pregnancies (19%) ended in a termination of pregnancy and 71 (46%) had post-mortem brain examinations, 62 of which were diagnostically adequate. Hence, the overall rate of successful post-mortem investigation was 40%, and for those cases there was a concordance rate of 84% between iuMRI and post-mortem examination. Detailed information is provided when the results of the post-mortem examination and the iuMRI study differed. CONCLUSIONS: We have shown tissue-validation of radiological diagnosis is hampered by a low rate of post-mortem studies in fetuses aborted with brain abnormalities, a situation further compounded by a 12% rate of autopsy being technically unsuccessful. The agreement between iuMRI and post-mortem findings is high, but our analysis of the discrepant cases provides valuable clues for improving how we provide information for parents. TWEETABLE ABSTRACT: iuMRI should be considered a reliable indicator of fetal brain abnormalities when post-mortem is not performed.

Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature.

Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.

Imaging regional variation of cellular proliferation in gliomas using 3'-deoxy-3'-[18F]fluorothymidine positron-emission tomography: an image-guided biopsy study.

AIM: To compare regional variations in uptake of 3'-deoxy-3'- [(18)F]-fluorothymidine (FLT) images using positron-emission tomography (PET) with measures of cellular proliferation from biopsy specimens obtained by image-guided brain biopsies. MATERIALS AND METHODS: Fourteen patients with a supratentorial glioma that required an image-guided brain biopsy were imaged preoperatively with dynamic PET after the administration of FLT. Maps of FLT irreversible uptake rate (K(i)) and standardized uptake value (SUV) were calculated. These maps were co-registered to a gadolinium-enhanced T1-weighted spoiled gradient echo (SPGR) sequence that was used for biopsy guidance, and the mean and maximum K(i) and SUV determined for each biopsy site. These values were correlated with the MIB-1 labelling index (a tissue marker of proliferation) from these biopsy sites. RESULTS: A total of 57 biopsy sites were studied. Although all measures correlated with MIB-1 labelling index, K(i)(max) provided the best correlation (Pearson coefficient, r=0.68; p<0.001). In low-grade gliomas the K(i)(mean) (+/-SD) was significantly higher than in normal tissue (3.3+/-1.7x10(-3)ml(plasma)/min/ml(tissue) versus 1.2+/-0.7x10(-3)ml(plasma)/min/ml(tissue); p=0.001). High-grade gliomas showed heterogeneous uptake with a mean K(i) of 7.7+/-4x10(-3)ml(plasma)/min/ml(tissue). A threshold K(i)(mean) of 1.8x10(-3) differentiates between normal tissue and tumour (sensitivity 84%, specificity 88%); however, the latter threshold underestimated the extent of tumour in half the cases. SUV closely agreed with K(i) measurements. CONCLUSION: FLT PET is a useful marker of cellular proliferation that correlates with regional variation in cellular proliferation; however, it is unable to identify the margin of gliomas.

Late onset in dysferlinopathy widens the clinical spectrum.

LGMD2B, Miyoshi Myopathy and Distal Anterior Compartment Myopathy are caused by mutations in the dysferlin gene (DYSF) leading to progressive muscular weakness and wasting with onset usually within the second or third decade of life. We here present a patient with disease onset at 73 years. The presenting symptom was exercise-induced stiffness of the trunk and proximal leg muscles without major progression over a period of 12 years. Gastrocnemius muscle biopsy revealed dystrophic morphology and biochemical depletion of dysferlin, while sequence analysis revealed compound heterozygous splicing mutations of the dysferlin gene. This case represents the eldest age of onset of dysferlinopathy reported so far and widens the clinical spectrum of this disease.

A second biopsy?--Tandem lesion.

This is a rare case of synchronous pituitary adenoma and PNET in an adult and first of this sort in the literature. The MR appearances suggest a single pathological entity causing the changes in the different anatomical location which can occur in cases of germ cell tumours, PNET and glioblastoma. In certain cases, histological confirmation may be warranted for the different lesions. Both pathologies have different treatment strategy and outlook depending on the age, extent of the disease and Karnofsky score.

Improved delineation of glioma margins and regions of infiltration with the use of diffusion tensor imaging: an image-guided biopsy study.

