Focal demyelinative damage and neighboring white matter integrity: an optic neuritis study.

BACKGROUND: Neuronal loss following damage is often greater than expected from the severity of injury to the nerve itself. The visual pathways, which comprise a well-defined system, and optic neuritis (ON), which is usually a discrete event, make a fine model to study this phenomenon. OBJECTIVE: Understand the effect of focal optic nerve demyelination on neighboring white matter. METHODS: Diffusion tensor imaging and probabilistic tractography were used to identify and characterize the optic tracts and radiations of 17 ON and matched controls. Data were correlated with retinal nerve fiber layer (RNFL) thickness. RESULTS: Patients' optic tracts exhibited reduced axial diffusivity, which correlated with RNFL thickness values. Patients' optic radiations demonstrated intact axial diffusivity but reduced fractional anisotropy and elevated radial diffusivity, which could be explained by intra-bundle lesions. No correlations were found between diffusivity measurements in patients' optic tracts and radiations; or between RNFL thickness and optic radiations' diffusivity. CONCLUSIONS: Following ON, chronic axonal loss develops distally in the optic tracts, demonstrating Wallerian degeneration. Degeneration did not proceed to the optic radiations, opposing anterograde trans-neuronal changes. DTI in ON provides fine in-vivo human model for studying histological abnormalities in normal appearing white matter, localized in close proximity to damaged bundle.

Novel pulsatile cerebrospinal fluid model to assess pressure manometry and fluid sampling through spinal needles of different gauge: support for the use of a 22 G spinal needle with a tapered 27 G pencil-point tip.

BACKGROUND: Parallel-walled spinal needles ≤ 22 G are routinely used for lumbar puncture, despite a reported ≥ 32% incidence of post-dural puncture headache. A tapered spinal needle (22 G shaft, 27 G tip) is in use in our institution. We hypothesized that despite the smaller dural puncture hole, this needle has similar cerebrospinal fluid (CSF) pressure equilibration times and CSF sampling times to a standard 22 G needle and assessed a range of spinal needles using an experimental pulsatile CSF reservoir. METHODS: The pulsatile CSF reservoir had an oscillating pressure varying between 25 and 15 cm H(2)O at a cycle frequency of 80 s(-1). We tested seven parallel-walled spinal needles (18-27 G) and the tapered 22/27 G needle. CSF pressure was measured every 2 s by manometry. The time to collect 1 ml CSF samples was measured. Saline 0.9% and mannitol 20% were tested separately. One-way ANOVA with Bonferroni post-hoc test was used to compare 22G, 27G and 22/27G needles. RESULTS: The mean [standard deviation (sd)] CSF pressure equilibration time (saline) was 40.7 (6.4), 108.7 (6.1), and 51.3 (4.6) s for the 22, 27, and 22/27 G needles (P< 0.0001 for comparisons between 27 G and other needles). The mean (sd) CSF sampling time (saline) was 40.3 (3.1), 225.3 (10.0), and 63.0 (5.2) s for the 22, 27, and 22/27 G needles (P< 0.0001 for comparisons between 27 G and other needles, and P= 0.019 between 22 and 22/27 G needles). Saline was different from mannitol for both measurements and all needles (P< 0.0001). CONCLUSIONS: A 22/27 G tapered spinal needle has similar flow properties to the 22 G needle, despite a 27 G tip.

Prior use of statins and outcome in patients with intracerebral haemorrhage.

BACKGROUND: Pre-treatment with cholesterol lowering drugs of the statin family may exert protective effects in patients with ischaemic stroke and subarachnoid haemorrhage but their effects are not clear in patients with intracerebral haemorrhage (ICH). METHODS: We recruited patients admitted to our University Hospital with an acute ICH and analysed pre-admission demographic variables, pre-morbid therapy, clinical and radiological prognostic markers and outcome variables including 90-day modified Rankin score and NIH stroke scale score (NIHSS). RESULTS: We recruited 399 patients with ICH of which 101 (25%) were using statins. Statin users more often had vascular risk factors, had significantly lower haematoma volumes (P = 0.04) and had lower mortality rates compared with non-users (45.6% vs. 56.1%; P = 0.11). However, statin treatment did not have a statistically significant impact on mortality or functional outcome on multiple logistic regression analysis. CONCLUSIONS: Treatment with statins prior to ICH failed to show a significant impact on outcome in this analysis despite lower haematoma volumes.

Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression.

Several lines of evidence implicate the pro-inflammatory cytokine interleukin-1 (IL-1) in the etiology and pathophysiology of major depression. To explore the role of IL-1 in chronic stress-induced depression and some of its underlying biological mechanisms, we used the chronic mild stress (CMS) model of depression. Mice subjected to CMS for 5 weeks exhibited depressive-like symptoms, including decreased sucrose preference, reduced social exploration and adrenocortical activation, concomitantly with increased IL-1 beta levels in the hippocampus. In contrast, mice with deletion of the IL-1 receptor type I (IL-1rKO) or mice with transgenic, brain-restricted overexpression of IL-1 receptor antagonist did not display CMS-induced behavioral or neuroendocrine changes. Similarly, whereas in wild-type (WT) mice CMS significantly reduced hippocampal neurogenesis, measured by incorporation of bromodeoxyuridine (BrdU) and by doublecortin immunohistochemistry, no such decrease was observed IL-1rKO mice. The blunting of the adrenocortical activation in IL-1rKO mice may play a causal role in their resistance to depression, because removal of endogenous glucocorticoids by adrenalectomy also abolished the depressive-like effects of CMS, whereas chronic administration of corticosterone for 4 weeks produced depressive symptoms and reduced neurogenesis in both WT and IL-1rKO mice. The effects of CMS on both behavioral depression and neurogenesis could be mimicked by exogenous subcutaneous administration of IL-1 beta via osmotic minipumps for 4 weeks. These findings indicate that elevation in brain IL-1 levels, which characterizes many medical conditions, is both necessary and sufficient for producing the high incidence of depression found in these conditions. Thus, procedures aimed at reducing brain IL-1 levels may have potent antidepressive actions.

Neural progenitors from human embryonic stem cells.

The derivation of neural progenitor cells from human embryonic stem (ES) cells is of value both in the study of early human neurogenesis and in the creation of an unlimited source of donor cells for neural transplantation therapy. Here we report the generation of enriched and expandable preparations of proliferating neural progenitors from human ES cells. The neural progenitors could differentiate in vitro into the three neural lineages--astrocytes, oligodendrocytes, and mature neurons. When human neural progenitors were transplanted into the ventricles of newborn mouse brains, they incorporated in large numbers into the host brain parenchyma, demonstrated widespread distribution, and differentiated into progeny of the three neural lineages. The transplanted cells migrated along established brain migratory tracks in the host brain and differentiated in a region-specific manner, indicating that they could respond to local cues and participate in the processes of host brain development. Our observations set the stage for future developments that may allow the use of human ES cells for the treatment of neurological disorders.

Polysialylated neural cell adhesion molecule-positive CNS precursors generate both oligodendrocytes and Schwann cells to remyelinate the CNS after transplantation.

Transplantation offers a means of identifying the differentiation and myelination potential of early neural precursors, features relevant to myelin regeneration in demyelinating diseases. In the postnatal rat brain, precursor cells expressing the polysialylated (PSA) form of the neural cell adhesion molecule NCAM have been shown to generate mostly oligodendrocytes and astrocytes in vitro (Ben-Hur et al., 1998). Immunoselected PSA-NCAM+ newborn rat CNS precursors were expanded as clusters with FGF2 and grafted into a focal demyelinating lesion in adult rat spinal cord. We show that these neural precursors can completely remyelinate such CNS lesions. While PSA-NCAM+ precursor clusters contain rare P75+ putative neural crest precursors, they do not generate Schwann cells in vitro even in the presence of glial growth factor. Yet they generate oligodendrocytes, astrocytes, and Schwann cells in vivo when confronted with demyelinated axons in a glia-free area. We confirmed the transplant origin of these Schwann cells using Y chromosome in situ hybridization and immunostaining for the peripheral myelin protein P0 of tissue from female rats that had been grafted with male cell clusters. The number and distribution of Schwann cells within remyelinated tissue, and the absence of P0 mRNAs in donor cells, indicated that Schwann cells were generated by expansion and differentiation of transplanted PSA-NCAM+ neural precursors and were not derived from contaminating Schwann cells. Thus, transplantation into demyelinated CNS tissue reveals an unexpected differentiation potential of a neural precursor, resulting in remyelination of CNS axons by PNS and CNS myelin-forming cells.

