Neural substrates of memory, affective functions, and conscious experience.

This review presents an account of the areas and circuits of the brain that are thought to be involved in such cognitive functions as memory, affect and consciousness. Considerable progress has been made in the past two decades in the identification of the cerebral areas and in our understanding of the brain mechanisms involved in these functions, thanks in large parts to a number of imaging observations (PET and fMRI), together with many clinical neurological and experimental studies. Thus, there is now convincing evidence that these high level functions are represented in a complex organization of interconnected cortical and subcortical areas that operate as spatially distributed systems, specialized for the different cognitive activities. Despite the progress that has been made, it is still not known how genetic and environmental factors interact during early development and throughout life to create the necessary conditions out of which these cognitive capacities emerge, nor is it evident to what extent they are shaped by adaptive changes in synaptic organization and other forms of neuronal plasticity.

Binswanger's disease is not a single entity.

The clinicopathological findings reported by Binswanger are insufficient to qualify as distinct entity the condition named "Binswanger's disease", and subsequently by Olszewski (1962) "subcortical arteriosclerotic encephalopathy (SAE) (Binswanger's type)". A short summary of the characteristic pathological, clinical and neuroimaging features of SAE is reported. The white matter changes detected by neuroimaging must be considered aspecific, since identical changes may be found in normal elderly as well as in patients with different diseases: different biochemical mechanisms can undoubtedly underlie identical neuroimaging patterns. Two other relevant points are noteworthy: the occurrence of pathological features of SAE in other diseases (CADASIL, pseudoxanthoma elasticum, antiphospholipid antibody syndrome) and the observation of some patients with pathological changes of SAE but an incomplete clinical picture. The clinicopathological features described as Binswanger's disease do not qualify as a separate entity since they are common to a variety of illnesses. The pathological picture identified by Olszewski can rightly be named, according to Caplan, "chronic microvascular leukoencephalopathy" (CML). The clinicopathological features of the so-called Binswanger's disease constitute a syndrome, the CML syndrome (CMLS), which can be found in some hereditary diseases and in acquired conditions. This syndrome shows peculiar cerebrovascular changes and, when clinically associated with dementia, identifies one of the subtypes of vascular dementia.

Internal borderzone infarction in patients with ischemic stroke.

OBJECTIVE: The mechanism underlying cerebral infarction in the borderzone between the territories of deep and superficial perforating arteries has not yet been clarified. This study was performed to investigate the prevalence, volume, site, and etiology of this type of subcortical infarction in a large unselected group of stroke patients. METHODS AND PATIENTS: We analyzed a continuous series of 383 patients with recent cerebral infarction observed in our Stroke Unit. Patients underwent a complete clinical and instrumental workup. The subgroup of subjects with internal borderzone infarct alone were compared with the subgroups of patients with other types of cerebral infarcts by uni- and multivariate statistical tests. RESULTS: There were 90 internal borderzone infarcts of 725 ischemic lesions (12%of the total), with a median volume of 0.32 ml (95% confidence interval 0.24-0.44; range: 0.012- 20.2 ml). Internal borderzone infarcts alone occurred in only 13 of 383 (3.4%) patients. A comparison between patients with 'pure' internal borderzone infarction and patients with other types of cerebral infarcts by multiple logistic regression analysis demonstrated a significant independent causal role of carotid stenosis or occlusion. CONCLUSION: Our study suggests that 'pure' internal borderzone infarctions are quite rare findings in patients with ischemic stroke, and that the hemodynamic impairment due to atherosclerotic occlusion or stenosis of the carotid system could be the cause in the large majority of cases.

[3H](azidophenyl)ureido taxoid photolabels peptide amino acids 281-304 of alpha-tubulin.

The taxoid binding site on porcine brain tubulin was covalently labeled, in the presence or absence of Taxotere, with the photoaffinity reagent [3H]-p-(azidophenyl)ureido taxoid derivative [3H]TaxAPU [Combeau, C., Commercon, A., Mioskowski, C., Rousseau, B., Aubert, F., & Goeldner, M. (1994) Biochemistry 33, 6676-6683]. After disulfide reduction and carboxymethylation, the alkylated tubulin samples were treated with trypsin and the mixtures of peptides were first fractionated by gel filtration over Sephadex G50. Anion exchange chromatography of the radioactive areas showed, for one area, three major radioactive signals which were further analyzed by reversed phase C18 HPLC, leading to well-resolved radioactive peaks. Microsequencing of these different peaks gave a complete sequence of a tryptic fragment on alpha-tubulin (alpha-281-304) and two partial peptide sequences of a tryptic fragment on beta-tubulin (beta-217-229) in addition to sequences of mixture of peptides. The radioactive signals were lost while concentrating the samples for microsequencing, preventing the identification of the modified amino acids. These results identify the first peptide on alpha-tubulin which binds to the taxoids and confirm the involvement of both alpha- and beta-tubulin in the taxoid binding site.

