Neurofilament light chain levels in pregnant multiple sclerosis patients: a prospective cohort study.

BACKGROUND AND PURPOSE: Neurofilament light chain is a cytoskeletal protein of neurons. Its levels are increasingly recognized as measures of neuroaxonal damage. The aim of this study was to explore serum neurofilament light chain (sNfL) levels in multiple sclerosis (MS) patients and healthy controls during pregnancy and puerperium. METHODS: This was a prospective, longitudinal, single-center study. sNfL concentration was assessed using a highly sensitive single-molecule array during pregnancy and in puerperium, in a cohort of 39 pregnant patients with relapsing multiple sclerosis (P-MS). Twenty-one healthy pregnant women (HPW) served as a control group. Eight P-MS suffered relapses during pregnancy (P-MS-R) in the first or second trimesters. RESULTS: No differences in pregnancy and delivery data were observed between P-MS and HPW. P-MS showed higher sNfL values than HPW in the first trimester, independently of the presence (P = 0.002) or not (P = 0.02) of relapses during pregnancy. However, in the third trimester, only P-MS-R showed higher sNfL values than HPW (P = 0.001). These differences extended to the puerperium, where P-MS-R showed higher sNfL values than those with no relapses during gestation (P = 0.02). CONCLUSION: These data strongly suggest that sNfL levels reflect MS activity during pregnancy. Additionally, the absence of relapses during pregnancy may have a beneficial effect on neurodegeneration during puerperium.

Genes differentially expressed by methylprednisolone in vivo in CD4 T lymphocytes from multiple sclerosis patients: potential biomarkers.

Intravenous methylprednisolone (IVMP) is the gold standard treatment in acute relapses of multiple sclerosis. Knowing the response to IVMP in advance could facilitate earlier selection of patients for subsequent courses of therapy. However, molecular mechanisms and changes in gene expression induced by methylprednisolone remain unknown. The aim of the study was to identify in vivo differentially expressed genes in relapsing-remitting multiple sclerosis patients after 3-6 days of treatment with IVMP. For this purpose, whole-genome transcription profiling of CD4+ T lymphocytes was performed before and after treatment with IVMP in 8 relapsing-remitting multiple sclerosis patients during relapse using Human GE 4x44K v2 microarrays. Differentially expressed genes were identified using a paired t test on GeneSpring v13.0 software. A P-value <0.001 and a twofold change were considered significant. Microarray data were confirmed using real-time PCR. Microarray revealed changes in gene expression: four genes were downregulated (B3GNT3, ZNF683, IFNG and TNF) and seven upregulated (DEFA4, CTSG, DEFA8P, AZU1, MPO, ELANE and PRTN3). Pathway analysis revealed the transforming growth factor-ß signaling pathway to be affected. Comparison with previously published data on in vitro methylprednisolone-regulated genes showed that SMAD7, TNF and CHI3L1 were also downregulated in vivo in relapsing-remitting multiple sclerosis patients. In summary, we performed the first in vivo transcriptome analysis in CD4+ T lymphocytes before and after the treatment with IVMP in patients with multiple sclerosis. Identification of differentially expressed genes in patients receiving IVMP could improve our understanding of the molecular mechanisms underlying the therapeutic effects of IVMP and highlight potential biomarkers of the response to IVMP.

Multiple sclerosis and pregnancy: a single-centre prospective comparative study. / Esclerosis múltiple y embarazo: estudio unicéntrico prospectivo y comparativo.

INTRODUCTION: Multiple sclerosis (MS) is a autoimmune disorder which preferentially affects young women of childbearing age. During pregnancy, the annualized relapse rate (AAR) is modified, but pregnancy has no harm effect on the long-term course of the disease. We aimed to study the clinical course of our MS patients during pregnancy, and compare their obstetrics outcomes with a control group of non-MS patients. METHODS: A single centre prospective observational study was conducted. We assessed the reproductive history, MS history, pregnancy course and new-born outcome of a cohort of MS patients who had had a pregnancy between january 2007 and july 2012. We compared the global outcomes with a control cohort of 58 age-matched healthy pregnancies. RESULTS: Complete data from 35 consecutive women were analyzed, 40 deliveries. Control groups: 58 patients, 60 deliveries. EDSS at pregnancy 0,7. ARR before pregnancy 0,5. During pregnancy 0,3, after pregnancy 0,4. Twelve patients were on disease-modifying drugs (DMD) before pregnancy, 4 prenatal exposure occurs. The comparison between relapse rate and EDSS before, during and after delivery showed no statistically significant difference. In addition, compared to control group, there were also no differences in the obstetric outcomes. In MS cohort, we found a higher incidence of assisted reproductive treatments and lower breastfeeding rate, both statistically significant. CONCLUSIONS: Our series confirms that pregnancy has no negative long term impact on the progression of MS and also suggest that there is no additional morbidity in the pregnancy, comparing to the rest of the population.

