Th1Th17CM Lymphocyte Subpopulation as a Predictive Biomarker of Disease Activity in Multiple Sclerosis Patients under Dimethyl Fumarate or Fingolimod Treatment.

Peripheral blood biomarkers able to predict disease activity in multiple sclerosis (MS) patients have not been identified yet. Here, we analyzed the immune phenotype of T lymphocyte subpopulations in peripheral blood samples from 66 RRMS patients under DMF (n = 22) or fingolimod (n = 44) treatment, by flow cytometry. A correlation study between the percentage and absolute cell number of each lymphocyte subpopulation with the presence of relapses or new MRI lesions during 12-month follow-up was performed. Patients who had undergone relapses showed at baseline higher percentage of Th1CM cells (relapsed: 11.60 ± 4.17%vs. nonrelapsed: 9.25 ± 3.17%, p < 0.05) and Th1Th17CM cells (relapsed: 15.65 ± 6.15%vs. nonrelapsed: 10.14 ± 4.05%, p < 0.01) before initiating DMF or fingolimod treatment. Kaplan-Meier analysis revealed that patients with Th1Th17CM (CD4+CCR7+CD45RA-CCR6+CXCR3+) cells > 11.48% had a 50% relapse-free survival compared to patients with Th1Th17CMcells < 11.48% whose relapse-free survival was 88% (p = 0.013, log-rank test). Additionally, a high percentage of Th1Th17CM cells was also found in patients with MRI activity (MRI activity: 14.02 ± 5.87%vs. no MRI activity: 9.82 ± 4.06%, p < 0.01). Our results suggest that the percentage of Th1Th17CM lymphocytes at baseline is a predictive biomarker of activity during the first 12 months of treatment, regardless of the treatment.

Multiple Intracranial Arteriovenous Fistulas in Cowden Syndrome.

Cowden syndrome is a rare autosomal dominant disease. It is characterized by multiple noncancerous tumorlike growths called hamartomas, which typically are found in the skin, oral mucosa, thyroid, breast, and gastrointestinal tract. It carries with it a potential risk of malignant transformation, especially of the breast and thyroid. In 80% of the cases, the human tumor suppressor gene, phosphatase and tensin homolog (PTEN), is mutated in the germ line. We report a patient with Cowden syndrome who presented with generalized seizure and left anterior temporal hemorrhage and a nontraumatic subarachnoid hemorrhage due to multiple intracranial arteriovenous fistulas (AVFs). We discuss previous reports about vascular malformations in patients with Cowden syndrome and PTEN mutations. Importantly, we hypothesize that the production of multiple AVFs in our patient was associated with PTEN mutation.

Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients.

AIMS: Fingolimod, an orally active immunomodulatory drug for relapsing-remitting multiple sclerosis (RRMS), sequesters T cells in lymph nodes through functional antagonism of the sphingosine-1-phosphate receptor, reducing the number of potential autoreactive cells that migrate to the central nervous system. However, not all RRMS patients respond to this therapy. Our aim was to test the hypothesis that by immune-monitoring RRMS patient's leukocyte subpopulations it is possible to find biomarkers associated with clinical response to fingolimod. METHODS: Prospective study. Analysis of peripheral blood mononuclear cell subpopulations by multiparametric flow cytometry, at baseline and +1, +3, +6, +12 months of follow-up in 40 RRMS patients starting fingolimod therapy. RESULTS: Fingolimod treatment induced a severe lymphopenia affecting mainly T and B cells. A relative increase in Treg (memory Treg : 3.8 ± 1.0% baseline vs 8.8 ± 4.4% month +1; activated Treg : 1.5 ± 0.7% baseline vs 3.7 ± 2.1% month +1, P < 0.001) as well as transitional B cells (10.5 ± 12.3% baseline vs 18.7 ± 14.6% month +1, P < 0.001) was observed. Interestingly, lymphocyte subpopulations were already at baseline significantly different in responder patients. The percentage of recent thymic emigrants (RTE) used to stratify fingolimod responder, and no responder patients was the best biomarker (4.0 ± 1.4% vs 7.4 ± 1.9%, respectively [P < 0.001]). CONCLUSION: The results support that immune-monitoring of lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.

