Lost in space(s): Multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.

Orientation is a fundamental cognitive faculty and the bedrock of the neurologic examination. Orientation is defined as the alignment between an individual's internal representation and the external world in the spatial, temporal, and social domains. While spatial disorientation is a recognized hallmark of Alzheimer's disease (AD), little is known about disorientation beyond space in AD. This study aimed to explore disorientation in spatial, temporal, and social domains along the AD continuum. Fifty-one participants along the AD continuum performed an ecological orientation task in the spatial, temporal, and social domains while undergoing functional MRI. Disorientation in AD followed a three-way association between orientation domain, brain region, and disease stage. Specifically, patients with early amnestic mild cognitive impairment exhibited spatio-temporal disorientation and reduced brain activity in temporoparietal regions, while patients with AD dementia showed additional social disorientation and reduced brain activity in frontoparietal regions. Furthermore, patterns of hypoactivation overlapped different subnetworks of the default mode network, patterns of fluorodeoxyglucose hypometabolism, and cortical atrophy characteristic of AD. Our results suggest that AD may encompass a disorder of orientation, characterized by a biphasic process manifesting as early spatio-temporal and late social disorientation. As such, disorientation may offer a unique window into the clinicopathological progression of AD. SIGNIFICANCE STATEMENT: Despite extensive research into Alzheimer's disease (AD), its core cognitive deficit remains a matter of debate. In this study, we investigated whether orientation, defined as the ability to align internal representations with the external world in spatial, temporal, and social domains, constitutes a core cognitive deficit in AD. To do so, we used PET-fMRI imaging to collect behavioral, functional, and metabolic data from 51 participants along the AD continuum. Our findings suggest that AD may constitute a disorder of orientation, characterized by an early spatio-temporal disorientation and followed by late social disorientation, manifesting in task-evoked and neurodegenerative changes. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD and as such could greatly benefit disease diagnosis, monitoring, and evaluation of treatment response.

Is Alzheimer disease a disease?

Dementia, a prevalent condition among older individuals, has profound societal implications. Extensive research has resulted in no cure for what is perceived as the most common dementing illness: Alzheimer disease (AD). AD is defined by specific brain abnormalities - amyloid-ß plaques and tau protein neurofibrillary tangles - that are proposed to actively influence the neurodegenerative process. However, conclusive evidence of amyloid-ß toxicity is lacking, the mechanisms leading to the accumulation of plaques and tangles are unknown, and removing amyloid-ß has not halted neurodegeneration. So, the question remains, are we making progress towards a solution? The complexity of AD is underscored by numerous genetic and environmental risk factors, and diverse clinical presentations, suggesting that AD is more akin to a syndrome than to a traditional disease, with its pathological manifestation representing a convergence of pathogenic pathways. Therefore, a solution requires a multifaceted approach over a single 'silver bullet'. Improved recognition and classification of conditions that converge in plaques and tangle accumulation and their treatment requires the use of multiple strategies simultaneously.

A single-center real-life study on the use of medical cannabis in patients with dystonia.

Background: While cannabis-based medicine is being commonly used in patients with movement disorders, there is a scarcity of publications regarding the effect of cannabis on dystonia. We aimed to describe medical cannabis use in patients with dystonia and related pain. Methods: We employed a structured interview to obtain data on the cannabis treatment regimen, perception of effectiveness and side effect profile. Eligible participants were patients diagnosed with dystonia from the movement disorders unit at the Tel-Aviv Medical Center who had used licensed medical cannabis between January 2019 and January 2021. Results: Twenty-three subjects were interviewed (11 women, mean age 52.7). The most common way of administration was smoking (n = 11). Following an average of 2.5 ± 2.9 years of use, those with widespread dystonia (generalized, hemi and multifocal, n = 11) self-reported on a numeric rating scale an average 63% (range 0%-100%) reduction in symptoms of dystonia, while those with more focal dystonia patterns reported a significantly lower treatment effect of 32%. Participants reported a positive impact in related pain and quality of life, with an average rating of 3.8 out of 5 (SD = 1.2, median = 4) and 3.6 out of 5 (SD = 1.15, median = 4), respectively. Most common side effects were dry mouth (65%), sedation (43%), dizziness (39%) and psychiatric disorders (26%). Three patients (13%) discontinued therapy. Conclusion: A subset of dystonia patients who use medical cannabis under clinical observation reported significant subjective improvement during 30 months of use in average. Further prospective randomized controlled trials are required to examine the effectiveness of cannabis in dystonia.

