Magnetic resonance markers of bilateral neuronal metabolic dysfunction in patients with unilateral internal carotid artery occlusion.

OBJECTIVES: To evaluate cerebral hemodynamic, metabolic and anatomic changes occurring in patients with unilateral occlusion of the internal carotid artery (ICA). MATERIALS AND METHODS: Twenty-two patients with unilateral occlusion of ICA and twenty age and sex matched healthy subjects were included in the study. Single voxel proton magnetic resonance spectroscopy (1H-MRS) of the centrum semiovale, semi-automated hippocampal volumetry in T1-weighted scans and transcranial Doppler examination (TCD) with calculation of Breath Holding Index (BHI) were performed in both groups. Metabolic, anatomic, and hemodynamic features were compared between the two groups. RESULTS: The N-acetylaspartate (NAA)/choline (Cho) ratio was significantly lower in both hemispheres of enrolled patients compared to controls (p = 0.005 for the side with occlusion, p = 0.04 for the side without occlusion). The hippocampus volume was significantly reduced bilaterally in patients compared to healthy subjects (p = 0.049). A statistically significant difference in BHI values was observed between the side with occlusion and without occlusion (p = 0.037) of the patients, as well as between BHI values of the side with occlusion and healthy volunteers (p = 0.014). DISCUSSION: Patients with unilateral ICA occlusion have reduced NAA/Cho ratio in the white matter of both hemispheres and have bilateral atrophy of hippocampus. The alteration of hemodynamics alone cannot explain these changes.

Difference in white matter microstructure in differential diagnosis of normal pressure hydrocephalus and Alzheimer's disease.

OBJECTIVES: Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) are both associated with cognitive decline and ventriculomegaly. While promising approach in differentiating between the two diseases, only a few diffusion tensor imaging (DTI) studies compared directly NPH and AD patients. The current study compares global whitematter (WM) alterations in AD and NPH addressing some of the methodological issues of previous studies. PATIENTS AND METHODS: Diffusion tensor images were obtained from 17 patients with NPH, 14 with AD, and 17 healthy controls. White matter integrity was quantified by fractional anisotropy (FA), mean (MD), axial (λ1) and radial diffusivity (RD). The diffusion parameters were compared between the groups in 'skeletonised' tracts representing the core of the fibre bundles. RESULTS: Reduced FA was found in NPH patients throughout the corpus callosum, particularly in the splenium, along with increased RD. On the other hand, FA, MD and RD were higher in NPH in the cortico-fugal fibres arising from the frontal and parietal cortex. While no FA changes were detected in AD patients compared to controls, widespread increased RD was observed. When comparing NPH and AD patients, higher FA, MD and RD was observed in the corona radiata in the periventricular fibres arising from the frontal and parietal cortex in NPH patients. The ventricular volumes were correlated with diffusivity parameters in the tracts next to the ventricles in AD and NPH patients. CONCLUSION: Our analysis identified a pattern of WM diffusion alterations that can differentiate NPH patients from controls and AD patients.

Familial temporal lobe epilepsy due to focal cortical dysplasia type IIIa.

PURPOSE: Focal cortical dysplasia (FCD) represents a common cause of refractory epilepsy. It is considered a sporadic disorder, but its occasional familial occurrence suggests the involvement of genetic mechanisms. METHODS: Siblings with intractable epilepsy were referred for epilepsy surgery evaluation. Both patients were examined using video-EEG monitoring, MRI examination and PET imaging. They underwent left anteromedial temporal lobe resection. RESULTS: Electroclinical features pointed to left temporal lobe epilepsy and MRI examination revealed typical signs of left-sided hippocampal sclerosis and increased white matter signal intensity in the left temporal pole. PET examination confirmed interictal hypometabolism in the left temporal lobe. Histopathological examination of resected tissue demonstrated the presence FCD type IIIa, i.e. hippocampal sclerosis and focal cortical dysplasia in the left temporal pole. CONCLUSION: We present a unique case of refractory mesial temporal lobe epilepsy in siblings, characterized by an identical clinical profile and histopathology of FCD type IIIa, who were successfully treated by epilepsy surgery. The presence of such a high concordance between the clinical and morphological data, together with the occurrence of epilepsy and febrile seizures in three generations of the family pedigree points towards a possible genetic nature of the observed FCD type IIIa.

