Cerebral Ischemia-Reperfusion Injury: Lysophosphatidic Acid Mediates Inflammation by Decreasing the Expression of Liver X Receptor.

Lysophosphatidic acid (LPA), a ubiquitous phospholipid, plays a crucial role in the pathogenesis and pathophysiological process of neurological diseases, which constitute the pathological course after cerebral ischemia. Nevertheless, the molecular mechanisms associated with the pathogenic roles of LPA remain elusive. In this study, we evaluated the expression of the liver X receptor (LXR) and nuclear factor kappa B (NFκB) by Western blotting, quantified the levels of IL-1ß, IL-6, TNF-α, and LPA by ELISA, and evaluated apoptosis and infarct by TUNEL (terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling) and TTC (triphenyltetrazolium chloride) staining respectively in Sprague-Dawley (SD) rats after middle cerebral artery occlusion (MCAO). The levels of LPA, an extracellular signaling molecule, increased after ischemia and caused neurological injury effect, decreased the expression level of LXR, and increased the expression level of inflammatory factors (IL-1ß, IL-6, and TNF-α) via the NFκB signaling pathway. This elevated LPA-induced pathological process is one of the pathological reactions associated with ischemic brain injury. We present a direct or indirect connection between LPA and LXR in the pathophysiological process. In conclusion, we speculate that the inhibition of LPA generation and administration of LXR agonist may be explored as potential cerebral infarction treatment strategies.

Glucose hypometabolism in the visual cortex proportional to disease severity in patients with essential blepharospasm.

Essential blepharospasm (EB) causes difficulty in eyelid opening because of involuntary movements of the orbicularis oculi muscle. Patients with EB have functional visual loss due to sustained eyelid closure. We examined cerebral glucose metabolism in 39 patients with EB (12 men and 27 women; mean age, 52.1 years) by using positron emission tomography with 18F-fluorodeoxyglucose. Forty-eight eye open healthy subjects and 48 eye close healthy subjects served as controls. We analyzed and compared the data between the patients and controls by using both statistical parametric mapping (SPM) and regions of interest (ROIs). We defined ROIs on both sides of the posterior striate cortex, anterior striate cortex, extrastriate cortex, and thalamus. In SPM analysis, glucose hypometabolism were observed in both sides of the extrastriate cortex compared to eye open controls but not to eye close controls. We also observed a significant negative correlation between the Jankovic Rating Scale (JRS) sum score and relative glucose metabolism level in the striate cortex of these patients. ROI analysis, a significant correlation was observed between the JRS sum score and glucose metabolism level in the posterior (right: r = -0.53, P = .0005; left: r = -0.65, P = .00001) and anterior (right: r = -0.33, P = .04; left: r = -0.37, P = .02) striate cortices of patients with EB. We surmise that the interruption of visual input cause glucose hypometabolism in the visual cortex of patients with EB.

Botulinum toxin injection and tear production.

PURPOSE OF REVIEW: In 1980, botulinum toxin type A (BTX-A) was introduced for the treatment of strabismus and benign essential blepharospasm. Since then, a number of additional indications have been introduced, which continue to expand, providing less invasive solutions in managing different ophthalmic conditions. RECENT FINDINGS: Successful trials of BTX-A injection into the lacrimal gland have been reported for the treatment of epiphora caused by primary lacrimal gland hyperlacrimation, functional tearing, gustatory tearing, and lacrimal outflow obstruction. This is achieved through blockage of the cholinergic receptors by BTX-A at the glandular level. Interestingly, BTX-A has also been found to be useful in treating patients with dry eyes by compromising the tear drainage from the eye through injection of BTX-A in the medial part of the lower eyelid. BTX-A may help provide effective relief for patients who have two different ophthalmic comorbidities such as benign essential blepharospasm and dry eye. SUMMARY: Better understanding of the mechanism of BTX-A action in the treatment of the growing applications in ophthalmology helps provide relatively noninvasive solutions for patients. Full awareness of possible side effects of BTX-A and the optimal way to manage them is vital for the success of this treatment option.