Vascular dementia: still a debatable entity?

Vascular dementia (VAD) is currently considered to be the second most common cause of dementia in Europe and the USA, second to dementia of the Alzheimer's type (DAT). However, in Asia and many developing countries the incidence of VAD exceeds that of DAT. The positive clinical diagnostic workup for VAD requires six steps: (1) clear-cut quantitative assessment of cognitive deficits utilizing standard neuropsychological tests to establish and quantify the dementia syndrome and rule out pseudo-dementia OF depression; (2) ascertaining the presence of risk factors for stroke; (3) identifying cerebral vascular lesions by neuroimaging (MRI, Iodine or Xenon contrasted CT, PET and SPECT); (4) exclusion of other causes of dementia; (5) differential diagnosis of possible, probable or definite VAD versus DAT and ascertaining when there are mixtures of the two; and (6) temporal identification of causality between onset and progression of the dementia with identified cerebral vascular lesions. There are eight subtypes of VAD: (1) multi-infarct dementias. These are due to large cerebral emboli, and are usually readily identifiable; (2) strategically placed infarctions causing dementia; (3) multiple subcortical lacunar lesions. Patients with these develop VAD at least five to twenty-five times more frequently than those in age-matched general population samples; (4) Binswanger's disease (arteriosclerotic subcortical leuko-encephalopathy). This form is rare. Neuroimaging confirms the diagnosis during life but the diagnosis can not be made by neuroimaging alone; (5) mixtures of two or more of above VAD subtypes; (6) hemorrhagic lesions causing dementia; (7) subcortical dementias due to cerebral autosomally dominant arteriolopathy with subcortical infarcts and leuko-encephalopathy (CADASIL), or to familial amyloid angiopathies and coagulopathies all of which present with multiple subcortical lacunar lesions similar to Binswanger's disease; (8) mixtures of DAT and VAD. The clinical significance of leukoaraiosis and its suspected relationships to VAD remains to be better established. The presence of ischemic infarctions, single or multiple large or multiple small (lacunar) by neuroimaging are necessary for the diagnosis of VAD, but identifying their presence, by neuroimaging alone, does not permit the diagnosis of dementia which can only be established by neuropsychological assessments. VAD is a clinical entity, identifiable in at least 30-70% of patients after strokes but mechanisms responsible for the cognitive impairments are complex. Some of these mechanisms are incompletely understood but provide subjects for important future research.

Value of early variables as predictors of short-term outcome in patients with acute focal cerebral ischemia.

Reliable, simple and safe criteria are needed for the early prediction of short-term outcome in patients with acute ischemic stroke. The aim of our study was to evaluate, in terms of their individual and combined power, the prognostic value of a few widely available clinical and instrumental variables obtained during the acute phase. The study involved 351 consecutive patients who were examined within 48 hours of their first ischemic stroke. Eight variables were chosen: age, initial level of consciousness, limb paresis, arterial blood pressure, glycemia, the results of electrocardiography and electroencephalography, and the infarct size revealed by computed tomography. Mortality and disability were evaluated on Day 30, when the variables that significantly correlated with disability were the severity of limb paresis, electroencephalographic abnormalities, infarct size and (less significantly) the level of consciousness and hyperglycemia. There was no statistical correlation with blood pressure. Logistic analysis confirmed only infarct size, the severity of limb paresis and electroencephalographic abnormalities as independent variables. The variables that significantly correlated with early death were the severity of limb paresis, infarct size, electrocardiographic abnormalities, the level of consciousness, electroencephalographic abnormalities and hyperglycemia. More intriguingly, logistic analysis confirmed only the electroencephalographic and electrocardiographic abnormalities as independent variables. The predictive prognostic value of limb paresis, infarct size, the level of consciousness and hyperglycemia is well known, but we would like to stress the fact that only a few independent variables are predictive of early death (electroencephalographic and electrocardiographic abnormalities) and poor recovery (infarct size, the severity of limb paresis, electroencephalographic abnormalities). The prognostic value of electroencephalography may express the potential involvement of dynamic non-structural phenomena, such as penumbra ischemica and diaschisis.

Asymptomatic cerebral infarctions in patients with ischemic stroke.

