Different responses to rivastigmine in subcortical vascular dementia and multi-infarct dementia.

Vascular dementia (VaD) is associated with a large amount of heterogeneity, as it groups together a broad category of patients in whom various manifestations of cognitive decline are attributed to cerebrovascular or cardiovascular disease. Thus, a study was designed to determine the effects of rivastigmine on cognitive function, global daily living performance, and behavioral disorders in VaD patients versus an active control (nimodipine), stratifying patients according to the type of VaD, subcortical vascular dementia (sVAD), and multi-infarct dementia (MID). The trial was a prospective study. This study shows that long-term treatment with rivastigmine, at dosages approved for therapeutic use in Alzheimer's disease, produces significant improvement in all behavioral symptoms in 2 forms of VaD, MID and sVaD, except delusions. It also suggests that rivastigmine may enable a reduction in concomitant neuroleptics and benzodiazepines in VaD, especially in MID. The results are discussed with an overview of the literature.

Effect of intravenous methylprednisolone on the number, size and confluence of plaques in relapsing-remitting multiple sclerosis.

The aim of the present study was to evaluate whether intravenous methylprednisolone (IVMP) pulses affect the confluence and enlargement of T2 lesions in the long term in patients with relapsing-remitting (RR) multiple sclerosis (MS). Of 88 RR MS patients, randomly assigned to regular pulses of IVMP (1 g/day for 5 days with an oral prednisone taper) or IVMP on the same dose schedule only for relapses, and followed up without other disease-modifying drug therapy for 5 years, 81 patients completed the trial as planned. Pulsed IVMP was given every 4 months for 3 years, and then every 6 months for the subsequent 2 years. Calculations were performed for number, size and lesion volume (LV) of T2- and confluent T2-lesions. At study entry, the number, size and LV of T2- and confluent T2-lesions were well matched in the two study arms. At the end of the study, patients who received IVMP pulses every 4-6 months for 5 years had significantly fewer confluent T2 lesions (105 vs. 270, p<0.0001), lower confluent T2-LV (5.4 ml vs. 17.4 ml, p<0.00001), fewer large T2 lesions (>10 mm) (165 vs. 541, p<0.00001), and lower T2-LV/N degrees T2 lesion index (0.52 vs. 1.1, p=0.007) when compared to patients who received IVMP only for relapses. There were more small T2 lesions (1082 vs. 288, p<0.000001) in the IVMP pulsed arm. Patients who received higher total doses of IVMP showed the smallest changes in confluent T2-LV during the study. This study suggests that treatment with pulses of IVMP may prevent the confluence of T2 lesions, which may in turn contribute to slower progression of disability in the long term. However, pulsed IVMP treatment did not significantly slow down accumulation of overall T2-LV and there were more smaller T2 lesions in the IVMP pulsed arm at the end of the study.

Positivity of cytomegalovirus antibodies predicts a better clinical and radiological outcome in multiple sclerosis patients.

OBJECTIVES: To establish the relationship between the presence and titer of virus-specific serum- and cerebrospinal fluid (CSF)-antibodies in multiple sclerosis (MS) patients and disease severity measured with different quantitative magnetic resonance imaging (MRI) techniques. METHODS: We investigated an association between clinical and MRI measures of disease activity and the presence and titer of IgG antibodies against seven common viruses (measles, rubella, herpes simplex virus type 1 and 2, varicella zoster virus, cytomegalovirus (CMV) and Epstein-Barr virus). One hundred and forty (90 female/50 male) patients with definite MS and 131 age and sex-matched controls participated in the study. Antibody positivity and titer were ascertained by the enzyme linked immunosorbent assay (ELISA) technique and clinical assessment was performed by evaluating the expanded disability status scale (EDSS) score and the lifetime relapse rate (LRR). T1- and T2-lesion loads (LL) and the brain parenchymal fraction (BPF) were calculated. RESULTS: Multiple analyses showed that there was an association between antibody positivity against CMV and higher titer and better clinical and MRI outcomes. The cluster analyses indicated that patients positive for antibodies against CMV had significantly older age at onset (uncorr p = 0.001 and corr p = 0.009), lower LRR (uncorr p = 0.003 and corr p = 0.03) and higher BPF (uncorr p = 0.004 and pcorr p = 0.04). CMV-positive patients who had higher antibody titer showed lower T2-LL (uncorr p = 0.003 and corr p = 0.03) and higher BPF (uncorr p = 0.006 and corr p = 0.05). DISCUSSION: Surprisingly, our results focused attention on the 'protective' role of a particular virus. CMV is probably capable of triggering some immunomodulating/immune evasion mechanisms which may decrease immune reactivity in MS patients. Further studies are needed to confirm and elucidate our study results on a larger sample of MS patients and in animal model studies.

