[Dementia: Where are the Lewy bodies?]. / Démences : où sont les corps de Lewy ?

Dementia with Lewy bodies (DLB) is the second cause of degenerative dementia in autopsy studies. In clinical pratice however, the prevalence of DLB is much lower with important intercenter variations. Among the reasons for this low sensitivity of DLB diagnosis are (1) the imprecision and subjectivity of the diagnostic criteria; (2) the underestimation of non-motor symptoms (REM-sleep behavior disorder, dysautonomia, anosmia); mostly (3) the nearly constant association of Lewy bodies with Alzheimer's disease pathology, which dominates the clinical phenotype. With the avenue of targeted therapies against the protein agregates, new clinical scales able to apprehend the coexistence of Lewy pathology in Alzheimer's disease are expected.

[The new 2011 recommendations of the National Institute on Aging and the Alzheimer's Association on diagnostic guidelines for Alzheimer's disease: Preclinal stages, mild cognitive impairment, and dementia]. / Les nouvelles recommandations 2011 du National Institute on Aging et de l'Alzheimer's Association sur le diagnostic de la maladie d'Alzheimer : stades précliniques, mild cognitive impairment et démence.

BACKGROUND: Criteria for the clinical diagnosis of Alzheimer's disease (AD) were established in 1984, and they needed to be updated and revised, in vue of the scientific knowledge acquired over the last decades. METHODS: The National Institute on Aging (NIA) and the Alzheimer's Association (AA) sponsored a series of advisory round table meetings to establish a revision of diagnostic and research criteria for AD. The workgroups reviewed the biomarker, epidemiological, and neuropsychological evidence, and proposed conceptual frameworks as well as operational research criteria based on the prevailing scientific evidence to date. RESULTS: Three preclinical stages of AD were proposed: asymptomatic amyloidosis, asymptomatic amyloidosis+neurodegeneration, amyloidosis+neurodegeneration+subtle cognitive decline. The preclinical workgroup developed recommendations to determine the factors, which best predict the risk of progression from normal cognition to mild cognitive impairment (MCI) and AD dementia. It is necessary to refine these models with longitudinal clinical research studies. The workgroups on MCI and AD dementia sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. The symptomatic predementia phase of AD was referred to as MCI due to AD. Core clinical and cognitive criteria of MCI were proposed, the final set of criteria for MCI due to AD has four levels of certainty, depending on the presence and nature of the biomarker findings. Criteria for all-cause dementia and for AD dementia were presented. Dementia caused by AD were classified in: probable AD dementia, possible AD dementia, and probable or possible AD dementia with evidence of the AD pathophysiological process, for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis. CONCLUSIONS: In the revised criteria, a conceptual distinction is made between AD pathophysiological processes and clinically observable syndromes. The core clinical criteria of the recommendations regarding MCI due to AD and AD dementia are intended to guide diagnosis in the clinical setting whereas the recommendations of the preclinical AD workgroup are intended purely for research purposes and do not have any clinical implications. Considerable work is needed to validate the criteria that use biomarkers and to standardize biomarker analysis for use in community settings.

Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation.

BACKGROUND: Male carriers of the FMR1 premutation are at risk of developing the fragile X-associated tremor/ataxia syndrome (FXTAS), a newly recognised and largely under-diagnosed late onset neurodegenerative disorder. Patients affected with FXTAS primarily present with cerebellar ataxia and intention tremor. Cognitive decline has also been associated with the premutation, but the lack of data on its penetrance is a growing concern for clinicians who provide genetic counselling. METHODS: The Mattis Dementia Rating Scale (MDRS) was administered in a double blind fashion to 74 men aged 50 years or more recruited from fragile X families (35 premutation carriers and 39 intrafamilial controls) regardless of their clinical manifestation. Based on previous publications, marked cognitive impairment was defined by a score

Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease.

BACKGROUND: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3). METHODS: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics. RESULTS: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients. CONCLUSIONS: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

[Semantic dementia: reflexions of a French working group for diagnostic criteria and constitution of a patient cohort]. / Démence sémantique: réflexions d'un groupe de travail pour des critères de diagnostic en français et la constitution d'une cohorte de patients.

Semantic dementia (SD) is a syndrome of progressive loss of semantic knowledge for objects and people. International criteria propose that SD be included in the frontotemporal lobar degeneration syndromes, with progressive non-fluent aphasia and frontotemporal dementia (FTD). However, several related syndromes have been defined that clinically and conceptually share both similarities and differences with SD: fluent progressive aphasia, progressive prosopagnosia, temporal variant of FTD. In order to establish a French consensus for the diagnosis and modalities of evaluation and follow-up of SD, a working group, composed of neurologists, neuropsychologists and speech-therapists, was established by the Groupe de réflexion sur les évaluations cognitives (GRECO). New criteria were elaborated, based on clinical, neuropsychological, and imaging data. They define typical and atypical forms of SD. A diagnosis of typical SD relies on an isolated and progressive loss of semantic knowledge, attested by a deficit of word comprehension and a deficit of objects and/or people identification, with imaging showing temporal atrophy and/or hypometabolism. SD is atypical if the deficit of semantic knowledge is present only within a single modality (verbal versus visual), or if non-semantic deficits (mild and not present at onset) and/or neurological signs, are associated with the semantic loss.

