Diffusion tensor imaging (DTI) in the detection of white matter lesions in patients with mild cognitive impairment (MCI).

Mild cognitive impairment (MCI) is recognized as a precursor to dementia. The amnestic MCI progresses usually to Alzheimer disease. Amnestic MCI multiple domain (md-MCI) seems to progress more rapidly than amnestic MCI single domain (a-MCI). In an attempt to identify patients at risk, we examined white matter changes in MCI subtypes using diffusion tensor imaging (DTI). We also tried to correlate DTI findings to neuropsychological tests. Forty-four amnestic single domain (a-MCI) patients, 19 amnestic multi domain (md-MCI), and 25 cognitively normal (NC) controls were included in the present study. All participants were assessed clinically using a battery of cognitive tests. DTI was performed to measure fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Areas studied were corpus callosum, posterior cingulum (PC), anterior cingulum (AC), and superior longitudinal fasciculus (SLF). ADC and FA of the above areas were related to the scores of certain neuropsychological tests that evaluate visual and verbal memory. No difference in DTI measurements was found between the two MCI subtypes. ADC in MCI cases was increased in comparison with NC in the genu, PC, right SLF, and left AC. FA was spared. Verbal memory was related to ADC of the genu, PC, right AC and right SLF, and to FA of the left SLF. Visual memory was related to ADC of the genu, PC, right AC, and SLF. The strongest correlation found was between the visual memory and the ADC of the right PC (Spearman ρ = 0.45, p < 0.001). DTI revealed that ADC was increased in certain brain areas in MCI patients. No difference in DTI measurements was found between the two MCI subtypes. DTI indices correlate with cognitive performance.

Immune cells after prolonged Natalizumab therapy: implications for effectiveness and safety.

BACKGROUND: Previous studies on Natalizumab (NAT) have shown increased circulation of most white blood cells (WBC) in multiple sclerosis (MS) patients shortly after its introduction. AIM: To describe peripheral immune cell phenotypes after more than 2 years of continuous NAT therapy and test for associations with clinical response to therapy. METHODS: Peripheral immune cell subsets were analyzed in 44 NAT-MS patients receiving NAT for over 24 months, and in 22 NAT-free control-MS patients. RESULTS: NAT-MS patients displayed significantly higher numbers of all WBC when compared with controls. B lymphocytes exhibited a more pronounced increase when compared with CD4+, CD8+ and NK T-cells (P = 0.011). CD4/CD8 ratio was significantly decreased in NAT-MS patients (P = 0.018) and showed no correlation with the number of NAT doses. The reduced CD4/CD8 ratio was attributable to the 'EDSS improvement' group only, irrespective of age, sex and disease severity. CONCLUSIONS: The study suggests that there is no desensitization effect after prolonged NAT exposure. A reduced CD4/CD8 ratio was associated with long-term response to therapy; thus, those patients who most benefitted from the drug might be at greater risk for opportunistic infections like progressive multifocal leucoencephalopathy (PML). We provide implications for future research for the CD4/CD8 ratio as a possible contributor to the recently developed risk stratification scheme for PML.

Memantine in everyday clinical practice: a comparison of studies in Germany and Greece.

BACKGROUND/AIMS: Results from German and Greek non-interventional studies were compared to investigate possible differences concerning efficacy, tolerability and compliance between both countries. METHODS: In two open-label, multicentre, non-interventional studies, 4,305 patients with mild to severe Alzheimer's disease (AD) were treated with daily doses of 20 mg memantine for 6 months. Efficacy was assessed using the Mini-Mental State Examination (MMSE) and instrumental activities of daily living (IADL) scales. Safety and tolerability were recorded. RESULTS: After 6 months, the patients showed an improvement of their cognitive performance by 2 MMSE points compared to baseline (p < 0.001). MMSE values were improved in 67.4% of the patients, while 15.1% remained stable, and MMSE deteriorated in 17.5% only. The ability to perform IADL increased, as is indicated by lower values (baseline: 70.5; after 6 months: 66.6 points). Improvement of cognition and IADL was nearly identical in both countries. Treatment discontinuation was significantly more frequent in the Greek population, mainly due to non-adherence (9.4% of the safety population). 345 adverse events were recorded in 245 patients (6.3%), and they were significantly associated with country and age. CONCLUSION: The results correspond to those of clinical trials and support the efficacy and good tolerability of memantine in a realistic setting. Differences between the countries were observed regarding the baseline characteristics of patients (more female, older and more severe patients in Germany as well as less pretreatment with cholinesterase inhibitors) and regarding premature discontinuation and reported adverse drug reactions, which were both higher in Greece.

