Papers by Georgios Koutsis
BMC Neurology, Oct 29, 2018
Background: Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of ... more Background: Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in Multiple Sclerosis (MS) patients compared to β-interferon. It acts against CD52, leading primarily to lymphopenia. Recent data have shown that mild neutropenia is observed in 16% of treated MS-patients whereas severe neutropenia occurred in 0.6%. Case presentation: Herein, we present the case of a 34-year-old woman with relapsing-remitting MS, with a history of treatment with glatiramer acetate and natalizumab, who subsequently received Alemtuzumab (12 mg / 24 h × 5 days). 70-days after the last Alemtuzumab administration, the patient displayed neutropenia (500 neutrophils/μL) with virtual absence of B-cells (0.6% of total lymphocytes), low values of CD4-T-cells (6.6%) and predominance of CD8-T-cells (48%) and NK-cells (47%); while large granular lymphocytes (LGL) predominated in the blood-smear examination. Due to prolonged neutropenia (5-days) the patient was placed on low-dose corticosteroids leading to sustained remission. Conclusion: This is the first case of a patient with relapsing-remitting MS with neutropenia two months post-Alemtuzumab, with simultaneous presence of LGL cells in the blood and a robust therapeutic response to prednisolone. We recommend testing with a complete blood count every 15 days in the first 3 months after the 1st Alemtuzumab administration and searching for large granular lymphocytes cell expansion on microscopic examination of the peripheral blood if neutropenia develops.
Clinical Neurology and Neurosurgery, 2022
BACKGROUND Hereditary angioedema (HAE) related to C1 esterase-inhibitor deficiency activates the ... more BACKGROUND Hereditary angioedema (HAE) related to C1 esterase-inhibitor deficiency activates the classic complement pathway and results to edematous crises. Although HAE is usually associated with multiple immunoregulatory disorders, neurologic manifestations are rare. CASE REPORT We report on the case study of a 33-year-old man diagnosed with HAE (SERPIN1G gene mutation) and multiple sclerosis (MS), followed up for at least 6 years. After a first clinical attack of HEA with scrotal edema, MS disease exacerbation was observed. Treatment with glatiramer acetate could not prevent either MS or HAE clinical attacks with recurrent exacerbations been observed. Remission of MS and significant amelioration of HAE attacks were achieved under fingolimod treatment. CONCLUSIONS Herein we provide long term evaluation of an extremely rare case of concomitant existence of HAE and MS and present the effects of MS current disease-modifying therapies in HAE attacks. Our case highlights the possible effect of fingolimod in immunoregulatory-mechanisms implicated in both diseases.
BMC Neurology, 2020
Background Baló’s Concentric Sclerosis (BCS) is a rare heterogeneous demyelinating disease with a... more Background Baló’s Concentric Sclerosis (BCS) is a rare heterogeneous demyelinating disease with a variety of phenotypes on Magnetic Resonance Imaging (MRI). Existing literature lacks data especially on the therapeutic approach of the disease which we intended to elucidate by means of suggesting a new possible BCS classification and introducing different therapeutic concepts based on each BCS-subgroup characteristics. Methods We present a retrospective study of eight treated patients with BCS-type lesions, emphasizing on MRI characteristics and differences on therapeutic maneuvers. Results Data analysis showed: at disease onset the BCS-type lesion was tumefactive (size ≥2 cm) in 6 patients, with a mean size of 2.7 cm (± 0.80 SD); a coexistence of MS-like plaques on brain MRI was identified in 7 patients of our cohort. The mean age was 26.3 years (±7.3 SD) at disease onset and the mean follow-up period was 56.8 months (range 9–132 months). According to radiological characteristics and...