[Amyotrophic lateral sclerosis: cognitive and behavioral evaluation]. / Evaluation cognitive et comportementale.

Cognitive impairment in nondemented ALS patients has been demonstrated, although its incidence remains to be determined. FTD is the most frequently form of dementia in ALS. The clinical profile of patients with dementia or mild cognitive deficit evokes neuropsychological deficits and behavioural changes resulting from executive dysfunction. The psychometric evaluation, centred on executive disturbances, goes with behavioural scales in order to accurately appreciate the repercussion of cognitive and behavioural changes on daily life.

[Measurement instruments and assessment scales for frontotemporal dementia]. / Instruments de mesure et échelles d'évaluation utilisés dans la démence fronto-temporale.

In frontotemporal dementia (FTD), evaluation scales and measurement instruments are less codified than in Alzheimer's disease. Some nonspecific scales are available, two of which are very useful for early diagnose of the disease: Lebert and Pasquier's Frontotemporal Behavioral Scale (FBS) to assess behavioral disturbances and Dubois's Frontal Assessment Battery (FAB) to assess executive ability. However, these scales do not contain enough items to follow up FTD. The main scale used to follow up the disease is the Neuropsychiatric Inventory (NPI). The Frontal Behavioural Inventory (Kertesz) seems to be interesting, but has not yet been validated in France. The Mattis Dementia Rating Scale, not specific for FTD, is used to assess the cognitive rate. The activities of daily living scales and caregiver burden are not well known in FTD.

[Dural arteriovenous fistula. A rare cause of treatable dementia]. / Fistules durales à drainage veineux cortical. Une cause rare de démence curable.

Dural fistulas are acquired arteriovenous shunts, accounting for 10-15p.cent of cerebrovascular malformations. Symptoms are commonly tinnitus or intracranial hemorrhage. Rarely, patients with dural fistulas can present with rapid cognitive impairment. We report two women with rapidly evolving dementia. Cerebral angiography revealed dural arteriovenous fistula, with retrograde drainage into cortical veins, related to thrombosis of both transverse sinuses. Intra-arterial and intra-venous endovascular approaches failed to cure the fistula. Venous embolization via a transcranial approach was required to occlude the fistula, leading to resolution of the symptoms. Dural arteriovenous fistulas may lead to dementia with diffuse white matter changes related to venous ischemia, and must be considered as a reversible cause of vascular dementia. A transcranial approach for venous embolization is sometimes required.

Iatrogenic Creutzfeldt-Jakob disease subsequent to dural graft: persisting risk after 1987.

The first case of Creutzfeldt-Jakob disease (CJD) related to the use of a dura mater graft of cadaveric origin was identified in 1987 and this procedure is now considered as one of the main causes of iatrogenic CJD. Although the decontamination procedure for the preparation of graft material was modified, the product was withdrawn from the market in many countries a few years later and replaced by synthetic material. In this context, two patients treated in our institution developed CJD following a cadaveric dural graft performed after cerebral and lumbar trauma. Their clinical presentation, showing predominant cerebellar symptoms, late deterioration and myoclonic jerks, and a rapid disease course until death, was similar to that of previously reported cases involving the iatrogenic form. As the graft for one of the patients was performed in 1991 (several years after modification of the decontamination procedure), this fourth reported case suggests that the risk of iatrogenic CJD may have persisted in some patients treated after 1987, when grafts of cadaveric origin were totally abandoned.

[Neuropsychological and scintigraphic aspects of frontotemporal dementia preceding amyotrophic lateral sclerosis]. / Aspects neuropsychologiques et scintigraphiques des démences fronto-temporales précédant l'atteinte du motoneurone.