Changes in B and T-cell subsets and NMO-IgG levels after immunoglobulins and rituximab treatment for an acute attack of neuromyelitis optica.

BACKGROUND: There is increasing evidence supporting that neuromyelitis optica (NMO) is an inflammatory humoral mediated disorder associated with NMO-IgG/AQP-4 antibodies. However, little is known about the subsets of B cells and T cells that contribute to the pathogenesis or therapy response. OBJECTIVES: To describe the clinical and immunological changes associated with intravenous immunoglobulins (IV-Igs) plus rituximab (RTX) in a patient with a severe acute attack of NMO and intrathecal synthesis of NMO-IgG/AQP-4, who previously did not respond to intravenous methylprednisolone and plasma exchange. METHODS: We sequentially analysed the levels of NMO-IgG/AQP-4 by immunohistochemistry, and B and T cells subsets by multiparametric flow-cytometry, in the CSF and peripheral blood (PB), before and alter IV-Igs plus RTX therapy. RESULTS: In the CSF before treatment, and compared with PB, there was a higher percentage of CD4(+) T cells and a lower percentage of CD8(+) T cells and CD19(+) B cells. After therapy, the percentage of CD4(+) T cells remained high, and that of CD8(+) T cells increased. The observed decrease in the percentage of CD19(+) B cells was lower than in the PB. When the CSF was compared, it was found that the percentage of effector-memory and effector CD8(+) T cells had increased after therapy, and that of IgM memory B cells and switched-memory B cells decreased. The observed changes paralleled the decrease of NMO-IgG/AQP-4 results to negative and the clinical improvement. CONCLUSIONS: Our findings confirm that, besides intrathecal humoral immune response against AQP4, B and T cell subsets are involved in the modulation of inflammation within and outside the central nervous system.

Consensus Statement on medication use in multiple sclerosis by the Spanish Society of Neurology's study group for demyelinating diseases.

Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment.

[Portal and mesenteric thrombosis associated with protein S deficiency]. / Trombosis portal y mesentérica asociada al déficit de la proteína S.

INTRODUCTION: liver cirrhosis is the main cause of portal thrombosis (PT), while hypercoagulability syndromes are rarely found as the etiology of PT. We report a case of portal and mesenteric thrombosis secondary to protein S deficiency. CASE REPORT: a 74-year-old woman was admitted with melena secondary to upper gastrointestinal bleeding. She reported mild, diffuse abdominal pain in the last 2 weeks. Endoscopy revealed ruptured esophageal varices. Doppler ultrasonography and CT demonstrated a heterogeneous liver, splenomegaly and ascites, and complete non-occlusive PT involving the hilum and portal branches, as well as the superior mesenteric vein, with portosystemic collaterals. At this point a complete study for cirrhosis etiologies was negative, including a liver biopsy that showed nonspecific architectural changes secondary to diminished blood flow, which suggested non-cirrhotic portal hypertension. The search for hypercoagulability states determined a deficiency of S protein, with total pS = 107% and free pS = 56%. The patient was started on anticoagulant treatment and no other thrombotic events occurred. DISCUSSION: PT usually manifests without specific symptoms. The most common presentation is upper gastrointestinal bleeding, as occurred in our patient. Liver cirrhosis is one of the most frequent cause of PT. Up to 65% of these patients present an associated prothrombotic state, including protein S deficiency. Our case reminds us of the importance of a systematic search for hipercoagulability syndromes in patients with TP, even when the etiology can be conferred to liver cirrhosis.

[Peritonsillar and retropharyngeal abscesses: study of 13 years]. / Abscesos periamigdalino y retrofaríngeo: estudio de 13 años.

