Rita Moretti

A longitudinal study of brain atrophy and cognitive disturbances in the early phase of relapsing-remitting multiple sclerosis

OBJECTIVE (a) To establish whether the cognitive decline of the early phase of relapsing-remitting multiple sclerosis depends on the progression of the burden of disease, or on the loss of brain parenchyma, or is influenced by both; (b) to monitor the loss of brain parenchyma in the early phase of the disease; and (c) to examine its possible relation with the progression of physical disability. METHODS For 2 years 53 patients with clinically definite relapsing-remitting multiple sclerosis with disease duration 1–5 years and expanded disability status scale⩽5.0 at baseline were monitored. The neuropsychological performances, the psychological functioning, the neurological impairment, and the disability have been assessed at baseline and after 2 years. Patients also underwent PD/T2 and T1 weighted brain MRI. T2 and T1 lesion volumes were measured by a semiautomatic technique. Quantification of brain parenchymal volumes was obtained using a highly reproducible computerised interactive program. The relation between cognitive impairment and MRI findings has been investigated by partial correlation and stepwise multiple regression analyses excluding the effects of age, education, anxiety, depression, and total days of steroid use. RESULTS In the 2 years of the study the mean change for T2 and T1 lesion volumes and brain parenchymal volumes were +1.7 ml (95% confidence interval (95% CI) 1.3–2.2, p=0.005, (29.8%); +0.2 ml, 95% CI 0.15–0.26, p=0.004, (25%); and –32.3 ml, 95% CI 24.2–42.3, p<0.0001, (2.7%), respectively. Overall, 14 patients (26.4%) were judged to be cognitively impaired at baseline and 28 (52.8%) at the end of the follow up. Of the 18 neuropsychological tests and subtests employed in the study, patients with multiple sclerosis failed 5.8 (SD 2.3) tests at the baseline and 8.4 (SD 2.9) (p<0.0001) tests at the end of the study. When the cognitive changes were examined in individual patients, five (9.4%) of them were considered cognitively improved, 33 (62.3%) remained stable, and 15 (28.3%) worsened over 2 years. T2 and T1 volume changes in improved, stable, and worsened patients did not show any significant difference, whereas brain parenchymal volume decrease in cognitively worsened patients was significantly greater (−66 ml (5.4%), 95% CI 37–108.9, p=0.0031). The cognitive impairment was independently predicted over 2 years only by the change of brain parenchymal volumes (R=0.51, p=0.0003). Ten patients (18.9%), who worsened by one or more points in the EDSS during the follow up period had significant decreases in brain parenchymal volumes (−99 ml (8%), 95% CI 47.6–182.3, p=0.005). At the end of the study the loss of brain parenchyma correlated significantly with change in EDSS (r= 0.59, p<0.0001). CONCLUSIONS In the early phase of relapsing-remitting multiple sclerosis the cognitive deterioration relies more on the development of brain parenchymal volume atrophy than on the extent of burden of disease in the brain. The loss of brain parenchymal volume underlies the progressive accumulation of physical disability from the initial phase of the disease, which becomes more demonstrable only if studied with longer observation periods. Probably, the main pathological substrate of brain atrophy in the early stage of the disease is early axonal loss, which causes the progression of neurological deficits and the development of cognitive impairment. These data support the debated opinion that disease modifying therapy should be initiated as early as possible.

Sexual dysfunction in multiple sclerosis: a case-control study. I. Frequency and comparison of groups.

Sexual dysfunction is a very important but often overlooked symptom of multiple sclerosis. To investigate the type and frequency of symptoms of sexual dysfunction in patient suffering from multiple sclerosis, we performed a case-control study comparing 108 unselected patient with definite multiple sclerosis, 97 patient with chronic disease and 1 10 healthy individuals with regard to sexual function, sphincteric function, physical disorders impeding sexual activity and the impact of sexual dysfunction on social life. Information has been collected from a face-to-face structured interview performed by a doctor of the same gender as the patient. The disability, the cognitive performances, the psychiatric conditions and the psychological profile of patien t a nd co ntrols have bee n assessed. Sexul a dysfu nction was prese nt in 73.1% of cases, in 39.2% of chronic disease co ntrols and in 12.7% of h e althy co ntrols (P < 0.000 1). Male cases reported symptoms of sexual dysfunction more freq ue ntly th an female cases (P <0.002). Symptoms of sexual dysfunction more commonly reported in patient with multiple scerosis were anorgasmia or hyporgasmia (37.1%), decreased vaginal lubrication (35.7%) and reduced libido (31.4%) in women, and impotence or erectile dysfunction (63.2%), ejaculatory dysfunction and/or orgasmic dysfunction (50%) and reduced libido (39.5%) in men. Seventy-five per cent of cases, 51.% of chronic disease controls and 28.2% of healthy controls (P <0.0001) experienced symptoms of sphincteric dysfunction. In conldusion, a substantial part of our sample of patient with multiple sclerosis reported symptoms of sexual and sphincteric dysfunction. Both sexual and sphincteric dysfunction were significantly more common in patient with multiple sclerosis than in either control group. Our findings suggest that a peculiar damage of the structures involved in sexual function is responsible for the dysfunction in patient with multiple scerosis, but the highly significant lower frequency of symptoms of depression and anxiety in healthy controls may also imply a possible causative role of psychological factors.