Effects of antimicrobial prophylaxis on asymptomatic bacteriuria and predictors of failure in patients with multiple sclerosis.

We studied the effects of antimicrobial prophylaxis and possible predictors of failure in multiple sclerosis patients with bacteriuria and bladder dysfunction. patients were categorized into 3 groups, according to post-voided residual urine volume (PVR): patients with indications for self-intermittent catheterization (SIC) who elected (Group A, n=39) or not (Group B, n=53) to use SIC and patients with no indication for SIC (Group C, n=75). In group A, 90% of patients developed bacteriuria after SIC. Rates of bacteriuria in groups B and C were significantly lower (34% and 24%, respectively, all p<0.001). Prophylaxis failed in 31% and 22% of patients in groups A and b, respectively whereas all group C patients responded to prophylaxis. Symptomatic urinary tract infection was observed only in 14% of group A patients. Significant predictors of prophylaxis failure were an expanded disability status scale (EDSS) score >6 (p<0.05), a high pVR (p<0.075) and resistance to prophylaxis regimen (p<0.007). SIC did not have a significant association with prophylaxis failure. In multivariate analysis only a higher eDSS score (>6) predicted prophylaxis failure (p=0.019).

The diagnostic value of earlier and later components of Vestibular Evoked Myogenic Potentials (VEMP) in multiple sclerosis.

AIM OF THE STUDY: To evaluate the ability of VEMP to disclose spatial dissemination of Multiple Sclerosis. MATERIALS AND METHODS: Forty-six MS patients with auditory and/or vestibular symptoms were studied. Patients were divided in two groups. Group 1 included 24 patients with brainstem MRI findings, and Group 2 included 22 patients without MRI findings. VEMP and BAEP have been recorded and assessed. RESULTS: Abnormal p13n23 wave was observed in 50%, while unilateral absence or bilateral delay of the n34p44 in 43% of the patients. The overall diagnostic value considering abnormal cases suggested by both first and second VEMP waves was increased to 71%. Statistically significant differences revealed between patients and controls for p13 latency (p=0.018). The p13n23 was abnormal in 7 patients, although MRI scanning did not reveal brainstem lesions. In 9 out of 18 MS patients suffering from unilateral hearing loss, n34p44 was present in the unaffected ears and absent in the affected side, although p13n23 was normal. CONCLUSION: Abnormal VEMP imply the presence of lesions undetected by MRI neuroimaging, which verifies the diagnostic value of the method. Unilateral absence of n34p44 complex was related with sensorineural hearing loss, supporting the hypothesis that n34p44 is of cochlear origin.

Using vestibular evoked myogenic potentials to localise brainstem lesions. A preliminary report.