Licensed Medical Cannabis Use in Gilles de la Tourette Syndrome: A Retrospective Long-term Follow-Up.

Background: Medical cannabis (MC) is widely used in clinical practice to treat Gilles de la Tourette syndrome (GTS). However, legislation, multiple modes of administration, and inconsistent plant preparations have limited trials to assess its benefits and long-term safety. For the past decade, licensed MC has been authorized in Israel for use in resistant GTS. We aimed to describe subjects' satisfaction, consumption habits, and THC dose increment during long-term usage. Materials and Methods: A retrospective longitudinal data collection (up to 9 years) on cannabis use habits and structured questionnaires evaluating disease characteristics and MC influence from GTS subjects being treated in the Movement Disorders Unit of the Tel-Aviv Medical Center, Israel. Results: Twenty-five patients (84% male) participated in the study. The mean duration of MC use was 4.0±2.3 years (range 0.5-10). The majority of patients (96%) consumed MC primarily, but not exclusively, through inhalation methods such as smoking or vaporizing dried inflorescence. A linear increase was observed in mean monthly THC dose (p<0.0001) with an average increase of 0.6-0.7 g/year. MC led to a subjectively reported reduction in tics (75% average reduction) and symptoms associated with common comorbidities of GTS. MC was generally well tolerated, although most participants (88%) reported experiencing side effects. Conclusions: A subset of GTS subjects who use MC long term under clinical observation may subjectively improve control of symptoms. Subject-led dose increase can indicate emerging tolerance. Large randomized controlled and observational long-term trials are required to confirm these observations.

Is There Horizontal Transmission of Creutzfeldt-Jakob Disease?

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (s-CJD) is a rare, fatal neurodegenerative disorder. Familial cases of Creutzfeldt-Jakob disease (f-CJD) due to mutations in the PRNP gene are even rarer around the world; however, in Israel there is a focus of f-CJD patients carrying the E200K mutation. As the number of CJD E200K carriers in Israel is high and increasing, transmission of CJD to normal people was suspected. If such transmission occurs, the incidence of s-CJD would be expected to increase as well, resulting in changes of the ratio of familial/sporadic cases. METHODS: Using data from the National CJD Registry and official statistics on the Israeli population, we studied incidence rates of f-CJD and s-CJD for the period from 1985 to 2018 applying the Surveillance Epidemiology and End Results (SEER) statistical packet developed in the US National Cancer Institute. RESULTS: In total, 621 CJD patients (405 f-CJD and 216 s-CJD) cases are included in the registry. In the cohort of f-CJD patients, the mean age-adjusted annual incidence rate over the abovementioned period was 1.88 ± 0.09 (95% CI: 1.7-2.08) per 1,000,000. In the cohort of s-CJD patients, the mean age-adjusted incidence rate over the same period was 0.93 ± 0.06 (95% CI: 0.81-1.06) per 1,000,000 people. No significant time trends were found over the observation period in either s-CJD or f-CJD. The ratio f-CJD/s-CJD decreases over the observation period from 2.2 to 1.80. CONCLUSION: Israel has a high predominance of f-CJD compared to s-CJD. The mean incidence rate of s-CJD in Israel is similar to most countries. Between 1985 and 2018, the annual age-adjusted incidence rates for both forms of CJD remained stable. Thus, there is no evidence that CJD is transmitted from affected individuals to others.

