Focal Neuronal Loss Research Articles

Secondary neurodegeneration following Stroke: what can blood biomarkers tell us?

Stroke is one of the leading causes of death and the primary source of disability in adults, resulting in neuronal necrosis of ischemic areas, and in possible secondary degeneration of regions surrounding or distant to the initial damaged area. Secondary neurodegeneration (SNDG) following stroke has been shown to have different pathogenetic origins including inflammation, neurovascular response and cytotoxicity, but can be associated also to regenerative processes. Aside from focal neuronal loss, ipsilateral and contralateral effects distal to the lesion site, disruptions of global functional connectivity and a transcallosal diaschisis have been reported in the chronic stages after stroke. Furthermore, SNDG can be observed in different areas not directly connected to the primary lesion, such as thalamus, hippocampus, amygdala, substantia nigra, corpus callosum, bilateral inferior fronto-occipital fasciculus and superior longitudinal fasciculus, which can be highlighted by neuroimaging techniques. Although the clinical relevance of SNDG following stroke has not been well understood, the identification of specific biomarkers that reflect the brain response to the damage, is of paramount importance to investigate in vivo the different phases of stroke. Actually, brain-derived markers, particularly neurofilament light chain, tau protein, S100b, in post-stroke patients have yielded promising results. This review focuses on cerebral morphological modifications occurring after a stroke, on associated cellular and molecular changes and on state-of-the-art of biomarkers in acute and chronic phase. Finally, we discuss new perspectives regarding the implementation of blood-based biomarkers in clinical practice to improve the rehabilitation approaches and post stroke recovery.

Neurovascular injury with complement activation and inflammation in COVID-19.

The underlying mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to acute and long-term neurological manifestations remains obscure. We aimed to characterize the neuropathological changes in patients with coronavirus disease 2019 and determine the underlying pathophysiological mechanisms.In this autopsy study of the brain, we characterized the vascular pathology, the neuroinflammatory changes and cellular and humoral immune responses by immunohistochemistry.All patients died during the first wave of the pandemic from March to July 2020. All patients were adults who died after a short duration of the infection, some had died suddenly with minimal respiratory involvement. Infection with SARS-CoV-2 was confirmed on ante-mortem or post-mortem testing. Descriptive analysis of the pathological changes and quantitative analyses of the infiltrates and vascular changes were performed.All patients had multifocal vascular damage as determined by leakage of serum proteins into the brain parenchyma. This was accompanied by widespread endothelial cell activation. Platelet aggregates and microthrombi were found adherent to the endothelial cells along vascular lumina. Immune complexes with activation of the classical complement pathway were found on the endothelial cells and platelets. Perivascular infiltrates consisted of predominantly macrophages and some CD8+ T cells. Only rare CD4+ T cells and CD20+ B cells were present. Astrogliosis was also prominent in the perivascular regions. Microglial nodules were predominant in the hindbrain, which were associated with focal neuronal loss and neuronophagia.Antibody-mediated cytotoxicity directed against the endothelial cells is the most likely initiating event that leads to vascular leakage, platelet aggregation, neuroinflammation and neuronal injury. Therapeutic modalities directed against immune complexes should be considered.

Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells.

Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage. Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB. Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure. These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.

Meningomyeloencephalitis secondary to Mycobacterium haemophilum infection in AIDS