BACKGROUND: Vestibular Evoked Myogenic Potentials (VEMPs) are saccular responses to acoustic stimuli. They can be recorded from the sternocleidomastoid muscle ipsilaterally to the stimulated ear. Their reflex arc includes the ipsilateral vestibular nuclei. OBJECTIVE: To determine the usefulness of VEMPs in localising brainstem lesions. METHODS: We used VEMPs, Blink Reflex (BR) and Brainstem Auditory Evoked Responses (BAERs) to evaluate six patients presenting with acute ischaemic or haemorrhagic brainstem lesions, or basilar dolichoectasia. RESULTS: MRI in patient one revealed a dorsolateral medullary infarct on the right. VEMP amplitude was reduced ipsilaterally. The R2 BR component was delayed bilaterally upon stimulation of the affected side. Patients two and three had suffered a left lateral lower pontine infarct and a right lateral lower pontine haemorrhage. In patients four and five, MRA revealed dolichoectasia of the basilar artery exerting pressure on the lower lateral pons. VEMP amplitude was reduced ipsilaterally. Patient six had an ischaemic lesion in the right upper lateral pons. The R1, R2i and R2c BR components were delayed ipsilaterally. BAERs waves IV and V were absent on the right. VEMPs were normal. CONCLUSIONS: VEMPs are affected by lesions of the lateral lower pons and upper medulla. Our results suggest that they may be a useful addition in the localisation of such lesions.

Octreotide: a therapeutic option for idiopathic intracranial hypertension.

PURPOSE: To study the effects of octreotide, a somatostatin analogue, in patients with Idiopathic Intracranial Hypertension (IIH). METHODS: We performed a prospective, open-label study of the effect of Octreotide on 26 patients with symptoms and signs of IIH, investigated by brain MRI and lumbar puncture. Octreotide was administered subcutaneously, at an initial dose of 0.3 mg/day; and was gradually increased until headache was relieved (upper-dose limit: 1 mg/day). Treatment with octreotide at 1 mg/day was administered for a maximum of six to eight months and afterwards the dose was gradually tapered. Patients were followed prospectively every month for three years. CSF opening pressure was measured before the treatment was started and again in the first follow-up examination, on month one. In all follow-up visits the presence of papilledema was evaluated by fundoscopy; visual fields and visual acuity were also examined. RESULTS: Overall 24/26 patients improved significantly (92%). Headache was relieved within days (1-10, median 7 days). Papilledema subsided in all 24 patients, in up to two months (35 to 68, median 45 days). Visual disturbances, initially presenting in 20 of our patients, improved in 18 (90%). The mean reduction in CSF pressure after treatment was 20.72A+/-10.7 cmH2O (range 2 to 48). Patients were followed for three years after cessation of treatment. No recurrence of papilledema, or any other symptoms, has been observed. CONCLUSIONS: Octreotide resulted in a significant and sustained improvement of IIH in our patients. These results suggest that it may be an effective alternative to existing treatments for IIH.

Glutathione-S-transferase T1 and M1 gene polymorphisms in Greek patients with multiple sclerosis: a pilot study.

Oxidative stress has been implicated in the pathogenesis of multiple sclerosis (MS). Glutathione-S-transferases (GSTs) are detoxification enzymes, evolved to protect cells against reactive oxygen metabolites. Both GSTT1 and GSTM1 genes exhibit a homozygous deletion polymorphism (null genotype) leading to abolished enzyme activity. We studied the impact of the GSTT1 and GSTM1 polymorphisms on MS susceptibility in a case-control study of 47 Greek patients and 165 controls. Correlations between genotype, gender and disability status were also investigated. The incidence of both GSTT1 and GSTM1 genotypes did not differ significantly between controls and patients. A significantly increased frequency of GSTM1 null genotype was found amongst female patients (65.5%) as compared with males (33.3%, P =0.04). The results suggest that GSTT1 and GSTM1 have no major pathogenetic role on the MS occurrence, nor any strong modifying effect on the disability status. The higher incidence of GSTM1 null genotype observed in female patients, suggests a possible role of the GSTM1 detoxification pathway in a gender-dependent manner.

Neurophysiological monitoring of brainstem function in a patient with Wallenberg syndrome, using Vestibular Evoked Myogenic Potentials.