Lost in space(s): multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.

Orientation is a fundamental cognitive faculty, allowing the behaving self to link his/her current state to their internal representations of the external world. Once exclusively linked to knowledge of the current place and present time, in recent years, the concept of orientation has evolved to include processing of social, temporal, and abstract relations. Concordantly with the growing focus on orientation, spatial disorientation has been increasingly recognized as a hallmark symptom of Alzheimer's disease (AD). However, few studies have sought to explore disorientation along the AD continuum beyond the spatial domain. 51 participants along the AD continuum performed an orientation task in the spatial, temporal and social domains. Under functional magnetic resonance imaging (fMRI), participants determined which of two familiar places/events/people is geographically/ chronologically/ socially closer to them, respectively. A series of analyses revealed disorientation along the AD- continuum to follow a three-way association between (1) orientation domain, (2) brain region, and (3) disease stage. Specifically, participants with MCI exhibited impaired spatio-temporal orientation and reduced task-evoked activity in temporoparietal regions, while participants with AD dementia exhibited impaired social orientation and reduced task-evoked activity in frontoparietal regions. Furthermore, these patterns of hypoactivation coincided with Default Mode Network (DMN) sub-networks, with spatio-temporal orientation activation overlapping DMN-C and social orientation with DMN-A. Finally, these patterns of disorientation- associated hypoactivations coincided with patterns of fluorodeoxyglucose (FDG) hypometabolism and cortical atrophy characteristic to AD-dementia. Taken together, our results suggest that AD may constitute a disorder of orientation, characterized by a biphasic process as (1) early spatio-temporal and (2) late social disorientation, concurrently manifesting in task-evoked and neurodegenerative changes in temporoparietal and parieto-frontal brain networks, respectively. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD.

Posttraumatic Stress Symptoms After Stroke: The Effects of Anatomy and Coping Style.

BACKGROUND: Posttraumatic stress disorder (PTSD) can be triggered by life-threatening medical emergencies, such as stroke. Data suggest that up to 25% of stroke survivors will develop PTSD symptomatology, but little is known about predisposing factors. We sought to examine whether neuroimaging measures and coping styles are related to PTSD symptoms after stroke. METHODS: Participants were survivors of first-ever, mild-moderate ischemic stroke, or transient ischemic attack from the TABASCO study (Tel Aviv Brain Acute Stroke Cohort). All participants underwent a 3T magnetic resonance imaging at baseline and were examined 6, 12, and 24 months thereafter, using neurological, neuropsychological, and functional evaluations. At baseline, coping styles were evaluated by a self-reported questionnaire. PTSD symptoms were assessed using the PTSD checklist. Data were available for 436 patients. RESULTS: Forty-eight participants (11%) developed probable PTSD (PTSD checklist ≥44) during the first year after the stroke/transient ischemic attack. Stroke was more likely to cause PTSD than transient ischemic attack. Stroke severity, larger white matter lesion volume, and worse hippocampal connectivity were associated with PTSD severity, while infarct volume or location was not. In a multivariate analysis, high-anxious and defensive coping styles were associated with a 6.66-fold higher risk of developing poststroke PTSD ([95% CI, 2.08-21.34]; P<0.01) compared with low-anxious and repressive coping styles, after adjusting for age, education, stroke severity, brain atrophy, and depression. CONCLUSIONS: In our cohort, PTSD was a common sequela among stroke survivors. We suggest that risk factors for PTSD development include stroke severity, white matter damage, and premorbid coping styles. Early identification of at-risk patients is key to effective treatment.

Medical Cannabis for Gilles de la Tourette Syndrome: An Open-Label Prospective Study.