Glucose hypermetabolism in the thalamus of patients with drug-induced blepharospasm.

We examined the difference in cerebral function alterations between drug-induced blepharospasm patients and essential blepharospasm (EB) patients by using positron emission tomography with (18)F-fluorodeoxyglucose. Cerebral glucose metabolism was examined in 21 patients with drug-induced blepharospasm (5 men and 16 women; mean age, 53.1 [range, 29-78] years), 21 essential EB patients (5 men and 16 women; mean age, 53.0 [range, 33-72] years) and 24 healthy subjects (6 men and 18 women; mean age, 57.9 [range, 22-78] years) with long-term history of benzodiazepines use (drug healthy subjects). Drug-induced blepharospasm patients developed symptoms while taking benzodiazepines or thienodiazepines. Sixty-three normal volunteers (15 men and 48 women; mean age, 53.6 [range, 20-70] years) were examined as controls. Differences between the patient groups and control group were examined by statistical parametric mapping. Additionally, we defined regions of interests on both sides of the thalamus, caudate nucleus, anterior putamen, posterior putamen and primary somatosensory area. The differences between groups were tested using two-sample t-tests with Bonferroni correction for multiple comparisons. Cerebral glucose hypermetabolism on both side of the thalamus was detected in drug-induced blepharospasm, EB patients and drug healthy subjects by statistical parametric mapping. In the analysis of regions of interest, glucose metabolism in both sides of the thalamus in the drug-induced blepharospasm group was significantly lower than that in the EB group. Moreover, we observed glucose hypermetabolism in the anterior and posterior putamen bilaterally in EB group but not in drug-induced blepharospasm group and drug healthy subjects. Long-term regimens of benzodiazepines or thienodiazepines may cause down-regulation of benzodiazepine receptors in the brain. We suggest that the functional brain alteration in drug-induced blepharospasm patients is similar to that in EB patients, and that alteration of the GABAergic system might be related to the pathology of both blepharospasm types.

The pallidopyramidal syndromes: nosology, aetiology and pathogenesis.

PURPOSE OF REVIEW: The aims of this review is to suggest a new nomenclature and classification system for the diseases currently categorized as neurodegeneration with brain iron accumulation (NBIA) or dystonia-parkinsonism, and to discuss the mechanisms implicated in the pathogenesis of these diseases. RECENT FINDINGS: NBIA is a disease category encompassing syndromes with iron accumulation and prominent dystonia-parkinsonism. However, as there are many diseases with similar clinical presentations but without iron accumulation and/or known genetic cause, the current classification system and nomenclature remain confusing. The pathogenetic mechanisms of these diseases and the causes of gross iron accumulation and significant burden of neuroaxonal spheroids are also elusive. Recent genetic and functional studies have identified surprising links between NBIA, Parkinson's disease and lysosomal storage disorders (LSD) with the common theme being a combined lysosomal-mitochondrial dysfunction. We hypothesize that mitochondria and lysosomes form a functional continuum with a predominance of mitochondrial and lysosomal pathways in NBIA and LSD, respectively, and with Parkinson's disease representing an intermediate form of disease. SUMMARY: During the past 18 months, important advances have been made towards understanding the genetic and pathological underpinnings of the pallidopyramidal syndromes with important implications for clinical practice and future treatment developments.

Peripheral kynurenine metabolism in focal dystonia.

Substantial evidence indicates that neuroactive kynurenine metabolites play a role in the normal physiology of the human brain, and are involved in the pathology of neurodegenerative disorders such as Parkinson's disease and Huntington's disease. A side-arm product of the pathway, kynurenic acid (KYNA), which is synthesized by the irreversible transamination of kynurenine (KYN) by kynurenine aminotransferases (KAT I and KAT II), is an excitatory amino acid receptor antagonist. In the present study, we measured the level of KYNA and the activities of the biosynthetic enzyme isoforms KAT I and KAT II in the plasma and in the erythrocytes (RBCs) of patients with cervical dystonia or blepharospasm and in age-matched controls. The KAT I and KAT II activities were significantly lower in the plasma of the patients in both subgroups. In the RBCs, only the KAT I activity was elevated significantly. The KYNA concentration was unchanged in both type of patients. These data support the contribution of an altered kynurenine metabolism to the pathogenesis of focal dystonia.