Behavioral alterations and vascular dementia.

BACKGROUND: Vascular dementia is one of the most frequent forms of dementia, where behavioral and cognitive symptoms coexist. Negative signs, such as apathy, abulia, opposition, and agnosia, are badly tolerated and dramatically experienced by caregivers, even worse than the other signs of cognitive decline. REVIEW SUMMARY: We have studied 120 subjects affected by subcortical vascular dementia (group A) and 120 subjects suffering from multiinfarct dementia (group B) for 24 months. The main outcomes of the study were the global performance, the global behavioral symptoms, the caregiver stress, the depression status, and the insight in their clinical situation. CONCLUSIONS: Group A manifested a reduction of depression, agitation and suicidal ideation during follow-up, with a constant tendency to refer somatic pain, to exhibit anxiety, and an evident increase in apathy, cognitive abulia, social withdrawal, and loss of insight. On the contrary, group B showed a constant tendency to manifest depression, somatic pain, anxiety, agitation, cognitive abulia, social withdrawal, and suicide ideations; they manifested a decrease of apathy and an increase in delusions, hallucinations, craving for food, and loss of insight and awareness. Their behavioral alterations were stronger than those exhibited by group A, and that was reflected by an increment of caregivers' burden score. Even from a behavioral perspective, multiinfarct dementia is not the same as subcortical vascular dementia. This opinion must be taken into account to find more suitable and tailored therapy to specific pathologies and not to a single, generic entity.

Cognitive impairment in the lateralized phenotype of corticobasal degeneration.

Corticobasal degeneration (CBD) is a rare disorder, which normally includes a combination of neurobehavioural features, movement disorders and other manifestations. It is now recognized that CBD patients usually present with two phenotypes: the lateralized phenotype and the dementia phenotype. The aim of our work was to determine the nature and the progression of cognitive and behavioural impairment in 10 lateralized CBD patients. In our patients, the most salient aspects of cognitive impairment were: an evident alteration of rapid alternating operative strategies, associated with the evident impairment of set shifting, of executive operations, of operative and sequential procedure and of implementation of judgement and abstract reasoning. The self-activation of retrieval processes is partly preserved in CBD. As all the other types of subcortical impairments, even CBD encompasses both cognitive impairment as well as a wide range of behaviour disturbances, such as progressive alterations of sleep, depression, and of anxiety (with a remarkable incidence of somatic pain). This suggests that in addition to neuropsychological assessment, quantification of the personality behaviour disorder is important for standardizing the diagnosis of subcortical vascular dementia and distinguishing it from any other dementias.

Olanzapine as a possible treatment of behavioral symptoms in vascular dementia: risks of cerebrovascular events. A controlled, open-label study.

