Iakovos Tsiptsios

Gastrointestinal Immune System and Brain Dialogue Implicated in Neuroinflammatory and Neurodegenerative Diseases

A common characteristic of the central nervous system (CNS) neurodegenerative disorders is neuroinflammation, marked by augmented numbers of activated and primed microglia, increased inflammatory cytokines and decreased anti-inflammatory molecules. CNS neuroinflammation is a critical component in the progression of several neurodegenerative diseases which sensitize the brain to produce an exaggerated response to immune stimuli in the periphery. Neuroinflammation might initiate from the periphery and peripheral conditions through disrupted blood-brain barrier powerfully influence various brain pathologies. Gastrointestinal tract (GIT) represents a vulnerable area through which pathogens influence the brain and induce CNS neuroinflammation. The pathogens may access the CNS through blood, the nasal olfactory pathways and the GIT. Potential GI pathogens, such as Helicobacter pylori, induce humoral and cellular immune responses that, owing to the sharing of homologous epitopes (molecular mimicry), cross-react with CNS components thereby contributing and possibly perpetuating neural tissue damage. GIT is strictly connected to the CNS and a bi-directional communication exists between them. The brain is involved in regulating the immune and gut system. Conversely, limited attention has been paid on the GIT role in the development and regulation of the CNS autoimmune diseases. The GIT is the primary immune organ with specialized immunoregulatory and anti-inflammatory functions, represented by the gastrointestinal immune system (GIS). This review focuses on the potential GIS and brain dialogue implicated in neurodegenerative diseases. Gaining a better understanding of the relationship between GIS and CNS could provide an insight on the pathogenesis and therapeutic strategies of these disorders.

Familial prevalence of autoimmune disorders in multiple sclerosis in Northern Greece.

Objective: The objective of this study was to evaluate for up to 7 years the prevalence of autoimmune disorders among naïve (untreated) multiple sclerosis family members compared with a contemporary general control population in Northern Greece, in a prospective case-control study, and to examine the possible relationship between immunomodulatory treatment and the appearance of additional autoimmune disorders. Methods: The patients and controls enrolled comprised 1383 patients with definite MS and 4392 relatives in their families and a total of 452 controls families with 1652 members. Results: At baseline, 891 multiple sclerosis families with 3112 members (73 multiplex multiple sclerosis families with 292 members and 818 simplex families with 2820 members) and 355 control families with 1580 members were examined regarding whether they had any of 12 autoimmune diseases. The baseline affected multiplex plus simplex multiple sclerosis families, the family members and the coexistent additional autoimmune disorders were higher compared with controls. There was an increase in longitudinally affected multiple sclerosis families, multiple sclerosis family members and coexistent additional autoimmune disorders compared with respective findings at the baseline observation. Comparison analysis between two time point observations (after a mean 7.1 ± 2.2 years) for each autoimmune disorder in overall multiple sclerosis family members revealed increased rates for longitudinal autoimmune Hashimoto’s thyroiditis, Graves’ disease, insulin-dependent diabetes mellitus, psoriasis and vitiligo (p = 0.02, p = 0.006, p = 0.0004, p = 0.05, and p = 0.05, respectively). Some 145 newly developed, longitudinally definite autoimmune cases were recognized in multiplex plus simplex multiple sclerosis families; 116 (80%) of these disorders were observed in patients with multiple sclerosis treated with immunomodulatory medications, and 68 of these 116 (58.6%) cases exhibited baseline positive autoreactive antibodies. Binary logistic regression analysis revealed that immunotherapy predisposes to autoimmunity (odds ratio 2.8, p < 0.001) independently of the presence of baseline autoantibodies and patients’ gender. Conclusions: There is a longitudinally increased frequency of additional autoimmune disorders among multiple sclerosis family members, probably related to immunomodulatory therapy.

Feasibility and safety of intravenous thrombolysis for acute ischaemic stroke in northern Greece.

