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.

Multimodal reperfusion therapy for large hemispheric infarcts in octogenarians: is good outcome a realistic goal?

BACKGROUND AND PURPOSE: MMRT may be beneficial in a subset of patients with large hemispheric stroke who cannot be treated with systemic thrombolysis. Because most previous studies only included relatively young patients, the outcome of very old patients given MMRT remains unknown. MATERIALS AND METHODS: Consecutive patients with large hemispheric stroke treated with MMRT and admitted to intensive care were included. We compared neurologic and functional outcomes between patients younger and older than 80 years. RESULTS: We included 14 patients older than 80 years and compared them with 66 patients who were younger than 80. Cerebrovascular risk factor profile, admission NIHSS scores, stroke etiology and pathogenesis, and procedure-related variables did not differ between the groups except for a higher prevalence of smoking in younger patients. Excellent target vessel recanalization (Thrombolysis in Myocardial Infarction score of 3) and good outcome at 90 days (modified Rankin Score ≤ 2) were more common in younger patients (45% versus 14%, P = .047, and 41% versus 0%, P = .008, respectively). In contrast, mortality rates were higher in octogenarians (43% versus 17%, respectively). CONCLUSIONS: In this study, very old patients had higher chances of mortality and a very low probability of achieving functional independence even after MMRT. Further prospective studies are needed to examine the futility of MMRT in the very old.

Rehabilitation outcomes of stroke patients treated with multi-modal endovascular reperfusion therapy.

AIM: The aim of this study was to investigate the influence of multi-modal endovascular reperfusion therapy (MMRT) on functional outcomes following rehabilitation. METHODS: Data from 14 MMRT-treated patients were analyzed and compared to MMRT-ineligible, age and stroke severity-matched patients treated at the same Neurological and Rehabilitation departments. Neurological evaluation was assessed with the NIH stroke scale (NIHSS). Activity of daily living was measured using the FIMTM instrument. Functional outcome was measured using the modified Rankin scale (mRS). RESULTS: The baseline characteristics of both groups were similar. NIHSS scores were lower in the MMRT group and they had slightly better functional and rehabilitation scores on admission to rehabilitation. At the end of rehabilitation, more MMRT-treated patients reached functional independence (mRS≤2; 50% vs. 7% respectively P=0.03). FIM scores were also higher in the MMRT group (mean score 93.3 vs. 87.7, respectively) but the difference did not reach significance. The delta in FIM and NIHSS scores obtained during rehabilitation did not significantly differ between the groups. MMRT remained a significant modifier of good outcome after regression analysis (OR 21.5 95% CI 1.1-410). CONCLUSION: MMRT-treated patients have better chances of attaining independence after rehabilitation therapy. However, the additional improvements gained while in active rehabilitation were independent of reperfusion status.

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.

Sustained motion perception deficit following optic neuritis: Behavioral and cortical evidence.

OBJECTIVE: To assess the recovery process in patients after an acute optic neuritis (ON) attack, comparing static and dynamic visual functions. METHODS: In this prospective controlled study, 21 patients with unilateral, first-ever ON were followed over the course of 1 year. Standard visual tests, visual evoked potentials, and optical coherence tomography were assessed repeatedly. In addition, we developed a novel set of motion perceptual tasks to test dynamic visual deficits. fMRI examinations were performed to study the neuronal correlates for the behavioral findings. RESULTS: Four months after the acute phase, the affected eyes had returned to normal performance levels in the routine visual testing. However, motion perception remained impaired throughout the 12-month period. In agreement with the clinical findings, fMRI studies showed recovery in cortical activation during static object recognition, as opposed to sustained deficit in tasks that require motion perception. CONCLUSIONS: Sustained motion perception deficit following ON may explain the continued visual complaints of patients long after recovery of visual acuity. Cortical activation patterns suggest that if plastic processes in higher visual regions contribute to the recovery of vision, this may be limited to static visual functions. Alternatively, cortical activation may reflect the visual percept (intact for visual acuity and impaired for motion perception), rather than demonstrating plastic processes. We suggest that motion perception should be included in the routine ophthalmologic tests following ON.

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.

Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain.

Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg(-1) heroin on gestation days 9-18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P<0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P<0.006) and reversed the behavioral defects (P<0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.

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.

Virus and host factors that mediate the clinical and behavioral signs of experimental herpetic encephalitis. A short auto-review.

