Treatment resistance in inclusion body myositis: the role of mast cells.

Inclusion body myositis is the commonest acquired myopathy in those over 50 years of age. Although it is classified as an idiopathic inflammatory myopathy and the most frequent finding on muscle biopsy in inclusion body myositis is an endomysial inflammatory infiltrate, it is clinically distinct from other myositis, including a lack of response to immunosuppressive medication. Neurogenic changes are commonly reported in inclusion body myositis and inflammatory changes are observed in muscle following neurogenic injury. The objective of our study was to explore whether neurogenic inflammation plays a role in the pathogenesis of inclusion body myositis, possibly explaining its resistance to immunosuppression. The number of mast cells and presence of neuropeptides, substance P and calcitonin gene-related peptide, were assessed in 48 cases of inclusion body myositis, 11 cases of steroid responsive myositis, two cases of focal myositis associated with neurogenic injury, and ten normal controls. The number of mast cells in inclusion body myositis focal and myositis associated to neurogenic injury were significantly greater than that observed in steroid responsive myositis. Our findings suggest that neurogenic inflammation mediated through mast cells may play a role in the pathogenesis of inclusion body myositis, and focal myositis associated to neurogenic injury, and thus, explain in some part its lack of response to immunosuppressive treatments.

Developmental changes in human dural innervation.

INTRODUCTION: There is limited published work on the abundant innervation of the human dura mater, its role and responses to injury in humans. The dura not only provides mechanical support for the brain but may also have other functions, including control of the outflow of venous blood from the brain via the dural sinuses. The trigeminal nerve supplies sensory fibres to the dura as well as the leptomeninges, intracranial blood vessels, face, nose and mouth. Its relatively large size in embryonic life suggests an importance in development; the earliest fetal reflexes, mediated by the trigeminal, are seen by 8 weeks. Trigeminal functions vital to the fetus include the coordination of sucking and swallowing and the protective oxygen-conserving reflexes. Like other parts of the nervous system, the trigeminal undergoes pruning and remodelling throughout development. METHODS: We have investigated changes in the innervation of the human dura with age in 27 individuals aged between 31 weeks of gestation and 60 years of postnatal life. Using immunocytochemistry with antibodies to neurofilament, we have found significant changes in the density of dural innervation with age RESULTS: The density of innervation increased between 31 and 40 weeks of gestation, peaking at term and decreasing in the subsequent 3 months, remaining low until the sixth decade. CONCLUSIONS: Our observations are consistent with animal studies but are, to our knowledge, the first to show age-related changes in the density of innervation in the human dura. They provide new insights into the functions of the human dura during development.

Mast cells in the human dura: effects of age and dural bleeding.

BACKGROUND: Animal studies have shown that the dura mater contains mast cells. We investigated the density of mast cells in the human dura mater, and the changes associated with subdural haemorrhage (SDH). METHODS: Samples of the human dura were stained with tryptase antibody and were examined for mast cells. We used control cases with no dural bleeding (n = 9) and cases of fresh (n = 24) and old (n = 18) dural haemorrhage. RESULTS: Mast cells were easily found in dural samples. The mean density in controls (11.05 cells per mm(2)) was less than that in fresh SDH (15.69), which was less than that in old SDH (23.09). CONCLUSIONS: Subdural haemorrhage is associated with an increase in dural mast cell density, and the density increases as the haematoma ages. We hypothesise that dural mast cells may contribute to neurogenic inflammation and the clinical features of subdural haemorrhage.

Spinal nerve root ß-APP staining in infants is not a reliable indicator of trauma.

This preliminary communication describes seven babies with ß-amyloid precursor protein (ßAPP) positive axonal swellings in nerve roots at multiple levels of the spinal cord. All seven babies died of natural causes. Two died in utero providing evidence for nerve root injury in the absence of trauma, two died within one day of birth and the possibility of birth related injury has to be considered. Three babies were over one month of age and had no history or pathological evidence of trauma. These findings show that if axonal injury is carefully sought in every infant death, not just in babies where trauma is suspected, it will be found in a proportion of babies dying from natural diseases. While spinal nerve root axonal injury in infants may suggest trauma, it is not, in itself, diagnostic of trauma.

Expression patterns of glial fibrillary acidic protein (GFAP)-delta in epilepsy-associated lesional pathologies.