Therapeutic Advances in Neurological Disorders, 2021
Aims:Our goal was to expand the spectrum of clinico-radiologic characteristics and the possible t... more Aims:Our goal was to expand the spectrum of clinico-radiologic characteristics and the possible therapeutic choices in patients with tumefactive demyelinating lesions (TDLs).Methods:A retrospective analysis of 50 patients with at least one TDL was performed at an academic neurology center (2008–2020).Results:Our cohort comprised mostly women (33/50) with a mean age of 38 years at TDL onset. The mean follow-up time was 76 months. The mean Expanded Disability Status Scale score at TDL onset and at the latest neurological evaluation was 3.7 and 2.3, respectively. We subcategorized the patients into seven groups based mainly on the clinical/radiological findings and disease course. Group A included patients presenting with a Marburg-like TDL ( n = 4). Groups B and C comprised patients presenting with monophasic ( n = 7) and recurrent TDLs ( n = 12), respectively. Multiple sclerosis (MS) patients who subsequently developed TDL ( n = 16) during the disease course were categorized as Group...
Journal of Neuroimmunology, 2021
We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin an... more We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.
Frontiers in Neurology, 2020
Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent ... more Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe a 50-year-old woman presenting with subacute onset of left hemiparesis, memory difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion with perilesional edema, mass effect and homogenous post-contrast enhancement, along with other small atypical lesions in the white-matter. Brain biopsy of cerebral lesion ruled out lymphoma or any other neoplastic process and patient placed on corticosteroids with complete clinical/radiological remission. Two years after disease initiation, there was disease exacerbation with reappearance of the tumor-like mass. The patient initially responded to high doses of corticosteroids but soon became resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance to therapeutic efforts led to a second biopsy that showed perivascular demyelination, predominantly consisting of macrophages, with a small number of T and B lymphocytes, and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient received high doses of cyclophosphamide with substantial clinical/radiological response but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with disease exacerbation and brainstem involvement. She eventually died with complicated pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions, with atypical tumor-like characteristics, with initial response to corticosteroids and cyclophosphamide, but subsequent development of drug-resistance and unexpected exacerbation upon rituximab administration. Our clinical case raises therapeutic dilemmas and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions with Marburg-like features.
Rheumatology International, 2020
IgG4-related disease (IgG4-RD) is a disorder with various clinical manifestations. Central nervou... more IgG4-related disease (IgG4-RD) is a disorder with various clinical manifestations. Central nervous system (CNS) involvement is well recognized, with hypertrophic pachymeningitis and hypophysitis being the most common manifestations. Spinal cord involvement is an extremely rare manifestation. We present the first case of an IgG4-RD patient with spinal cord parenchymal disease and concurrent hypophysitis. We review also the current literature about CNS parenchymal involvement in the context of IgG4-RD. A young female presented with clinical symptoms of myelitis. Cervical spinal cord magnetic resonance imaging (MRI) displayed features of longitudinally extensive transverse myelitis (LETM). Brain MRI showed a small number of high-intensity lesions in the deep white matter and enlargement of hypophysis with homogeneous gadolinium enhancement (asymptomatic hypophysitis). Diagnostic workup revealed elevated IgG4 serum levels (146 mg/dL). Our patient fulfilled the organ-specific diagnostic criteria of IgG4-hypophysitis. Treatment with intravenous glucocorticoids led to rapid clinical response, and to the substantial resolution of imaging findings. Azathioprine was used as a maintenance treatment. One relapse occurred 2 years after the initial diagnosis and patient was retreated with glucocorticoids. Three years after relapse, patient is in remission with azathioprine. We present the first case of myelitis with radiological features of LETM associated with increased IgG4 serum levels and the simultaneous presence of asymptomatic IgG4-related hypophysitis.
Journal of Neurology, Neurosurgery & Psychiatry, 2016
in HD datasets, each of them shedding particular light on transcriptional codes and network dynam... more in HD datasets, each of them shedding particular light on transcriptional codes and network dynamics in HD. We tested for HD sub-graphs that may be consistently highlighted by several of these mathematical formalisms and whether this may be linked to specific features of the HD process and translate into a more selective level of gene prioritisation. We will present data based on integrating two types of HD networks and discuss how network comparison methods may add value to systems modelling in HD.