Intravenous tissue plasminogen activator (IV-TPA) is the only approved therapeutic agent for acute ischaemic stroke (AIS) within 3 h of stroke-onset (1). Data regarding intravenous thrombolysis for AIS in Greece are scarce and exclusively limited to 48 patients enrolled from three centres in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) (2). Moreover, there was no Greek centre participating in the European Cooperation Acute Stroke Study (ECASS) (3) or ECASS II (4), while only two patients were enrolled from Greece in ECASS III (5). After the completion of SITS-MOST, we aimed to evaluate the safety and feasibility of IV-TPA in AIS patients hospitalised in public health care facilities (funded by the Greek National Health Service) in Northern Greece. Consecutive patients presenting with symptoms of acute cerebral ischaemia were treated with IV-TPA (0 9 mg/kg, 10% bolus, maximum dose 90 mg) according to the SITS-MOST criteria (2) in two tertiary care centres in Northern Greece (Thessaloniki and Alexandroupolis) over a two-year period (2008–2009). One centre (Thessaloniki) had previous experience in intravenous thrombolysis and had enrolled previously 15 patients in SITS-MOST. Intravenous thrombolysis was not implemented as a potential therapy for AIS in any other public hospital in Northern Greece during the study period. Baseline stroke severity was assessed using the NIH Stroke Scale (NIHSS). All patients treated with IVTPA underwent a brain CT-scan at 22–36 h posttreatment independent of potential neurological deterioration. Symptomatic intracranial haemorrhage (sICH) was defined (per the SITSMOST protocol) as local or remote parenchymal haemorrhage (on the 22– 36 h posttreatment brain CT-scan) combined with a neurological deterioration of 4 points or more on the NIHSS-score from baseline, or from the lowest NIHSS value between baseline and 24 h, or leading to death. Asymptomatic intracranial haemorrhage (aICH) was defined as evidence of intracranial bleeding on the 22–36 h posttreatment brain CT-scan (3–5). Functional independence at three-months was evaluated using the modified Rankin Scale (mRS) score. Patients with an mRSscore of 0–2 were considered as functionally independent (2, 6). A total of 31 patients were treated with IV-TPA (mean age 58 2711 7-years, 61% men) during the study period (24 patients from Thessaloniki and seven patients from Alexandroupolis). The median onset-to-treatment time approached 212 h (145 min, interquartile range 130–168), while the median NIHSS-score at baseline was 8 points (interquartile range 6–11). The sICH did not occur in any patient (0%, 95% CI by the adjusted Wald method: 0–9 6%). The rate of aICH was 3 2% (n 5 1; 95% CI by the adjusted Wald method: 0–17 6%). There was no neurological deterioration related to the detection of haemorrhagic infarct type 1 changes on posttreatment brain CT-scan in the only patient with aICH. The rate of functional independence at three-months was 77 4% (n 5 24; 95% CI by the adjusted Wald method: 59 9–88 9%), while an mRSscore of 0–1 was achieved in 23 patients at the three-month follow-up evaluation (74 2%; 95% CI by the adjusted Wald method: 56 5–86 5%). A total of four patients died during the three-month follow-up period. The cause of death was neurological deterioration due to malignant middle cerebral artery infarction in two cases, myocardial infarction in one individual and severe congestive heart failure in the remaining fourth patient. The three-month mortality rate was 12 9% (95% CI by the adjusted Wald method: 3 6–29 8%). The median NIHSS-score reduction at hospital discharge (from the baseline NIHSS-score) was 5 5 points (interquartile range 4–7 5). The present findings are comparable to those reported by SITS-MOST investigators (Table 1) and underscore the safety of intravenous thrombolysis in everyday clinical practice outside the rigorous setting of a phase III (5) or IV (2) clinical trial. It is of note that we treated young patients with lower stroke severity AIS compared with the SITS-MOST cohort. Our encouraging preliminary experience regarding the feasibility and safety of intravenous thrombolysis for the management of AIS supports further initiatives among Greek stroke physicians to develop its wider implementation in the treatment of acute cerebral ischaemia.

Headache patients in the emergency department of a Greek tertiary care hospital

The aim of this study was to record the demographic and epidemiological data on adult patients with headache who attend the emergency department (ED) and the diagnoses that made by the neurologists in the ED of a tertiary care hospital in metropolitan Thessaloniki (Greece). In an open prospective study, demographic and epidemiological data were collected on all patients who reported headache (as chief complaint or not) and presented to the ED of Papageorgiou Hospital between August 2007 and July 2008. Headache patients accounted for 1.3% of all ED patients and for 15.5% of patients primarily referred to the ED neurologist. Tension type headache was the most frequent diagnosis, followed by secondary headaches and migraine. The large number of patients without final ED diagnosis and ward admission for further evaluation sheds a light on the immense workload of Greek ED physicians. Furthermore, we found evidence for the misuse of Emergency Medical Services by chronic headache patients. These findings indicate shortcomings in the pre-hospital (primary care) management of headache patients in the Greek National Health System to an extent unreported so far.

Impaired executive functioning after left anterior insular stroke: a case report

Given the insular’s anatomic complexity and functional interconnectivity, acute lesions may result in varied clinical presentations, including autonomic, somatosensory, perceptual, motor, affective, and cognitive deficits. Although functional neuroimaging studies have demonstrated its role in executive functions, no clinical manifestations have been reported to date. We present the case of a woman with an acute left anterior insular infarction leading to executive (i.e., word and design fluency, mental flexibility, sustained attention, inhibitory control), but not language, visuoperceptual, or memory impairment. This case confirms the left anterior insula’s involvement in executive functioning and suggests that an infarction may result in executive impairment.

