A case of Alemtuzumab-induced neutropenia in multiple sclerosis in association with the expansion of large granular lymphocytes.

BACKGROUND: Alemtuzumab has been demonstrated to reduce the risks of relapse and accumulation of sustained disability in Multiple Sclerosis (MS) patients compared to ß-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.

Treatment of neuromyelitis optica and neuromyelitis optica spectrum disorders with rituximab using a maintenance treatment regimen and close CD19 B cell monitoring. A six-year follow-up.

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.

Pulsed corticosteroid treatment in MS patients stabilizes disease activity following natalizumab withdrawal prior to switching to fingolimod.

PURPOSE: Interruption of natalizumab (NTM) treatment in multiple sclerosis (MS) patients may be followed by disease reactivation. On the other hand, patients with positive John Cunningham virus (JCV) antibodies treated with NTM over 24 months demonstrate a higher risk for developing progressive multifocal encephalopathy (PML). No established therapeutic approach is available for treating these patients to prevent disease reactivation. MATERIALS AND METHODS: Of the MS patients treated with NTM at the authors' institution, 30 were found positive for JCV abs. NTM was interrupted followed by a washout period of 6 months. During this period, 20/30 patients received monthly intravenous (i.v.) methylprednisolone (MPD) 1000 mg infusion and regular clinical assessment. On months 3 and 6, brain MRI was performed and 1000 mg MPD was administered for 5 days. RESULTS: All patients were clinically and radiologically stable at the time of NTM break. No clinical relapse was observed during the six-month washout period for the MS patients under monthly MPD treatment, while one patient had a relapse and active lesions in the MRI on month 6. Of the other patients not receiving i.v. MPD regularly after NTM withdrawal, one showed several active lesions in brain MRI and the other had a severe relapse. CONCLUSIONS: Despite the limited size of this patients' cohort, the results of this study support that monthly MPD treatment for 6 months may result in a clinically stable disease status, thus ensuring safe transition to another second-line therapy such as fingolimod, following NTM withdrawal.

Silver(I) complexes of N-methylbenzothiazole-2-thione: synthesis, structures and antibacterial activity.

Three silver(I) complexes containing N-methylbenzothiazole-2-thione (mbtt) have been prepared and structurally characterized by X-ray single-crystal analysis. Silver(I) nitrate, and silver(I) triflate react with mbtt to give homoleptic complexes of formula [(mbtt)2Ag(µ-mbtt)2Ag(mbtt)2](NO3)2 (1) and [Ag(mbtt)3](CF3SO3) (2) respectively, while silver(I) chloride gives the binuclear halide-bridged [(mbtt)2Ag(µ2-Cl)2Ag(mbtt)2] (3). In the binuclear complex 1 the two metal ions, separated by 3.73 Å from each other, are doubly bridged by the exocyclic S-atoms of two mbtt ligands, with the tetrahedral environment around each silver ion being completed by the S-atoms of two terminally bonded mbtt units. Compound 2 is mononuclear with the metal ion surrounded by the exocyclic S-atoms of three mbtt ligands in a nearly ideal trigonal planar arrangement. The new complexes showed significant in vitro antibacterial activity against certain Gram-positive and Gram-negative bacterial strains.

Intermittent Atrioventricular Block following Fingolimod Initiation.

A 47-year-old female patient with multiple sclerosis (MS) developed symptomatic intermittent 2nd degree atrioventricular block (AVB) of five-hour duration, five hours after the first two doses of fingolimod, that resolved completely. Frequency domain analysis of heart rate variability (HRV) revealed increased parasympathetic activity and decreased sympathetic tone, while modified Ewing tests were suggestive of impaired cardiac sympathetic function. We hypothesize that expression of this particular arrhythmia might be related to autonomic nervous system (ANS) dysfunction due to demyelinating lesions in the upper thoracic spinal cord, possibly augmented by the parasympathetic effect of the drug.

Prevalence of cerebrospinal fluid oligoclonal IgG bands in Greek patients with clinically isolated syndrome and multiple sclerosis.