Infections by opportunistic non-tuberculous mycobacteria (NTM) are rising in global incidence. One emerging, slowly growing NTM is Mycobacterium haemophilum, which can cause skin, lung, bone, and soft tissue infections in immunocompromised patients as well as lymphadenitis in immunocompetent individuals. Detection of this microorganism is difficult using conventional culture-based methods and few reports have documented involvement of this pathogen within the central nervous system (CNS).We describe the neuropathologic autopsy findings of a 39-year-old man with AIDS who died secondary to M. haemophilum CNS infection. He initially presented with repeated bouts of pyrexia, nausea and vomiting, and altered mental status that required numerous hospitalizations. CSF infectious workups were consistently negative. His most recent admission identified hyperintensities within the brainstem by MRI and despite antibiotic therapies for suspected CNS infection, he died. Autopsy revealed a swollen brain with marked widening of the brainstem. Microscopic examination of the brain and spinal cord showed focal lymphohistiocytic infiltrates, gliosis and neuronal loss that were associated with acid-fast bacilli (AFB). The brainstem was the most severely damaged and AFB were found to congregate along arterial territories lending support to the notion of hematogenous spread as a mechanism for the organisms’ dissemination. 16S rRNA sequencing on formalin-fixed paraffin-embedded tissue enabled post-mortem identification of M. haemophilum. This sequencing methodology may permit diagnosis on CSF intra-vitam.

Effects of Non-invasive, Targeted, Neuronal Lesions on Seizures in a Mouse Model of Temporal Lobe Epilepsy

Surgery to treat drug-resistant epilepsy can be quite effective but remains substantially underutilized. A pilot study was undertaken to test the feasibility of using a non-invasive, non-ablative, approach to produce focal neuronal loss to treat seizures in a rodent model of temporal lobe epilepsy. In this study, spontaneous, recurrent seizures were established in a mouse model of pilocarpine-induced status epilepticus. After post-status epilepticus stabilization, baseline behavioral seizures were monitored for 30 d. Non-invasive opening of the blood–brain barrier targeting the hippocampus was then produced by using magnetic resonance-guided, low-intensity focused ultrasound, through which a neurotoxin (quinolinic acid) administered intraperitoneally gained access to the brain parenchyma to produce focal neuronal loss. Behavioral seizures were then monitored for 30 d after this procedure, and brains were subsequently prepared for histologic analysis of the sites of neuronal loss. The average frequency of behavioral seizures in all animals (n = 11) was reduced by 21.2%. Histologic analyses along the longitudinal axis of the hippocampus revealed that most of the animals (n = 8) exhibited neuronal loss located primarily in the intermediate aspect of the hippocampus, while sparing the septal aspect. Two other animals with damage to the intermediate hippocampus also exhibited prominent bilateral damage to the septal aspect of the hippocampus. A final animal had negligible neuronal loss overall. Notably, the site of neuronal loss along the longitudinal axis of the hippocampus influenced seizure outcomes. Animals that did not have bilateral damage to the septal hippocampus displayed a mean decrease in seizure frequency of 27.7%, while those with bilateral damage to the septal hippocampus actually increased seizure frequency by 18.7%. The animal without neuronal loss exhibited an increase in seizure frequency of 19.6%. The findings indicate an overall decrease in seizure frequency in treated animals. And, the site of neuronal loss along the longitudinal axis of the hippocampus appears to play a key role in reducing seizure activity. These pilot data are promising, and they encourage additional and more comprehensive studies examining the effects of targeted, non-invasive, neuronal lesions for the treatment of epilepsy.

The effects of chronic smoking on the pathology of alcohol-related brain damage

Both pathological and neuroimaging studies demonstrate that chronic alcohol abuse causes brain atrophy with widespread white matter loss limited gray matter loss. Recent neuroimaging studies suggest that tobacco smoking also causes brain atrophy in both alcoholics and neurologically normal individuals; however, this has not been confirmed pathologically. In this study, the effects of smoking and the potential additive effects of concomitant alcohol and tobacco consumption were investigated in autopsied human brains. A total of 44 cases and controls were divided into four groups: 16 non-smoking controls, nine smoking controls, eight non-smoking alcoholics, and 11 smoking alcoholics. The volumes of 26 gray and white matter regions were measured using an established point-counting technique. The results showed trends for widespread white matter loss in alcoholics (p<0.007) but no effect on gray matter regions. In contrast, smoking alone had no effect on brain atrophy and the combination of smoking and alcohol showed no additional effect. Neuronal density was analyzed as a more sensitive assay of gray matter integrity. Similar to the volumetric analysis, there was a reduction in neurons (29%) in the prefrontal cortex of alcoholics, albeit this was only a trend when adjusted for potential confounders (p<0.06). There were no smoking or combinatorial effects on neuronal density in any of the three regions examined. These results do not support the hypothesis that smoking exacerbates alcohol-related brain damage. The trends here support previous studies that alcohol-related brain damage is characterized by focal neuronal loss and generalized white matter atrophy. These disparate effects suggest that two different pathogenic mechanisms may be operating in the alcoholic brain. Future studies using ultrastructural or molecular techniques will be required to determine if smoking has more subtle effects on the brain and how chronic alcohol consumption leads to widespread white matter loss.

