Dysfibrinogenemia and multiple sclerosis: spuriously associated or causally linked?

BACKGROUND: The inherited dysfibrinogenemias comprise rare congenital coagulation disorders which are clinically characterized by bleeding diathesis and, in occasional patients, by thrombotic tendency or combined bleeding-thrombotic events. In recent years, accumulating evidence suggested that fibrinogen has a critical role in the pathogenesis of neuroinflammatory disorders, including multiple sclerosis. We describe the presentation and long-term follow-up of a patient with inherited dysfibrinogenemia and concomitant clinical and laboratory evidence of demyelinating disease.   Case description:  A 16-year-old male patient presented in 2003 with bilateral sensory symptomatology preceded by an episode of epistaxis. His past medical history included episodes of spontaneous nosebleeds as well as Duane syndrome and mild atrophy of the right upper limb. Coagulation testing of the patient and his asymptomatic father revealed in both the presence of a clotting defect, consistent with inherited dysfibrinogenemia (named Fibrinogen Thessaloniki). Within seven months, the patient presented with a new episode of motor semiology whereas serial brain magnetic resonance imaging (MRI) scans revealed T2 lesions with bilateral distribution, some of which with gadolinium enhancement. The cerebrospinal fluid examination disclosed the presence of oligoclonal bands in the central nervous system compartment. The patient was started on azathioprine (2.5 mg/kg/24h) which led to clinical and radiological stabilization for nine years. In 2013, the dose of azathioprine was reduced, due to an elevation of his amylase levels, resulting in radiological deterioration with an increased T2 lesion load. The reinstitution of azathioprine at therapeutic doses led to radiological improvement and clinical stability as of today. CONCLUSION: The described case of inherited dysfibrinogenemia and concomitant multiple sclerosis provides speculative evidence for a causal link, rather than a chance association, between these two entities. Further studies are warranted to corroborate this hypothesis in experimental and clinical settings. HIPPOKRATIA 2017, 21(1): 49-51.

Central motor pathways in tropical spastic paraparesis: a combined transcranial magnetic stimulation and diffusion tensor imaging study.

BACKGROUND: Previous transcranial magnetic stimulation (TMS) studies in patients with tropical spastic paraparesis (TSP) have focused on central motor conduction time measurements while other TMS parameters remained unexplored. From a neuroradiological point of view, pyramidal tract involvement with magnetic resonance imaging and diffusion tensor imaging (DTI) has been rarely reported in TSP.  Accordingly, the present study investigated the mean threshold (MT) and silent period (SP) as well as DTI measurements in TSP. CASE DESCRIPTION: A 35-year-old female patient presented with a 15-year history of spastic paraparesis with minimal upper-limb involvement. Serum and cerebrospinal fluid samples were positive for HTLV-I. TMS was performed with a figure-of-eight coil (recording, abductor hallucis and first dorsal interosseous muscles). Thr was measured at 1 % steps. SPs were elicited at 5 % increments from 0 to 100 % maximum stimulus intensity (SI), and data were used to construct a stimulus/response (S/R) curve of SI vs SP. The resulting S/R curves were fitted to a Boltzmann equation and statistically compared to control data. Voxel-based DTI analysis was performed with SPM 99. Corticospinal tractography was based on diffusion tensor data. The TMS examination disclosed that MT was significantly increased (54.5 ± 6.36 % vs 41.08 ± 7.85 % in a group of 82 controls, p=0.019). The patient's SP S/R curve had significantly reduced Max values compared to 13 age-matched controls (160.4 ± 0.91 ms vs 228.36 ± 38.69 ms, p <0.001). Fractional anisotropy was decreased in a cluster of voxels corresponding to the area of the pyramidal tract (0.388 ± 0.015 vs 0.506 ± 0.02 in 20 age-matched controls, p <0.001). CONCLUSION: The described results provide novel neurophysiological and imaging evidence for central motor pathways malfunctioning in TSP. HIPPOKRATIA 2017, 21(4): 191-193.

The Hemiconvulsions-Hemiplegia-Epilepsy (HHE) syndrome: a transcranial magnetic stimulation-EEG study.