Rivastigmine in frontotemporal dementia: an open-label study.

ObjectiveThis 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 MethodsStudy 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.ResultsRivastigmine 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.ConclusionIn 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.

Frontotemporal Dementia: Paroxetine as a Possible Treatment of Behavior Symptoms

Frontotemporal dementia (FTD) represents an important cause for degenerative disruption and is increasingly recognized as an important cause (up to 25%) of degenerative dementia among late-middle-age individuals. The serotoninergic system is tightly bound to frontal circuits, whose degeneration subserves FTD. Patients aged 64–68 years, with a diagnosis of FTD, were randomized to receive paroxetine up to 20 mg/day (n = 8) or piracetam up to 1,200 mg/day (n = 8). At 14 months, the patients treated with paroxetine showed significant improvements in behavioral symptoms, reflected by a reduction of caregiver stress. Side effects were easily tolerable, and there was no dropout. The results are presented with an overview of the literature on the topic.

Language impairments in patients with cerebellar lesions

Abstract In the present study language abilities in four patients with focal cerebellar lesions of different types and localized in different areas of the cerebellum were assessed before and after surgery in order to verify possible linguistic deficits and ascertain if these deficits were stable or evolved after the operation. All patients showed minor language impairments, mainly affecting morphosyntactic features and lexical access. In two patients, AZ (with an arachnoidal cyst compressing the superior portion of the vermis) and LP (with a hemangioblastoma compressing the right cerebellar hemisphere), linguistic deficits partially recovered after surgery. The remaining two patients, FR (with an astrocytoma in the vermis) and MG (with an astrocytoma compressing the left cerebellar hemisphere), did not show any improvement following the partial surgical removal of their cerebellar tumors. Minor linguistic deficits consequent to cerebellar lesions in our patients may be due to an alteration of language control processes rather than an impairment of language components. Some cerebellar structures (portions of the vermis and the cerebellar hemispheres) seem to be particularly involved in the control of language processing, and it is proposed that they accomplish this by integrating their activity with that of the so-called ‘frontal lobe system’.

Rivastigmine in subcortical vascular dementia: an open 22-month study.

Further to recent data indicating that patients with vascular dementia (VaD) show a cholinergic deficit, we aimed to determine whether rivastigmine, a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), has any effects on the symptoms of VaD. Patients aged 65-80, with a diagnosis of dementia and probable VaD, received rivastigmine 3-6 mg/day (n=8) or cardioaspirin (n=8) in an open study for 22 months. At 22 months, patients treated with rivastigmine showed significant improvements in executive function and behavioural symptoms (both p<0.05 vs. both baseline and control group), which were reflected in reduced caregiver stress (p<0.05 vs. baseline and controls). Baseline scores of global response, cognition, word fluency and activities of daily living were maintained in patients receiving rivastigmine, and there was no increase in benzodiazepine or neuroleptic intake. In contrast, the control group showed no improvements in any domain, and significant deterioration in global response and executive function (both p<0.05 vs. baseline and rivastigmine group). Side effects in both groups were tolerable and there were no study withdrawals. Long-term rivastigmine treatment appeared to be safe and effective in this patient population. In particular, improvements in domains particularly relevant to this condition were observed. These benefits may reflect the drugs dual inhibitory effects on the cholinergic system, and its particular activity in frontal areas of the brain. A large, double-blind study of rivastigmine in patients with VaD would be worthwhile.