Objectives: Assessing the effectiveness and tolerability of medical cannabis (MC) treatment on Gilles de la Tourette syndrome (GTS) patients. Methods: We report on an open-label, prospective study on the effect of MC on adult GTS patients. MC mode of use was decided by the treating neurologist and the patient. Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) content within MC product and monthly dose were titrated during the study. Following treatment initiation, patients were assessed after 4 and 12 weeks for efficacy, tolerability, and side effects. Results: Eighteen patients entered the study. Baseline Yale Global Tic Severity Scale- (YGTSS) Total (range 0-100) was 60.3 ± 17.1. Three patients did not reach the end of follow-up period. The most common mode of administration was smoking (80%). Following twelve weeks of treatment, a significant 38% average reduction (p = 0.002) of YGTSS-Total and a 20% reduction (p = 0.043) of Premonitory Urge for Tic Scale (PUTS) were observed. Common side effects were dry mouth (66.7%), fatigue (53.3%), and dizziness (46.7%). Three patients suffered from psychiatric side effects including worsening of obsessive compulsive disorder (stopped treatment), panic attack, and anxiety (resolved with treatment modification). Six patients (40%) reported cognitive side effects regarding time perception, visuospatial disorientation, confusion, slow processing speed, and attention. Conclusions: MC treatment demonstrates good efficacy and tolerability in adult GTS patients. Predilection for smoking rather than using oil drops requires further comparative studies to evaluate the efficacy of each. Cognitive and psychiatric side effects have to be monitored and addressed.

Alzheimer's disease research progress in the Mediterranean region: The Alzheimer's Association International Conference Satellite Symposium.

As research and services in the Mediterranean region continue to increase, so do opportunities for global collaboration. To support such collaborations, the Alzheimer's Association was due to hold its seventh Alzheimer's Association International Conference Satellite Symposium in Athens, Greece in 2021. Due to the COVID-19 pandemic, the meeting was held virtually, which enabled attendees from around the world to hear about research efforts in Greece and the surrounding Mediterranean countries. Research updates spanned understanding the biology of, treatments for, and care of people with Alzheimer's disease (AD_ and other dementias. Researchers in the Mediterranean region have outlined the local epidemiology of AD and dementia, and have identified regional populations that may expedite genetic studies. Development of biomarkers is expected to aid early and accurate diagnosis. Numerous efforts have been made to develop culturally specific interventions to both reduce risk of dementia, and to improve quality of life for people living with dementia.

Surveying Global Availability of Parkinson's Disease Treatment.

BACKGROUND: Parkinson's disease (PD) is a debilitating neurodegenerative disease with both motor and non-motor manifestations. Available treatment reduces symptoms and is critical for improving quality of life. Treatment options include drugs, device-aided therapies, and non-pharmacological therapies. Complementary and alternative therapies (CATs) are also used in some countries. OBJECTIVE: To examine the availability of PD treatment by country, and differences by national income as defined by the World Bank (high income countries (HICs), upper middle income countries (UMICs), lower middle income countries (LMICs) and low income countries (LICs)). METHODS: This study was conducted by surveying International Parkinson and Movement Disorders Society members about availability of PD treatment. LMICs and LICs (LMICs/LICs) were analysed together. RESULTS: There were 352 valid responses from 76 countries (41.5% from HICs, 30.4% from UMICs, and 28.1% from LMICs/LICs). Levodopa was widely available across all income groups (99%). Availability of other PD drugs decreased with national income. Availability of device-aided therapies decreased with national income (100% availability in HICs, 92.5% among UMICs, and 57.6% among LMICs/LICs). A similar trend was observed for CATs (37.0% availability in HICs, 31.8% in UMICs, and 19.2% in LMIC/LICs). Physiotherapy was the most available non-pharmacological therapy (> 90% respondents). Occupational therapy and SALT were less available in LMIC/LICs (49.5% and 55.6% respectively) compared to HICs (80.1% and 84.9% respectively). CONCLUSION: Our survey highlights significant discrepancies in availability of PD treatments between countries and income groups. This is concerning given the symptomatic benefit patients gain from treatment. Improving equitable access to PD treatment should be prioritised.