Multiple Sclerosis and Related Disorders, 2017
Background: Spastic paretic hemifacial contracture (SPHC) is characterized by sustained unilatera... more Background: Spastic paretic hemifacial contracture (SPHC) is characterized by sustained unilateral contraction of the facial muscles associated with mild ipsilateral facial paresis. Rarely described in the context of multiple sclerosis (MS), it has never been reported as presenting symptom of MS. Case reports: Two patients developed SPHC within the context of a clinically isolated syndrome suggestive of MS. EMG revealed continuous resting activity of irregularly firing motor unit potentials, associated with impaired recruitment upon voluntary contraction. SPHC remitted fully in both patients. Conclusions: SPHC, a rare but distinct clinical and EMG entity, can occasionally be the presenting feature of MS.
Journal of the Neurological Sciences, 2017
Neuromyelitis optinca (NMO) represents a serious demyelinating disease of the central nervous sys... more Neuromyelitis optinca (NMO) represents a serious demyelinating disease of the central nervous system selectively attacking the spinal cord and optic nerve. Early differential diagnosis from multiple sclerosis is of vital importance, as NMO mandates immunosuppressive and not immunomodulatory treatment. Rituximab has been recently introduced as a treatment option for NMO. However, optimal surrogate measures and treatment intervals are still unclear. Five patients (females, mean age 54±10.21years) with NMO and NMO spectrum disorders (NMOSD) were evaluated with respect to disability and relapse rate. All patients were found positive for NMO IgG. All patients (three with NMO and two with NMOSD, 1 patient with recurrent optic neuritis and 1 patient with recurrent myelitis) had received rituximab treatment for six years. One patient with NMOSD received cyclophosphamide prior to rituximab while two were misdiagnosed as multiple sclerosis and had received interferon treatment. All received rituximab infusion of 375mg/m2 once per week for 4weeks and then every two months for the first two years and then every six months. B-cell counts were measured every two months and were kept in almost undetectable levels. No relapse was noted during the treatment period while EDSS score was improved in all patients. No severe adverse effects occurred during RTX treatment. Rituximab treatment on NMO and NMOSD patients showed significant improvement in disability and relapse-rate without any significant adverse effects.
Annals of Neurology, 2016
ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinoce... more ObjectiveThe polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases.MethodsWe assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study.ResultsIn the analysis of DNA repair genes ...
International Journal of Cardiology, 2016
Neurourology and Urodynamics, 2015
AimsBladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up ... more AimsBladder dysfunction is frequent during the course of multiple sclerosis (MS), observed in up to 75% of patients. Urinary symptomatology can be a feature of the first episode of MS in a minority of cases, and most often shows characteristics of an overactive bladder (OAB), with voiding symptoms seen less frequently, often in combination with OAB. The neural control of micturition is complex, involving systems located in the brain, spinal cord, and periphery, and implicating central noradrenergic, serotonergic, and dopaminergic activities. Urinary disorders are also linked to anxiety and depression, conditions connected to hypothalamus–pituitary–adrenal axis activity. In this study we aimed to investigate neurochemical and neuroendocrine correlates of bladder dysfunction in early MS.MethodsWe included 101 patients at first demyelinating episode suggestive of MS that were drug‐free at assessment. We evaluated the presence of urinary symptomatology and estimated CSF levels of the ma...
Case Reports in Medicine, 2011
A 45-year-old female suffering from severe thoracic pain was admitted to the emergency department... more A 45-year-old female suffering from severe thoracic pain was admitted to the emergency department of our hospital. Thorough clinical examination revealed paresis of the left lower limb and sensory deficit at the level of the Th4 vertebra. MRI of the thoracic spine demonstrated a lesion at the level of Th1–Th7. Despite initial improvement following i.v. corticosteroid administration, the patient's clinical status deteriorated, with recurrence of myelitis and extension of the lesion to Th12. She developed paraparesis, hyperreflexia and spasticity of both legs, symmetrical sensory deficit below Th4, and sphincter dysfunction. Differential diagnosis included infectious, metabolic, neoplastic/paraneoplastic, and ischemic causes as well as multiple sclerosis. NMO IgG was found positive and led to the diagnosis of longitudinal extensive transverse myelitis (LETM) in the NMO spectrum disorders. Administration of immunosuppressive therapy resulted in gradual improvement of the patient...