Glucose hypermetabolism in the thalamus of patients with essential blepharospasm.

Essential blepharospasm (EB) is classified as a form of focal dystonia characterized by involuntary spasms of the musculature of the upper face. The basic neurological process causing EB is not known. The purpose of this study was to investigate cerebral glucose metabolism in patients with EB whose symptoms were suppressed by an injection of botulinum-A toxin. Earlier studies were confounded by sensory feedback activities derived from dystonic symptom itself. Cerebral glucose metabolism was examined by positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) in 25 patients (8 men and 17 women; age 52.6 +/- 10.1 years) with EB. The patients were awake but with the spasms suppressed by an injection of botulinum-A toxin. Thirty-eight normal volunteers (14 men and 24 women; age 58.2 +/- 7.3 years) were examined as controls. The difference between the two groups was examined by statistical parametric mapping (SPM99). A significant increase in the glucose metabolism was detected in the thalamus and pons in the EB patients. Hyperactivity in the thalamus may be a key pathophysiological change common to EB and other types of focal dystonia. The activity of the striatum and cerebellum are likely to be sensory dependent.

Positron emission tomography scanning in essential blepharospasm.

PURPOSE: To localize in the brain using positron emission tomography neuroimaging with (18)fluorodeoxyglucose [PET ((18)FDG)] differences in glucose metabolism between patients with essential blepharospasm (EB) and controls. DESIGN: Prospective case-control study. METHODS: Positron emission tomography neuroimaging with (18)fluorodeoxyglucose was performed in 11 patients with EB and 11 controls matched for age and gender. Global analysis of images was used to localize differences in glucose metabolism between groups. RESULTS: Multiple cortical and subcortical abnormalities were observed in EB patients in comparison with controls. Cortical areas with the largest and most significant clusters of increased glucose uptake were the inferior frontal gyri, right posterior cingulate gyrus, left middle occipital gyrus, fusiform gyrus of the right temporal lobe, and left anterior cingulate gyrus. Cortical areas with the largest and most significant clusters of decreased glucose uptake were the inferior frontal gyri, ventral to the area of increased glucose metabolism. Subcortical abnormalities, consisting of increased glucose uptake, involved the right caudate and consisting of decreased glucose uptake, involved the left inferior cerebellar hemisphere and thalamus. CONCLUSIONS: Global analysis of positron emission tomography neuroimaging with (18)fluorodeoxyglucose neuroimaging in EB patients in comparison with controls demonstrates a pattern of abnormalities involving several cortical and subcortical areas that control blinking, including the inferior frontal lobe, caudate, thalamus, and cerebellum.

Positron emission tomography in patients with benign essential blepharospasm.

PURPOSE: To identify possible abnormalities in regional cerebral glucose metabolism in patients with benign essential blepharospasm or Meige syndrome using positron emission tomography. METHODS: Ten patients with benign essential blepharospasm and one patient with Meige syndrome were examined using positron emission tomography with deoxyglucose labeled with fluorine 18. The severity of muscle spasm at the time of positron emission tomography was recorded in each patient. In five patients, positron tomography was performed on two occasions (once before and again 1 to 2 weeks after botulinum injection) to look for reproducibility of the findings on positron emission tomography also to see if there was any correlation between the severity of symptoms and positron emission tomography findings. RESULTS: The mean reference ratio for fluorodeoxyglucose F18 metabolism was significantly elevated in the striatum compared with the frontal, temporal, or parietal regions. Glucose metabolism was also elevated in the thalami. There was no correlation between the severity of blepharospasm and the degree of hyperactivity in the striatum. In the patients who underwent positron emission tomography scanning on two occasions, there was no significant difference between the two studies in any of the regions analyzed. CONCLUSIONS: The authors' findings support the hypothesis that benign essential blepharospasm and Meige syndrome may be associated with overactivity of the striatum and the thalamus. Positron emission tomography may prove to be a useful research tool and a possible adjunct diagnostic technique for benign essential blepharospasm and Meige syndrome.