We studied 383 consecutive patients with stroke and ischemic lesions on CT scan for the presence of symptomatic cerebral infarction (SCI) and asymptomatic cerebral infarction (ACI). We evaluated risk factors as well as volume, site and number of the lesions. ACIs occurred in 34% of the cases (130/383); 88% of ACIs were lacunes and internal borderzone infarctions, with a volume of less than 2 ml. Larger infarctions were asymptomatic in 27 patients (20.8%); 114 (68.7%) out of 166 patients with two or more SCIs (68.7%) had one or more ACIs. Infarctions in the lateral middle cerebral artery (MCA) territory were SCIs, in the medial MCA territory ACIs. Independent risk factors for ACI were age above 70 years and smoking; cardioembolism prevailed in SCI, small vessel disease in ACI; high levels of disability prevailed in SCIs.

Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism.

OBJECTIVE: To test the hypothesis that long-term postnatal development may be modified by metabolic experiences in utero. RESEARCH DESIGN AND METHODS: We enrolled offspring of women with pregestational diabetes (this included insulin-dependent diabetes mellitus [IDDM] and non-insulin-dependent diabetes mellitus [NIDDM]) and gestational diabetes in a prospective study from 1977 through 1983. Fetal beta-cell function was assessed by measurement of amniotic fluid insulin (AFI) at 32-38 weeks gestation. Postnatally, plasma glucose and insulin were measured yearly from 1.5 years of age after fasting and 2 h after 1.75 g/kg oral glucose. Control subjects had a single oral glucose challenge at 10-16 years. RESULTS: In offspring of diabetic mothers, the prevalence of impaired glucose tolerance (IGT) (2-h glucose concentration > 7.8 mmol/l) was: 1.2% at < 5 years, 5.4% at 5-9 years, and 19.3% at 10-16 years. The 88 offspring of diabetic mothers (12.3 +/- 1.7 years), when compared with 80 control subjects of the same age and pubertal stage, had higher 2-h glucose (6.8 +/- 1.4 vs. 5.7 +/- 0.9 mmol/l, P < 0.001) and insulin (660 +/- 720 vs. 455 +/- 285 pmol/l, P < 0.03) concentrations. The 17 subjects with IGT at > 10 years of age (9 boys and 8 girls) include one girl with NIDDM. IGT was not associated with the etiology of the mother's diabetes (gestational versus pregestational) or macrosomia at birth. IGT was found in only 3.7% (1 of 27) of adolescents whose AFI was normal ( < or = 100 pmol/l) and 33.3% (12 of 36) of those with elevated AFI (P < 0.001). Although most of the children with IGT are obese, AFI and obesity are independently associated with IGT by multiple logistic analysis. CONCLUSIONS: In confirmation of our original hypothesis, IGT in the offspring is a long-term complication of maternal diabetes. Excessive insulin secretion in utero, as assessed by AFI concentration, is a strong predictor of IGT in childhood.

Dementia due to lacunar infarctions: a misnomer or a clinical entity?

The following points should be considered in dealing with dementia occurring in patients with lacunar infarctions. Lacune is a pathological term and its definition rests on its size (from 2 to 15 mm in diameter). However, terms such as lacunar syndromes and lacunar infarctions are currently used in clinical parlance and recent papers. Patients with lacunar infarctions differ from patients with large infarctions, being more often hypertensive, showing a characteristic but not specific clinical syndrome, and disclosing a significantly lower recurrence rate for new episodes and a significantly higher survival rate. Patients with lacunar infarctions develop a state of dementia 5 times as often as the general population and 25 times as often as in the age group of our patients (65-69 years). Leukoaraiosis, significantly related to arterial hypertension, to lacunar infarction, to an extra risk of future stroke, may be considered an increased risk of cerebral vascular lesions possibly leading to dementia. The relationship between vascular lesions and dementia includes: the strategic location of the lesion (thalamus, corticothalamic areas, bilateral lesions); the whole cerebral hypoperfusion apart from the infarcted area, as shown by PET and SPET; remote effects of cerebral infarctions (diaschisis phenomenon); the so-called incomplete infarction; cerebral atrophy and, particularly, the enlargement of cerebral ventricles, significantly higher in patients with lacunes and dementia as compared with patients with lacunes without dementia.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term observations on the clinical use of lamotrigine as add-on drug in patients with epilepsy.