The assessment of cognitive and behavioural disturbances in vascular cognitive impairment (VCI) - recommendations of an expert working group.

With newer research-based classification systems, the term Vascular Cognitive Impairment (VCI) is now preferred to vascular dementia. VCI is an umbrella term that includes all forms of cognitive deficits ranging from mild cognitive impairment of vascular origin (VaMCI) to vascular dementia (VaD). The new VCI construct takes into account the fact that in addition to single strategic infarcts, multiple infarcts, and leukoaraiosis, there are other mechanisms of cerebrovascular disease such as chronic hypoperfusion that might account for the pattern of cognitive deficits associated with vascular dementia. The key to defining the spectrum of VCI is neuropsychological testing, bedside or office-based clinical examination, and neuroimaging. The lack of specific cognitive tools that are sufficiently sensitive to detect subtle deficits makes the assessment of cognitive impairment difficult. Prospective cross-sectional and longitudinal studies of VCI from different settings are therefore required. Although there have been few published reports, behavioural and psychological symptoms (BPS) are inherently present in VCI from the onset and during the course of the disease. Besides the type of population (i.e. clinical, community or nursing-home settings), the definition of VCI/VaD and the instruments used, and differences in the prevalence and pattern of BPS between various studies, could be due to other, often unconsidered, factors such as gender, age, education, use of medication and VCI/VaD severity.

The Interrelation Between Chronic Headache, Cognitive Scores, and MRI Markers Among Stroke Survivors.

BACKGROUND: Migraine is known to mildly increase the risk for ischemic stroke and is associated with vascular MRI markers. However, the potential effect of chronic headache (CH) on stroke outcomes has not been studied. OBJECTIVE: We aimed to assess the interrelation between CH and post-stroke cognitive impairment. METHODS: Data from 455 patients with a first ever stroke from the TABASCO study was available. All patients underwent 3T brain MRI, blood analysis, and a serial cognitive assessment at baseline and 6, 12, and 24 months after. RESULTS: Eighty-five (18.7%) patients reported suffering from CH, of whom 53 (62.4%) reported symptoms of photophobia or nausea, and 34 (40%) reported an aura. CH was associated with female sex, lower prevalence of T2DM (p < 0.001), and lower HbA1C levels (p < 0.001). Multiple regression analysis, controlling for age, sex, education, vascular risk factors, and the presence of acute lesions in MRI, revealed that CH was an independent predictor of better cognitive scores 6, 12, and 24 months post-stroke (p = 0.015, p = 0.01, and p = 0.012, respectively). Stroke patients suffering from CH had also higher normalized gray, white matter, and thalamus volumes, and better white matter microstructural integrity (p < 0.001, p = 0.037, p < 0.001, p = 0.008, respectively)Conclusion:In this study, CH was consistently associated with better long term cognitive scores among post stroke subjects. These surprising findings may partially arise from the higher prevalence of T2DM among subjects without CH, that may represent the existence of chronic cerebrovascular disease, and may reflect mechanisms involving glucose metabolism.

Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes.

Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.

Can the RAVLT predict deterioration from MCI to dementia? Data from long term follow up.

OBJECTIVE: To assess whether the Rey Auditory Verbal Learning Test (RAVLT) could differentiate deterioration from Mild Cognitive Impairment (MCI) to dementia. METHODS: Twenty-six participants who were diagnosed with MCI performed the RAVLT and the Mini Mental State Examination (MMSE) at baseline and after nearly a decade (M = 8.8 years, SD = 3.16), in order to evaluate whether they progressed to dementia. RESULTS: Twelve participants [5 males, 7 females; age M = 63.7 (7.7)] kept their diagnoses of MCI; 14 participants [11 males, 3 females; age M = 75.0 (6.5)] converted to dementia. Both groups had similar MMSE scores at baseline [26.6 (0.6); and 26.6 (0.7) respectively]. Significant differences between dementia and MCI groups were found on most measures of the RAVLT at baseline: Immediate memory [p = .04], delayed recall [p = .003], total learning [p = .01], learning rate [p = .002], retrieval efficiency [p = .004], and false alarms [p = .004]. Thus, the RAVLT results were significantly worse at baseline in those who later converted. The results remain the same when controlling for age. CONCLUSION: The results extend previous findings with follow-up of nearly a decade demonstrating that most of the RAVLT measures are sensitive to differentiate conversion from MCI to dementia.