INTRODUCTION: Peritonsillar and retropharyngeal abscesses are the most common deep head and neck infections. We present a series of patients with these infections. MATERIAL AND METHODS: We performed a retrospective study of peritonsillar and retropharyngeal abscesses in children admitted to the Infectious Diseases Unit of our hospital between January 1991 and January 2004. Diagnosis was based mainly on clinical and laboratory findings. RESULTS: We studied 54 patients, 10 with retropharyngeal abscess and 44 with peritonsillar abscess. The mean age was 6.7 and 7.5 years respectively. There was a slight predominance of boys (1.45:1). The number of cases diagnosed increased from 1997, with a maximum (nine cases) in 2002. Twenty-nine children had received previous antibiotic therapy. The main symptoms and signs were: fever, odynophagia, cervical lymphadenitis, and asymmetric tonsillar hypertrophy. All children received intravenous antibiotic therapy. Puncture-aspiration was carried out in seven patients. Eleven children underwent tonsillectomy, two with retropharyngeal abscess and nine with peritonsillar abscess. Of these 11 patients, five had had several episodes of tonsillitis and three had previously had a peritonsillar abscess. Three children who developed an abscess had previously undergone tonsillectomy. In most patients, outcome was favorable. CONCLUSIONS: In the last few years the frequency of peritonsillar and retropharyngeal abscesses has increased in the pediatric population. Most of the children have a good response to conservative treatment. The main risk factor for abscess recurrence is a previous history of repeated tonsillitis. Consequently, these patients are candidates for tonsillectomy.

Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients.

BACKGROUND: Antibodies to glutamic acid decarboxylase (GAD-Ab) are described in patients with insulin-dependent (type 1) diabetes mellitus (IDDM), in stiff-man syndrome, and, recently, in a few patients with cerebellar ataxia. OBJECTIVES: To show a link between GAD-Ab and some patients with cerebellar ataxia and to clarify their clinical and immunologic profiles. METHODS: Serum samples were selected from 9000 samples of 4 laboratories. The selection criterion was an immunohistochemical pattern compatible with GAD-Ab that was confirmed by radioimmunoassay. We identified 22 patients with stiff-man syndrome and 14 with cerebellar ataxia and GAD-Ab. RESULTS: Thirteen of the 14 patients with cerebellar ataxia and GAD-Ab were women, and 11 had late-onset IDDM. Patients did not have clinical or radiologic evidence of brainstem involvement. Ten patients had oligoclonal IgG bands in the cerebrospinal fluid, and intrathecal GAD-Ab synthesis was observed in 5 of the 6 patients studied. The level of GAD-Ab of these patients was similar to those with stiff-man syndrome and significantly higher than those with IDDM or with polyendocrine autoimmunity (P<.001). However, the GAD-Ab levels of 6 of the 9 patients with polyendocrine autoimmunity overlapped with those of patients with cerebellar ataxia. CONCLUSIONS: These results suggest a link between high level of GAD-Ab and some cases of cerebellar ataxia, particularly women with IDDM. If high serum levels of GAD-Ab are detected, the cerebrospinal fluid should be evaluated for the presence of oligoclonal IgG bands and intrathecal synthesis of GAD-Ab to further prove an autoimmune origin of the syndrome.

Simultaneous occurrence of Hodgkin's disease, nodal Langerhans' cell histiocytosis and multiple myeloma IgA(kappa).

A 35-year-old man suffered simultaneously from nodular sclerosis Hodgkin's disease (HD), Langerhans' cell histiocytosis and multiple myeloma (MM). There was no prior history of irradiation or chemotherapy, and clinically the lymphoma was confined to cervical lymph nodes. Immunohistochemically, neoplastic lymphoma cells reacted with CD15 and CD30 markers. The patient's bone marrow exhibited a diffuse infiltration by rather atypical plasma cells showing kappa immunoglobulin light-chain restriction. At 14 months after the diagnosis, after autologous bone marrow transplantation, the clinical evolution is favourable with complete remission of the diseases. This is the first time that the coexistence of these three haematological disorders has been discussed, and only the fourth documented case of simultaneous HD and MM. Speculations about the significance of this finding are discussed.

Cerebrospinal fluid levels of alpha-tocopherol in patients with multiple sclerosis.

We compared cerebrospinal fluid (CSF) and serum levels, and the CSF/serum ratio of alpha-tocopherol (vitamin E), measured by HPLC, in 36 patients with multiple sclerosis (MS) and 32 matched controls. The mean CSF vitamin E levels and the CSF/serum vitamin E ratio did not differ significantly between the two study groups. The serum levels of vitamin E and the serum vitamin E/cholesterol ratio were significantly lower in MS patients when compared with controls (P < 0.05 and P < 0.01, respectively). These values were not correlated with age, age at onset and duration of the disease in the patients group. These results suggest that CSF vitamin E concentrations are not a marker of activity of MS activity.