Behavioral problems produce excess disability, potentially devastating in cognitively impaired patients. These behavioral symptoms can be a major cause of stress, anxiety and concern for caregivers. While psychotropic drugs are frequently used to control these symptoms, they have the potential for significant side effects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonism and akathisia. We followed up (for 12 months) a group of 346 consecutive outpatients, with a diagnosis of subcortical vascular dementia or multi-infarctual dementia. Patients eligible for this open-label study were required to have behavioral problems (BPSD). Patients were divided into two groups, Group A received olanzapine 2.5-7.5 mg/day while Group B received typical antipsychotics. Patients in both groups were allowed to continue any previous therapy. Patients in both groups were significantly improved in their BPSD. Our patients had a host of medical conditions and received numerous concomitant medications. Given the potential complications associated with these therapeutic agents, these patients tolerated olanzapine quite well. On examination of consequences of adverse events, particularly somnolence, postural instability, and postural hypotension, it appeared that cerebrovascular events were not present. Moreover, no anticholinergic effect was recorded. These findings suggest that olanzapine could be a safe and effective treatment even for elderly population in suitable doses and receiving the adequate follow-up.

Frontal lobe dementia and subcortical vascular dementia: a neuropsychological comparison.

We compared the performance of 40 patients with frontal lobe dementia to that of 40 patients with subcortical vascular dementia (80 patients including, 46 men and 34 women) in a set of tasks assessing attentional, executive, and behavioural tasks. The frontal lobe dementia represents an important cause for degenerative disruption and is increasingly recognised as an important form (up to 25%) of degenerative dementia among individuals of late-middle-age. The main involvement is the frontal-subcortical pathway, which is the final target of impairment even in subcortical vascular dementia. A wider involvement of the cortical (decisional) layers in frontal dementia, in contrast with the prominent and widespread involvement of the subcortical pathways (refinement and corrections programs) creates the different profiles of the two groups. Frontal patients have more difficulties in abstract reasoning, focusing attention, and implementing strategies to solve problems. They exhibit more profound behavioural alterations in personality and social conduct and show only moderate depression, and a total lack of insight concerning their dinical condition. In contrast, the patients with subcortical vascular dementia have poor general cognitive functions, high insight, and important depression and apathy as the principal and most salient characteristic of their behavioral conduct.

Neuropsychological evaluation of late-onset post-radiotherapy encephalopathy: a comparison with vascular dementia.

It is known that radiotherapy (RT) may cause cerebral injury. The most frequent neurotoxic effect of RT at any age is diffuse cerebral injury. Brain injury by therapeutic irradiation has traditionally been classified according to its time of onset into acute, early delayed, and late forms. The latter is not reversible. The neurocognitive sequelae of cranial irradiation can be mediated through vascular injury. Because the pathologic changes are most profound in the white matter, we compared a group of patients treated by RT (n=34) with a group of patients affected by subcortical vascular dementia (sVaD, n=34). Patients with a total radiation does <35 cGy did not show any sign of cognitive impairment. All the patients with a total irradiation dose >45 cGy did show profound cognitive and behavioural alteration. The patients who received a total dose of brain radiation comprised between 35 and 45 cGy did show slowness of executive function, and profound alterations of frontal functions, such as attention focusing, mentation control, analogical judgement and insight. The patients who suffered from the consequences of RT had slowness of executive functions, and profound alterations of frontal functions, such as attention focusing, mentation control, analogical judgement and insight, similar to those obtained by the patients suffering from subcortical vascular dementia. High dose RT might result in a severely demented, bedridden patient, who "has been cured" from his primary disease, the brain tumour. This constellation demands serious consideration before RT is given.

Use of the ten-point clock test to compare executive functioning across 24 months in patients with subcortical vascular dementia.

The Ten-point Clock Test can be used to identify early forms of Alzheimer's disease because it is reliable, well accepted, and easily administered at the bedside. Nevertheless, its clinical role in the detection of early dementia and its correlations with other cognitive processes is still under investigation. Vascular dementia is an uncertain nosological entity, in which unevenly distributed patterns of cognitive deficits comprising slowing of cognitive processing and impairment of executive function occur. The present study assessed how the Clock Test scores correlated with a number of other neuropsychological and functional tests in a sample of 144 patients with vascular dementia, who were followed for a period of 24 mo. At baseline, at 12 mo. and at 24 mo. subjects were administered a battery of tests, including the Mini-Mental State Examination, word fluency, visuospatial skills, an evaluation of hetero- and autotopognosia (knowledge of self), the Proverbs Test, and the Ten-point Clock Test. For these patients scores on the Clock Test correlated significantly with semantic abilities, with abstract reasoning capacities, visuospatial perception, and with right and left recognition.