Steroid hormones in prediction of normal pressure hydrocephalus.

Normal pressure hydrocephalus (NPH) is a treatable neurological disorder affecting elderly people with the prevalence increasing with age. NPH is caused by abnormal cerebrospinal fluid (CSF) reabsorption and manifested as a balance impairment, urinary incontinence and dementia development. These symptoms are potentially reversible if recognized early. Diagnosis of NPH is difficult and can be easily mistaken for other neurodegenerative disorders, which makes NPH one of the major misdiagnosed diseases worldwide. The aim of the study was to find out the appropriate combination of indicators, based on CSF steroids, which would contribute to a clearer NPH diagnosis. The levels of CSF cortisol, cortisone, dehydroepiandrosterone (DHEA), 7α-OH-DHEA, 7ß-OH-DHEA, 7-oxo-DHEA, 16α-OH-DHEA and aldosterone (all LC-MS/MS) were determined in our patients (n=30; NPH, 65-80 years) and controls (n=10; 65-80 years). The model of orthogonal projections to latent structures (OPLS) was constructed to predict NPH. Cortisone, 7α-OH-DHEA, 7ß-OH-DHEA, 7-oxo-DHEA, aldosterone, 7α-OH-DHEA /DHEA, 7-oxo-DHEA/7α-OH-DHEA, 7ß-OH-DHEA/7-oxo-DHEA and 16α-OH-DHEA/DHEA in the CSF were identified as the key predictors and the model discriminated patients from controls with 100% sensitivity and 100% specificity. The suggested model would contribute to early and accurate NPH diagnosis, enabling promptly treatment of the disease.

Determination of seven selected neuro- and immunomodulatory steroids in human cerebrospinal fluid and plasma using LC-MS/MS.

Dehydroepiandrosterone (DHEA) and its 7-oxo- and 7-hydroxy-metabolites occurring in the brain are considered neurosteroids. Metabolism of the latter is catalysed by 11ß-hydroxysteroid dehydrogenase (11ß-HSD) which also interconverts cortisol and cortisone. The concurrent metabolic reaction to DHEA 7-hydroxylation is the formation of 16α-hydroxy-DHEA. The LC-MS/MS method using triple stage quadrupole-mass spectrometer was developed for simultaneous quantification of free DHEA, 7α-hydroxy-DHEA, 7ß-hydroxy-DHEA, 7-oxo-DHEA, 16α-hydroxy-DHEA, cortisol and cortisone in human plasma and cerebrospinal fluid (CSF). The method employs 500 µL of human plasma and 3000 µL of CSF extracted with diethyl ether and derivatized with 2-hydrazinopyridine. It has been validated in terms of sensitivity, precision and recovery. In plasma, the following values were obtained: limit of detection: 2-50p g/mL; limit of quantification: 5-140 pg/mL; within-day precision 0.58-14.58%; between-day precision: 1.24-13.89% and recovery: 85-113.2%). For CSF, the values of limit of detection: 2-28 pg/mL; limit of quantification: 6-94 pg/mL; within-day precision; 0.63-5.48%; between-day precision: 0.88-14.59% and recovery: 85.1-109.4% were acquired. Medians and concentration ranges of detected steroids in plasma and CSF are given in subjects with excluded normal pressure hydrocephalus (n=37; 65-80 years). The method enables simultaneous quantification of steroids important for the estimation of 11ß-HSD activity in human plasma and CSF. It will be helpful in better understanding various degenerative diseases development and progression.

The comparison of selected cerebrospinal fluid and serum cytokine levels in patients with multiple sclerosis and normal pressure hydrocephalus.