Workload of the emergency room neurologists and the neurological inpatient department in a Greek tertiary care hospital

BACKGROUND Data concerning the number of patients presenting to the emergency room (ER) and the workload in the departments in the European Union countries are scarce. In contrast to most European practice, Greek public hospitals in cities with more than one public health facilities are on-call not on a daily, but on a rotational basis. Exact data from Greece on the number of patients referred to the ER or the number of patients admitted to regular inpatient departments of the public hospitals under these conditions is lacking. PATIENTS AND METHODS From February 1st, 2006 to January 31st, 2007, we performed an open prospective study on the workload at the ER as well as the inpatient department of the Neurological Clinic of Papageorgiou General Hospital in Thessaloniki, Greece. In addition, we performed an analysis of the number of inpatient admission to the Department of Neurology per trimester from January 1st, 2002 until March 31st, 2008. RESULTS During the study period, a total of 5901 patients required neurological examination in the ER (8.75% of all ER patients). In parallel, 2054 patients were admitted to the neurological ward for hospitalization exceeding 24h with a mean hospitalization of 3.95 days. CONCLUSION These data suggest that the workload of a tertiary care neurological in- and outpatient department is large. More research is needed to determine the impact this has on patient outcomes.

Familial case of speech-induced tongue-protrusion dystonia

Lingual dystonia is a rare type of focal dystonia. In clinical practice, it is typically observed in tardive dystonias or other secondary/heredo-degenerative dystonias in disorders such as neuroacanthocytosis, pantothenate kinase-associated neurodegenerations, neuroferritinopathy, or Wilson’s disease. Primary lingual dystonia induced by speaking is usually idiopathic in origin and is characterized by increased tonus of the tongue, which causes protrusion only during speaking. We present a familial form of dystonia in 2 siblings, in which speech-induced primary lingual dystonia remained the only clinical feature for many years until it slowly progressed to multifocal dystonia. Potential genetic susceptibility factors for primary focal dystonia were investigated.

Long-term lack of progression after initial treatment of idiopathic hypertrophic pachymeningitis

Idiopathic hypertrophic cranial pachymeningitis (IHCP) is a rare inflammatory disease which is sometimes difficult to diagnose and can lead to misinterpretations of the clinical and imaging findings. The main clinical manifestations are headache, ataxia and cranial nerve palsy. In most of the reported patients continuous medication is needed to avoid disease recurrence. We present a female patient with an 8-year follow-up, no clinical regression and no need for any further medical treatment. Even though most patients with IHCP experience recurrence after diagnosis and initial treatment there were no clinical or imaging signs of relapse in our patient. Our patient is still not under any medical or surgical treatment due to the lack of any significant symptoms.

Intravenous thrombolysis for acute ischaemic stroke - results from 25 patients treated in a Greek tertiary care hospital

In 2003, the EMEA approved the use of intravenousthrombolysis with rt-PA (Actilyse®) for therapy of acuteischaemic stroke within three hours from system onset,under the condition that these patients are treated accord-ing to the SITS-MOST protocol (Safe Implementation ofThrombolysis for Stroke - MOnitoring STudy - http://www.acutestroke.org) and referred to the SITS-MOST reg-istry. Since then, thrombolytic treatment is offered tostroke patients in Greece in a limited number of centers.

Multiple sclerosis, idiopathic dilated cardiomyopathy, and insulin-dependent diabetes mellitus: a common mechanism of irregular immune regulation.

BackgroundMultiple sclerosis (MS), idiopathic dilated cardiomyopathy (DCM), and diabetes mellitus-1 (DM-1) are polygenic autoimmune diseases with a pivotal autoimmune component affecting young adults. They share a number of characteristics, thereby suggesting common underlying pathways or mechanisms. Typically, the aforementioned diseases are organ-specific autoimmune disorders of unknown etiology, but with strong evidence of tissue-destructive activity of the humoral and/or cellular immune system in the end-organ tissues affected (ie, the myelin components in MS, the myocytes of myocardium in DCM, and the insulin-secreting &bgr; islets in DM-1). Case ReportWe herein describe a 35-year-old white Greek man who presented with coexisting MS, DCM, and DM-1 diagnosed over a period of 7 years. The patient was successfully treated and is asymptomatic until present time. ConclusionThe clustering of these 3 autoimmune diseases in our patient supports the concept of an immune-mediated damage in these diseases, an important aspect for an effective therapeutic choice by neurologists. However, the immunopathogenetic association between MS and other autoimmune remains speculative, thereby warranting further clarification.