Cerebellar hemorrhagic injury in premature infants occurs during a vulnerable developmental period and is associated with wider neuropathology

BackgroundCerebellar hemorrhagic injury (CHI) is being recognized more frequently in premature infants. However, much of what we know about CHI neuropathology is from autopsy studies that date back to a prior era of neonatal intensive care. To update and expand our knowledge of CHI we reviewed autopsy materials and medical records of all live-born preterm infants (<37 weeks gestation) autopsied at our institution from 1999–2010 who had destructive hemorrhagic injury to cerebellar parenchyma (n = 19) and compared them to matched non-CHI controls (n = 26).ResultsCHI occurred at a mean gestational age of 25 weeks and involved the ventral aspect of the posterior lobe in almost all cases. CHI arose as a large hemorrhage or as multiple smaller hemorrhages in the emerging internal granule cell layer of the developing cortex or in the nearby white matter. Supratentorial germinal matrix hemorrhage occurred in 95% (18/19) of CHI cases compared to 54% (14/26) of control cases (p = 0.003). The cerebellar cortex frequently showed focal neuronal loss and gliosis (both 15/19, 79%) in CHI cases compared to control cases (both 1/26, 4% p < 0.0001). The cerebellar dentate had more neuronal loss (8/15, 53%) and gliosis (9/15, 60%) in CHI cases than controls (both 0/23, 0%; p < 0.0001). The inferior olivary nuclei showed significantly more neuronal loss in CHI (10/17, 59%) than in control cases (5/26, 19%) (p = 0.0077). All other gray matter sites examined showed no significant difference in the incidence of neuronal loss or gliosis between CHI and controls.ConclusionsWe favor the possibility that CHI represents a primary hemorrhage arising due to the effects of impaired autoregulation in a delicate vascular bed. The incidences of neuronal loss and gliosis in the inferior olivary and dentate nuclei, critical cerebellar input and output structures, respectively were higher in CHI compared to control cases and may represent a transsynpatic degenerative process. CHI occurs during a critical developmental period and may render the cerebellum vulnerable to additional deficits if cerebellar growth and neuronal connectivity are not established as expected. Therefore, CHI has the potential to significantly impact neurodevelopmental outcome in survivors.

Cortical endogenic neural regeneration of adult rat after traumatic brain injury.