UNLABELLED: Lower prevalence of cerebrospinal fluid oligoclonal IgG bands (IgG-OCBs) has been reported in multiple sclerosis (MS) patients from Southern Europe compared to other western countries. OBJECTIVES: We aimed to determine the prevalence of CSF OCBs in Greek MS patients and to examine their relation with some selected clinical and demographical features. METHODS: Included patients fulfilled the 2005 McDonald criteria for definite MS (CDMS) or clinically isolated syndrome (CIS) and had a spinal tap performed between 2006 and 2010. Paired CSF and plasma samples were analyzed using isoelectric focusing followed by IgG-specific immunofixation. A pattern of two or more bands present only in the CSF was defined as positive. OCB status was correlated with age at disease onset, initial symptomatology, relapse rate, disease subtype, disease duration, medication, EDSS score and MSSS. RESULTS: Of the 231 included patients (53.2% with CDMS and 48.6% with CIS) 67.5% had OCBs. The prevalence of positive patterns did not differ between CIS and CDMS patients (67.6% vs. 67.5%, respectively). OCB-positive patients were younger than OCB-negative patients (35.2±10.3 vs. 38.7±11.8 years respectively, p=0.022) and had more frequently cervical spinal cord lesions (x2=7.08, p=0.008). No difference was observed between the two subgroups in the other studied disease parameters. CONCLUSION: Despite the lower frequency of positive IgG-OCB patterns in our patients, both subgroups were mostly similar with regard to their clinical and demographic characteristics suggesting that the OCB status lacks prognostic significance in MS.

Demyelinating Disease following Anti-TNFa Treatment: A Causal or Coincidental Association? Report of Four Cases and Review of the Literature.

Tumor necrosis factor antagonists (anti-TNFa) are an established therapeutic option for several autoimmune and inflammatory bowel diseases. Despite their clinical effectiveness, neurological adverse events have been reported and literature data suggest a potential role of anti-TNFa in the induction of demyelination of the CNS. We present four patients treated with anti-TNFa who developed symptoms suggestive of CNS demyelination. The first patient, a 17-year-old male who received etanercept for psoriatic arthritis for eight months, presented with dysesthesias up to T4 level. The second patient, a 30-year-old male treated with adalimumab for three years due to ankylosing spondylitis, presented with right unilateral tinnitus. The third case, a 47-year-old female, received etanercept for four years because of psoriatic arthritis and developed persistent headache and left-sided face and head numbness. Finally, the fourth patient, a 57-years-old female treated with etanercept for six years due to ankylosing spondylitis, presented with difficulty in speech, swallowing, and ptosis of the right corner of the mouth. In all cases, brain MRI showed lesions suggestive of demyelination, while positive oligoclonal bands were detected in the CSF. Anti-TNFa treatments were discontinued and patients showed clinical improvement with pulsed intravenous corticosteroid therapy. CNS demyelination following anti-TNFa treatment represents a relatively rare but potential serious complication. Close follow-up and MRI monitoring of these patients is mandatory to elucidate whether the clinical manifestations represent adverse events occurring during anti-TNFa therapy or a first demyelinating episode.

Copper(I) halide complexes of N-methylbenzothiazole-2-thione: synthesis, structure, luminescence, antibacterial activity and interaction with DNA.

The reactions of copper(I) halides, CuX (X=Cl, Br, I) with N-methylbenzothiazole-2-thione (mbtt), independent of the molar ration chosen (1:2 or 1:3), led to the formation of dinuclear complexes of the formula [CuX(mbtt)2]2, whereas the reactions of CuX and mbtt in the presence of two equivalents of triphenylphosphine (PPh3) afforded mononuclear mixed-ligand complexes of the formula [CuX(PPh3)2(mbtt)]. The molecular structure of a representative compound from each of the two above types of complexes, namely [CuCl(mbtt)2]2 and [CuI(PPh3)2(mbtt)] have been established by single-crystal X-ray diffraction. The new complexes are strongly emissive both in the solid state and in solution. The complexes were also screened for antibacterial activity and their ability to interact with native calf thymus DNA (CT-DNA) in vitro. Both types of complexes showed significant activities against all the bacteria tested as compared to that of standard antibiotic ampicillin, however, the three mixed-ligand complexes including triphenylphosphane as ligand exhibited perceptibly stronger antibacterial activity than the three homoleptic ones possessing only the mbtt ligand. DNA electrophoretic mobility experiments showed that all complexes bind to CT-ds DNA resulting in high molecular weight complexes ending in DNA degradation.