PURPOSE: We evaluated the use of Vestibular Evoked Myogenic Potentials (VEMPs) in the assessment of neural function, following medullary lesions. METHODS: A 54-year-old male presented with symptoms and signs typical of right lateral medullary (Wallenberg) syndrome. He underwent brain MRI and three successive neurophysiological investigations, which included VEMPs, Brainstem Auditory Evoked Responses (BAERs) and the blink reflex. RESULTS: VEMPs amplitude on the left (unaffected) side was 256.8 microv in the first investigation and remained approximately equal to that value in the following two ones. Their amplitude on the right (affected) side was 37.9 microv, 154.2 microv and 235.2 microv correspondingly. At the same time vertigo, diplopia and nystagmus gradually improved. Right blink reflex comprised a normal R1, but delayed R2 ipsilateral and R2 contralateral responses, which remained unaltered during the follow-up period. Brain MRI disclosed a right dorsolateral medullary infarct. CONCLUSIONS: VEMPs amplitude progressively increased, parallel to the improvement of vestibular symptoms. The blink reflex evolved differently, while BAERs were not affected. As the three evoked responses are mediated by separate neural circuits, they provide information on different aspects of brainstem function. Thus, VEMPs seem to be a useful method that complements existing ones in the assessment of brainstem lesions.

Auditory event related potentials in patients with epilepsy on sodium valproate monotherapy.

OBJECTIVES: The effects of antiepileptic drugs on event related potentials (ERPs) have been studied, but with contradictory results. In this study we examine the effect of sodium valproate (VPA) on ERPs in patients with epilepsy. MATERIALS AND METHODS: Auditory event related potentials were recorded in 40 patients with idiopathic generalized epilepsy, 20 on monotherapy with sodium valproate (VPA), 20 on monotherapy with carbamazepine and 20 age and sex matched controls. All subjects performed a simple auditory discrimination task in which a target tone was presented on 20% of the trials. RESULTS: Mean P3 latency of the VPA group was significantly prolonged but not in carbamazepine group and healthy controls. CONCLUSION: We conclude that VPA monotherapy has an effect on P300 latency in patients with epilepsy. This difference might be attributed to effects of treatment with VPA and may clarify in the future the mechanism of P300.

EEG and topographic frequency analysis in migraine attack before and after sumatriptan infusion.

Electroencephalographic changes occurring in patients with migraine have received much attention. Although in migraineurs a number of studies have been done after nitroglycerin-induced attacks, there is no reported EEG study before and after nitroglycerin-induced sumatriptan-treated attacks. We, therefore, studied the EEG topographic frequency analysis in 19 symptom-free, otherwise healthy, unmedicated patients with common migraine and in 19 age- and sex-matched controls before nitroglycerin, at the time of maximum pain, and 30 minutes after sumatriptan. During headache attacks, an increase of slow rhythmic activity of the theta and delta range and a decrease of activity in the alpha and beta range were observed. These abnormalities disappeared 30 minutes after a sumatriptan injection. This suggests that common migraine is associated with disturbances of cortical electrogenesis and may provide insight into the causes of migraine and aid in the development of effective therapies.

Severe facial ischaemia caused by ergotism.

A case of ergotamine induced severe face ischaemia mimicking acute arteritis is presented. The unique clinical picture was due to bilateral involvement of both external carotid arteries. No case of ergotism with such a localization has been previously described in the literature.

Effect of enzyme induction on bioavailability of hetacillin in patients treated with anticonvulsants and chlorpromazine.

The effect of liver enzyme induction on bioavailability of hetacillin was studied in patients chronically treated with anticonvulsants or chlorpromazine. 24 chronic psychiatric patients classified according to their medication in two groups (anticonvulsants, chlorpromazine) and one group of 11 healthy volunteers, received an i.m. administration of 500 mg hetacillin. Serum levels of ampicillin derived from hetacillin in blood samples taken 2, 4 and 6 hours after the injection were measured and the half-life of the antibiotic was determined for each group. Urinary D-glucaric acid was considered the induction index. Correlation coefficients between the induction index and pharmacokinetic parameters of hetacillin were also determined. Anticonvulsants and chlorpromazine induced the liver microsomal enzymes as demonstrated by the increased D-glucaric acid excretion (P less than 0.001 - P less than 0.05). No statistically significant differences were found in serum levels and half-life of the antibiotic. Correlation coefficients suggest that enzyme induction and hetacillin bioavailability are not significantly related.