Focal and diffuse neuronal loss happened after traumatic brain injury (TBI). With little in the way of effective repair, recent interest has focused on endogenic neural progenitor cells (NPCs) as a potential method for regeneration. Whether endogenic neural regeneration happened in the cortex of adult rat after TBI remains to be determined. In this study, rats were divided into a sham group and a TBI group, and the rat model of medium TBI was induced by controlled cortical impact. Rats were injected with BrdU at 1 to 7 days post-injury (dpi) to allow identification of differentiated cells and sacrificed at 1, 3, 7, 14 and 28 dpi for immunofluorescence. Results showed nestin+/sox-2+ NPCs and GFAP+/sox-2+ radial glial (RG)-like cells emerged in peri-injured cortex at 1, 3, 7, 14 dpi and peaked at 3 dpi. The number of GFAP+/sox-2+ cells was less than that of nestin+/sox-2+ cells. Nestin+/sox-2+ cells from posterior periventricle (pPV) immigrated into peri-injured cortex through corpus callosum (CC) were found. DCX+/BrdU+ newborn immature neurons in peri-injured cortex were found only at 3, 7, 14 dpi. A few MAP-2+/BrdU+ newborn neurons in peri-injured cortex were found only at 7 and 14 dpi. NeuN+/BrdU+ mature neurons were not found in peri-injured cortex at 1, 3, 7, 14 and 28 dpi. While GFAP+/BrdU+ astrocytes emerged in peri-injured cortex at 1, 3, 7, 14, 28 dpi and peaked at 7 dpi then kept in a stable state. In the corresponding time point, the percentage of GFAP+/BrdU+ astrocytes in BrdU+ cells was more than that of NPCs or newborn neurons. No CNP+/BrdU+ oligodendrocytes were found in peri-injured cortex. These findings suggest that NPCs from pPV and reactive RG–like cells emerge in peri-injured cortex of adult rats after TBI. It can differentiate into immature neurons and astrocytes, but the former fail to grow up to mature neurons.

The effects of chronic alcoholism on cell proliferation in the human brain

Neurogenesis continues in the human subventricular zone and to a lesser extent in the hippocampal subgranular zone throughout life. Subventricular zone-derived neuroblasts migrate to the olfactory bulb where survivors become integrated as interneurons and are postulated to contribute to odor discrimination. Adult neurogenesis is dysregulated in many neurological, neurovascular and neurodegenerative diseases. Alcohol abuse can result in a neurodegenerative condition called alcohol-related brain damage. Alcohol-related brain damage manifests clinically as cognitive dysfunction and the loss of smell sensation (hyposmia) and pathologically as generalized white matter atrophy and focal neuronal loss. The exact mechanism linking chronic alcohol intoxication with alcohol-related brain damage remains largely unknown but rodent models suggest that decreased neurogenesis is an important component. We investigated this idea by comparing proliferative events in the subventricular zone and olfactory bulb of a well-characterized cohort of 15 chronic alcoholics and 16 age-matched controls. In contrast to the findings in animal models there was no difference in the number of proliferative cell nuclear antigen-positive cells in the subventricular zone of alcoholics (mean±SD=28.7±20.0) and controls (27.6±18.9, p=1.0). There were also no differences in either the total (p=0.89) or proliferative cells (p=0.98) in the granular cell layer of the olfactory bulb. Our findings show that chronic alcohol consumption does not affect cell proliferation in the human SVZ or olfactory bulb. In fact only microglial proliferation could be demonstrated in the latter. Therefore neurogenic deficits are unlikely to contribute to hyposmia in chronic alcoholics.

S.03.04 Neuronal stem cells in psychiatric diseases

Progranulin (PGRN) is involved in wound repair, inflammation, and tumor formation, but its function in the central nervous system is unknown. Roles in development, sexual differentiation, and long-term neuronal survival have been suggested. Mutations in the GRN gene resulting in partial loss of the encoded PGRN protein cause frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions. We sought to understand the neuropathological consequences of loss of PGRN function throughout the lifespan of GRN-deficient (−/+ and −/−) mice. An aged series of GRN-deficient and wild-type mice were compared by histology, immunohistochemistry, and electron microscopy. Although GRN-deficient mice were viable, GRN−/− mice were produced at lower than predicted frequency. Neuropathologically, GRN−/+ were indistinguishable from controls; however, GRN−/− mice developed age-associated, abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin. Lipofuscin was noted in aged GRN+/+ mice at levels comparable with those of young GRN−/− mice. GRN−/− mice developed microgliosis, astrogliosis, and tissue vacuolation, with focal neuronal loss and severe gliosis apparent in the oldest GRN−/− mice. Although no overt frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions type- or TAR DNA binding protein-43-positive lesions were observed, robust lipofuscinosis and ubiquitination in GRN−/− mice is strikingly similar to changes associated with aging and cellular decline in humans and animal models. Our data suggests that PGRN plays a key role in maintaining neuronal function during aging and supports the notion that PGRN is a trophic factor essential for long-term neuronal survival.