Reversal of vision metamorphopsia: clinical and anatomical characteristics.

BACKGROUND: Metamorphopsia is a visual illusion that distorts the size, shape, or inclination of objects. Reversal of vision metamorphopsia (RVM) is a rare transient form of metamorphopsia described as an upside-down, 180 degrees rotation of the visual field in the coronal plane. The pathophysiological characteristics of RVM remain unclear. DESIGN: Patients with RVM had a complete neurologic examination during or shortly after an episode of metamorphopsia, with particular emphasis on gaze disorders, visual fields, visually guided hand movements, and perceptual or cognitive deficits. Workup included imaging studies, visual field examinations, and brainstem auditory and visual evoked response. SETTING: Department of Neurology, Hadassah University Hospital, Hebrew University-Hadassah Medical School, Jerusalem, Israel. PATIENTS: Six consecutive patients were evaluated from 1991 to 1996. RESULTS: Five patients had parieto-occipital brain insult sparing the primary visual cortex, and 3 also had evidence of a concomitant brainstem or cerebellar syndrome. One patient had pure brainstem syndrome underlying the RVM. Three patients had complete RVM as well as oblique RVM of less than 180 degrees. CONCLUSIONS: These cases imply a possible anatomical localization of the central integrator of visual extrapersonal orientation. Our observations suggest that a separate central mechanism of visual orientation might exist in each cerebral hemisphere and that occipital and parietal lesions that spare the optic radiations may account for the oblique and complete RVM. We postulate that failure to perceive space in an allocentric coordinate frame, particularly in the coronal roll plane, is potentially the critical event underlying RVM.

Bilateral focal motor status epilepticus with retained consciousness after stroke.

Bilateral motor seizures with retained consciousness are rare and often mistaken for pseudoseizures. In the few reported cases, the seizures were brief and the underlying lesion usually was a tumor. Here the authors describe a patient with bilateral focal motor status epilepticus with retained consciousness after a stroke. A seizure should be considered as the possible cause of continuous bilateral limb movements with retained consciousness.

Headache characteristics in patients after migrainous stroke.

Six patients who fulfilled strictly defined criteria for migrainous cerebral infarction and in whom other causes of stroke were ruled out were observed. All had a long-standing history of migraine with aura. In most, stroke was mild with good recovery and no recurrence. Headache frequency and severity decreased after the stroke. It is hypothesized that the improvement in migraine may be due to reduced nociceptive transmission as result of loss in vasoreactivity of the affected cerebral blood vessel.

Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNF-alpha inhibitor and an effective neuroprotectant.

Traumatic brain injury triggers a cascade of events resulting in delayed edema, necrosis and impaired function. Harmful mediators are accumulating in the brain after injury and recently, the role of cytokines in the pathophysiology of brain injury has been suggested. We have developed an experimental model for closed head injury (CHI), in which edema, blood-brain-barrier disruption, motor and memory dysfunctions have been demonstrated. In this study, spatial and temporal induction of IL-1, IL-6 and TNF-alpha gene mRNA transcription and of TNF-alpha and IL-6 activity in rat brain after CHI are shown. Dexanabinol, HU-211, is a synthetic cannabinoid devoid of cannabimimetic effects; it exhibits pharmacological properties of N-methyl-D-aspartate (NMDA)-receptor antagonist and is an effective cerebroprotectant. We report here that HU-211 is a novel inhibitor of TNF-alpha production at a post-transcriptional stage. HU-211, pentoxyfilline and TNF-binding protein improved the outcome of CHI. We suggest that TNF-alpha is a primary mediator of neurotoxicity after CHI, as inhibition of TNF-alpha is associated with better clinical recovery. TNF-alpha modulating agents, if given within the early time window post-injury, may improve the final neurological outcome in victims of brain trauma.