BACKGROUND AND PURPOSE: The efficacy of radiation therapy, the mainstay of treatment for malignant gliomas, is limited by our inability to accurately determine tumor margins. As a result, despite recent advances, the prognosis remains appalling. Because gliomas preferentially infiltrate along white matter tracks, methods that show white matter disruption should improve this delineation. In this study, results of histologic examination from samples obtained from image-guided brain biopsies were correlated with diffusion tensor images. METHODS: Twenty patients requiring image-guided biopsies for presumed gliomas were imaged preoperatively. Patients underwent image-guided biopsies with multiple biopsies taken along a single track that went into normal-appearing brain. Regions of interest were determined from the sites of the biopsies, and diffusion tensor imaging findings were compared with glioma histology. RESULTS: Using diffusion tissue signatures, it was possible to differentiate gross tumor (reduction of the anisotropic component, q > 12% from contralateral region), from tumor infiltration (increase in the isotropic component, p > 10% from contralateral region). This technique has a sensitivity of 98% and specificity of 81%. T2-weighted abnormalities failed to identify the margin in half of all specimens. CONCLUSION: Diffusion tensor imaging can better delineate the tumor margin in gliomas. Such techniques can improve the delineation of the radiation therapy target volume for gliomas and potentially can direct local therapies for tumor infiltration.

Chronic encephalitis and temporal lobe epilepsy: a variant of Rasmussen's syndrome?

The authors report two adult patients with chronic temporal lobe epilepsy and pathologic features consistent with Rasmussen's encephalitis. Although seizures persisted after temporal lobe surgery no progressive cognitive or neurologic deficit has emerged. Prominent auditory auras in each suggested a persisting epileptogenic focus in the superior temporal gyrus. The current findings expand the clinical spectrum of Rasmussen's encephalitis and suggest that chronic nonprogressive encephalitis may serve as the pathologic substrate of medically intractable temporal lobe epilepsy.

The distribution of acetylcholinesterase in the lateral geniculate nucleus of the cat and monkey.

The distribution of acetylcholinesterase (AChe) has been examined histochemically in the lateral geniculate nucleus (LGN) of the cat and the monkey, and in the cat visual cortex. It was found that in the cat, AChE is most concentrated in laminae A and A1. Lamina C-proper possessed a weak band of AChE in its ventral part. Only restricted patches of activity were observed in the medial interlaminar nucleus. Laminae C1-3 and the central interlaminar nucleus possessed very little AChE. This pattern of enzyme distribution suggests that in the cat LGN, AChe activity coincides with the sites of neurophysiologically recorded X-cells, which are predominantly found in laminae A and A1 and are scarce in the C laminae and the medial interlaminar nucleus. The presence of AChE over neurones in layer VI of both areas 17 and 18 of the cerebral cortex in the cat suggests the corticothalamic pathway as one possible source of geniculate AChE activity. In the monkey LGN, AChE activity was observed in the parvocellular and magnocellular layers. The activity was greatest in the magnocellular layers, which are believed to contain neurones driven predominantly by retinal Y-cells. Thus, for this species the correlation between AChE activity and X-cells does not seem to hold.

Extracellular matrix-modulated differential invasion of human meningioma cell lines in vitro.

The in vitro invasive behaviour of six meningioma cell lines of various histological sub-type and grade was assessed using Boyden chemotaxis chambers ('Transwell' units) precoated with various extracellular matrix proteins. The cell lines included a benign meningothelial (IPGS), two benign transitional (IPCBR and IPGC), one atypical (IPIH) and two malignant (IPSE and IPIR) meningiomas. IPGC was a recurrent tumour. The results showed that IPCBR was most invasive through laminin and vitronectin. IPIH was moderately invasive through collagen type IV, laminin, vitronectin and fibronectin. However, both IPSE and IPIR were less invasive than IPIH whereas, IPGS was least invasive of all. Moreover, laminin was the most permissive extracellular matrix protein for most cell lines and collagen type IV, the least permissive. These results show that there is a differential in vitro invasive behaviour of cell lines derived from different histological types of meningiomas according to extracellular matrix substrate and suggests that invasion and migration of meningiomas in situ might be modulated by various extracellular components.

Adaptation-induced alteration of the relation between response amplitude and contrast in cat striate cortical neurones.

The activity of neurones in cat striate cortex in response to laterally moving sinusoidal gratings has been examined. The effect of prolonged visual stimulation with a high contrast moving grating stimulus of optimal orientation and spatial frequency was investigated in terms of the changes wrought in the relationship between response amplitude and stimulus contrast. The adaptation which resulted was characterized by an elevation of contrast threshold by about 0.4 log units and a reduction in the steepness of the relation between response and contrast by about 0.36 log units. Both simple and complex cells exhibited this behaviour. The similarity of these values to the size of contrast threshold elevations demonstrated psychophysically suggests a possible physiological basis for the perceptual phenomenon.

The statistical reliability of signals in single neurons in cat and monkey visual cortex.

The variability of the discharge of visual cortical neurons in cats and macaque monkeys limits the reliability with which such neurons can relay signals about weak visual stimuli. In general, the variance of a neuron's firing rate is directly proportional to its mean firing rate. The probability that a neuron will fire a criterion number of impulses on a stimulus trial grows monotonically with the contrast of a sinusoidal grating stimulus. Neural probability functions prepared either by computing the probability of criterion response or by integrating receiver operating characteristics to yield the probability of correct choice in a two-alternative forced-choice situation resemble psychometric functions obtained in psychophysical and behavioral experiments on humans and animals, but are shallower in slope. The slopes of neuronal probability functions are slightly higher when they are estimated over short time periods, but even so do not equal the slopes measured psychophysically in human and monkey observers. This discrepancy in slope could be explained if the whole observer responded only when about four neurons were active together.