Comparative study of the effects of some inducers with or without protein binding properties on bioavailability of isoxazolylpenicillins in rats.

The effect of various inducers with or without protein binding properties on serum levels and half life of Oxacillin, Cloxacillin and Dicloxacillin was studied. A total of 102 male rats classified in 3 "categories" according to the administered penicillin with 6 groups of rats in each of them were used. Each group was pretreated for 15 days with the following inducers: phenobarbital, diphenylhydantoin, diazepam, chlorpromazine and phenylbutazone. The control groups received saline. The d-glucaric acid concentration in the urine prior to and after the administration of inducers and the liver weight were taken as enzyme induction indices. The results showed a decrease of serum levels and half life of three penicillins with a negative correlation between urine d-glucaric acid and serum penicillin levels. Phenobarbital, diphenylhydantoin and chlorpromazine affected the 3 penicillins in the following statistically significant order: oxacillin, dicloxacillin, cloxacillin. Diazepam affected: cloxacillin, dicloxacillin, oxacillin, and phenylbutazone: dicloxacillin, cloxacillin and oxacillin. However all drugs finally produced a uniform effect on all 3 penicillins in the following decreasing order: phenobarbital (r = -0.910), diphenylhydantoin (r = -0.864), phenylbutazone (r = -0.851), chlorpromazine (r = -0.842) and diazepam (r = -0.821). For all inducers, the effect was most significant for oxacillin (r = -0.869), second most significant for dicloxacillin (r = -0.811) and finally for cloxacillin (r = -0.778). The results suggested an interaction of isoxazolylpenicillins and the above drugs.

Bioavailability of hetacillin in rats after liver enzyme induction by various inducers with or without protein binding properties.

The serum levels and the half life of ampicillin derived from Hetacillin after administration of the latter to a total of 61 rats classified in 7 groups were determined. Each of these groups was pre-treated for 15 days with the following inducers; phenobarbital, diphenylhydantoin, diazepam, chlorpromazine and phenylbutazone. The control group received saline. The d-glucaric acid concentration in the urine prior to and after the administration of inducers and the liver weight were taken as enzyme induction indices. Results showed a positive correlation between the indices of induction and the levels of ampicillin originating from hetacillin with a significant correlation coefficient between the serum levels of ampicillin and urine d-glucaric acid for all drugs studied. The different effect of the various drugs indicated that they could be classified into the following two groups: a) those that induced a significant increase of the levels and half life (t1/2) of ampicillin. The effect was significant in decreasing order for phenylbutazone (r = 0,990), diazepam (r = 0,990) and diphenylhydantoin (r = 0,753). b) those which initially resulted in a significant increase of the levels of ampicillin and thereafter in a decrease with a significant shortening of its t1/2 too. The effect was most significant for phenobarbital (r = 0,887) and less so for chlorpromazine (r = 0,800). Only for these two drugs was a significant and actually negative correlation observed between d-glucaric acid and t1/2 that is: phenobarbital (r = -0,967) chlorpromazine (r = -0,752). Results suggest an interaction of Hetacillin and the above inducers.

Concentration of antibacterial agents in rat bone. A comparative study of gentamicin, ampicillin and cephaloridine.

The concentrations of Gentamicin, Ampicillin and Cephaloridine in thigh rat bone were studied. Measurements were done after a 24 h administration for 3 different times. Measurable quantities in the bone for the three antibiotics were detected. The best levels in relation with the M.I.C. of 4 microorganisms occurred in Cephaloridine (and in measurements of serum and bone (microgram/g). The concentration in the serum does not represent concentration in the bone. The most convenient parity was for Cephaloridine. The elimination of the drug in the bone was impressive after 2h. The slower fall occurred in Cephaloridine. Ampicillin had the same level in 4 and 6h. Gentamicin and Cephaloridine had failed to present measurable quantities in some of the animals of the last measurement.