[Role of the cerebellum in the control of distal motor activities in patients with akinetic-rigid Parkinson disease]. / Ruolo del cervelletto nel controllo dell'atto motorio distale in pazienti con malattia di Parkinson acinetico-rigida.

Using f-MRI, we have studied the changes induced by the performance of a complex sequential motor task in the cortical areas of nine akinetic PD patients and compared to that of healthy volunteers. Compared with normal subjects, PD patients showed a reduction of activation of motor and SMA areas, an increase of activation of parietal areas and a bilateral activation of cerebellar hemispheres, which are likely to participate in the attempt to recruit parallel motor circuits in order to overcome the striatocortical defective loop.

Rivastigmine in frontotemporal dementia: an open-label study.

OBJECTIVE: This preliminary open-label study aims to investigate the effects of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in 20 patients diagnosed with frontotemporal dementia (FTD). PATIENTS AND METHODS: Study subjects were men and women 60-75 years of age diagnosed with probable FTD. The rivastigmine group received doses of 3-9 mg/day. The control group included matched patients receiving antipsychotics, benzodiazepines and selegiline (deprenyl). All patients completed a 12-month follow-up period. RESULTS: Rivastigmine treatment was well tolerated. At 12 months, there was a general amelioration of behavioural changes as demonstrated by reductions in Neuropsychiatric Inventory (p<0.001 vs baseline and control), Behavioral Pathology in Alzheimer's Disease Rating Scale (p<0.001 vs baseline and control) and Cornell Scale for Depression in Dementia scores (p<0.05 vs baseline, p<0.001 vs control) in the rivastigmine group. Caregiver burden was reduced, as shown by reduced Relative Stress Scale scores (p<0.001 vs baseline and control). Mean scores on outcome measures evaluating executive function stabilised in the rivastigmine group (p<0.05 vs controls). Rivastigmine did not prevent the disease-related deterioration of cognition as assessed using the Mini-Mental State Examination. CONCLUSION: In this open-label study, rivastigmine-treated patients were less behaviourally impaired, and caregiver burden was reduced, at 12 months, compared with baseline. The use of cholinesterase inhibitors in FTD warrants further research.

Vitamin B12 and folate depletion: clinical evidence in a neurological population.

In cross-sectional studies, low levels of folate and vitamin B12 have been associated with poor cognition and dementia. Results are quite controversial and a debate continues in the literature. Still not completely understood are the differential roles of folate and vitamin B12 in memory acquisition and cognitive development. More intriguing and not fully understood is the rule that treating a vitamin B12-deficient patient with folate may exacerbate the neurological consequences of either deficiency. Starting from these quite confusing perspectives, the aim of this study was to define a possible role of vitamin B12 and folate in cognitive disruption. Data were collected among a cohort of people, admitted to the Neurology Clinic of the University of Trieste, in a period between November 1,2000, and November 1, 2002. We examine potential risk factors, concomitant drug-therapies, and cognitive global performance and correlate these parameters with folate and vitamin B 12 serum levels.We discuss the results with an overview of the literature.

Vitamin B12 and folate depletion in cognition: a review.

In cross-sectional studies, low levels of folate and B12 have been shown to be associated with cognitive decline and dementia Evidence for the putative role of folate, vitamin B12 in neurocognitive and other neurological functions comes from reported cases of severe vitamin deficiencies, particularly pernicious anemia, and homozygous defects in genes that encode for enzymes of one-carbon metabolism. The neurological alterations seen in these cases allow for a biological role of vitamins in neurophysiology. Results are quite controversial and there is an open debate in literature, considering that the potential and differential role of folate and B12 vitamin in memory acquisition and cognitive development is not completely understood or accepted. What is not clear is the fact that vitamin B12 and folate deficiency deteriorate a pre-existing not overt pathological situation or can be dangerous even in normal subjects. Even more intriguing is the interaction between B12 and folate, and their role in developing hyperhomocysteinemia. The approach to the rehabilitation of the deficiency with adequate vitamin supplementation is very confusing. Some authors suggest it, even in chronic situations, others deny any possible role. Starting from these quite confusing perspectives, the aim of this review is to report and categorize the data obtained from the literature. Despite the plausible biochemical mechanism, further studies, based on clinical, neuropsychological, laboratory and (lastly) pathological features will be necessary to better understand this fascinating biochemical riddle.