A novel permissive role for glucocorticoids in induction of febrile and behavioral signs of experimental herpes simplex virus encephalitis.

Herpes simplex virus type 1 (HSV-1) encephalitis may present with fever and behavioral changes, to the extent of a psychotic state and psychomotor agitation. We developed a clinically relevant experimental model of HSV-1 encephalitis and investigated host brain responses associated with its clinical signs and whether these responses depend on the presence of circulating glucocorticoids. Intracerebral inoculation of HSV-1 in rats induced fever, motor hyperactivity and aggressive behavior. In adrenalectomized rats HSV-1 failed to induce these signs, although mortality rate was identical to sham-operated rats. Hypophysectomy or blocking glucocorticoid receptors also prevented HSV-1-induced fever. Dexamethasone replacement therapy to adrenalectomized rats restored the HSV-1-induced fever and behavioral abnormalities. HSV-1 inoculation produced hyperproduction of prostaglandin E(2) by brain slices. This effect was abolished in adrenalectomized rats and was restored by dexamethasone treatment. In intact rats HSV-1 induced brain interleukin-1beta (IL-1beta) gene expression. Adrenalectomy alone caused brain IL-1beta expression, which did not increase after HSV-1 infection. Similarly, HSV-1 induced IL-1beta expression in astrocyte cultures. Removal of cortisol from the culture medium caused basal IL-1beta mRNA expression which was not increased by infection. In conclusion, fever, motor hyperactivity and aggressive behavior during experimental HSV-1 encephalitis are dependent on brain responses, including prostaglandin E(2) and IL-1beta synthesis. Circulating glucocorticoids play an essential permissive role in the induction of these host brain responses.

Comparative analysis of the transcripts mapped in the BamHI DNA fragment B of avirulent HSV-1 HFEM, virulent HSV-1 F, and their intratypic recombinant viruses.

HSV-1 HFEM, whose genome harbors a deletion of 4.1 kbp (0.762 to 0.789 map units (mu] is avirulent for mice and tree shrews by the intraperitoneal (i.p.) application route. Insertion of the BamHI DNA fragment B (0.738 to 0.809 mu) and/or the MluI DNA fragment (0.7615 to 0.796 mu) molecularly cloned from virulent HSV-1 F, restored the i.p. pathogenicity to strain HFEM and led to the isolation of virulent intratypic recombinants. In order to determine the RNA transcripts mapped in the BamHI DNA fragment B of the HSV-1 HFEM, HSV-1 F, and their intratypic recombinants R15, R19, R26, and R-Ml-C1, a comparative analysis was performed using Northern blot hybridizations. Two novel RNA transcripts of 3.5 and 1.5 kb were detected which hybridize to the left terminus (0.738 to 0.746 mu) of the BamHI DNA fragment B. The 1.5 kb RNA transcript was missing in the avirulent HSV-1 HFEM. Hybridization with the BssHII DNA fragment F (0.760 to 0.762 mu) led to detection of a 3.5 kb RNA transcript by HSV-1 HFEM which was missing in all other viruses tested. In contrast a 1.5 kb RNA transcript was detectable in all other virus strains with the exception of HSV-1 HFEM. The 3.5 kb transcript hybridized to the right-hand flank of the deleted region in the genome of HSV-1 HFEM (Asp718/SalI DNA fragment; 0.786 to 0.79 mu). The detection of the novel 1.5 kb RNA, which is missing in HSV-1 HFEM, and the appearance of the newly transcribed 3.5 kb RNA in HSV-1 HFEM only, indicates a new open reading frame in this particular region as a consequence of the fusion of the DNA sequences at both ends of the deletion in the genome of HSV-1 HFEM.