Seminal vesicle epithelium as a potential pitfall in the cytodiagnosis of presacral masses. A report of two cases.

BACKGROUND: Whenever abdominoperineal resection is performed because of a rectal adenocarcinoma, the prostate and seminal vesicles may be displaced backward to the presacral space, giving rise to a false radiologic image of a presacral tumor. Due to cytologic atypia associated with the epithelium of seminal vesicles, there is a real possibility, in fine needle aspiration biopsy (FNAB), of erroneously giving a malignant diagnosis. CASES: Two men, aged 53 and 57 years, presented with presacral masses three months and six years, respectively, after abdominoperineal resection for rectal adenocarcinoma. In both cases, FNAB smears showed some groups and single cells with large and irregular nuclei. These cells suggested a recurrence of carcinoma. The presence of cytoplasmic coarse pigment and a background with spermatozoa and blobs of inspissated secretory product were sufficient to determine that these presacral masses represented the seminal vesicles. CONCLUSION: Awareness that seminal vesicles may give rise to a radiologic impression of presacral tumor after abdominoperineal resection of the rectum will avoid unnecessary FNAB and a cytologic false positive diagnosis of colorectal adenocarcinoma.

Hepatic metastases from the spindle cell variant of medullary thyroid carcinoma: report of a case with diagnosis by fine needle aspiration biopsy.

BACKGROUND: The liver is a common site of neuroendocrine tumors (NTs) metastatic from primaries in the gastrointestinal tract, pancreas, biliary system and lungs. Medullary thyroid carcinoma (MTC) is also a potential source of metastases of NTs. Their metastases to the liver are frequent and can appear several years after the primitive tumor. Although a wide variety of cytomorphologic features are normally exhibited by MTC in smears, a spindle-shaped cell pattern can predominate, complicating the correct interpretation of a metastasis. CASE: A 63-year-old man presented with multiple liver nodules two years after a total thyroidectomy for MTC. Fine needle aspiration biopsy smears of the liver revealed neoplastic cells occurring in loose groupings or lying singly, most of them with a spindle shape and elongated nucleus with the characteristic "salt and pepper" chromatin pattern of a neuroendocrine tumor. Cytoplasmic dendritic processes and intranuclear inclusions were frequently seen. The cytomorphologic features of the tumor were essentially the same as those of the primary MTC. Immunoreactivity for calcitonin confirmed the diagnosis. CONCLUSION: In fine needle aspiration biopsy of liver masses, knowledge of the spindle pattern of the NT is important in order to achieve a correct diagnosis when metastases are the first manifestation of an occult primary tumor. Among neuroendocrine tumors, MTC must be included in the differential diagnosis.

[Autoimmune hepatitis in patients with a diagnosis of multiple sclerosis]. / Hepatitis autoinmune en pacientes con diagnóstico de esclerosis múltiple.

Autoimmune hepatitis (AIH) is a chronic necroinflammatory liver disorder associated with hypergammaglobulinemia and circulating autoantibodies. Two patients previously diagnosed with multiple sclerosis who developed AIH are reported. One patient showed acute presentation with fulminant hepatic failure requiring liver transplantation. Serum autoantibodies were negative in both patients but a characteristic clinical course in the first patient as well as the hepatic histological features with typical pathological changes of AIH in both patients and a score compatible with AIH established the diagnosis.

[The interest of multiple sclerosis attacks. Physiopathology and therapy]. / Interes de los brotes en la esclerosis multiple. Fisiopatologia y tratamiento.

AIMS: To review the clinical concept of an attack, the physiopathological mechanisms underlying the symptoms of the attack, in the recovery phase, and those corresponding to the progressive or degenerative phase of the disease. DEVELOPMENT: Although they do not explain the exact mechanisms responsible for the onset of the attack or the processes that account for the clinical and pathological heterogeneity, most research studies suggest that the lesions produced in multiple sclerosis are the consequence of complex immunological interactions that take place mostly in the white matter of the central nervous system. These lesions affect, to variable extents, the myelin and the axon. We survey how these events are reflected in the images obtained by magnetic resonance. Clinical observations have shown that, in some patients, infections and hormones can exert an influence on the activity of the disease. Recovery, in the initial stages at least, would be produced by the action of poorly understood mechanisms that limit inflammation, and by local or cortical neuroplasticity or repair processes. Finally, we discuss the mechanisms behind the action of corticoids that justify their use when treating these attacks. CONCLUSION: A more thorough understanding of these events opens up the way to providing better therapy in the future.