MMP-9 microsatellite polymorphism and multiple sclerosis.

A polymorphism (PM) in the microsatellite of the promoter region of matrix metalloproteinase 9 (MMP-9), modulating its expression, could play a role in susceptibility to multiple sclerosis (MS). MMP-9 PM was determined in 95 patients with MS (MS Group) and 95 age- and sex-matched controls (Control Group). Comparison of allelic frequencies showed that a higher number of CA repeats characterized the MS group (P<0.0001) and prevalence of carriers of > or =22 CA repeats was higher in the MS than in the Control Group (OR 3.4, 95% CI: 1.7-6.8, P<0.0001). An earlier age at disease onset was a characteristic of patients with >22 CA repeats (33+/-10 vs. 28+/-10, P=0.027). No differences were found in the main MRI parameters.

Rivastigmine in vascular dementia.

Patients with vascular dementia (VaD) show cholinergic deficits that may result in characteristic clinical syndromes for different subtypes of the condition. Subcortical VaD is characterised by executive dysfunction and behavioural problems, reflecting deterioration of the frontal lobe. Based on limited open-labelled controlled studies of rivastigmine in VaD, this article aims to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effects on the typical symptoms of subcortical VaD. Long-term rivastigmine treatment is safe and effective. Improvements in domains that characterise subcortical VaD were observed, indicating that rivastigmine may have provided targeted treatment in areas of the brain that are particularly affected in this patient population. A large, double-blind study of rivastigmine in patients with VaD is clearly warranted.

Olanzapine as a possible treatment for anxiety due to vascular dementia: an open study.

Disabilities caused by behavioral problems can be potentially devastating in cognitively impaired patients. These behavioral symptoms can be a major cause of stress, anxiety, and concern for caregivers. While psychotropic drugs are frequently used to control these symptoms, they can be accompanied by significant side effects, which include sedation, disinhibition, depression, falls, incontinence, parkinsonism, and akathisias. Agitation is a major problem in older patients with dementia. Agitation and aggression have always been difficult behaviors to manage, and when it is severe, agitation can be a behavioral emergency that requires urgent and immediate intervention. This six-month study included a group of 94 outpatients (48 men and 46 women) who had a diagnosis of subcortical vascular dementia (VaD). To be eligible for the study, patients needed a score of at least 3 for agitation/aggression on the Neuropsychiatric Inventory (NPI), suggesting at least moderate frequency and/or severity, and 0 for delusions and hallucinations. Patients were divided into two homogenous groups. Group A received olanzapine (2.5-5 mg/day) and Group B received bromazepam (0.25 percent, 15 drops, three times per day). Patients in both groups were allowed to continue any previous therapy. Patients receiving olanzapine at an average dose of 3.21 +/- 1.02 mg/day showed statistically significant improvement on the anxiety rating compared with those receiving bromazepam. Our patients had a host of medical conditions and received numerous concomitant medications. Given the potential complications associated with these therapeutic agents, these patients tolerated olanzapine quite well. It appeared that adverse events, particularly somnolence, postural instability, and postural hypotension, were mild and transient. Moreover, no anticholinerigic effect was registered. These findings suggest that olanzapine could be a safe and effective treatment for anxiety in cognitively impaired patients.

Gabapentin as a drug therapy of intractable hiccup because of vascular lesion: a three-year follow up.