OBJECTIVES: Cytokine production and immune activation are associated with various pathological conditions including neurodegenerative disorders. One of them is multiple sclerosis (MS), known autoimmune disease. Inflammatory changes were also reported in normal pressure hydrocephalus (NPH), neurodegenerative disorder, which pathophysiology remains still unclear. The aim of this research was to compare the group of MS subjects with NPH patients and controls and to evaluate the potential inflammatory substance of NPH in comparison with autoimmune inflamed MS. METHODS: The levels of IL-1ß, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40L and TNF-α were measured in cerebrospinal fluid (CSF) and plasma in subjects with MS (n=15), NPH (n=18) and controls (n=11) by multiplex assay. RESULTS: The increased levels of IL-1ß, IL-6, IL-10, IL-21 and TNF-α in cerebrospinal fluid of NPH subjects in comparison with MS patients and controls were found. Regarding the MS patients, we have confirmed increased IL-33 levels in cerebrospinal fluid and periphery as well as the increase of IL-1ß and IL-10 in cerebrospinal fluid and IL-4 and sCD40L in plasma. CONCLUSION: The enlarged brain ventricles in NPH may repress and activate brain structures to the production of IL-1ß, IL-6, IL-10, IL-21 and TNF-α, reflecting the inflammatory basis in NPH affected brain. The elevation of the above mentioned cytokines in MS was confirmed.

Selected pro- and anti-inflammatory cytokines in cerebrospinal fluid in normal pressure hydrocephalus.

OBJECTIVES: Normal pressure hydrocephalus (NPH) is a treatable neurological syndrome developing in the elderly. It is characterized by balance impairment, urinary incontinence and dementia development caused by disorders in the cerebrospinal fluid (CSF) circulation. The diagnosis can be easily mistaken for other neurodegenerative diseases, which are often accompanied by inflammation and the production of cytokines. The aim of our study was to determine and compare selected CSF and plasma cytokines with respect to their informative value for laboratory diagnostics of NPH. METHODS: The levels of IL-1ß, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, INF-γ, sCD40L and TNF-α were measured in the CSF and plasma in age-matched subjects with NPH (n=20) and controls (n=20) by multiplex assay. RESULTS: CSF IL-1ß, IL-6 and IL-10 were significantly increased on the 1st day of lumbar drainage in NPH (p<0.01). No significant changes were observed in the plasma. The CSF cytokines were one to three orders of magnitude higher compared to the plasma. CONCLUSION: CSF can better show the neurodegenerative changes in the brain. The cytokines IL-1ß, IL-6 and IL-10 may be helpful in NPH diagnostics.

SISCOM and FDG-PET in patients with non-lesional extratemporal epilepsy: correlation with intracranial EEG, histology, and seizure outcome.

AIMS: To assess the practical localising value of subtraction ictal single-photon emission computed tomography (SISCOM) coregistered with MRI and (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with extratemporal epilepsy and normal MRI. METHODS: We retrospectively studied a group of 14 patients who received surgery due to intractable epilepsy and who were shown to have focal cortical dysplasia, undetected by MRI, based on histological investigation. We coregistered preoperative SISCOM and PET images with postoperative MRI and visually determined whether the SISCOM focus, PET hypometabolic area, and cerebral cortex, exhibiting prominent abnormalities on intracranial EEG, were removed completely, incompletely, or not at all. These results and histopathological findings were compared with postoperative seizure outcome. RESULTS: Two patients underwent one-stage multimodal image-guided surgery and the remaining 12 underwent long-term invasive EEG. SISCOM findings were localised for all but 1 patient. FDG-PET was normal in 3 subjects, 2 of whom had favourable postsurgical outcome (Engel class I and II). Complete resection of the SISCOM focus (n=3), the area of PET hypometabolism (n=2), or the cortical regions with intracranial EEG abnormalities (n=7) were predictive of favourable postsurgical outcome. Favourable outcome was also encountered in: 4 of 8 patients with incomplete resection and 1 of 2 with no resection of the SISCOM focus; 4 of 7 patients with incomplete resection and 1 of 2 with no resection of the PET hypometabolic area; and 2 of 7 patients with incomplete resection of the area corresponding to intracranial EEG abnormality. No correlation between histopathological FCD subtype and seizure outcome was observed. CONCLUSION: Complete resection of the dysplastic cortex localised by SISCOM, FDG-PET or intracranial EEG is a reliable predictor of favourable postoperative seizure outcome in patients with non-lesional extratemporal epilepsy.