Sexual dysfunction in multiple sclerosis: a 2-year follow-up study

BACKGROUND AND OBJECTIVE Sexual dysfunction severely affects the quality of life of patients, but longitudinal studies of sexual function in multiple sclerosis are lacking. We performed a study on a group of patients with multiple sclerosis to evaluate the change in sexual function and to examine the relationship between sexual dysfunction and other clinical variables over time. METHODS A 2-year follow-up study on 99 patients with definite multiple sclerosis. Information on sexual and sphincteric disturbances have been collected through face-to-face structured interviews. Disability, independence, cognitive performances and psychological functioning have also been assessed. Spearman rank correlation analysis corrected for multiple comparisons, and linear regression analysis have been performed to test variables relationship and remove the effect of potential confounding covariates. RESULTS The proportion of patients with sexual dysfunction remained over 70% and did not change during the 2-year follow-up, but the extent and number of symptoms increased significantly The number of symptoms of sexual dysfunction did not change significantly after an exacerbation. Significantly, more patients than before the study resorted to counseling and discussed with doctors of sexual matters. In the univariate analysis, changes in sexual function over time correlated with changes in bladder function (r=0.47, p<0.0001) and EDSS score (r=0.41, p<0.0001), but the multivariate analysis demonstrated that only bladder dysfunction was independently related to sexual dysfunction (R=0.36, p=0.003) when the effect of psychological factors were removed. CONCLUSIONS Symptoms of sexual dysfunction increase in significance and number over time in patients with multiple sclerosis. Relapses did not influence the number of symptoms of sexual dysfunction, but a worsening of pre-existing symptoms cannot be excluded. The change of sexual function appears to be independently associated to bladder dysfunction.

Olanzapine as a treatment of neuropsychiatric disorders of Alzheimer's disease and other dementias: a 24-month follow-up of 68 patients.

Although the core feature of all types of dementia is progressive cognitive disruption, most demented patients also express noncognitive behavioral problems. These noncognitive problems lead to potentially devastating disabilities, and are often a major cause of stress, anxiety and concern for caregivers. Psychotropic drugs are frequently used to control these symptoms, but they have the potential for significant side effects, such as sedation, disinhibition, depression, falls, incontinence, parkinsonisms and akathisias. For 24 months, we monitored 68 outpatients suffering from Alzheimers disease, vascular dementia, frontal lobe dementia, Parkinson dementia complex, and Lewy body disease. Our purpose was to identify the role and efficacy of olanzapine and the side effects which emerged during the treatment of behavioral alteration resulting from five etiological causes. This paper will discuss the results of this study, and will provide an overview of the existing literature.

Risk factors for vascular dementia: Hypotension as a key point

Physiologically, the cerebral autoregulation system allows maintenance of constant cerebral blood flow over a wide range of blood pressure. In old people, there is a progressive reshape of cerebral autoregulation from a sigmoid curve to a straight line. This implies that any abrupt change in blood pressure will result in a rapid and significant change in cerebral blood flow. Hypertension has often been observed to be a risk factor for vascular dementia (VaD) and sometimes for Alzheimer disease although not always. Indeed, high blood pressure may accelerate cerebral white matter lesions, but white matter lesions have been found to be facilitated by excessive fall in blood pressure, including orthostatic dysregulation and postprandial hypotension. Many recent studies observed among other data, that there was a correlation between systolic pressure reduction and cognitive decline in women, which was not accounted for by other factors. Baseline blood pressure level was not significantly related to cognitive decline with initial good cognition. Some researchers speculate that blood pressure reduction might be an early change of the dementing process. The most confounding factor is that low pressure by itself might be a predictor of death; nevertheless, the effect of low blood pressure on cognition is underestimated because of a survival bias. Another explanation is that clinically unrecognized vascular lesions in the brain or atherosclerosis are responsible for both cognitive decline and blood pressure reduction. We discuss the entire process, and try to define a possible mechanism that is able to explain the dynamic by which hypotension might be related to dementia.

Reading errors in patients with cerebellar vermis lesions

Abstract Dyslexia, both developmental and acquired, has been considered the result of cerebrocortical dysfunction, affecting the temporo-parieto-occipital brain regions. However, dyslexia may involve abnormalities of the magnocellular component of the visual system, leading to binocular instability or alterations of accommodation. To test the hypothesis of cerebellar involvement in the reading process – justified by its emergent role in language and cognition – we studied 10 patients with cerebellar vermis/paravermis lesions using reading tests and we compared the results with those produced by 10 normal volunteers. The data obtained demonstrate an increased number of reading mistakes in the patient group, resulting from a possible alteration of the diffuse connection system from the cerebellum to different cerebrocortical and subcortical structures. Acquired dyslexia due to cerebellar impairment may be due to oculomotor alteration or, more subtly, to the intimate cerebellar-encephalic projections, connecting the cerebellum to the attentive and alerting processes and to the language system. We discuss the data with an overview of literature.