Interleukin-1α expression precedes IL-1β after ischemic brain injury and is localised to areas of focal neuronal loss and penumbral tissues

BackgroundCerebral ischemia is a devastating condition in which the outcome is heavily influenced by inflammatory processes, which can augment primary injury caused by reduced blood supply. The cytokines interleukin-1α (IL-1α) and IL-1β are key contributors to ischemic brain injury. However, there is very little evidence that IL-1 expression occurs at the protein level early enough (within hours) to influence brain damage after stroke. In order to determine this we investigated the temporal and spatial profiles of IL-1α and IL-1β expression after cerebral ischemia.FindingsWe report here that in mice, as early as 4 h after reperfusion following ischemia induced by occlusion of the middle cerebral artery, IL-1α, but not IL-1β, is expressed by microglia-like cells in the ischemic hemisphere, which parallels an upregulation of IL-1α mRNA. 24 h after ischemia IL-1α expression is closely associated with areas of focal blood brain barrier breakdown and neuronal death, mostly near the penumbra surrounding the infarct. The sub-cellular distribution of IL-1α in injured areas is not uniform suggesting that it is regulated.ConclusionsThe early expression of IL-1α in areas of focal neuronal injury suggests that it is the major form of IL-1 contributing to inflammation early after cerebral ischemia. This adds to the growing body of evidence that IL-1α is a key mediator of the sterile inflammatory response.

Repeated Physical Training and Environmental Enrichment Induce Neurogenesis and Synaptogenesis Following Neuronal Injury in an Inducible Mouse Model

Neuronal loss as a consequence of brain injury, stroke and neurodegenerative disorders causes functional impairments ranging from cognitive impairments to physical disabilities. Extensive rehabilitation and trainning may lead to neuroprotection and promote functional recovery, although little is known about the molecular and cellular mechanisms driving this event. To investigate the underlying mechanisms and levels of functional recovery elicited by repeated physical training or environmental enrichment, we generated an inducible mouse model of selective CA1 hippocampal neuronal loss. Following the CA1 neuronal injury, mice underwent one of the above mentioned conditions for 3 months. Exposure to either of these stimuli promoted functional cognitive recovery, which was associated with increased neurogenesis in the subgranular zone of dentate gyrus and enhanced synaptogenesis in the CA1 subfield. Notably, a significant correlation was found between the functional recovery and increased synaptogenesis among survived CA1 neurons. Collectively, these results support the utilization of cognitive and physical stimulation as approaches to promote recovery after neuronal loss and demonstrate the potential of this novel mouse model for the development of therapeutic strategies for various neurological disorders associated with focal neuronal loss.

Accelerated Lipofuscinosis and Ubiquitination in Granulin Knockout Mice Suggest a Role for Progranulin in Successful Aging

Progranulin (PGRN) is involved in wound repair, inflammation, and tumor formation, but its function in the central nervous system is unknown. Roles in development, sexual differentiation, and long-term neuronal survival have been suggested. Mutations in the GRN gene resulting in partial loss of the encoded PGRN protein cause frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions. We sought to understand the neuropathological consequences of loss of PGRN function throughout the lifespan of GRN-deficient ((-/+) and (-/-)) mice. An aged series of GRN-deficient and wild-type mice were compared by histology, immunohistochemistry, and electron microscopy. Although GRN-deficient mice were viable, GRN(-/-) mice were produced at lower than predicted frequency. Neuropathologically, GRN(-/+) were indistinguishable from controls; however, GRN(-/-) mice developed age-associated, abnormal intraneuronal ubiquitin-positive autofluorescent lipofuscin. Lipofuscin was noted in aged GRN(+/+) mice at levels comparable with those of young GRN(-/-) mice. GRN(-/-) mice developed microgliosis, astrogliosis, and tissue vacuolation, with focal neuronal loss and severe gliosis apparent in the oldest GRN(-/-) mice. Although no overt frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions type- or TAR DNA binding protein-43-positive lesions were observed, robust lipofuscinosis and ubiquitination in GRN(-/-) mice is strikingly similar to changes associated with aging and cellular decline in humans and animal models. Our data suggests that PGRN plays a key role in maintaining neuronal function during aging and supports the notion that PGRN is a trophic factor essential for long-term neuronal survival.