[Symptomatic treatment of multiple sclerosis]. / Tratamiento sintomático de la esclerosis múltiple.

INTRODUCTION: Multiple sclerosis is a chronic neurological disorder which affects middle aged adults. It usually means serious physical, psychological, social and employment problems for the patients concerned. METHOD: From the anatomo pathological point of view, it is characterized by demyelination and axon damage in the central nervous system. The clinical features are variable, depending on the course of the disease, its clinical form and the sites of the lesions. Symptoms may appear in bouts, as relapses of the disorder or as a result of incomplete recovery from these episodes and cause severe disability. CONCLUSION: We review the physiopathology and most widely used treatment for management of the commonest symptoms of multiple sclerosis.

[Fatty diet and multiple sclerosis]. / Dieta grasa y esclerosis múltiple.

INTRODUCTION AND DEVELOPMENT: Multiple sclerosis (ME) is an inflammatory disease of the myelin of the central nervous system, the origin of which is still unknown. Genetic, infectious, immunological and environmental factors have all been blamed, but none of these factors on their own can explain the whole spectrum of this disease. Of the environmental factors, fat in the diet has given rise to most discussion. At the present time, it is known that polyunsaturated essential fatty acids form a part of biological membranes. A relationship has been found between the dietary fat consumed and the plasma levels and cell membrane content. CONCLUSIONS: The possible immuno-modulation function of these fatty acids justify rigorous evaluation of this hypothesis.

[Approach to quality of life changes in patients with multiple sclerosis]. / Una aproximación sobre la calidad de vida en pacientes con esclerosis múltiple.

INTRODUCTION AND OBJECTIVES: Multiple sclerosis (MS), as a chronic, incurable and often severely disabling disease, greatly affects patients normal life. The objectives of the study are to analyze which aspects of daily life are more affected by the disability and to investigate whether the degree of support demanded by patients is related to their level of incapacity. PATIENTS AND METHODS: Group of 60 ambulatory patients with Poser defined MS, mean age of 44.5 years, Expanded Disability Status Scale (EDSS) of 3.1, and average period of disease evolution 13.2 years. Test instrument was a structured 12 items questionnaire given during a visit to the attending physician and regarding social and family aspects, financial needs, professional life and emotional well being. RESULTS: 58.3% of the professionally active patients had to give up their jobs; 8.3% experienced changes in their marital status and general family life somewhat changed in 41.7% of the cases due to either physical or psychical disease consequences. Social relationships were altered in 68.2% of the cases; 43.3% required some level of economical support, and 80% went through episodes of emotional distress. CONCLUSION: Statistically significant relationships exist between level of incapacity and professional and social life changes but not with family life changes, emotional alterations and level of support required.

[Plasma immunoadsorption treatment of malignant multiple sclerosis with severe and prolonged relapses]. / Tratamiento con plasma inmunoadsorción en brotes graves y prolongados de esclerosis múltiple maligna.

INTRODUCTION: The treatment of prolonged, severe relapses in multiple sclerosis (MS) patients who respond poorly to high-dose intravenous corticosteroids is not yet established. Plasma immunoadsortion (IA) removes immunoglobulins (IgG), immune complexes, and complement from plasma. It may bear some advantages compared to plasmapheresis, a nonselective procedure that requires substitution of patient plasma by colloids solutions or plasma, which may carry a potential risk for viral infections. PATIENTS AND METHODS: Three relapsing-remitting MS patients with a malignant course received IA. All they were experiencing a prolonged relapse unresponsive to high-dose intravenous corticosteroids, causing a locked-in state in two of the patients and severe pseudobulbar impairment in the third one. Five to six IA consecutive sessions were administered along a 7-10 days course. RESULTS: IA was followed by a prompt and unequivocal clinical response in all three patients, which paralleled a decrease in IgG, fibrinogen, and C3 complement serum levels. IA administration was followed by immunosuppressor therapy, either with cyclophosphamide and intravenous ACTH (2 cases) or mitoxantrone (1 case). Improvement has been sustained along a mean follow-up of 7.6 years (range: 7-8.5 years), only one of the patients suffering two mild clinical relapses. CONCLUSION: We believe that IA may be useful, either as a coadyuvant or alternative treatment in severe relapses in MS patients that do not respond to high-dose intravenous corticosteroid therapy.