The congenital cranial dysinnervation disorders.

Congenital cranial dysinnervation disorders (CCDD) encompass a number of related conditions and includes Duane syndrome, congenital fibrosis of the external ocular muscles, Möbius syndrome, congenital ptosis and hereditary congenital facial paresis. These are congenital disorders where the primary findings are non-progressive and are caused by developmental abnormalities of cranial nerves/nuclei with primary or secondary dysinnervation. Several CCDD genes have been found, which enhance our understanding of the mechanisms involved in brain stem development and axonal guidance.

Gliomatosis presenting as a relative pupil-sparing third nerve palsy in a hypertensive diabetic.

We present an unusual case of a 41-year-old male patient who presented to the ophthalmology department giving a 3-month history of right sided ptosis, weight loss, diplopia and headache. Clinical examination revealed a right sided relative pupil-sparing third nerve palsy. MRI scan of brain showed thickening of both third nerves. Further investigations revealed a glioblastoma.

Neuroborreliosis in the South West of England.

Although Lyme borreliosis is increasingly diagnosed in the United Kingdom, few systematic studies have been performed there. UK data suggest that the commonest complications are neurological, but inadequate information exists about their nature and the incidence of late neuroborreliosis. Local data are necessary because clinical presentations may show geographical variation. This study aimed to provide data on clinical manifestations in an area of South West England and to estimate treatment delay. We reviewed clinical records of 88 patients in the Royal Devon and Exeter Hospital catchment area who had positive Borrelia antibody tests during a 5-year period. Fifty-six (64%) reported tick bites. The commonest presentations were erythema migrans (65%) and arthralgia/myalgia (27%). However, 22 patients (25%) had neurological symptoms other than headache alone. Fourteen had facial palsy, eight had confusion/drowsiness, four had meningism, five had radiculopathy, two had sixth nerve palsies, and two had peripheral neuropathies. No late, progressive or atypical neurological syndromes were found. Neurological manifestations were generally predictable and usually included either (or all) of meningoencephalitis, facial palsy or radiculopathy.

Peroxiredoxin V in multiple sclerosis lesions: predominant expression by astrocytes.

Oxidative stress is implicated in the pathogenesis of multiple sclerosis (MS). Defence against oxidative damage is mediated by antioxidants. Peroxiredoxin V (PRDX V) is an intracellular anti-oxidant enzyme with peroxynitrite reductase activity. It is increased during inflammation, when free radical production intensifies, and is protective in an animal model of brain injury. However, little is known about PRDX V expression in the human brain. We investigated PRDX V expression in white matter from normal human brain (n = 5) and MS patients (n = 18), using immunohistochemistry and immunoblotting. A global increase in PRDX V was evident in MS normal-appearing white matter (NAWM) but the most striking increase was in astrocytes in MS lesions. PRDX V- positive hypertrophic reactive astrocytes were seen in acute lesions where inflammation was present. Yet surprisingly, in chronic lesions (CL), where inflammation has abated and a glial scar formed, there was strong PRDX V staining of post-reactive, scar astrocytes. Furthermore, immunoblotting analysis of tissue from two MS cases confirmed a substantial increase in PRDX V expression in CL compared with NAWM from the same individual. This might indicate ongoing oxidative stress despite the absence of histologically defined inflammation. Further investigations of this phenomenon will be of interest for therapeutic targeting.

Astrocyte characterization in the multiple sclerosis glial scar.

Dense astrocytic scarring in chronic multiple sclerosis (MS) plaques produces an inhibitory environment which can impede tissue repair. Animal studies have shown that the antigenic phenotype of the most abundant cell type in the brain, the astrocyte, varies depending on astrocyte type and location. To identify the phenotype of scar astrocytes (SAs) in chronic lesions, markers of reactive astrocytes characterized in animal studies were investigated. To date these are the only established markers. Cerebral subventricular deep white matter from normal control, MS normal appearing white matter and lesions (acute, subacute and chronic) were examined by immunohistochemistry and immunoblotting. The antigenic profile of SAs revealed significant modification of astrocyte protein expression in chronic MS lesions. SAs express nestin, embryonic neural cell adhesion molecule, fibroblast growth factor receptor 4, epidermal growth factor receptor, nerve growth factor and a subpopulation of SAs also express basic fibroblast growth factor. These are in addition to the expected markers glial fibrillary acidic protein, vimentin, and the tenascins C and R. Therefore, an SA antigenic phenotype has now been defined. This knowledge may allow the development of therapeutic strategies that prevent scar formation and promote tissue repair.

Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31.

Duane's syndrome is a congenital abnormality of eye movement, which may be inherited as an autosomal dominant trait but usually occurs sporadically. Genetic mapping in a Mexican family has recently identified a locus for Duane's syndrome within a 17.8-cM region of chromosome 2q31. The region was flanked by the microsatellite markers D2S2330 and D2S364. We performed linkage and haplotype analysis in a four-generation UK family with autosomal dominant transmission of Duane's syndrome. Linkage to 2q31 was confirmed with a maximum logarithm of differences (lod) score of 3.3 at theta = 0. The genetic interval was reduced to an 8.8-cM region between markers D2S326 and D2S364 that includes the candidate homeobox D gene cluster.

Duane's syndrome.

