A European Academy of Neurology guideline on medical management issues in dementia.

BACKGROUND AND PURPOSE: Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important medical management issues including systematic medical follow-up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia. METHODS: A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated. RESULTS: Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk-benefit ratio should be performed at regular intervals. Regular, preplanned medical follow-up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non-pharmacological measures have been proven to be without benefit or in the case of severe self-harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first-line therapy (Good Practice statement). CONCLUSION: This GRADE-based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas.

Brain atrophy accelerates cognitive decline in cerebral small vessel disease: the LADIS study.

OBJECTIVE: To examine the independent contributions and combined interactions of medial temporal lobe atrophy (MTA), cortical and subcortical atrophy, and white matter lesion (WML) volume in longitudinal cognitive performance. METHODS: A total of 477 subjects with age-related WML were evaluated with brain MRI and annual neuropsychological examinations in 3-year follow-up. Baseline MRI determinants of cognitive decline were analyzed with linear mixed models controlling for multiple confounders. RESULTS: MTA and subcortical atrophy predicted significantly steeper rate of decline in global cognitive measures as well as compound scores for psychomotor speed, executive functions, and memory after adjusting for age, gender, education, lacunes/infarcts, and WML volume. Cortical atrophy independently predicted decline in psychomotor speed. WML volume remained significantly associated with cognitive decline even after controlling for the atrophy scores. Moreover, significant synergistic interactions were found between WML and atrophy measures in overall cognitive performance across time and the rate of cognitive decline. Synergistic effects were also observed between baseline lacunar infarcts and all atrophy measures on change in psychomotor speed. The main results remained robust after exclusion of subjects with clinical stroke or incident dementia, and after additional adjustments for progression of WML and lacunes. CONCLUSIONS: Brain atrophy and WML are independently related to longitudinal cognitive decline in small vessel disease. MTA, subcortical, and cortical atrophy seem to potentiate the effect of WML and lacunes on cognitive decline.

Incident lacunes influence cognitive decline: the LADIS study.

BACKGROUND: In cerebral small vessel disease, the core MRI findings include white matter lesions (WML) and lacunar infarcts. While the clinical significance of WML is better understood, the contribution of lacunes to the rate of cognitive decline has not been established. This study investigated whether incident lacunes on MRI determine longitudinal cognitive change in elderly subjects with WML. METHODS: Within the Leukoaraiosis and Disability Study (LADIS), 387 subjects were evaluated with repeated MRI and neuropsychological assessment at baseline and after 3 years. Predictors of change in global cognitive function and specific cognitive domains over time were analyzed with multivariate linear regression. RESULTS: After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WML lesion load, and WML progression, the number of new lacunes was related to subtle decrease in compound scores for executive functions (p = 0.021) and speed and motor control (p = 0.045), but not for memory or global cognitive function. Irrespective of lacunes, WML progression was associated with decrease in executive functions score (p = 0.016). CONCLUSION: Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment.

White matter changes and diabetes predict cognitive decline in the elderly: the LADIS study.

OBJECTIVE: We aimed to study if age-related white matter changes (WMC) and vascular risk factors were predictors of cognitive decline in elderly subjects with WMC living independently. METHODS: The Leukoaraiosis and Disability prospective multinational European study (LADIS) evaluates the impact of WMC on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and a neuropsychological battery. Additionally, dementia, subtypes of dementia, and cognitive decline without dementia were classified according to usual clinical criteria. MRI was performed at entry and at the end of the study. RESULTS: A total of 639 subjects were included (74.1 +/- 5 years, 55% women, 9.6 +/- 3.8 years of schooling). At end of follow-up, 90 patients had dementia and 147 had cognitive impairment no dementia. Using Cox regression analysis, WMC severity independently predicted cognitive decline (dementia and not dementia), independently of age, education, and medial temporal atrophy (MTA). Diabetes at baseline was the only vascular risk factor that independently predicted cognitive decline during follow-up, controlling for age, education, WMC severity, and temporal atrophy. Considering subtypes of dementia, Alzheimer disease (AD) was predicted only by MTA, while vascular dementia was predicted by previous stroke, WMC severity, and MTA. CONCLUSION: WMC severity and diabetes are independent predictors of cognitive decline in an initially nondisabled elderly population. Vascular dementia is predicted by previous stroke and WMC, while AD is predicted only by MTA.

Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study.

OBJECTIVES: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes. METHODS: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders. RESULTS: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (beta = -0.61; p = 0.043), and worse compound scores for speed and motor control (beta = -0.25; p = 0.006), executive functions (beta = -0.19; p = 0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (beta = -0.13; p = 0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus. CONCLUSION: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.