Anti-myelin-associated glycoprotein polyneuropathy coexistent with CREST syndrome.

Clinical involvement of the peripheral nervous system in the calcinosis cutis, raynaud's phenomenon, esophageal dismotility, sclerodactyly and telangiectasia (CREST) variant of systemic sclerosis occurs infrequently and is characterized by axonal degeneration due to necrotizing vasculitis. We report a female patient with a known history of CREST syndrome, which developed a slowly progressive, distal symmetric demyelinating sensorimotor polyneuropathy (PN), with tremor and ataxia as prominent features, compatible with anti-myelin associated glycoprotein (MAG) PN. The diagnosis of PN was established by the presence of monoclonal immunoglobulin M anti-MAG antibodies (Thin-Layer Chromatography, Western Blot and enzyme-linked immunoabsorbent assay). Given the evidence that in CREST activation of T-helper cells is observed and that anti-MAG antibodies, despite the fact that they are T-cell-independent, may be influenced by an increase in T-helper function, the coexistence of these two rare autoimmune disorders in the same patient may not be incidental but related to the underlying immunological mechanisms involved.

Neuromyelitis optica spectrum disease with positive autoimmune indices: a case report and review of the literature.

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's clinical status and stabilization for five years. In the setting of LETM, patients with antiaquaporin 4 IgGs can present features of coexisting systemic involvement. A thorough differential diagnosis is required to guide appropriate therapy.

The onset of multiple sclerosis in Greece: a single-center study of 1,034 consecutive patients.

BACKGROUND/AIMS: The onset of multiple sclerosis (MS) in Greece has not been systematically studied. We sought to provide data on the onset of MS in Greece with detailed information regarding initial symptoms, and to confirm the prognostic significance of demographic and clinical factors at onset. METHODS: We studied 1,034 consecutive patients with MS and independently assessed 265 patients 'seen at onset'. We used the MS severity score and survival analysis (time to reach an Expanded Disability Status Scale score of 4.0) to evaluate the prognostic significance of factors at onset. RESULTS: Female-to-male ratio was 1.9:1 and mean age at onset was 30.7 +/- 9.9 years. MS was primary progressive in 9.6%. Initial symptoms were optic neuritis in 20.1%, brainstem dysfunction in 14.7%, dysfunction of long tracts in 49.3%, cerebral dysfunction in 1% and a combination of symptoms in 14.9%. In 'seen at onset' patients, detailed data on initial symptoms are presented. Female gender, earlier age at onset, 'bout onset' and onset with optic neuritis were associated with less severe disease and longer time to disability. CONCLUSION: The onset of MS in Greece is similar to Western populations. Initial symptoms are within the expected spectrum. Prognostic significance of factors at onset is as previously identified.

CSF biomarker profile and diagnostic value in vascular dementia.

BACKGROUND AND PURPOSE: The differential diagnosis between vascular dementia (VD) and Alzheimer's disease (AD) or mixed dementia (MD) is not always easy in clinical practice. The purpose of the present study was to evaluate the cerebrospinal fluid (CSF) biomarkers tau protein in its total (tau(T)) or hyperphosphorylated at threonin-181(tau(P-181)) form and beta amyloid peptide 1-42 (A beta 42) alone and their combinations to investigate their diagnostic value in the discrimination between VD and AD or MD. METHODS: The above CSF biomarkers were determined in duplicate and blind to the clinical diagnosis by double sandwich, enzyme-linked immunosorbent assay (ELISA) commercial kits (Innogenetics, Gent, Belgium) in 92 AD patients, 23 VD patients, 17 patients with MD and 68 controls. RESULTS: Alzheimer's disease and MD showed increased levels of tau(T), tau(P) and reduced levels of A beta 42 as compared with the controls. The best discrimination between VD and AD or MD was achieved by the combination of all three biomarkers, correctly classifying >or=85% of patients, either in the form of a discriminant function or in the form of the tau(T) x tau(P-181)/A beta 42 formula. CONCLUSIONS: Cerebrospinal fluid biomarkers may be a useful adjunct for the discrimination between AD/ MD and VD in every day clinical practice.

Circulating interleukin-10 and interleukin-12 in Parkinson's disease.