Measures of folding applied to the development of the human fetal brain.

Previous work has suggested the existence of differences between the cerebral cortex of normal individuals, and those of patients with diseases such as epilepsy and schizophrenia. These shape abnormalities may be of developmental origin. Improved shape measures could provide useful tools for neuroscience research and patient diagnosis. We consider the theoretically desirable properties of measures of brain shape. We have implemented seven measures, three from the neuroscience literature, and four new to this field. Three of the measures are zero-order and four are second-order with respect to the surface. We validate the measures using simple geometrical shapes, and a collection of magnetic resonance scans of ten histologically normal ex vivo fetal brains with gestational ages from 19-42 weeks. We then apply the measures to MR scans from two histologically abnormal ex vivo brains. We demonstrate that our implementation of the measures is sensitive to anatomical variability rather than to the discreteness of the image data. All the measures were sensitive to changes in shape during fetal development. Several of the measures could distinguish between the normal and abnormal fetal brains. We propose a multivariate approach to studying the shape of the cerebral cortex, in which both zero-order and second-order measures are used to quantify folding.

Correlation of MR relative cerebral blood volume measurements with cellular density and proliferation in high-grade gliomas: an image-guided biopsy study.

BACKGROUND AND PURPOSE: As newer MR imaging techniques are used to assist with tumor grading, biopsy planning, and therapeutic response assessment, there is a need to relate the imaging characteristics to underlying pathologic processes. The aim of this study was to see how rCBV, a known marker of tumor vascularity, relates to cellular packing attenuation and cellular proliferation. MATERIALS AND METHODS: Nine patients with histologically proved high-grade gliomas and 1 with a supratentorial PNET requiring an image-guided biopsy were recruited. Patients underwent a DSC study. The rCBV at the intended biopsy sites was determined by using a histogram measure to derive the mean, maximum, and 75th centile and 90th centile values. This measure was correlated with histologic markers of the MIB-1 labeling index (as a marker of glioma cell proliferation) and the total number of neoplastic cells in a high-power field (cellular packing attenuation). RESULTS: There was a good correlation between rCBV and MIB-1 by using all the measures of rCBV. The mean rCBV provided the best results (r = 0.66, P < .001). The only correlation with cellular packing attenuation was with the 90% centile (rCBV(90%), r = 0.36, P = .03). The increase in rCBV could be seen over 1 cm from the edge of enhancement in 4/10 cases, and at 2 cm in 1/10. CONCLUSIONS: rCBV correlated with cellular proliferation in high-grade gliomas but not with cellular packing attenuation. The increase in rCBV extended beyond the contrast-enhancing region in 50% of our patients.

The variability of discharge of simple cells in the cat striate cortex.

The relationship between the variance and mean rate of discharges of simple cells in the cat striate cortex has been examined when mean rate was varied by changing either stimulus spatial frequency or contrast. In both cases, the variance was related to the mean discharge rate by an exponent of about 1.15; the relation was thus roughly linear. The discharge variance was on average 1.7 times the mean rate for data obtained from measurements of the neurones' spatial frequency tuning curves, and 1.48 times the mean for data from the response-contrast determination. However, this difference was not statistically significant.

The relationship between response amplitude and contrast for cat striate cortical neurones.

1. The activity of forty-three neurones in the cat's striate cortex in response to laterally moving sinusoidal gratings of various contrasts was recorded, in order to examine the relationship between response amplitude and contrast. 2. Neurones seemed to exhibit contrast thresholds: stimuli of very low contrast failed to evoke a change in the response amplitude from the concurrent levels of spontaneous activity. 3. The suprathreshold portion of the response-contrast relation was found to be monotonic. Typically, the relation was adequately described as linear up to contrasts of about 0.3, above which, varying degrees of saturation were evident. 4. The response-contrast relation had a higher threshold and a shallower slope when the spatial frequency was not optimal for the neurone. 5. The slope, or gain, of the response-contrast relation for a stimulus of optimal orientation and spatial frequency varied considerably from neurone to neurone. The gains of special complex cells were significantly greater than those of either standard complex cells or simple cells. 6. The distributions of contrast threshold and contrast gain were examined for their dependence on optimal spatial frequency. Contrast threshold was significantly positively correlated with optimal spatial frequency, while contrast gain was significantly negatively correlated with optimal spatial frequency. This behaviour is consistent with an optical contribution to the measured response properties of striate cortical neurones.

Evaluation of a linear model of directional selectivity in simple cells of the cat's striate cortex.