Steroids and their metabolites in CSF from shunt as potential predictors of further disease progression in patients with hydrocephalus and the importance of 11ß-hydroxysteroid dehydrogenase.

Abstract Hydrocephalus is the result of an imbalance between the formation and drainage of cerebrospinal fluid (CSF), characterized by an elevation of the CSF pressure within the brain. A primary method of its treatment is the surgical insertion of a shunt. The patient's condition is usually improved and he or she attends the hospital for periodic controls, at which CSF can be easily and repeatedly collected. Unfortunately, the effect of the operation is not durable and the number of patients in which the improvement of the clinical stage is recorded sinks considerably, and many of them develop dementia. Various biochemical markers in CSF have been searched to assess the response to surgical treatment and the further prognosis. They include classic clinical biochemistry parameters, some proteins occurring in excess in patients with Alzheimer's disease, other biomarkers generally reflecting the overall neuronal injury, and hormones, including steroids. The existing as well as the potential biomarkers enabling to predict the patient's fate after shunt operation are critically reviewed here. Special attention is paid to corticosteroids with respect to their role in influencing electrolyte balance in choroidal cells and consequently CSF and water flow among the ventricles. The importance of the local activity of steroid 11ß-hydroxysteroid dehydrogenase (11ß-HSD) of both types for regulation of the actual corticosteroid concentration is emphasized, and an original method for determination of cortisol/cortisone concentration in CSF is described. Preliminary results showing the changes of 11ß-HSD activity in ten patients with hydrocephalus immediately after shunt introduction and after 1 month are provided.

Steroid sulfatase and sulfuryl transferase activities in human brain tumors.

Neuroactive steroids (dehydroepiandrosterone, pregnenolone) and their sulfates act as modulators of glutamate and gamma-aminobutyrate type A receptors in the brain The physiological ratio of these neuromodulators is maintained by two enzymes present in the brain, namely, steroid sulfatase (STS) and steroid sulfuryl transferase (SULT). Following previous determination of their activities in monkey brains, their activities were evaluated in human brain tumors. Radioimmunoassay and GC-MS were used for determination of products. Both enzyme activities were measured in the 55 most frequent human brain tumors (glioblastomas, pituitary adenomas, meningiomas, astrocytomas). Significant differences were found in STS activity among investigated types of tumors except the pair of pituitary adenomas-glioblastomas, while significant differences were found in SULT activity among investigated types of tumors. Spontaneous tendency to form clusters was revealed when both enzyme activities were taken as coordinates. Clustering indicated an individual metabolic behavior of glioblastomas and 72.7% of pituitary adenomas. Astrocytomas, meningiomas and remaining 27.3% pituitary adenomas showed similarities in both enzymes' activities. Differences in STS and SULT activity did not depend on the sex or age of subjects.

Clinical characteristics in patients with hippocampal sclerosis with or without cortical dysplasia.