BACKGROUND: The Hemiconvulsions-Hemiplegia-Epilepsy (HHE) syndrome is currently regarded as an extremely rare condition. The etiological and pathophysiological mechanisms underlying this medical rarity as well as the optimal therapeutic approaches remain poorly defined and understood. We present the clinical, radiological and electroencephalography (EEG) findings of a patient with the HHE syndrome and describe the response of the continuously present epileptiform abnormalities to transcranial magnetic stimulation (TMS). CASE DESCRIPTION: A 33-year old male patient was referred to our department for investigation and management of intractable epilepsy. His seizures began at the age of three months when, during the course of a common febrile illness, he developed repetitive clonic seizures involving the left upper and lower limbs, followed by permanent left hemiplegia. After extensive investigations, he was diagnosed with "idiopathic" HHE syndrome. Currently, he suffers from left hemiplegia, severe intellectual impairment [Intelligence Quotient (IQ) <30] and asymmetric, bilateral tonic seizures occurring 1-3 times daily despite treatment with valproate, topiramate, lamotrigine, rufinamide, and perampanel. Brain magnetic resonance imaging revealed atrophy of the right hemisphere and serial EEGs disclosed continuous sharp waves, the generators of which were localized by electrical source imaging (ESI) to two distinct sources within the right hemisphere. Repetitive TMS [210 stimuli of 1 Hz at 100 % corticomotor threshold applied with a circular coil over the generators of epileptic discharges (EDs)] resulted in a statistically significant decrease of ED counts compared to sham stimulation and the post-verum TMS period. CONCLUSION: We present the clinical-laboratory profile and the long-term follow up of a patient with the HHE syndrome. Further, we describe the effects of TMS on EDs. The latter observation raises the possibility that TMS-EEG may be used in select cases with intractable epilepsy as a surrogate marker of responsiveness to more invasive modalities (i.e., cortical stimulation). HIPPOKRATIA 2017, 21(2): 101-104.

Ultrastructural aspects of the effects of L-carnitine administration on epithelial cells in the aging rat tongue.

BACKGROUND: The investigators hypothesized that degenerative changes accumulate in epithelial cells in the aging rat tongue and that carnitine administration is effective at reversing these alterations. MATERIAL AND METHODS: To gain insights into the effects of carnitine on epithelial cells of the tongue, the investigators used 15 Wistar rats [3 experimental groups: 5- (A), 12- (B) and 18- (C) month old rats] with 4 rats per group and 1 control group with 1 rat per age group). L-carnitine was administered intraperitoneally to animals of the experimental group for 35 days. Samples of the tongue were processed for electron microscopy. RESULTS: Degeneration of epithelial cells of the rat tongue was shown to begin early in life (5 months) and alterations were shown to accumulate while aging. L-carnitine administration eliminated degenerative changes when administered in the first age group A, while in the older rats the regeneration was only partial for the epithelium (groups B and C). CONCLUSIONS: The results of this study suggest that profound ultrastructural alterations commence in the degenerating rat tongue and that L-carnitine administration results into partial regeneration of epithelial cells.

Cognitive event-related potentials: longitudinal changes in mild cognitive impairment.

OBJECTIVE: To measure changes over time in the latency and amplitude of the major waves of auditory event-related potentials (AERP) and their correlation with the memory status of patients with mild cognitive impairment (MCI). METHODS: AERPs were recorded in 22 MCI patients (mean±SD age=67.4±7.8, median (interquartile range-IQR) MMSE score=28 (27-29) in three consecutive exams and in 30 age-matched controls at baseline. During this time period, 3 patients converted to Alzheimer disease (AD). Latencies and amplitudes of N200, P300 and Slow Wave and the N200-P300 peak-to-peak amplitudes and latencies were determined, and correlation coefficients (CC) between them and MMSE scores were calculated. RESULTS: A significant increase in the P300 latency and a decrease in the N200 amplitude were observed between the exams. Only N200 latency correlated with baseline MMSE scores, whereas P300 and Slow Wave latencies correlated with age. CONCLUSIONS: N200 amplitude is more sensitive in identifying differences over time at the early stages of the disease, whereas P300 latency at later stages. SIGNIFICANCE: A new N2-P3 inter-peak index that incorporates changes in N200 and P300 latencies and amplitudes into a single parameter is introduced in order to adequately describe the gradual progress of MCI and its transition to AD.

Consensus statement on dementia education and training in Europe.