We have compared the responses of simple cells to laterally moving sinusoidal gratings and to stationary temporally-modulated gratings. From the amplitudes and temporal phases of the responses to stationary gratings of different spatial phases, it should be possible to predict the preferred direction of movement, the amplitudes of the responses to gratings moving in the preferred and nonpreferred directions and, thence, the degree of directional preference (Reid et al., 1987). The preferred direction can be predicted reliably. However, the magnitude of the directional preference cannot be predicted, since the measured amplitude of the response in the nonpreferred direction of movement is very much less than that predicted by a linear theory. Nonlinearities in the relationship between response amplitude and contrast may contribute to the failure of the predictions, but this contribution is small. We conclude that the magnitude of the directional preference seems to be determined predominantly by nonlinear suppression of the response in the nonpreferred direction of movement.

Spatial summation by simple cells in the striate cortex of the cat.

Spatial summation has been studied in simple cells of the cat's visual cortex by examining the responses of pairs of lines. One line was placed in an ON region of the receptive field; the other was placed in an OFF region. When the luminances of the lines were modulated in anti-phase, the excitatory responses to the individual lines were almost synchronous. A simple cell's overt response to the composite stimulus was usually greater than the sum of the overt responses to the two components. The result could be explained by supposing that the underlying response was the linear sum of the excitatory signals but that an overt response occurred only when the underlying response exceeded a fixed threshold value. This was true even of simple cells which exhibited non-linearities of spatial summation, as judged from the waveforms of their responses to moving sinusoidal gratings. When the two lines were modulated in phase, the excitatory responses occurred in different halves of the temporal cycle. Some cells summed antagonistic signals linearly. The waveforms of their responses to moving sinusoidal gratings also implied linear spatial summation. However, other cells whose responses to moving gratings implied linearity of summation did not, in fact, sum antagonistic signals linearly. The excitatory responses evoked in a receptive field region were weaker than the inhibitory responses that could be evoked in the same region. The remaining cells did not sum antagonistic signals linearly. There was imperfect cancellation, resulting in the generation of ON-OFF response components. The excitatory responses evoked in a receptive field region were stronger than the inhibitory responses that could be evoked in the same region. These cells gave responses to sinusoidal gratings that did imply nonlinear spatial summation.

Factors influencing the temporal phase of response to bar and grating stimuli for simple cells in the cat striate cortex.

We have characterized the speed of response of simple cells in cat striate cortex by the temporal phase of the response to bar and grating stimuli. Stimulation of the most responsive subregion (either ON or OFF) in the receptive field with a 1 Hz temporally modulated bar elicited responses whose phase led the excitatory phase of the stimulus by about 25 degrees. The response to stationary gratings whose contrast was sinusoidally modulated at 2 Hz also showed a phase lead. The differences in the phase of response of ON and OFF sub-regions exhibited a marked scatter about the expected value of 180 degrees. The phase of response to both temporally modulated bars and laterally moving gratings advanced by 20-35 degrees as the stimulus contrast was raised by a factor of 5.

On the distinctness of simple and complex cells in the visual cortex of the cat.

The behaviour of neurones in cat striate cortex was examined in response to moving sinusoidal gratings and flashed bright and dark lines. The responses were summarized by three indices: discreteness was a measure of the degree of separation of inhibitory and excitatory regions in the receptive field; spatial summation ratio showed the degree of spatial summation within each region; relative modulation was a measure of the degree of modulation in the response to a moving grating. Some neurones had receptive fields with completely discrete excitatory and inhibitory regions; others responded equally to stimulus onset and offset throughout their receptive fields; however, some had overlapping excitatory and inhibitory regions. The degree of overlap varied continuously from complete separation to complete overlap. For neurones with discrete receptive fields, the widths of the regions were compared with the width of the bars in a grating of optimum spatial frequency to assess the degree of spatial summation within the regions. Most neurones with discrete receptive fields showed roughly predictable spatial summation, in that the two width measures agreed; but about 10% of them had receptive field regions that were too large by a factor of over two. The neurones which showed incomplete spatial summation also had considerable overlap of their excitatory and inhibitory regions. The waveforms of the responses to moving gratings of optimal spatial frequency were examined. The degree of modulation in the response was continuously distributed between low values typical of complex cells and high values typical of simple cells; the distribution was not bimodal. The degree of response modulation was closely correlated with the degree to which the excitatory and inhibitory regions in the receptive field were discrete. Both the degree of spatial summation and the degree of response modulation have been previously proposed as means for distinguishing simple and complex cells. In the present study, the continuity of the distributions of both indices ensured that neither index alone could be used to class all neurones unequivocally. However, a criterion based on two indices did allow classification. Simple and complex cells showed distinctive behaviour. However, complex cells with distinguishable excitatory and inhibitory regions in their receptive fields were not distinctly different from other complex cells.