BACKGROUND: Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) constitutes a distinct clinical syndrome with variable pathogenesis. Extrahippocampal regions may be affected in MTLE/HS, association with cortical dysplasia is common and temporal polar cortex is frequently involved in seizure onset. Patients with dual pathology may have favourable outcome from the surgery provided that both pathologies are removed. The aim of the study was to review clinical variables of MTLE/HS patients in order to distinguish preoperatively patients with associated microscopic cortical dysplasia in the temporal pole. METHODS: A series of 38 patients with the clinical diagnosis of MTLE and histopathologically proven HS were analysed. Patients were divided into two groups on the basis of histopathological finding in the temporal polar cortex: HS associated with malformation of cortical development (group HS+, n = 19) and a group with isolated HS (group HS, n = 19). Demographic, clinical, electrographic and seizure semiology variables were obtained and their prevalence compared between both groups. RESULTS: At least one insult was identified in early childhood history of 18 patients in the HS group in comparison to 10 patients in the HS+ group (p < 0.01). Complicated febrile seizures were found in both groups with similar prevalence, the history of early childhood CNS infection prevailed in the HS group (p < 0.01). Absence of aura was reported in HS group only. Patients in the the HS+ group had earlier surgery (p < 0.05) but the seizure outcome was comparable between groups. CONCLUSIONS: Microscopic dual pathology is common in MTLE/HS patients. This group of patients is difficult to distinguish preoperatively on the basis of noninvasive electrographic features or ictal clinical semiology. Detailed information regarding the possible precipitating insult in the history may be of critical importance.

Aminothiols in human brain tumors.

BACKGROUND: Aminothiols are sulfur-containing amino acids involved in methionine metabolism. Changes in their levels play negative roles in the genesis of many diseases. These mechanisms involve direct toxicity, either on glutamate neurotransmitter receptors or cerebrovascular endothelium, and have an indirect inhibitory effect on transmethylation reactions. Oxidative stress and excitotoxicity are factors that may rise as a consequence of increased homocysteine levels in brain tissues. We discovered new information concerning concentrations of the main aminothiols in human neoplastic brain tissues. METHODS: The cytosolic fractions of 73 tissue samples from human brain tumors were used for the determination of total homocysteine, total cysteine and methionine levels. Gas chromatography with flame ionization detection after reduction of disulfide bonds was the method used. RESULTS: Average concentrations of the aminothiols examined were as follows: total homocysteine, 0.58-1.51 nmol/mg; methionine, 1.16-2.07 nmol/mg; and total cysteine 5.08-7.82 nmol/mg of total protein. Significantly higher levels of total homocysteine were found in pituitary adenoma and glioblastoma multiforme compared with other types of tumors. Methionine and cysteine concentrations did not differ significantly according to diagnosis. CONCLUSIONS: This is the first work concerning the concentrations of aminothiols in brain tissues. The results obtained indicate the metabolic pathways that are involved in tumor formation and/or its progress, including the toxic effects of homocysteine.

Recanalization of long-lasting middle cerebral artery occlusion by a combination of surgical and interventional approaches: technical case report.

OBJECTIVE AND IMPORTANCE: In strictly selected cases of middle cerebral artery (MCA) occlusion, revascularization by extracranial-intracranial (EC-IC) bypass can be considered. The interventional recanalization of the occlusion under direct surgical control has not been reported in the literature so far. CLINICAL PRESENTATION: A 39-year-old Caucasian female patient had experienced an ischemic stroke 15 years before she came to our attention. At that time, occlusion of the right MCA was diagnosed by angiography. Her neurological deficit resolved within 6 months. Fifteen years later, the patient experienced repeated numbness of her left-sided extremities, which was refractory to medical treatment. Angiography revealed an occluded M1 segment of the MCA. Perfusion computed tomography without and after CO2 stimulation disclosed impaired cerebrovascular capacity. INTERVENTION: The patient was scheduled for EC-IC bypass. The MCA tree was exposed, and the occluded portion was found to be 10 mm long. We then decided to reopen the vessel by balloon dilation under direct visual control. A catheter was advanced to the M1 origin, where a glidewire was passed into the vessel lumen. With only a little help from the surgeon, it was surprisingly easy to direct the glidewire through the occluded segment. At this time, flow through the M1 segment was re-established. Flow through the MCA that had occluded for 15 years was re-established. CONCLUSION: On the basis of our experience, in nonatherosclerotic occlusions, intravascular intervention may be considered.