BACKGROUND: Persistent and intractable hiccups indicate multiple neurologic and extraneurologic disorders. Chronic hiccup is not so rare in patients suffering from stroke: its impact on quality of life and on rehabilitation management is substantial, and it may be closely related to aspiration pneumonia, respiratory arrest and nutritional depletion. REVIEW SUMMARY: Intractable hiccups can be associated with potentially fatal consequences and safe management may require inpatient rehabilitation. It has been suggested that hiccups could be a form of myoclonus, caused by repeated and abnormal activity of the solitary inspiratory nucleus. Because of this cause we decided to treat intractable hiccups in patients with ischemic lesions of the medulla with a short course of gabapentin. CONCLUSIONS: The results were promising, with the immediate disappearance of the hiccups, and the complete absence of side effects. The 36-months follow up was favorable to all the patients, who, after 6 days of treatment remain asymptomatic.

Cholinesterase inhibition as a possible therapy for delirium in vascular dementia: a controlled, open 24-month study of 246 patients.

The goal of this study was to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effect on delirium in vascular dementia (VaD). The results from this follow-up study suggest that although delirium is frequent in elderly, cognitively impaired patients, it might not be a simple consequence of acute disease and hospitalization. Rather, delirium can be secondary to brain damage and to metabolic disturbances. According to the Lewy body dementia model, delirium could be induced by a lack of acetylcholine in the brain. Rivastigmine may help reduce the frequency of delirium episodes and help shorten their duration. Additional studies are required to better define the causes of delirium, which currently has no definitive treatment.

Gabapentin for the treatment of behavioural alterations in dementia: preliminary 15-month investigation.

BACKGROUND: Although the core feature of dementia is progressive cognitive disruption, non-cognitive behavioural problems are expressed in most patients with dementia during the course of their illness. While psychotropic drugs are frequently used to control behavioural symptoms, comorbidities, which are very common in the geriatric population, could often limit their use. Gabapentin may be a potential treatment in such situations. METHODS: In this open, baseline comparison study 20 patients with probable Alzheimer's disease with behavioural alterations and serious comorbidities (paralytic ileus, open-angle glaucoma, ischaemic cardiopathy, hepatic failure or severe prostatic hyperplasia) received gabapentin for 15 months. Patients were allowed to continue any previous therapy for concurrent diseases. However, concomitant antipsychotic or benzodiazepine intake was not permitted. RESULTS: Gabapentin appeared to be efficacious and well tolerated in this patient population, and did not appear to interact with other drugs. General benefit is reflected by a reduction of caregiver stress. No patients withdrew before the end of the study and no serious adverse events were reported. CONCLUSION: The results of this study in patients with probable Alzheimer's disease with behavioural alterations and serious comorbidities indicate that gabapentin provides significant and sustained efficacy in terms of behaviour, with associated reductions in caregiver burden. The results of an ongoing larger, randomised, double-blind study of gabapentin are keenly awaited and may help to provide a safer and more efficacious treatment option for this group of patients.

Neuropsychological changes after subthalamic nucleus stimulation: a 12 month follow-up in nine patients with Parkinson's disease.

Deep brain stimulation of the subthalamic nucleus has been recognized as one of the most promising techniques to decrease 'off' motor symptoms and motor fluctuations, allowing a reduction of drug therapy and limiting side effects of drug therapy. However, there is still open debate on the possible consequences of chronic subthalamic stimulation on general cognitive performance. A general amelioration of cognitive performance, in particular of executive functions has been reported but results are not homogeneous. We studied nine patients with Parkinson's Disease for 12 months following surgery for deep stimulation, studying their cognitive performances, paying particular attention to linguistic tests and selective alternating words production. Our results may be consistent with a slowing of cognitive activity, with a reduction of quantitative production, but with an increase in control of linguistic production, which is more precise and definite. We discuss the possible significance of these results, fully aware that only nine patients were involved, and that the potential for generalization is seriously limited, with a particular overview on the frontal-subthalamic pathway, which in our opinion is responsible for the results we observed.