Neuropatía óptica inflamatoria recurrente crónica: revisión de la bibliografía / Chronic relapsing inflammatory optic neuropathy: a literature review

Introducción. La neuropatía óptica inflamatoria recurrente crónica (CRION) es una enfermedad inflamatoria caracterizada por episodios recurrentes de neuritis óptica dolorosa con una clara respuesta a corticoides y recaídas debido a su retirada. Objetivos. Se realiza una revisión de la bibliografía sobre CRION desde 2003 hasta la actualidad en bases de datos médicas. Se excluyen artículos en edad pediátrica o de investigación animal. Los términos de búsqueda fueron: CRION, neuritis óptica, neuropatía óptica inflamatoria remitente crónica, neuritis óptica recurrente, neuritis óptica corticodependiente y neuritis óptica dependiente de inmunosupresores. Desarrollo. La CRION es una neuritis óptica recurrente de etiología no conocida. Su fuerte respuesta a corticoides, que evita las recaídas, sugiere un origen inmunomediado. La CRION se manifiesta como una neuropatía óptica subaguda y recurrente con grave afectación de la agudeza visual. Los principales diagnósticos diferenciales son las enfermedades desmielinizantes, como la esclerosis múltiple, el espectro de neuromielitis óptica y la enfermedad por anticuerpos anti-MOG, las enfermedades sistémicas, sobre todo la sarcoidosis, y las enfermedades infecciosas. La CRION tiene una excelente respuesta a corticoides, pero es corticodependiente; para evitar los efectos adversos de la corticoterapia se utilizan inmunosupresores a largo plazo para el tratamiento. Conclusión. La CRION es una rara enfermedad recurrente del nervio óptico corticodependiente. Su reconocimiento precoz y tratamiento preciso mejorarán el pronóstico

Introduction. Chronic relapsing inflammatory optic neuropathy (CRION) is an inflammatory disease characterized by painful recurrent episodes of optic neuritis with clear response to steroids and relapses with treatment withdrawal. Aims. To performed a systematic review of the literature about CRION, since 2003 to present in medical database. We excluded pediatric or animal research articles. Search terms: CRION, chronic relapsing inflammatory optic neuropathy, recurrent optic neuritis, steroid dependent optic neuritis, and immunosuppression dependent optic neuritis. DEvelopment. CRION is a relapsing optic neuritis of unknown aetiology. The strong response to corticosteroids to avoid recurrence suggests that it might be an immune-mediated disease. CRION typically presents as a subacute and recurrent optic neuropathy with severe visual loss. The principal differential diagnoses are the demyelinating (multiple sclerosis, neuromyelitis optica spectrum disorders and anti-MOG), systemic (mostly sarcoidosis) and infectious diseases. CRION has a dramatic and dependent corticoids response; to avoid adverse events, we use immunosuppressive treatment in long-term. Conclusion. CRION is a rare, recurrent and cortico-dependent disease of optic nerve. An early diagnosis and accuracy treatment will improve the prognosis

[Encephalopathy and neuromyelitis optica: the importance of recognising atypical symptoms]. / Encefalopatía y neuromielitis óptica: importancia del reconocimiento de la sintomatología atípica.

INTRODUCTION: Neuromyelitis optica (NMO), or Devic's disease, is an autoimmune, inflammatory and demyelinating disease of the central nervous system which mainly and characteristically involves the optic nerve and the spinal cord. Anti-aquaporin-4 (AQ-4) antibodies are a specific biomarker of the entity and, since their discovery, both the number of symptoms and the radiological data about the disease have progressively increased, and the concept of clinical spectrum of NMO has been defined. CASE REPORT: A 66-year-old female diagnosed with NMO after suffering attacks of optic neuritis and recurrent myelitis, and showing positive for AQ-4 antibodies. The patient presented a diminished level of consciousness, and magnetic resonance imaging of the head revealed a number of lesions in the white matter, without contrast enhancement, which resolved without treatment. One month later, her general state had declined and was accompanied by symptoms of confusion and blindness. A magnetic resonance imaging scan showed new lesions in the white matter and an increase in the size of those already present. The patient was diagnosed as suffering from encephalopathy within the context of NMO and she was treated with intravenous immunoglobulins and corticoids, which resulted in a clinical and radiological improvement. CONCLUSIONS: Since the discovery of AQ-4 antibodies, there has been an increase in the number of clinical and radiological manifestations of NMO beyond involvement of the optic nerve and the spinal cord, including manifestations in the brain. It is important to recognise them in order to make an early diagnosis, to avoid unnecessary complementary tests and to establish the most suitable treatment.