We report open-label clinical observations of additional lamotrigine (LTG) in 16 adult patients with refractory epilepsy, aimed to assess the long-term efficacy and safety of LTG in clinical use. LTG was added to the current antiepileptic drug (AED) regimen at a daily dosage of 200-400 mg depending on the concomitant treatment. Ten patients completed one year's treatment and were followed up to an overall exposure ranging 15-38 months. Six patients (38% of the initial group) had a reduction of seizure frequency greater than 50% of pre-treatment baseline after one year; the further follow-up indicated some efficacy decline, since the percentage of improved patients dropped to 19% after 2 years and 13% after 3 years. The dropouts during the first year were due to seizure breakthrough (two patients), Steven-Johnson-like syndrome (one patient) and reasons unrelated to treatment (three patients); in one patient LTG treatment was stopped due to macrocytic anemia after 23 months. Other reported adverse events were dizziness, mild ataxia, diplopia and localized purpura. No other hematological or biochemical changes were noted. LTG was not associated with any significant changes in plasma concentrations of concomitant AEDs. These findings confirm the moderate efficacy and low toxicity of long-term LTG in severe epilepsy.

Focal cerebral ischemia and patent cardiac foramen ovale.

By means of transthoracic contrast echocardiography, the prevalence of a patent foramen ovale (PFO) was studied, in a continuous series of 48 patients aged less than 50 years with a recent episode of acute cerebral ischemia. A PFO was found in 11 subjects (23%). In the subgroup of younger patients (aged less than 30 years), the prevalence was much higher than in those aged 30 or more (58% against 11%, p = 0.0022). In the 19 patients with clear evidence of extracardiac causal factors of cerebral ischemia, there was no PFO; of the remaining 29 subjects, a PFO was present in 11 (38%) (p = 0.0015). In conclusion, the possible presence of a PFO must be carefully investigated in subjects with cerebral ischemia aged less than 30, as well as in subjects aged between 30 and 50 in whom there is no acceptable explanation for their cerebral ischemic episode.

GABA and phosphatidylserine in human photosensitivity: a pilot study.

Previous experimental studies have shown that the simultaneous administration of gamma-aminobutyric acid (GABA) and phosphatidylserine (PS) can exert an anticonvulsant activity in different seizure models; moreover, a preliminary trial showed some effect of the association GABA-PS in patients with absence seizures. The aim of this study was to investigate the antiepileptic properties of GABA-PS in the model of human photosensitivity. Nine patients with epilepsy associated with an EEG pattern of photoconvulsive response at intermittent photic stimulation entered a 3-day study. The photosensitivity range (PSR) was determined at hourly intervals both in basal conditions and after the administration of a single oral dose of GABA (3000 mg) and PS (600 or 1200 mg). The administration of GABA-PS was not associated with any systematic changes of PSR, nor with any significant differences of time course profiles on each daily session. No correlation was found between PSR percent deviations from baseline and GABA serum levels. These results indicate that a single acute administration of GABA-PS has no effect in the human photosensitivity model, and suggest that the efficacy of GABA-PS in human epilepsy, as shown by a preliminary investigation, may possibly require chronic administration.

Silent cerebral infarcts in patients with ischemic infarction.

Silent cerebral infarcts occur in patients with chronic nonvalvular atrial fibrillation and asymptomatic or symptomatic carotid stenosis. There is not a well-defined prevalence of asymptomatic lesions in patients with transient ischemic attack or completed strokes. We attempted to determine the occurrence rate of silent brain infarction in a hospital population, including a comparison of the risk factors with those of symptomatic infarction and an evaluation of the relevance of infarction size and location.

Vigabatrin in chronic epilepsy: a 7-year follow-up study of responder patients.

Data on efficacy and safety of vigabatrin over very protracted treatment periods are still limited. This study reports the follow up of 23 responder epileptic patients who continued vigabatrin treatment after completion of the first year, to an overall long-term exposure ranging 21-84 months (median 60; mean 58.0 +/- 24.0 sd). The seizure frequency during the follow up was compared with that at the end of the first year on vigabatrin. The rates of patients who gained a further improvement and those who deteriorated were almost identical, ranging 33-45% and 33-46% respectively at individual time points. At the trial endpoint, nine patients (39%) were improved, five (22%) were unchanged and nine (39%) showed some deterioration. All patients still had a 14-100% decrease of seizure frequency as compared with pretreatment baseline. Two patients discontinued vigabatrin for occasional reasons. No patient experienced new adverse events during the follow up after the first year on vigabatrin. No significant effects were noted on any of the routine hematologic or metabolic screening assessments. Although reduction of concomitant treatment was rarely possible, the overall number of associated antiepileptic drugs dropped from 42 at entry to 40 at the trial endpoint. These findings indicate that vigabatrin retains its efficacy and safety in responder patients for periods up to 7 years.