BACKGROUND: Interleukin (IL)-12 is a heterodimeric cytokine produced by activated blood monocytes, macrophages and glial cells. It enhances differentiation and proliferation of T cells and increases production of proinflammatory cytokines. IL-10 is a pleiotropic cytokine produced by both lymphocytes and mononuclear phagocytes including microglia. Recent studies demonstrated the neuroprotective effect of IL-10. There is little information about the involvement of IL-12 or IL-10 in the pathophysiology of Parkinson's disease (PD). OBJECTIVES: The objective of our study was to assess the role of IL-12 as a potential marker of immune reactions in patients with PD and to investigate whether IL-10, an immunosuppressive cytokine, may have a neuroprotective effect in the pathogenesis of PD. PATIENTS AND METHODS: We measured using immunoassay serum IL-12 and IL-10 levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects (controls) age and sex matched. IL-12 and IL-10 levels were tested for correlation with sex, age, disease duration, Hoehn and Yahr stage and the UPDRS III score. RESULTS: The PD group presented with significantly increased IL-10 levels when compared with the control group (P = 0.02). The increase observed was not affected by the treatment status. A strong and significant correlation between IL-10 and IL-12 levels was observed in patients with PD (R(S) = 0.7, P < 0.000001). CONCLUSIONS: Our findings suggest that IL-10 may be involved in the pathogenetic mechanisms of PD. The elevation of IL-10 and the significant correlation between IL-10 and IL-12, a proinflammatory cytokine, may suggest that immunological disturbances and neuroprotective mechanisms are involved in patients with PD.

Circulating interleukin-15 and RANTES chemokine in Parkinson's disease.

UNLABELLED: Interleukin-15 promotes T-cell proliferation, induction of cytolytic effector cells including natural killer (NK) and cytotoxic cells and stimulates B-cell to proliferate and secrete immunoglobulins. RANTES is a C-C beta chemokine with strong chemoattractant activity for T lymphocytes and monocytes. OBJECTIVES: The objective of our study was to find out whether IL-15 and RANTES are involved in the possible inflammatory reactions of PD. PATIENTS AND METHODS: We measured by immunoassay serum IL-15 and RANTES levels in 41 patients with PD in comparison with serum levels in 19 healthy subjects age and sex-matched. IL-15 and RANTES levels were correlated with sex, age, disease duration. H-Y stage and the UPDRS III score in all the studied groups and were also correlated with treatment status in PD patients. RESULTS: The PD group presented with significantly increased RANTES levels as compared to the control group (P = 0.0009). No difference was observed as regards IL-15 levels. A strong and significant correlation between RANTES levels and UPDRS III score was observed in PD patients (R(s) = 0.42, P = 0.007). Untreated patients had significantly higher RANTES levels as compared to the controls. CONCLUSIONS: Our findings may suggest a recruitment of activated monocytes, macrophages and T lymphocytes to sites of inflammation in the central nervous system of PD patients.

Stiff person syndrome: avoiding misdiagnosis.

Stiff person syndrome (SPS) is a rare neurological disorder characterised by muscular rigidity and superimposed spasms of the trunk and limbs that may be precipitated by voluntary movements and unexpected tactile, auditory or emotional stimulation. The high prevalence of autoantibodies against glutamic acid decarboxylase (antiGAD) in both serum and cerebrospinal fluid, as well as the frequent association of SPS with other autoimmune disorders, suggest an autoimmune pathogenesis. SPS is frequently misdiagnosed as axial dystonia or psychogenic movement disorder. We report a patient with SPS in order to emphasise the reasons for this common misdiagnosis.

Differential expression of cytokines and chemokines in human monocytes induced by lipid formulations of amphotericin B.