Duane's syndrome is an unusual congenital form of strabismus where there is paradoxical anomalous lateral rectus innervation of the affected eye due to misdirection of axons destined for the medial rectus. Three types of Duane's syndrome are recognized. Most cases of Duane's syndrome are sporadic but up to 10% are familial, usually with autosomal dominant inheritance. Several autosomal dominant syndromes with dysmorphic features are associated with Duane's syndrome. Chromosomal loci for genes contributing to Duane's syndrome have been suggested at 4q, 8q and 22q. Duane's syndrome is heterogeneous at multiple levels with variations in its ocular manifestations, accompanying systemic manifestations and in the chromosomal loci with which it may be associated. The definition clinically and genetically of the various subgroups of Duane's syndrome will provide a valuable insight into brainstem axonal guidance to the extraocular muscles during human development.

Oligodendroglial gliomatosis cerebri: (1)H-MRS suggests elevated glycine/inositol levels.

Oligodendroglial gliomatosis cerebri is very rare. We describe 42-year-old woman who had low-grade oligodendroglial gliomatosis cerebri confirmed on stereotactic biopsy. The diffuse nature of the tumour was apparent clinically, neurophysiologically, on MRI and on proton magnetic resonance spectroscopy (MRS). She also had an isolated, false-localising partial seventh nerve palsy. MRS, of which there are no previous reports, suggested elevated glycine/inositol levels. This might be explained by the cell lineage from which the tumour arose.

Tenascin-R and C in multiple sclerosis lesions: relevance to extracellular matrix remodelling.

In the present study the distribution of the inhibitory extracellular molecules tenascin-R (TN-R) and tenascin- C (TN-C) was examined by immunocytochemistry during evolution of the multiple sclerosis (MS) lesion, in which astrogliosis is a prominent feature. Sections were cut from five control cases and from 22 blocks containing lesions representing different pathological stages in 18 cases of secondary progressive MS. Widespread expression of TN-R was found in the normal human central nervous system (CNS), while that of TN-C was in general restricted to white matter. In acute MS plaques however, there was a similar striking loss of both TN-R and TN-C up to the edge of the lesion, where the macrophage density is greatest, extending into the apparently normal white matter. In subacute lesions a TN-C and/or TN-R-immunopositive reactive astrocyte subpopulation was prominent, reflecting synthesis of extracellular matrix molecules. Both tenascins were expressed throughout chronic MS plaques at levels similar to those seen in adjacent white matter. The loss of TN-R and TN-C in acute plaques is indicative of enzyme-mediated breakdown of the matrix which may be a marker of blood-brain barrier breakdown and leucocyte extravasation. Subsequent production of tenascins by reactive astrocytes may result in glial scar formation impeding remyelination and axonal repair in MS lesions.

Genetic aberrations in glioblastoma multiforme: translocation of chromosome 10 in an O-2A-like cell line.

We have examined the genetic aberrations in two near-diploid glioblastoma multiforme cell lines that appear to have arisen from different glial lineages. One cell line, Hu-O-2A/Gb1, expresses antigens and metabolic profiles characteristic of the oligodendrocyte-type-2 astrocyte (0-2A) lineage of the rat central nervous system. This line generates, in vitro, cells with characteristics of 0-2A progenitor cells, oligodendrocytes and astrocytes. The second cell line, IN1434, is derived from an astrocyte or a precursor cell restricted to astrocytic differentiation. In Hu-O-2A/Gb1 the sole homologue of chromosome 10 is disrupted at band 10p11-12.1 by translocation with chromosomes X and 15. The translocation breakpoint is localized between genetic markers D10S2103 and [D10S637, D10S1962, D10S355]. Other aberrations include a 5;14 translocation, deletion of the long and short arms of chromosome 16 and loss of one copy of the CDKN2 gene. IN1434 cells share some cytogenetic abnormalities with Hu-O-2A/Gb1 cells, despite their apparent derivation from a different biological origin, but also have translocations involving the long and short arms of chromosome 1 and the long arm of chromosome 7, and deletion of chromosome 13 at bands 13q12-21.

Free radicals in inflammatory neurological disease: increased lipid peroxidation and haptoglobin levels in Guillain Barré syndrome.

Oxidative damage in three inflammatory neurological disorders; Guillain Barré syndrome (GBS), multiple sclerosis and aseptic meningitis, were assessed by measuring the peroxidation of lipids in body fluids. The results were compared to a control group consisting of patients with either migraine, chronic/tension headaches, benign intracranial hypertension or psychological disorders. Antioxidant status was assessed by the measurement of the extracellular proteins, haptoglobin, albumin, caeruloplasmin and transferrin. The results of the study suggested that firstly, haptoglobin levels might be a useful, easily obtainable marker to aid the diagnosis of GBS. Secondly, free radical damage may be implicated in the pathology of GBS and therefore appropriate free radical scavenging might have beneficial effects.

Early impairment of foveal magno- and parvocellular pathways in juxta chiasmal tumours.

Foveal pathway visual function was assessed in 11 patients having tumours extending into the suprasellar region but without evidence of visual impairment as assessed by visual acuity and Bjerrum screen campimetry. Psychophysical and routine visual evoked potential (VEP) measurements were obtained from the eye ipsilateral to the maximal suprasellar extension. The sensitivity of luminance and chromatic pathways was assessed psychophysically by measuring increment thresholds for white and red flashes of light presented on a white adapting field. Temporal sensitivity was assessed psychophysically by measuring threshold modulation sensitivity for sinusoidally modulating stimuli (de Lange attenuation characteristic). The patient group showed approximately equal significant psychophysical losses in chromatic, luminance and temporal sensitivities relative to normal controls. Midline VEP P100 latencies of the patient group did not significantly differ from those of the normal control group. It is concluded that tumours extending into the suprasellar region can cause foveal pathway dysfunction affecting both magno- and parvocellular pathways, even in the presence of normal visual acuity and fields suggesting a more widespread and insidious abnormality of the visual pathways in this condition than previously thought.