Headache in acute stroke. A prospective study in the first 8 days.

We aimed to describe and classify headaches associated with acute stroke, by interviewing patients consecutively admitted to a stroke unit using a validated headache questionnaire and the International Classification of Headache Disorders of the International Headache Society (IHS). One hundred and twenty-four patients (61% ischaemic and 39% haemorrhagic stroke) reported headache. Headaches started mostly on the day of stroke, were more often continuous, pressure-type, bilateral and located in the anterior region, were increased by movement and by cough and lasted for a mean of 3.8 days. Tension-type was the most frequent type of headache. Eleven per cent of headaches could not be classified using the criteria of the IHS. Previous primary headache was documented in 71 patients. The presence of nausea/vomiting due to acute stroke can confound headache classification using the IHS criteria. In up to half of the patients, headache seems to be a reactivation of previous primary headache.

Self-perceived memory impairment and cognitive performance in an elderly independent population with age-related white matter changes.

OBJECTIVES: To determine whether self-perceived memory impairment is associated with the severity of white matter changes (WMC) and is related to cognitive impairment. METHODS: Data were drawn from the multinational Leukoaraiosis and Disability Study (LADIS), which investigates the impact of WMC on global functioning. WMC severity was rated using the Fazekas scale. Medial temporal lobe atrophy (MTA) was scored visually and mean values were calculated. The neuropsychological battery consisted of the Mini-Mental State Examination, a modified version of the VADAS-Cog, Trail making and Stroop tests. A question about self-perceived memory impairment was used as a measure for presence of memory complaints. Cognitive performance was analysed test-by-test and in three main domains: memory, executive functions and speed/motor control. The Geriatric Depression Scale (GDS) was used as a measure of depressive symptoms. RESULTS: Six hundred and thirty-eight subjects were included in this study. No association was found between memory complaints and the severity of WMC. Subjects with memory complaints (n = 399) had a higher GDS score [t((637)) = -7.15; p<0.02] and performed worse on almost all cognitive tests and on the three cognitive domains. Multiple linear regression showed that the worse performance on the memory domain was associated with memory complaints independently of depressive symptoms, WMC severity and MTA (R(2) = 0.183; F = 17.09, beta = -0.126; p<0.05). CONCLUSION: In a sample of non-disabled elderly subjects with WMC, self-perceived memory impairment is significantly associated with objective memory impairment independently of the WMC severity, depressive symptoms and MTA.

Depressive symptoms after stroke and relationship with dementia: A three-year follow-up study.

OBJECTIVE: To determine frequency, determinants, and time course of poststroke depressive symptoms (DS) and their relationship with dementia. METHODS: Two hundred two consecutive stroke patients were prospectively evaluated for DS, followed up over a 3-year period. Patients with Montgomery and Asberg Depression Rating Scale (MADRS) scores of >/==" BORDER="0">7 were considered as having DS. The severity of the neurologic deficit, functional outcome, and dementia were quantified with the Orgogozo Scale, modified Rankin Scale, Informant Questionnaire on Cognitive Decline in the Elderly, and an extensive battery of neuropsychological tests. RESULTS: DS were present in 43% of survivors after 6 months, 36% after 12 months, 24% after 24 months, and 18% after 36 months. The severity of the neurologic deficit at admission was the only independent predictor of DS at month 6. DS at month 6 were more frequent in patients with previous depression, dementia, and right superficial lesions. Younger age and right superficial lesions were the two variables independently associated with the presence of DS at month 36. The time course of the various DS differed, sadness remaining frequent 3 years after stroke (50%), whereas slowness, psychic slowness, lack of energy, and concentration difficulties remained frequent at month 36 in patients with dementia. CONCLUSION: DS are frequent after stroke. Their time course varies and depends on the cognitive status; this variation contributes to differences among previous studies on poststroke depression.

[Cerebral venous thrombosis and familial prothrombin gene G20210a mutation]. / Trombosis venosa cerebral y mutación G20210A del gen de la protrombina familiar.