AIMS: Glial fibrillary acidic protein (GFAP)-delta is a novel isoform that differs in its C-terminal sequence from other GFAP isoforms. Previous studies suggest restriction of expression to the subpial layer, subventricular zone and the subgranular zone astrocytes, with an absence in pathological conditions causing reactive gliosis. GFAP-delta is speculated to have roles in regulation of astrocyte size and motility and a subpopulation of GFAP-delta-positive glia may be multipotent stem cells. The aim of this study was to investigate its expression in common causes of lesion-related refractory epilepsy. METHODS: Hippocampal sclerosis (HS), focal cortical dysplasia (FCD) type IIB, cortical tuberous sclerosis (TSC) lesions, gangliogliomas, grey matter heterotopias and hemimegalencephaly from a wide age range of patients using both surgical and post mortem tissue specimens were studied. RESULTS: GFAP-delta expression was observed in CA4 and CA1 astrocytes in HS with less frequent labelling in the granule cell layer, even where granule cell dispersion was present. No significant labelling was noted in the subiculum in HS cases or in any subfields in non-HS epilepsy cases. Balloon cells in FCDIIB and hemimegalencephaly, giant cells in TSC and the astrocytic component of gangliogliomas showed immunoreactivity, colocalizing with conventional GFAP. No neuronal expression for GFAP-delta was seen in any of the pathologies. Quantitative analysis in 10 FCDIIB and five TSC cases revealed greater numbers of GFAP-delta-positive balloon cells than conventional GFAP. There was no GFAP-delta expression within nodular heterotopia. CONCLUSIONS: GFAP-delta expression patterns in HS overall appears to mirror regional reactive gliosis. It is a useful marker for the demonstration of balloon cells in FCD and TSC, which may be relevant to their abnormal size and localization. The lack of GFAP-delta within heterotopia supports their composition from cells destined for deeper cortical layers.

Demonstration of fluid channels in human dura and their relationship to age and intradural bleeding.

PURPOSE: This paper aims to make a systematic study of human dura to establish the presence of fluid transport channels and their relationship to age. METHODS: Samples of parasagittal dura from autopsy cases from mid-gestation to the ninth decade were examined by light microscopy. RESULTS: We have demonstrated the presence of unlined rounded spaces, uncommon in the fetus and neonate but increasingly evident after 30 weeks of postnatal life. We have shown that intradural bleeding is inversely correlated with the presence of these channels and with age. CONCLUSIONS: We suggest that dural maturation, involving the development of arachnoid granulations, may be related to dilatation of intradural fluid channels, allowing them to be identified histologically. The risk of reflux of blood into the dura appears to reduce with age.

A spectrum of unusual neuroimaging findings in patients with suspected Sturge-Weber syndrome.

BACKGROUND AND PURPOSE: Sturge-Weber syndrome (SWS) is frequently associated with neurologic complications such as seizures, so diagnosing this condition has important implications for patient management. The purpose of this study was to report unusual neuroimaging findings in patients with facial port-wine stain (PWS) and clinically suspected SWS. MATERIALS AND METHODS: Cranial MR imaging was reviewed for all children with facial port-wine stain (PWS) involving the upper face and eyelids who were referred to Great Ormond Street Hospital between 2003 and 2007 for investigation of suspected SWS. Patients were excluded from further analysis if the imaging findings were normal on initial and subsequent scans and the subject remained free of neurologic disease, or if the imaging showed the well-recognized pattern of exclusively supratentorial pial enhancement representing the pial angioma of SWS. For the remaining patients, the neurologic, dermatologic, and ophthalmologic records were examined and all available imaging was reviewed by a neuroradiologist. We documented the presence and distribution of pial enhancement; corroborative features of SWS, such as atrophy, calcification, choroid plexus changes, and ocular abnormalities; and all other intracranial abnormalities. RESULTS: Of the 62 patients referred for assessment, imaging findings were considered typical of SWS in 32 (52%) and were normal or showed abnormalities attributable to an unrelated pathology in 20 (32%). Of the remaining 10 patients, in 7 (11%), there was evidence of a pial angioma in an unusual distribution involving infratentorial structures, with the angioma in 1 patient being diagnosed at postmortem only; in 2 (3%), there were imaging abnormalities with some features in common with typical SWS, such as subcortical calcification, but with no evidence of pial enhancement; in 1 (1.6%), the initial MR imaging finding was normal, but repeat imaging subsequently revealed pial enhancement. CONCLUSIONS: Involvement of infratentorial structures is common but may be relatively subtle and should be actively sought. Cases in which there are certain patterns of imaging abnormalities but an apparent absence of supratentorial pial enhancement on MR imaging may represent formes frustes of SWS; visualization of pial angiomatosis may also be delayed until later in childhood than expected.

Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct "pseudo-TORCH" phenotype.

The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients-two male-female sibling pairs, one pair born to consanguineous parents, and an unrelated female-with a distinct pattern of band-like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post-natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable "pseudo-TORCH" phenotype inherited as an autosomal recessive trait.