Creutzfeldt-Jakob and Vascular Brain Diseases: Their Overlap and Relationships.

Only a few case reports of stroke-like onset of Creutzfeldt-Jakob disease (CJD) have previously been published. We aimed to analyze the neurological, imaging, electroencephalographic (EEG), and laboratory features of patients with this very rare phenomenon. Here, we review the clinical characteristics, onset features, and clinical course variants of stroke-like CJD in 23 such patients. The median age of the patients was 71 years (range: 56-84 years); 12 were women. In 20 patients, CJD was sporadic. Thirteen patients developed apoplexy-like onset of symptoms, whereas the others had prodromal non-specific complaints. Most often the patients manifested with pyramidal signs (n = 13), ataxia (n = 9), and aphasia (n = 8). On MRI DWI sequence, all subjects had abnormal hyperintensities in various parts of the cerebral cortex, striatum, or thalamus, while EEG detected periodic triphasic waves only in 11. CSF 14-3-3 protein and total τ-protein were abnormal in 17 of 23 cases. All patients died, median lifespan being 2 months (range: 19 days-14 months). In conclusion, a complex of clinical, radiological, and laboratory manifestations of stroke-like onset of CJD is outlined. The clinical relationships between CJD and stroke are considered, in an attempt to highlight this rare presentation of an uncommon disease.

Towards a computerized estimation of visual complexity in images: Data to assess the association of computed visual complexity features to human responses in visual tasks.

Artificial vision has been extensively studied in the mathematical and computational Sciences. Concurrently, psychological studies attempt to describe visual cognition and the complexity of visual tasks as perceived by humans. The methods and the definitions of vision used by these two disciplines are disjointed. Particularly, an explanation of computer vision performance by human-perceived attributes, if attempted, can only be inferred. This article describes a dataset collected to explore the association between computer-extracted visual attributes and human-perceived attributes in the context of cognitive tasks. The data was acquired from a cohort of 406 subjects, ages 40-90, in the presence of a healthcare professional who assessed that the subjects had no cognitive or motor disorder. The subjects performed computerized cognitive tests which entailed tasks of recognition or recall of an image in a set of three images, presented on the computer screen. The images were simple black and white abstract square shapes. The latencies of the subjects' responses, by keyboard key press, to each task were logged. The data contains 3 parts: the images presented in each task, described by binary vectors for black and white coding, a response time logged for each task and the subjects' age, gender, and computer proficiency. A preliminary comparison of computationally-extracted complexity features and subjects' performance is provided in the article entitled "Linking computerized and perceived attributes of visual complexity" [1].

Atypical duration of epileptic and psychogenic nonepileptic events.