INTRODUCTION: The prothrombin gene variant G20210A was first described as a risk factor for deep vein thrombosis, and recently for cerebral venous thrombosis, although reported cases had other concomitant risk factors. CLINICAL CASES: A 33 years old woman, with no previous vascular nor thrombotic risk factors, was admitted with thrombosis of superior longitudinal, lateral and sigmoid right sinus. The father had deep venous thrombosis 3 years before. One year later, the 29 year old sister of the proband, developed massive deep venous thrombosis, when she was 8 months pregnant. Laboratory investigations showed elevated anticardiolipin antibodies titer in the proband. Prothrombin activity was in the normal range in the 3 patients. Prothrombin gene mutation G 20210A was detected in the 3 patients. CONCLUSION: As the presence of more than one thrombophilic factor (in the reported case, prothrombin G20210A mutation and anticardiolipin antibodies) increases the likehood of a thrombotic event, it is useful to screen for thrombotic genetic conditions, even when other vascular risks are present, and vice versa.

Trombosis venosa cerebral y mutación G20210Adel gen de la protrombina familiar / Cerebral venous thrombosis and familiar prothrombin gene G20210a mutation

Introducción. La mutación del gen de la protrombina (variante G20210A) se ha descrito como un factor de riesgo para la trombosis venosa profunda. Más recientemente, esta mutación se ha asociado con la trombosis venosa cerebral, aunque todos los casos informados tuvieran otros factores de riesgo concomitantes. Casos clínicos. Describimos una mujer de 33 años de edad, sin factores de riesgo trombóticos vasculares, que se admitió con signos focales bilaterales y letargo. La RM mostró trombosis del seno longitudinal superior, lateral y seno sigmoideo. El padre tuvo trombosis venosa profunda tres años antes. Un año después, la hermana de 29 años desarrolló trombosis venosa profunda masiva, cuando estaba embarazada de ocho meses. Las investigaciones del laboratorio mostraron valores elevados del anticuerpo anticardiolipina en el probando. La actividad de la protrombina estaba dentro de los límites de la normalidad en los tres pacientes. La mutación G20210A del gen de la protrombina se detectó en los tres pacientes. El factor V Leiden y otras condiciones protrombóticas fueron negativas en todos los casos. Conclusión. Este caso familiar de desarrollo de trombosis venosa cerebral y profunda confirma el papel de la mutación G20210A del gen de la protrombina, como un factor predisponente para estas patologías. Como la presencia de más de un factor trombótico, en este caso, mutación G20210A del gen de la protrombina y anticuerpo anticardiolipina, incrementa la probabilidad de complicaciones trombóticas, se recomienda indagar las condiciones genéticas aun cuando están presentes otros factores de riesgo vasculares, y viceversa (AU)

[Multiple vertebro-basilar infarcts and cardio-embolism]. / Infartos múltiples en el territorio vertebrobasilar y cardioembolismo.

INTRODUCTION: Stroke characteristics do not inform much about its etiology, even if they can suggest a specific mechanism. We thought that multiple vertebrobasilar infarcts could be related with embolism, namely cardioembolism. PATIENTS AND METHODS: From a hospital prospective registry of stroke we retrieved 73 cases of acute non-lacunar vertebrobasilar infarcts, without previous episodes of stroke in any territory or vertebrobasilar transient ischemic accidents (TIA). Two groups were compared: patients with single cerebral posterior artery infarct (49) and patients with multiple vertebrobasilar infarcts (24), in respect to conventional risk factors for cerebrovascular disease, ancillary procedures performed, and associated pathologic conditions, as possible infarct pathogenesis. RESULTS: Proportions of risk factors and ancillary procedures performed were similar in both groups, except for hypercholesterolemia, which was more frequent in multiple infarcts, and for transcranial Doppler, which was performed more frequently in multiple infarcts. In multiple infarct group, cardioemboligenic pathology was more frequent, as were medium-high emboligenic risk cardiac diseases and atrial fibrillation, although the difference did not reach statistical significance. CONCLUSIONS: Our results support the hypothesis that multiple non-lacunar vertebrobasilar infarcts, from a first ever stroke event, suggest cardioembolic etiology, and recommend performing an exhaustive cardiac investigation.

[Two myopathy cases]. / Dos casos de miopatía.

INTRODUCTION: Early diagnosis and therapeutic measures of frequent pathologies like hyperthyroidism made their neurological complications less frequent. In spite of well known, these neurological complications are some times forgotten. CLINICAL CASES: We describe two myopathy cases, which presentation was namely fatigue. The inespecificity of this complaint create aetiology and syndromatic diagnosis difficulties, and therapeutic decision. In first case, the symptoms were very gradual, what is usual in older patients, and became extremely incapacitate, depending on others for every daily activity. In the second case, a young patient with diplopia suggested myasthenia. Both cases were diagnosed with hyperthyroidism and a quick improvement occurred with proper medication. Based in these cases, a thyrotoxic myopathy brief comment is made, as in spite of being frequent, these cases presented diagnosis difficulties.