TITLE: Encefalopatia y neuromielitis optica: importancia del reconocimiento de la sintomatologia atipica.Introduccion. La neuromielitis optica (NMO) o enfermedad de Devic es un trastorno autoinmune, inflamatorio y desmielinizante del sistema nervioso central, que afecta principal y caracteristicamente al nervio optico y a la medula espinal. Los anticuerpos antiacuaporina-4 (AQ-4) son un biomarcador especifico de esta entidad y, desde su descubrimiento, se ha ampliado el numero de sintomas y datos radiologicos de la enfermedad y se ha definido el concepto de espectro clinico de NMO. Caso clinico. Mujer de 66 años diagnosticada de NMO por haber sufrido brotes de neuritis optica y mielitis de repeticion junto con anticuerpos AQ-4 positivos. Presento un cuadro de disminucion del nivel de conciencia, con resonancia magnetica cerebral que mostro multiples lesiones en la sustancia blanca, sin realce de contraste, que se resolvio sin tratamiento. Un mes despues, sufrio empeoramiento del estado general, sindrome confusional y ceguera. En la resonancia magnetica cerebral se observaron nuevas lesiones en la sustancia blanca y aumento del tamaño de otras ya existentes. Se emitio el diagnostico de encefalopatia en el contexto de NMO y se trato a la paciente con corticoides e inmunoglobulinas intravenosas, con lo que se produjo mejoria clinica y radiologica. Conclusiones. Desde el descubrimiento de los anticuerpos AQ-4, ha aumentado el numero de manifestaciones clinicas y radiologicas de la NMO mas alla de la afectacion del nervio optico y de la medula espinal, entre ellas las manifestaciones cerebrales. Reconocerlas es muy importante para hacer un diagnostico precoz, evitar pruebas complementarias no necesarias e instaurar el tratamiento adecuado.

Encefalopatía y neuromielitis óptica: importancia del reconocimiento de la sintomatología atípica / Encephalopathy and neuromyelitis optica: the importance of recognising atypical symptoms

Introducción. La neuromielitis óptica (NMO) o enfermedad de Devic es un trastorno autoinmune, inflamatorio y desmielinizante del sistema nervioso central, que afecta principal y característicamente al nervio óptico y a la médula espinal. Los anticuerpos antiacuaporina-4 (AQ-4) son un biomarcador específico de esta entidad y, desde su descubrimiento, se ha ampliado el número de síntomas y datos radiológicos de la enfermedad y se ha definido el concepto de espectro clínico de NMO. Caso clínico. Mujer de 66 años diagnosticada de NMO por haber sufrido brotes de neuritis óptica y mielitis de repetición junto con anticuerpos AQ-4 positivos. Presentó un cuadro de disminución del nivel de conciencia, con resonancia magnética cerebral que mostró múltiples lesiones en la sustancia blanca, sin realce de contraste, que se resolvió sin tratamiento. Un mes después, sufrió empeoramiento del estado general, síndrome confusional y ceguera. En la resonancia magnética cerebral se observaron nuevas lesiones en la sustancia blanca y aumento del tamaño de otras ya existentes. Se emitió el diagnóstico de encefalopatía en el contexto de NMO y se trató a la paciente con corticoides e inmunoglobulinas intravenosas, con lo que se produjo mejoría clínica y radiológica. Conclusiones. Desde el descubrimiento de los anticuerpos AQ-4, ha aumentado el número de manifestaciones clínicas y radiológicas de la NMO más allá de la afectación del nervio óptico y de la médula espinal, entre ellas las manifestaciones cerebrales. Reconocerlas es muy importante para hacer un diagnóstico precoz, evitar pruebas complementarias no necesarias e instaurar el tratamiento adecuado (AU)

Introduction. Neuromyelitis optica (NMO), or Devic’s disease, is an autoimmune, inflammatory and demyelinating disease of the central nervous system which mainly and characteristically involves the optic nerve and the spinal cord. Antiaquaporin- 4 (AQ-4) antibodies are a specific biomarker of the entity and, since their discovery, both the number of symptoms and the radiological data about the disease have progressively increased, and the concept of clinical spectrum of NMO has been defined. Case report. A 66-year-old female diagnosed with NMO after suffering attacks of optic neuritis and recurrent myelitis, and showing positive for AQ-4 antibodies. The patient presented a diminished level of consciousness, and magnetic resonance imaging of the head revealed a number of lesions in the white matter, without contrast enhancement, which resolved without treatment. One month later, her general state had declined and was accompanied by symptoms of confusion and blindness. A magnetic resonance imaging scan showed new lesions in the white matter and an increase in the size of those already present. The patient was diagnosed as suffering from encephalopathy within the context of NMO and she was treated with intravenous immunoglobulins and corticoids, which resulted in a clinical and radiological improvement. Conclusions. Since the discovery of AQ-4 antibodies, there has been an increase in the number of clinical and radiological manifestations of NMO beyond involvement of the optic nerve and the spinal cord, including manifestations in the brain. It is important to recognise them in order to make an early diagnosis, to avoid unnecessary complementary tests and to establish the most suitable treatment (AU)