ISRN Neurology, 2013
Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinical... more Body weight and height of patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome suggesting MS (CIS) in the age range 18 to 60 years (154 males and 315 females) were compared with those of subjects (146 males and 212 females) free of any major neurological disease. In drug-free patients, CSF levels of the metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA), neurotransmitters involved in eating behavior, were estimated in searching for associations with body mass index (BMI). Statistical evaluations were done separately for males and females. Lower BMI was found in female MS patients compared to female controls, more pronounced in RRMS. BMI was not associated with duration of illness, smoking, present or previous drug treatment, or disability score. Body height showed a shift towards greater values in MS patients compared to controls. Patients in the lower BMI quartile (limits defined from control subjects) had lower 5-HIAA...
Autoimmune Diseases, 2014
Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with som... more Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P=.003) and female CIS patients (P=.001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients wi...
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2010
Reduced central serotonergic activity and low total serum cholesterol have been related to increa... more Reduced central serotonergic activity and low total serum cholesterol have been related to increased aggression, violent behavior, and suicidality. Searching for a correlation between them, we estimated serum total cholesterol and CSF levels of the main serotonin metabolite 5-HIAA in medication free male and female subjects for whom diagnostic lumbar puncture was performed. To eliminate age influence, we included in the study subjects in the age range 26 to 45 years. In a group of 62 subjects (30 males), found negative after diagnostic neurological examination, the correlation was not significant for the whole group, but after sex stratification, a significant positive correlation was revealed for males but not for females. These results were replicated in a second group of 76 subjects (31 males) with clinical and laboratory findings suggestive of multiple sclerosis (clinically isolated syndrome). The results link low cholesterol to low serotonergic activity only in males, predisposing them for violent and risky behaviors. This phenomenon could be seen as an evolutionary trait, possibly a result of the distinct role of males in a hunter-gatherer environment of evolutionary adaptedness, and may contribute to the understanding of the higher incidence of violent behavior observed in males.
Obesity, 2013
Neurotransmitter systems participate in the regulation of food intake, and their activities are e... more Neurotransmitter systems participate in the regulation of food intake, and their activities are expected to influence eating behavior. Design and Methods: We investigated possible associations between body mass index (BMI) and central noradrenaline, serotonin, and dopamine activities, as reflected by the cerebrospinal fluid levels of their main metabolites methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA), respectively. We studied 192 subjects (111 males, 81 females) admitted to neurologic clinic for diagnostic investigations that included CSF analysis, and were found not to suffer from any major neurological disease. Subjects were categorized in three groups, namely in lower, in the two middle, and in upper BMI quartiles, the limits calculated separately for males and females. Results: No differences were found in MHPG levels between groups, while subjects in the upper BMI quartile showed significantly elevated levels of 5-HIAA and HVA compared to the levels of subjects in lower and middle quartiles. Conclusions: The results provide evidence that in overweight subjects there are enhanced demands in serotoninergic and dopaminergic signaling for their reward system that may lead to increased motivation for food consumption. The implication of reward centers in eating behavior supports the hypothesis of common mechanisms in obesity and drug addiction.
Neurobiology of Aging, 2014
Genome wide association studies (GWAS) have been shown to be a powerful approach to identify risk... more Genome wide association studies (GWAS) have been shown to be a powerful approach to identify risk loci for neurodegenerative diseases. Recent GWAS in Parkinson's disease (PD) have been successful in identifying numerous risk variants pointing to novel pathways potentially implicated in the pathogenesis of PD. Contributing to these GWAS efforts, we performed genotyping of previously identified risk alleles in PD patients and controls from Greece. We showed that previously published risk profiles for Northern European and American populations are also applicable to the Greek population. In addition, while we were largely underpowered to detect individual associations we replicated 5 of 32 previously published risk variants with nominal pvalues <0.05. Genome-wide complex trait analysis (GCTA) revealed that known risk loci explain disease risk in 1.27% of Greek PD patients. Collectively, these results indicate that there is likely a substantial genetic component to PD in Greece similarly to other worldwide populations that remains to be discovered.
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Papers by Georgios Koutsis