Replacement of the deletion in the genome (0.762-0.789 mu) of avirulent HSV-1 HFEM using cloned MluI DNA fragment (0.7615-0.796 mu) of virulent HSV-1 F leads to generation of virulent intratypic recombinant.

The HFEM strain of HSV-1 is apathogenic for the tree shrew by the intraperitoneal (i.p.) route because of a deletion in the genome coordinates 0.762-0.789. Insertion of the MluI DNA fragment (coordinates 0.7615-0.789) cloned from HSV-1 strain F, which is pathogenic for the tree shrew, restored the i.p. pathogenicity to strain HFEM. The recombinant designated R-M1-C1 was highly pathogenic for the tree shrew, but slightly virulent for inbred mouse strain A. It thus appears that the viral DNA sequence involved in the i.p. pathogenicity of HSV-1 is located within the genome coordinates 0.761-0.796. This sequence is recognized differently by the cellular elements involved in HSV-1 infection in the tree shrew and the mouse.

Severe influenza infection in a chronic hepatitis C carrier: failure of protective serum HI antibodies after IM vaccination.

BACKGROUND: Influenza is an important cause of morbidity and mortality in immunocompromised hosts. Recommendations exists for vaccination each year, yet disease can still occur. OBJECTIVES: To describe the course of fulminant influenza infection in a patient with HCV. STUDY DESIGN: Case study in which correlation was made between immunoglobulin response to influenza vaccination to the disease and its unique clinical course caused by influenza virus. RESULTS: Influenza A/Jerusalem 17/98 (H(1)N(1)) was isolated from the throat of a chronic hepatitis C carrier who, presented with shortness of breath, and subsequent massive bilateral pneumonia. The patient was previously immunized IM with inactive influenza vaccine. He developed protective levels of humoral antibodies (1:80 hemagglutination inhibition (HI) antibodies) against the three strains of the vaccine that evidently did not prevent respiratory infection. The development of massive bilateral pneumonia and continued presence of influenza virus in the respiratory tract may have been due to his underlying medical condition and possible lack of mucosal secretory IgA (SIgA) antibodies. CONCLUSION: We have presented a case of prolonged influenza infection post vaccination. This case emphasizes the importance of an improved vaccine that would stimulate a better immunologic response, especially in immunocompromised patients.

Adrenocortical activation by herpes virus: involvement of IL-1 beta and central noradrenergic system.

We investigated the involvement of brain cytokines and central monoamines in mediating the effect of the neurotropic herpes simplex virus-1 (HSV-1) on adrenocortical activity in rats. Corneal inoculation with a neurovirulent HSV-1 strain, but not with an avirulent strain, induced interleukin-1 beta (IL-1 beta) gene expression mainly in the pons and hypothalamus, and caused an elevation in serum corticosterone levels. Infectious virus was isolated in low titres only from the trigeminal ganglia and pons. Viral DNA was detected by PCR in these tissues and in other brain regions. Virus-induced adrenocortical activation was abolished in rats in which hypothalamic norepinephrine (NE) was depleted by 6-hydroxydopamine. Depletion of hypothalamic serotonin by 5,7-dihydroxytryptamine did not prevent adrenocortical activation. These results suggest that central IL-1 and NE are involved in HSV-1 induced adrenocortical activation.

Effects of HSV-1, a neurotropic virus, on the hypothalamic-pituitary-adrenocortical axis in rats.

It is well established that the hypothalamic-pituitary-adrenocortical (HPA) axis is activated during systemic viral diseases. In this study we examined the effects of a neurotropic virus, herpes simplex virus type 1 (HSV-1), on the HPA axis in male rats. Following corneal inoculation with HSV-1, the virus invaded the nervous system and replicated in the brainstem without clinical signs of disease. During this asymptomatic brainstem infection with HSV-1, significant changes were found in the function of the HPA axis: On days 3, 7 and 14 post-infection (p.i.) basal ACTH and corticosterone (CS) levels were markedly elevated, and photic stressful stimulation failed to further increase the levels of these hormones. In addition, the elevated basal serum levels of ACTH and CS could not be suppressed by pretreatment with dexamethasone. The content of CRF-41 in the paraventricular nucleus of the hypothalamus and in the median eminence measured at 6 days p.i. was similar to that of vehicle inoculated rats. By 4 weeks p.i. the basal levels of ACTH and CS returned to normal and these animals responded to photic stimulation and dexamethasone similar to vehicle inoculated rats. Systemic (intraperitoneal) inoculation of HSV-1 did not induce any changes in the HPA axis responses. We therefore suggest that asymptomatic acute infection of the brainstem with HSV-1 may affect brain regions involved in the regulation of the HPA axis, and that those effects are mediated centrally and not by a systemic mechanism.