Experimental models that mimic the clinical syndrome of human viral encephalitis and represent HSV-1 neurotropism were utilized to investigate neuro-pharmacologic changes mediating clinical and behavioral manifestations of encephalitic infection of the central nervous system with HSV-1-induced rapid activation of the hypothalamic--pituitary--adrenocortical (HPA) axis and production of brain derived interleukin-1 (IL-1) and prostaglandin E2 (PG-E2), independently of viral replication. HSV-1 infection induced clinical signs of fever, motor hyperactivity and aggressive behavior. These manifestations were dependent on a permissive action of circulating glucocorticoids and not related to the degree of viral replication in the brain. Hyperthermia and HPA axis activation were also specifically dependent on HSV-1-induced brain IL-1 and PG-E2. The chronic neurological sequel or fatal outcome of HSV-1 encephalitis may be due to viral replication and brain tissue destruction, which are dependent on virus encoded virulence genes. In contrast, the clinical and behavioral signs in the acute phase are a result of activation of neurochemical systems, including cytokines, prostaglandinds and catecholamines. Circulating glucocorticoids play an essential role in mediating the physiologic actions of HSV-1-induced brain products and the clinical syndrome of encephalitis.

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.

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.

Acute effects of purified and UV-inactivated Herpes simplex virus type 1 on the hypothalamo-pituitary-adrenocortical axis.

UNLABELLED: Herpes simplex virus type 1 (HSV-1) is a common cause of viral encephalitis, manifested by neuroendocrine and behavioral changes. We have previously demonstrated that HSV-1 induces marked hypothalamo-pituitary-adrenocortical (HPA) axis activation. In this study we characterized the acute effects of HSV-1 on the HPA axis occurring before viral replication and appearance of clinical signs of encephalitis. Since in previous studies we used crude virus preparations which may contain immune factors produced by the infected cells, we tested here the effects of purified HSV-1 virions. HSV-1 was propagated on Vero cells and virions were purified by centrifugation in sucrose gradients. Inactivation of viral infectivity was achieved by UV-irradiation, which caused a million-fold decrease in virus titer, as determined by plaque assay. Intracerebroventricular (ICV) inoculation of crude or purified virions induced a dose dependent increase in serum corticosterone and corticotropin (ACTH). This effect was maximal within 3.5 h postinfection and lasted for 72 h. ICV inoculation of UV-inactivated purified virions caused a marked increase in serum corticosterone and ACTH at 3.5 h, but in contrast to the effect of the active virus, the hormone levels gradually decreased at 24 h, and returned to basal levels at 72 h postinfection. HSV-1-induced HPA axis activation at 3.5 h was completely abolished by pretreatment with interleukin-1 receptor antagonist, injected ICV. Adrenalectomized rats failed to respond to ICV inoculation of purified HSV-1 by increase in ACTH. In contrast, these rats responded to ICV injection of LPS. IN CONCLUSION: (1) HSV-1 can acutely activate the HPA axis before and independently of any viral replication; (2) HSV-1-induced HPA axis activation depends on a permissive action of circulating glucocorticoids and on host derived brain interleukin-1.

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.

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.

Prognostic factors in artificially ventilated stroke patients.

OBJECTIVES: To evaluate the reasons for implementing artificial ventilation (AV) in patients with acute ischemic stroke (AIS), determine their outcome and characterize prognostic variables in these patients. METHODS: Consecutive patients presenting with AIS were evaluated. All patients who received AV were treated in a neurological semi-intensive care setting. RESULTS: Of the 173 patients included in the study, 27 (16%) needed AV, 16 (9%) received AV and five of these patients (31%) survived. The mean NIH stroke scale score prior to AV was 14.5+/-5.6 (vs. 9.1+/-6.2 in non-intubated patients, P=0.001). Six patients were ventilated because of neurological deterioration. Most of these patients had large hemispheric infarctions with evident herniation and midline shift on CT scans. The only one who survived the acute hospitalization did not recover and died within 3 months. In the other 10 patients, AV was instituted during cardiopulmonary decompensation (CPD). These patients generally fared better; four of them survived and were discharged after a lengthier hospital stay when compared to non-intubated patients. Variables associated with survival among intubated patients were a lower neurological disability score on admission and on day 7 after the stroke, and intubation during CPD. CONCLUSIONS: Implementing AV in semi-intensive care settings does not seem to improve survival in AIS patients with neurological deterioration. Stroke patients who need AV during CPD and those that have less severe neurological deficits may have better chances for survival.

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.