Between 1993 and 2001, we observed fifteen patients (ten men and five women, mean age 63 years) with frontotemporal dementia (FTD) which preceded signs of amyotrophic lateral sclerosis (ALS) which developed 21 months later. Mean disease duration in the fourteen deceased patients was 38 months. FTD associated with ALS is characterized by rapid course, predominance of disinhibited forms (orbito-basal), presence of aphasia with neologisms, and semantic memory disorders. Performed in all patients, single-photon emission computed tomography demonstrated a bifrontal pattern of low uptake, sometimes associated with low uptake in the anterior temporal region. In one patient, neuropathology revealed neuron atrophy and loss in the frontotemporal region, the anterior horns, and the hypoglossal nucleus. Ubiquitin-positive inclusions were visible in the dentate gyrus of the hippocampus and in the anterior horns. The dementia/ALS association is classically described is uncommon. It belongs to the FTD group since the Lund and Manchester consensus. Approximately 15 p.100 of patient with FTD can be expected to develop ALS. About 250 cases have been reported in the literature, half of them in the Pacific area where the incidence of ALS is high (55/100,000 inhabitants versus 1/100,000 in the rest of the world). Intermediary forms of FTD, semantic dementia, and progressive non-fluent aphasia are discussed since several cases of non-fluent progressive aphasia associated with ALS are reported in the literature. The links between these two degenerative diseases are discussed.

[Analysis of neuropsychological disorders coupled with 99m Tc-HMPAO Spect in amyotrophic lateral sclerosis. Prospective study of 16 cases]. / Analyse des troubles neuropsychologiques couplée à la tomographie à émission monophonique au HMPAO Tc99 m dans la sclérose latérale amyotrophique. Etude prospective de 16 cas.

A prospective psychometric study was conducted in 16 patients who recently developed classic sporadic amyotrophic lateral sclerosis and had no signs of anxiety or depression. Tests included PM38, MMS, Rey word and Rey image tests, span, Stroop test, verbal fluency, Wisconsin test and London Tower test coupled with 99m Tc HMPAO tomography. Results demonstrated that the patients had no intellectual degradation nor visual constructive disorders but had disturbed verbal and visual memory with a reduced verbal fluency (particular bulbar forms), perseverance errors on the Wisconsin test (half of the cases) and an increased number of movements in the London Tower test. These disorders were moderate with no clinical impact and variable (the neuropsycological examination was normal in 4/16 patients). 99m Tc HMPAO tomography was normal in 4 cases, showed slight rolandic hypoperfusion in 6 and extensive hypoperfusion outside the motor zone in 2. Visual analysis of the 99m Tc HMPAO images did not reveal any clinico-metabolic correlations.

Frontal type dementia preceding amyotrophic lateral sclerosis: a neuropsychological and SPECT study of five clinical cases.

Between 1993 and 1995, we observed five sporadic cases of frontotemporal dementia (FTD) which in all cases preceded the appearance of typical amyotrophic lateral sclerosis (ALS). The FTD rapidly became severe (within 12-18 months) and the delay between the presumed onset of mental change and ALS was short (12-26 months). The frontal dysfunction was characteristic (disinhibited, jocular, impatient, gluttonous, stereotypical gestures). The language impairment (less talkative, persistent errors, fantastic and semantic paraphasia, neologistic errors, echolalia) was constant. Single photon emission computed tomography (SPECT) with 99 Tcm HMPAO (hexamethyl propylamine oxime) was done at the same time as neuropsychological testing in four cases and showed serious diffuse bifrontal defect, sometimes with less serious internal temporal hypofixation. All patients died with bulbar ALS complications. The total course can last from 14-48 months. Most of the reported cases suggested a relationship between dementia-ALS and frontal dysfunction. The mechanism underlying dementia-ALS remains to be solved. Our five cases resemble those reported by Mitsuyama (1993), who suggested that dementia-ALS has the same clinicopathological entity.

[Frontal type dementia and amyotrophic lateral sclerosis. 3 cases with (HmPAO Tc99m) single-photon emission tomography study]. / Démence de type frontal et sclérose latérale amyotrophique. Trois cas avec étude en tomographie d'émission monophotonique (HmPAO Tc99m).

Three cases of rapid onset neuropsychological frontal dementia preceded the development of sporadic amyotrophic lateral sclerosis by 12 to 24 months. HmPAO Tc99m scintigraphy demonstrated hypoactivity in the cortex, predominantly in the frontal region. Three hypotheses are discussed: 1) coincidence between two degenerative diseases, Alzheimer's disease or Pick's disease and ALS; 2) an amyotrophic form of Creutzfeld Jakob disease; 3) pre-senile dementia associated with a motoneuron disease, a clinical pathology entity recently described by Mitzuyama.

[Anarthria, progressive apraxia and extrapyramidal syndrome: an uncommon clinical form of corticobasal degeneration? A case studied by HMPAO Tc99m single-photon emission tomography]. / Anarthrie, apraxie progressive et syndrome extra-pyramidal: forme clinique particulière de dégénérescence cortico-basale? Un cas avec étude en tomographie par émission monophotonique au HMPAO Tc99M.