OBJECTIVES: We aimed to estimate the frequency of epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) with atypical duration in our epilepsy monitoring unit (EMU), in order to raise awareness of atypical durations of both types of events. MATERIALS & METHODS: We retrospectively reviewed all consecutive video-electroencephalogram (vEEG) recordings in our medical center's EMU from January 2013 to December 2017 and identified patients with seizures with atypical duration. Short PNES were defined as those lasting fewer than 2 min and long ES as those lasting for more than 5 min. RESULTS: The files of 830 adult (age >16 years) patients were reviewed, of whom 26 patients (3.1%, mean age: 33.3 ±â€¯9.8 years, 12 females) were diagnosed as having an unusual seizure duration. Among 432 patients with ES during monitoring, fourteen patients [3.2% (95% confidence interval (CI): 1.5%-5.0%), mean age: 33.0 ±â€¯12.2, 5 females [had long ES durations (exceeding 5 min). In 64% of patients with long ES, the events were provoked by antiepileptic drug (AED) withdrawal during vEEG, 62% had focal lesion on brain imaging, and 64% had a frontotemporal or a temporal seizure focus. Among 223 patients diagnosed with PNES, 12 patients [5.4% (95% CI: 2.2%-8.6%), mean age: 33.6 ±â€¯6.6, 7 females] had short PNES durations (less than 2 min) and demonstrated motor (9/12, 75%), altered responsiveness (6/12, 50%), and vocalization (5/12, 42%) as the most prominent clinical features. CONCLUSIONS: The data from our case files highlight two main considerations in the diagnosis of paroxysmal events: prolonged event can be due to ES, while short events can be psychogenic.

Familial Creutzfeldt-Jakob disease homozygous to the E200K mutation: clinical characteristics and disease course.

OBJECTIVE: To characterize the demographic, clinical features and disease course of familial Creutzfeldt-Jakob disease (fCJD) patients homozygous to the E200K mutation. METHODS: The Israeli National CJD Database was screened for patients homozygous to the E200K mutation. Patients' demographic data, clinical presentation and neurological findings, tau protein levels in the cerebrospinal fluid (CSF) and EEG, were assessed. RESULTS: Ten homozygous E200K patients were identified (80% males). Average age of onset was 47.5 ± 6.1 years (range 40-56) and the average age of death was 49.3 ± 7. 7 years (range 42-63) with average disease duration of 27.7 ± 9.7 months (range 2-97). Initial clinical presentation included behavioral change in 4/10 patients, cognitive decline in 3/10 patients and focal neurological deficits in 2/10 patients. Throughout the disease course, the clinical signs in descending order of prevalence included cerebellar (70%), brainstem (60%), extrapyramidal (50%), pyramidal (50%), frontal lobe signs (30%), and disturbances of ocular motility (30%) Compared to the 228 heterozygous E200K fCJD patients, the 10 homozygous patients were significantly younger at disease onset (47.5 vs 59.7 years, p < 0.001), had a longer disease duration (27.7 vs 8.5 months, p < 0.001) and presented more frequently with behavioral changes as initial manifestation (4/10 vs. 34/228, p = 0.05). CONCLUSIONS: Homozygous E200K fCJD patients are characterized by a relatively younger age of onset and longer disease duration. Behavioral changes as a presenting symptom were more common in homozygous patients and cerebellar dysfunction was the most common neurological manifestation throughout the disease course.

Management of mild cognitive impairment (MCI): The need for national and international guidelines.

Objectives: To review available evidence of pharmacological and non-pharmacological treatment for MCI and analyse information and limitations in national and international guidelines.Methods: Experts from several European countries conducted a qualitative review of the literature on MCI and treatments for MCI, as well as respective chapters in national and international guidelines on dementia/MCI. Psychotherapeutic/psychosocial treatments were excluded from the review.Results: Consensus diagnostic criteria for MCI are available, making early recognition and accurate classification of MCI subtypes possible. MCI can be identified in a primary care setting. Further corroboration and differential diagnosis should be done at specialist level. Mixed pathologies are the rule in MCI, thus a multi-target treatment approach is a rational strategy. Promising evidence has been generated for multi-domain interventions. Limited evidence is available for different pharmacological classes that have been investigated in MCI clinical trials (e.g. acetylcholinesterase inhibitors). EGb 761® improved symptoms in some clinical trials; it is the only pharmacological treatment recommended in existing guidelines for the symptomatic treatment of MCI.Conclusions: MCI is recognised as an important treatment target and some recent national guidelines have considered symptomatic treatment recommendations for MCI. However, more needs to be done, especially at an international level.