Focal neuronal loss in patients with neuropsychological impairment following traumatic brain injury: evaluation of central benzodiazepine receptor using 11C-flumazenil positron emission tomography

Focal neuronal loss in patients with neuropsychological impairment following traumatic brain injury: evaluation of central benzodiazepine receptor using ¹¹C-flumazenil positron emission tomography

Focal neuronal loss, reversible subcortical focal T2 hypointensity in seizures with a nonketotic hyperglycemic hyperosmolar state

Neuroimaging in seizures associated with nonketotic hyperglycemia (NKH) is considered normal. We report magnetic resonance imaging (MRI) abnormalities in four patients with NKH and seizures. We prospectively evaluated clinical and radiological abnormalities in four patients with NKH during the period March 2004 to December 2005. All patients presented with seizures, either simple or complex partial seizures or epilepsia partialis continua. Two of them had transient hemianopia. MRI showed subcortical T2 hypointensity in the occipital white matter and in or around the central sulcus (two patients each), T2 hyperintensity of the overlying cortex (two patients), focal overlying cortical enhancement (three patients) and bilateral striatal hyperintensity (one patient). Diffusion-weighted imaging (DWI) performed in three patients showed restricted diffusion. The ictal semiology and electroencephalographic (EEG) findings correlated with the MRI abnormalities. On clinical recovery, the subcortical T2 hypointensity and striatal hyperintensity reversed in all patients. The initial cortical change evolved to FLAIR hyperintensity suggestive of focal cortical gliosis. The radiological differential diagnosis considered initially included encephalitis, malignancy and hemorrhagic infarct rendering a diagnostic dilemma. We identified subcortical T2 hypointensity rather than hyperintensity as a characteristic feature of seizures associated with NKH. Only very few similar reports exist in literature. Reversible bilateral striatal T2 hyperintensity in NKH has not been reported to the best of our knowledge.

Surgery: All Ages

Surgery: All Ages

Neuronal loss in familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions

The neuronal density in the frontal, temporal, and parietal lobes was determined in nine cases of familial frontotemporal dementia with ubiquitin-positive, tau-negative inclusions (FTDU). The mean age at onset was 56.9 ± 2.2 years and the duration of disease was 6.7 ± 0.5 years. The mean age at death was 63.6 ± 2.2 years. There was substantial loss (34%) of brain weight (877 ± 73 g) in the familial cases in comparison with 10 normal aged controls (1326 ± 50 g, P < 0.001). All of the familial FTDU cases showed atrophy of the frontal, temporal, and parietal lobes; neuronal loss; vacuolation in superficial laminae; reactive astrocytosis; and ubiquitin-positive, tau-negative intracytoplasmic and intranuclear inclusions and dystrophic neurites in varying sites and numbers. Neuronal loss was estimated in nine cases of familial FTDU and in 10 aged controls using a stereological probe, the optical “disector,” and a computerized stereology system (CAST-Grid, Olympus, Denmark). There was a significant reduction in neuronal density in the frontal lobe (22.3 ± 3.8 × 10 3/mm 3) of familial FTDU in comparison to aged controls (33.1 ± 1.7 × 10 3 per mm 3, P < 0.05). An estimate of the relative numbers of neurons was calculated by multiplying the numerical density by the cortical thickness, which showed a striking loss of neurons of 56% in the frontal lobe, 52% loss in the temporal lobe, and a 49% loss in the parietal lobe of familial FTDU when compared to controls. This study shows that familial FTDU has profound focal neuronal loss in multiple association areas that relate to the clinical symptoms characteristic of the disease.