A 48-year-old man presented with impaired joint movement and buccofacial apraxia. The disease progressed for six years associating an akineto-hypertonic syndrome, marked anarthria, saliva incontinence, bi-opercular syndrome, bucco-facial apraxia, severe global gestual apraxia and a frontal syndrom. Oculo-motricity and gait were normal. Magnetic resonance imaging of the brain demonstrated fronto-parietal atrophy and HMPAO Tc99 tomography revealed hypoperfusion of the cortex clearly predominating in the left parietal region. These particular findings with predominantly intense joint involvement is similar to the clinical picture in corticobasal degeneration--subcortical signs (progressively uncontrollable hypertonia) together with cortical signs (severe gestual apraxia). The neuroradiological imaging and functional results also suggest a degenerative process.

[Paroxysmal kinesigenic choreoathetosis: autonomic disease or reflex epilepsy?]. / Choréo-athétose paroxystique kinésigénique: affection autonome ou épilepsie réflexe?

Motor attacks induced by voluntary movements are infrequent. Paroxysmal kinesigenic choreoathetosis (PKC) is rare and has only recently been individualized (Kertesz, 1967). We report the case of an 8 year-old boy who developed unilateral or bilateral attacks of abnormal, choreoathetotic movements during certain voluntary movements, especially when rising after a rest. The attacks were short (13 to 18 seconds) and frequent. Neurological examination was normal, as were the intelligence quotient, the inter-critical and critical EEG: CT and MRI. The patient's mother had suffered from the same disorder. The attacks disappeared during treatment with phenytoin but reappeared when it was stopped. This case is concordant with data from the literature, with male predominance, age from 6 to 15 years at the onset, shortness of the attacks (less than 1 minute in 80% of the cases) and normality of investigations in almost every patient. A familial factor has been found in 50% of the cases. The frequency of epilepsy in the family is above average. PKC can easily be distinguished from Mount and Reback' syndrome where the attacks are choreoathetotic but longer and unprovoked by movements and where there is also a familial factor. The relationship of PKC with epilepsy is asserted by some authors and denied by others, and in the literature the distinction between movement-induced tonic seizures and PKC is not always clear. Some authors have blamed a disturbance in the maturation of basal ganglia. To sum up, PKC is a very rare condition which is easy to diagnose, has a good prognosis and readily responds to antiepileptic drugs.

[Contraception and pregnancy in epileptics]. / Contraception et grossesse chez les épileptiques.

PIP: Young epileptic women frequently question their physicians concerning appropriate contraception for them, the effects of pregnancy on epilepsy, and the effects of the disease on the fetus. In 1/2 of cases the frequency of epileptic crises is unaffected by pregnancy, in 1/4 it is augmented and in 1/4 it is decreased. An increase in crises may be caused by psychological factors or by changing the treatment to avoid injuring the fetus. Recent studies show that the plasma level of the medications tends to decline during pregnancy and to increase postpartum. During the past decade several cases of pregnancy in young women taking oral contraceptives (OCs) and antiepileptic drugs have been observed. The inactivation of OCs, which occurs with all antiepileptics except sodium valproate and the benzodiazepines, appears to be due to a mechanism of enzymatic induction. Most cases of pregnancy were in women using sequential pills with 50 mcg or less of ethinyl estradiol. (EE) Sodium valproate can be prescribed for women with primary epilepsy, but in cases of incompletely controlled epilepsy or those requiring various drugs, it is better not to modify a successful regimen. Another method of contraception such as the IUD can be prescribed, or possibly a higher dose formulation of OC can be selected. The vascular risk of a stronger dose of contraceptive steroids should be weighed, but it may be that the process of enzymatic induction maintains a level of EE comparable to that of the minipill. If combined OCs are used, the appearance of metrorrhagia should be noted and the temperature shift should be recorded for the 1st months of treatment to guard against possible failure to inhibit ovulation. The teratogenic risk of antiepileptic medications has not been entirely evaluated, but diphenylhydantoines have been shown experimentally to cause malformations in monkeys. Statistics indicate a doubled risk of malformation in the children of epileptic mothers treated during pregnancy. All antiepileptic drugs were found to be involved. In a personal series of 170 babies of treated epileptic mothers, there were 4 malformations and 1 fatal neonatal hemorrhage. It would be reasonable to assume that malformations result from the interaction of genetic factors related to the severity of the disease, maternal age at pregnancy, and medication used. The role of the anticonvulsants may possibly be explained by their effect on nucleic acid metabolism or by deficiencies of folic acid and vitamin K, which in turn may play a role in neonatal hemorrhage. In case of pregnancy, the patient should be reassured about the small risk of malformation. The smallest possible doses and, if possible, single drugs should be used. Injections of vitamin K for the mother before delivery and for the infant may prevent coagulation problems. The infant may have withdrawal symptoms for which replacement medication may be prescribed for a few weeks. Breastfeeding does not appear to be contraindicated.^ieng