An investigation of the expression of G1-phase cell cycle proteins in focal cortical dysplasia type IIB.

Balloon cells (BCs) are the pathologic hallmark of focal cortical dysplasia type IIB, a common cause of pharmacoresistent epilepsy. Expression of markers of cell immaturity and of the proliferation marker minichromosome maintenance protein 2 (mcm2) have been previously shown in BCs, suggesting that these cells might represent a pool of less-differentiated cells licensed for replication. An alternative explanation is that these cells are the remnants of early cortical plate cells that have failed to differentiate or to be eliminated during development and are arrested in the cell cycle, a hypothesis that this study aims to explore. Using immunohistochemical methods and semiquantitative analysis in 19 cases of focal cortical dysplasia (ages 1-81 years), we studied the expression of cell cycle proteins important either in regulating progression through the G1 phase or inducing cell arrest and promoting premature senescence. Only a small fraction of BCs expressed geminin, suggesting that few BCs enter the S phase or complete the cell cycle. Variable expression of nonphosphorylated retinoblastoma protein (Rb), cdk4, and p53 was noted in BCs. Cyclin E, D1, cdk2, phosphorylated Rb (795 and 807/811), and checkpoint 2 expression levels were low in BCs. These findings suggest early rather than late G1 arrest. Cell senescence could be induced by an undefined cerebral insult during development or alternatively represent a physiologic replicative senescence. These findings also suggest that dysregulation of cell cycle pathways may occur in focal cortical dysplasia, which opens further areas for exploration as potential new treatment avenues.

Epidural haemorrhage of the cervical spinal cord: a post-mortem artefact?

Spinal epidural haemorrhage is a rare entity that occurs uncommonly in adults and rarely in children. It has a typical clinical presentation, although to date, the cause for the majority of cases remains unknown. We present a series of cases where epidural haemorrhage was identified at post-mortem, principly to the cervical cord, in cases outside the age range usually reported for clinical epidural haemorrhage, and with no underlying pathology to account for the finding. We present a hypothesis for a post-mortem cause for this finding and consider that, in the absence of any other identifiable causation, then this is a post-mortem occurrence similar to that of the Prinsloo-Gordon artefact of the soft tissues of the neck. This finding must be interpreted with care so as not to make the mistaken diagnosis of a nonaccidental head injury based on its finding, especially in the absence of intracranial, cranial nerve, optic nerve or eye pathologies.

Acute ataxia complicating Langherans cell histiocytosis.

A case is reported of a 3 year old boy with an acute history of cerebellar impairment and x ray evidence of apparent chest infection. At postmortem examination, his lungs but not the nervous system were found to be massively infiltrated by Langherans histiocytes. In retrospect, the acute ataxia was diagnosed as a paraneoplastic phenomenon secondary to Langherans cell histiocytosis (LCH). This represents a unique occurrence complicating LCH in childhood.

Mycoplasma pneumoniae infection, meningoencephalitis, and hemophagocytosis.

Central nervous system manifestations are a common extrapulmonary complication of Mycoplasma pneumoniae infection, of which encephalitis is a well-recognized abnormality in children. In this report the first description of M. pneumoniae infection simultaneously complicated by meningoencephalitis and hemophagocytosis is presented.

Mapping of autosomal dominant progressive external ophthalmoplegia to a 7-cM critical region on 10q24.

OBJECTIVE: To map the gene responsible for autosomal dominant progressive external opthalmoplegia. BACKGROUND: The pathogenesis of progressive external ophthalmoplegia (PEO) can be associated with multiple deletions of mitochondrial DNA (mtDNA). PEO may show autosomal dominant (adPEO) or autosomal recessive (arPEO) patterns of inheritance, indicating that the genetic defect has a Mendelian basis and most likely involves a nuclear gene encoding a protein that interacts with the mitochondrial genome. adPEO is heterogeneous genetically, and thus far disease loci have been identified on chromosomes 3 and 10. The locus on chromosome 10q23-q25 was assigned by linkage analysis in a single Finnish family. METHODS: Samples from a large Pakistani family with adPEO, in which clinical symptoms are bilateral ptosis, limitations of eye movements, and varying degrees of proximal muscle weakness, were collected. Muscle biopsy and mtDNA rearrangement analysis was used to confirm the diagnosis. Genomewide linkage analysis was set up using a set of 391 microsatellite markers. RESULTS: The muscle biopsy from an affected member showed ragged red fibers, increased succinic dehydrogenase staining, lack of cytochrome oxidase activity, and multiple deletions of mtDNA. The disease locus was mapped to 10q23.31-q25.1 by linkage analysis, and a maximum lod score of 5.72 was obtained with D10S1267. CONCLUSION: By analysis of meiotic recombinations in affected individuals, the critical region was restricted to the 7-cM interval between D10S198 and D10S1795.