The immunomodulatory effects of liposomal amphotericin B (LAMB), amphotericin B lipid complex (ABLC), and amphotericin B colloidal dispersion (ABCD) on mRNA and protein profiles of five cytokines and chemokines expressed by human monocyte-enriched mononuclear leukocytes (MNCs) were comprehensively evaluated by semiquantitative reverse transcription-PCR and enzyme-linked immunosorbent assays; they were compared to those of deoxycholate amphotericin B (DAMB). mRNAs of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1ra), tumor necrosis factor alpha (TNF-alpha), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1beta (MIP-1beta) were assessed after treatment of MNCs with each drug for 0.5, 2, 6, and 22 h. The cytokine protein profiles were obtained after incubation of MNCs with the drugs for 2 h (TNF-alpha) or 6 h (all the others). In the mRNA studies, DAMB resulted in an early increase of inflammatory cytokines or chemokines IL-1beta, TNF-alpha, MCP-1, and MIP-1beta (2 to 6 h) and in a late increase of anti-inflammatory IL-1ra (22 h). ABCD showed a general similar trend of inflammatory gene up-regulation. LAMB and ABLC decreased or did not affect IL-1beta and TNF-alpha, whereas ABLC additionally decreased MIP-1beta. In protein measurement studies, DAMB and ABCD up-regulated production of IL-1beta (P < 0.05), decreased the IL-1ra/IL-1beta ratio, and up-regulated the production of MCP-1 and MIP-1beta. In comparison, LAMB and ABLC down-regulated or did not affect the production of these cytokines/chemokines compared to untreated MNCs; furthermore, ABLC tended to increase the IL-1ra/IL-1beta ratio. These studies demonstrate that amphotericin B formulations differentially affect gene expression and release of an array of proinflammatory and anti-inflammatory cytokines that potentially may explain the differences in infusion-related reactions and dose-dependent nephrotoxicity as well as modulation of the host immune response to invasive fungal infections.

Frontal lobe dysfunction in amyotrophic lateral sclerosis.

The aim of the present study was to investigate the involvement of frontal lobe dysfunction in amyotrophic lateral sclerosis (ALS) using ocular motor paradigms and neuropsychological testing. Fifty-one patients with ALS participated in the following ocular motor tasks: (1) a three-choice task and (2) a remembered saccade task. The patients underwent a clinical and neuropsychological evaluation. One-third of ALS patients presented with signs of frontal dysfunction, as determined by their high distractibility factors (DF) in the three-choice task and their performances in both the Wisconsin and Stroop tests. ALS patients exhibited longer latencies to eye movement than controls in the performance of the remembered saccade task, specifically in performance of both remembered and delayed saccades, but saccade accuracy was not impaired. Finally, performance indices of the ocular motor tasks, in particular the DF, was correlated only with the degree of dysarthria.

Blood lead levels of traffic- and gasoline-exposed professionals in the city of Athens.

During the past 10 y, blood lead levels in the population of Athens, Greece, have decreased steadily. This decrease has paralleled the reduction of tetraethyl lead in gasoline and the introduction of unleaded fuel. Blood lead levels and other parameters were studied in 42 gas-station employees, 47 taxi drivers, 47 bus drivers, and 36 controls, all of whom worked in Athens. The blood lead levels did not differ significantly among the four groups (5.64+/-1.7 microg/dl, 5.96+/-1.7 microg/dl, 5.88+/-1.3 microg/dl, and 5.76+/-1.7 microg/dl, respectively). Glutamic-oxaloacetic transaminase (i.e., aspartate aminotransferase) and glutamic-pyruvic transaminase (i.e., alanine aminotransferase) were elevated in gas-station employees, and the former was elevated in taxi drivers. Gas-station employees who smoked had higher blood lead levels than their nonsmoking counterparts. The absence of any difference in the blood lead levels of individuals for whom physical examinations were either normal or abnormal suggests that either lead was not the cause of increased blood lead levels or that its contribution may have been important in the past.

Subcortical frontal lesions on MRI in patients with motor neurone disease.

MRI was performed in 32 patients with motor neurone disease (26 men and 6 women, aged 40-77 years) and in a control group of 21 subjects. Of the patients studied, 19 had definite and 11 probable amyotrophic lateral sclerosis (ALS) and two had progressive bulbar palsy. In 10 patients there were asymmetrical bilateral foci of increased signal intensity on proton-density and T2-weighted images, confined to the white matter. Two patients had only cortical frontal atrophy and slightly increased ventricular size, whereas 20 had normal MRI. The focal lesions were not confined to corticospinal tracts, but were also observed in subcortical frontal areas. While the lesions along the corticospinal tracts correspond to pyramidal tract degeneration, the subcortical foci correlate with degeneration of the frontal bundles and indicate generalised involvement of the central nervous system.