Increased very long-chain fatty acids in erythrocyte membranes of patients with aceruloplasminemia.

Aceruloplasminemia is a newly recognized autosomal recessive disorder of iron metabolism that causes neurodegeneration of the retina and basal ganglia as well as diabetes mellitus. Our previous studies suggested that increased susceptibility to plasma lipid peroxidation secondary to iron accumulation may contribute to the pathogenesis in this disease. We now have identified increases in the very long-chain fatty acids cis-17-hexacosenoic (C26:1) and hexacosanoic (C26:0) acid in the erythrocyte membranes of three family members affected with aceruloplasminemia. All of them had elevated C26:1/C22:0 and C26:0/C22:0 ratios. These findings suggest that free radicals generated in persons with aceruloplasminemia may interrupt the peroxisomal beta-oxidation of fatty acids.

Botulinum toxin increases tearing in patients with Sjögren's syndrome: a preliminary report.

Three patients with Sjögren's syndrome (SS) who had severe xerophthalmia and blepharospasm received botulinum toxin injections for the treatment of their blepharospasm. They had a remarkable increase in tearing, measured by Schirmer's test, and a decrease in signs and symptoms of dry eyes after botulinum toxin injection periorbitally for blepharospasm. The mechanism for this increased tearing is unclear, but suggests a potential treatment for patients with severe xerophthalmia with SS.

Decreased [18F]spiperone binding in putamen in idiopathic focal dystonia.

In this study we have investigated the pathophysiology of two idiopathic focal dystonias: hand cramp with excessive cocontractions of agonist and antagonist hand or forearm muscles during specific tasks, such as writing, and facial dystonia manifested by involuntary eyelid spasms (blepharospasm) and lower facial and jaw spasms (oromandibular dystonia). We used positron emission tomography (PET) to measure the in vivo binding of the dopaminergic radioligand [18F]spiperone in putamen in 21 patients with these two focal dystonias and compared the findings with those from 13 normals. We measured regional cerebral blood flow and blood volume in each subject as well as the radiolabeled metabolites of [18F]spiperone in arterial blood. A stereotactic method of localization, independent of the appearance of the images, was used to identify the putamen in all of the PET images. We analyzed the PET and arterial blood data with a validated nonsteady-state tracer kinetic model representing the in vivo behavior of the radioligand. An index of binding called the combined forward rate constant was decreased by 29% in dystonics, as compared with normals (p < 0.05). There were no significant differences between dystonics and normals in regional blood flow, blood volume, nonspecific binding, permeability-surface area product of [18F]spiperone or the dissociation rate constant. These findings are consistent with a decrease of dopamine D2-like binding in putamen and are the first demonstration of a receptor abnormality in idiopathic dystonia. These results have important implications for the pathophysiology of dystonia as well as for function of the basal ganglia.

Botulinum toxin treatment in the facial muscles of humans: evidence of an action in untreated near muscles by peripheral local diffusion.

In a population of subjects with blepharospasm and facial hemispasm treated for the first time with botulinum toxin type A (BT) in the orbicularis oculi muscle, we performed an electrophysiologic study (compound muscle action potential and motor evoked potential) to assess whether BT effect could be detected in near untreated muscles (orbicularis oris and masseter). There was a significant BT action in nearly untreated muscles with different peripheral innervation that can be explained by local diffusion of the drug.

Closed-lid factors influencing human corneal oxygen demand.

A micropolarographic system was used to measure the flux of oxygen crossing the tear-epithelial interface of the human cornea just following stabilization of four lid closure conditions. In all, 215 oxygen flux measurements were made on the corneas of 6 young healthy subjects, including 2 reference conditions: the normal open eye and anterior surface oxygen deprivation. When compared with the temperatures associated with certain of those conditions, oxygen demands greater than those predicted by a previous Q10 measurement were found. Proportional contributions of the non-temperature factor are presented, and the nature of its components suggested.