Expression of endothelial nitric oxide synthase in the ischemic penumbra: relationship to expression of neuronal nitric oxide synthase and vascular endothelial growth factor.

Expressional patterns of the endothelial and neuronal forms of nitric oxide synthase (NOS) in cerebral ischemia were studied utilizing a permanent middle cerebral artery occlusion (PMCAO) model. Motor performance and infarct volumes were determined in the rats. Immunohistochemical staining for eNOS, nNOS and neurofilament were performed at 1, 2, 3, 5, 7 and 14 days after PMCAO. Vascular endothelial growth factor (VEGF) expression was determined by in-situ hybridization. PMCAO caused a reproducible cortical infarct with motor deficits in the rats. Double immunohistochemical stainings indicated that eNOS and nNOS were induced in ischemic neurons. Most stained neurons were positive for both NOS forms but some reacted with only one NOS antibody. nNOS expression peaked at 24-48 h after PMCAO, stained mainly the cytoplasm of core neurons, and disappeared after the 3rd day. eNOS expression increased until the 7th day, stained mainly the cytoplasm and membrane of penumbral cells and disappeared by the 14th day after PMCAO. VEGF expression was significantly induced in the penumbral zone in a similar distribution to eNOS. The anatomical and temporal pattern of VEGF and eNOS induction in the brain after permanent ischemia suggest that these mediators may play a role in protecting penumbral tissue from additional ischemic damage.

The role of brain cytokines in mediating the behavioral and neuroendocrine effects of intracerebral mycoplasma fermentans.

Intracerebral administration of Mycoplasma fermentans (MF), a small microorganism that has been found in the brain of some AIDS patients, induces behavioral and neuroendocrine alterations in rats. To examine the role of tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) in mediating these effects we measured MF-induced expression of TNFalpha and IL-1beta mRNA in various brain regions, and the effects of TNFalpha synthesis blockers and IL-1 receptor antagonist (IL-1ra) on MF-induced sickness behavior and adrenocortical activation. Intracerebroventricular (i.c.v.) administration of heat-inactivated MF induced the expression of both TNFalpha and IL-1beta mRNA in the cortex, dorsal hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either TNFalpha synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not attenuate MF-induced anorexia, body weight loss, and suppression of social behavior. However, simultaneous administration of both pentoxifylline and IL-1ra markedly attenuated MF-induced anorexia and body weight loss, but had no effect on the suppression of social behavior. Pre-treatment with pentoxifylline, but not with IL-1ra, significantly attenuated MF-induced corticosterone (CS) secretion. Together, these findings indicate that both TNFalpha and IL-1 participate, in a complementary manner, in mediating some of the behavioral effects of MF, whereas only TNFalpha, but not IL-1, is involved in mediating MF-induced adrenocortical activation. We suggest that cytokines within the brain are involved in mediating at least some of the neurobehavioral and neuroendocrine abnormalities that may be produced by MF in AIDS patients.

Valproate encephalopathy and hypocarnitinaemia in diabetic patients.

Two patients with epilepsy and diabetes mellitus developed encephalopathy while on valproate monotherapy. Low plasma carnitine levels were found. Discontinuation of valproate was followed by clinical recovery and normalization of carnitine levels. Both valproate treatment and diabetes mellitus may contribute to secondary carnitine deficiency, with resultant encephalopathy. Thus, diabetic patients may be at increased risk of developing valproate encephalopathy associated with hypocarnitinaemia.