Relationship between MR imaging and histopathologic findings of the brain in extremely sick preterm infants.

BACKGROUND AND PURPOSE: MR imaging can now be used safely in extremely preterm infants. The aim of this study was to compare the MR imaging appearance of the immature brain with neuropathologic findings at postmortem examination. METHODS: Seven extremely sick preterm infants, born at a median of 24 weeks' gestation, were studied using T1- and T2-weighted MR sequences. Infants died at a median of 3 days after initial MR imaging, and postmortem examinations were carried out. RESULTS: The cortex and germinal matrix were seen as areas of low signal intensity on T2-weighted images, which corresponded to their highly cellular histologic appearance. The periventricular and subcortical layers of white matter had a high signal intensity, corresponding to high fiber and relatively low cellular density; the intermediate layer of low signal intensity corresponded to a dense band of migrating cells. Regions of acute hemorrhage were seen as low signal intensity and regions of infarction as high signal intensity on T2-weighted images. One infant with mild periventricular leukomalacia had some low signal intensity on T1-weighted images, but no focal changes on T2-weighted images. Regions of neuronal mineralization, seen in association with infarction and capillary proliferation, within the basal ganglia and thalami were characterized by very low signal intensity on T2-weighted images and by very high signal intensity on T1-weighted images. There were no imaging abnormalities detected in regions with more subtle histologic abnormalities, such as increased glial or apoptotic cells. CONCLUSION: MR imaging can be used to observe normal developing brain anatomy in extremely premature infants; it can detect areas of hemorrhage and infarction within the developing brain, but conventional MR imaging may not detect more subtle histologic abnormalities.

Severe amnesia: an usual late complication after temporal lobectomy.

A patient developed the severe amnesic syndrome 8 years after temporal lobe surgery for epilepsy. He underwent left temporal lobectomy (6 cm, 43.5 g; hippocampal sclerosis) aged 19, and remained seizure free for 8 years until a convulsion followed a head injury. He became severely amnesic after a fourth convulsion 16 months later. He was right-handed, pre-operative IQ was average, verbal memory poor and non-verbal memory normal. Post-operatively, these were unchanged. After the first post-operative seizure he began professional training. After onset of amnesia IQ was unchanged, anterograde memory severely impaired and retrograde amnesia dense for at least 16 months. He died 2 years later. Magnetic resonance imaging before amnesia showed absence of anterior left temporal lobe, atrophy of left fornix and mamillary body, and normal right temporal lobe. Four months after onset of amnesia, right hippocampal volume had reduced by 36%. Autopsy showed: previous left temporal lobectomy with absence of left amygdala and hippocampus, atrophy of fornix and mamillary body; neuronal loss in the right hippocampus, severe in CA1 and CA4; intact right amygdala and parahippocampal gyrus; recent diffuse damage associated with cause of death. A convulsion can cause severe hippocampal damage in adult life. Hippocampal zones CA1 and/or CA4 are critical for maintaining memory and the amygdala and parahippocampal gyrus cortex alone cannot support acquisition of new memories.

Evidence of nuclear DNA fragmentation following hypoxia-ischemia in the infant rat brain, and transient forebrain ischemia in the adult gerbil.

Wistar rats, eight days old, were subjected to permanent bilateral forebrain ischemia, followed by hypoxia for 15 minutes. A cerebral infarct, mainly involving the cerebral neocortex, hippocampus, amygdala, striatum and subcortical white matter was produced. Neurons and glia showing punctate chromatin condensation and karyorrhectic cells were observed 12 hours after hypoxia-ischemia. Their number increased during the first two days and recruitment of cells with degenerating nuclei occurred until day five. In situ labeling of nuclear DNA fragmentation stained many normal-appearing nuclei, as well as punctate chromatin condensations and nuclear fragments in karyorrhectic cells. Delayed neuronal death in the CA1 area of the hippocampus was observed after 20 minutes of transient forebrain ischemia in the adult gerbil. In situ labeling of nuclear DNA fragmentation demonstrated stained punctate chromatin condensation in a few degenerating cells at 48 hours post-ischemia. Substantial labeling of CA1 neurons occurred in the fourth day. Agarose gel electrophoresis of extracted brain DNA from ischemic infant rats and adult gerbils showed a ladder-type pattern which is typical of nuclear DNA fragmentation into oligonucleosomal fragments (internucleosomal cleavage). These findings suggest that endonuclease(s) activation may play a role in cell death induced by different forms of hypoxia-ischemia.