Neuroimaging evidence of progressive neuronal loss and dysfunction in temporal lobe epilepsy.

Whether temporal lobe epilepsy is the result of an isolated, early injury or whether there is ongoing neuronal dysfunction or loss due to seizures is often debated. We attempt to address this issue by using magnetic resonance techniques. Proton magnetic resonance spectroscopic imaging can detect and quantify focal neuronal dysfunction or loss based on reduced signals from the neuronal marker N-acetylaspartate (NAA), and magnetic resonance imaging (MRI)-based measurements of hippocampal volumes (MRIvol) can quantify the amount of atrophy in this structure. We performed magnetic resonance spectroscopic imaging and MRIvol in 82 consecutive patients with medically intractable temporal lobe epilepsy to determine whether there was a correlation between seizure frequency, or type or duration of epilepsy, with NAA to creatine (Cr) values or hippocampal volumes. Volumes and spectroscopic resonance intensities were categorized as to whether they were measured from the temporal lobe ipsilateral or contralateral to the predominant electroencephalographic focus. Ipsilateral and contralateral NAA/Cr was negatively correlated with duration of epilepsy. Hippocampal volumes were negatively correlated with duration ipsilaterally but not contralaterally. Frequency of complex partial seizures was not correlated with any of the magnetic resonance measures. However, patients with frequent generalized tonic-clonic seizures had lower NAA/Cr bilaterally and smaller hippocampal volumes ipsilaterally than patients with none or rare generalized tonic-clonic seizures. The results suggest that although an early, fixed injury may cause asymmetric temporal lobe damage, generalized seizures may also cause progressive neuronal dysfunction or loss.

Early microglial response in experimental thiamine deficiency: an immunohistochemical analysis.

Early glial changes have consistently been reported in experimental thiamine deficiency (TD) (Tellez and Terry, Am. J. Pathol. 52:777-794, 1968.) and in Wernicke Encephalopathy in humans (Victor et al., F.A. Davis Co., Philadelphia, 1989.). However, the precise nature of these changes and their relationship to the phenomenon of selective neuronal cell loss in TD has not been elucidated. In the present studies, antibodies against GFAP and ED1 were used to evaluate astrocytic and microglial/macrophagic changes respectively in adjacent sections of the brains of thiamine-deficient rats at various stages (n = 6 per stage) during the progression of encephalopathy. Additionally, the integrity of the blood-brain barrier at the same stages was assessed using IgG immunohistochemistry. Counts of immuno-positive cells revealed significant increases of ED1-immunostaining in the inferior olive, medial geniculate nucleus, and medial thalamic nuclei on day 8 of the treatment paradigm, prior to any evidence of increased IgG immunostaining or significant neuronal cell loss. ED1 immunostaining increased over time, resulting in intense staining by the loss of righting reflex stage (day 13-15). Focal increases of IgG-immunoreactivity in inferior olive, medial dorsal thalamus, and medial geniculate nucleus were observed on day 10, followed by increased GFAP-immunostaining consistent with reactive gliosis. Early microglial activation leading to the release of cytotoxic substances including reactive oxygen species, glutamate and cytokines appears to be the initial cellular response to TD and could be responsible for the focal neuronal loss characteristic of this disorder.

Neuroimaging and spectroscopy in children with epileptic encephalopathies

AIMSTo investigate the nature of the unifocal cortical abnormalities on FDG positron emission tomography (PET) in children with an epileptic encephalopathy but no focal abnormality on electroencephalogram or standard magnetic...