OBJECTIVES: The aim of the current statement is to agree on: (1) what is the current situation with education and training on dementia in Europe; (2) what are the minimum educational requirements for professionals (neurologists, psychiatrists, primary care providers, nurses, biologists, neuroradiologists, etc.) regarding Alzheimer's disease and dementia, and (3) how to start a course of action for the future. DESIGN: In 2005, a simple questionnaire was sent to members of the European Alzheimer's Disease Consortium (EADC) concerning the education and training on dementia in their countries. Fourteen universities of the respective countries responded to this simple questionnaire. The answers varied, and the conclusion of this effort was that little was done concerning the training of students and health professionals on dementia. In 2008, another more structured and specified questionnaire was sent to professors in different universities of the same countries. RESULTS: The answers obtained were different from those of the previous questionnaire and demonstrated that it is very difficult to know about training and education in the field of dementia in every European country. CONCLUSION: From the data collected, it seems that although in the recent past little had been done concerning training on dementia, nowadays training has been developed in most European countries, and relevant educational projects exist both for medical students and doctors during their specialty training. Our main purpose is to develop training material or develop specific courses to improve the professional knowledge about dementia so that best medical and non-medical practice is implemented.

Combination of P300 and CSF ß-amyloid(1-42) assays may provide a potential tool in the early diagnosis of Alzheimer's disease.

BACKGROUND/AIMS: The aim of this study was to investigate the diagnostic role of CSF beta amyloid(1-42) levels and auditory event-related potentials (AERPs) in the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). METHODS: In fifty three MCI patients a lumbar puncture was performed and beta amyloid(1-42) levels were determined. Twenty patients were re-examined after 11 months. During this period five of them progressed to AD. Neuropsychological and ERP examinations were performed in all patients at both exams. RESULTS: Compared to MCI stable patients, AD-converters showed significantly lower beta-amyloid(1-42) values both for group 1 (Mann Whitney test, Z=-2.952, p=0.003, effect size r=-0.41) and group 2 (Z=-2.458, p=0.011; effect size r=-0.55). On the other hand, the patients of group 1 who converted to AD had prolonged latencies and lower amplitudes of the P300 wave compared to those of the MCI-stable patients, although the differences were not significant. CONCLUSIONS: Compared to the separate use of CSF beta-amyloid(1-42) and AERPs, higher values of sensitivity and specificity were achieved by the combined use of beta-amyloid(1-42) levels and P300 latencies (80% and 98%) or amplitudes (100% and 89%) in the discrimination between AD converters and MCI stable patients. Therefore the combination of an electrophysiological and a biological marker is potentially of high diagnostic value for the early diagnosis of AD converters.

Prediction of conversion from mild cognitive impairment to Alzheimer's disease by CSF cytochrome c levels and N200 latency.

The aim of the present study was to investigate the role of CSF cytochrome c levels and auditory event-related potentials (AERPs) on the progress of mild cognitive impairment (MCI) to Alzheimer's disease (AD). Fifty one patients diagnosed with MCI and fourteen healthy individuals underwent lumbar puncture at baseline and their CSF cytochrome c levels were determined. A follow-up examination of cytochrome c levels took place in 20 patients after 11 months and in this period five of the patients progressed to AD. ERP examinations were also performed in all patients both at baseline and follow-up. MCI patients had significantly higher cytochrome c levels compared to healthy controls (Mann-Whitney test, Z=-2.110, p=0.018). Compared to MCI patients who remained stable, the AD-converters, had a higher increase over time in cytochrome c levels (Mann-Whitney test, p=0.002; effect size r=0.63) and significantly prolonged N200 latency (Mann-Whitney test, p<0.001; effect size r=0.50). Amongst investigated ERP variables, only N200 amplitude was significantly correlated with CSF cytochrome c levels (rs=0.310, p=0.03). Both parameters were proved capable of discriminating AD converters from those MCI patients who remained stable, with sensitivity and specificity >75%. Our results suggest that conversion from MCI to AD is associated with a marked elevated N200 latency at baseline and a high increase in cytochrome c levels during a relatively short period of time, and that both parameters could be possibly considered as candidate markers for the discrimination between MCI patients who convert to AD and those who remain stable.

The proteins and the mechanisms of apoptosis: a mini-review of the fundamentals.

Apoptosis or programmed cell death is a physiological mechanism, characterized by specific morphological and biochemical changes such as cell shrinkage, chromatin condensation, protein cleavage, DNA breakdown and phagocytosis. Apoptosis is a significant contributor to the morphologic and functional development of multicellular organisms. It is also involved in the pathogenesis of several diseases including degenerative diseases of the central nervous system (CNS) like Alzheimer's disease or Parkinson's disease, cancer and immune system dysfunction. There are many factors, mainly proteins, which are involved in the activation, regulation and execution of related events. A fairly detailed outline of apoptotic mechanisms has also started to emerge and to be verified. In this short, focused mini-review, we attempt to outline current evidence regarding the mechanisms and the regulation of apoptosis.