Intramuscular Injection of Bone Marrow Stem Cells in Amyotrophic Lateral Sclerosis Patients: A Randomized Clinical Trial.

BACKGROUND: Preclinical studies suggest that stem cells may be a valuable therapeutic tool in amyotrophic lateral sclerosis (ALS). As it has been demonstrated that there are molecular changes at the end-plate during the early stages of motorneuron degeneration in animal models, we hypothesize that the local effect of this stem cell delivery method could slow the progressive loss of motor units (MUs) in ALS patients. METHODS: We designed a Phase I/II clinical trial to study the safety of intramuscularly implanting autologous bone marrow mononuclear cells (BMMCs), including stem cells, in ALS patients and their possible effects on the MU of the tibialis anterior (TA) muscle. Twenty-two patients participated in a randomized, double-blind, placebo-controlled trial that consisted of a baseline visit followed by one intramuscular injection of BMNCs, follow-up visits at 30, 90, 180, and 360 days, and an additional year of clinical follow-up. In each patient, one TA muscle was injected with a single dose of BMMCs while the contralateral muscle was given a placebo; the sides were selected randomly. All visits included a complete EMG study of both TA muscles. RESULTS: Our results show that (1) the intramuscular injection of BMMCs is a safe procedure; (2) ALS patients show heterogeneities in the degree of TA injury; (3) a comparison of placebo-injected muscles with BMMC-injected muscles showed significant differences in only one parameter, the D50 index used to quantify the Compound Muscle Action Potential (CMAP) scan curve. This parameter was higher in the BMMC-injected TA muscle at both 90 days (placebo side: 29.55 ± 2.89, n = 20; experimental side: 39.25 ± 3.21, n = 20; p < 0.01) and 180 days (placebo side: 29.35 ± 3.29, n = 17; experimental side: 41.24 ± 3.34, n = 17; p < 0.01). CONCLUSION: This procedure had no effect on the TA muscle MU properties, with the exception of the D50 index. Finding differences in just this index supports the fact that it may be much more sensitive than other electrophysiological parameters when studying treatment effects. Given the low number of patients and their heterogeneity, these results justify exploring the efficacy of this procedure in further patients and other muscles, through Phase II trials. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov (identifier NCT02286011); EudraCT number 2011-004801-25.

Estrategia de tratamiento de la enfermedad de Fabry tras un ictus. Réplica / Treatment strategy for Fabry's disease following a stroke. Reply

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Enfermedad de Fabry desde la perspectiva del neurólogo: ¿una causa infrecuente de ictus? / Fabry disease from the neurologist’s point of view: is it a rare cause of strokes?

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Ovarian teratoma-associated anti-NMDAR encephalitis: a systematic review of reported cases.

The association of ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a serious and potentially fatal pathology that occurs in young women and that is under-recognized. Our objectives were to analyze prevalence and outcome of this association, and increase awareness over this pathology. MEDLINE and SCOPUS for all studies published prior to November 30, 2013 including the search terms: "encephalitis" and "teratoma" were considered. All articles (119) reporting one or more cases of anti-NMDAR encephalitis and confirmed ovarian teratoma (174 cases) were included. No language restrictions were applied. Suspicious cases with no evidence of ovarian teratoma (n = 40) and another type of encephalitis also associated to ovarian teratoma (n = 20) were also considered for comparison and discussion. Data of publication and case report, surgery and outcome were collected. The distribution of published cases is heterogeneous among different countries and continents, probably in relation with level of development and health care. The mean patient age is 24 years and in the majority of cases (74%), a mature teratoma was identified, sometimes microscopically following ovarian removal or at autopsy. The clinical presentation featured psychiatric symptoms and behavioural changes, with a median delay for surgery of 28 days. Twelve women died (7%), most frequently from encephalitis-related complications. In conclusion, the association ovarian teratoma and anti-NMDAR encephalitis is relatively unknown or not reported in many countries and among gynecologists. Heightened recognition of behavioral changes, diagnosis through transvaginal ultrasound and subsequent tumor removal in addition to diagnostic confirmation through the presence of anti-NMDAR antibodies must be emphasized.

Active human herpesvirus 6 infection in patients with multiple sclerosis.

CONTEXT: Human herpesvirus 6 (HHV-6) has been linked with multiple sclerosis (MS). OBJECTIVES: To determine HHV-6 viral load in patients with MS, and to analyze separately its 2 variants, HHV-6A and HHV-6B. PATIENTS AND METHODS: We analyzed 149 blood and serum samples; 103 were from patients with relapsing-remitting MS (33 during an MS relapse and 70 during remission), and 46 were from healthy blood donors. To determine whether the HHV-6 genome and its variants were present, we analyzed viral DNA using quantitative real-time polymerase chain reaction, which has a sensitivity of 1 copy. RESULTS: We found HHV-6 DNA in the peripheral blood mononuclear cells of 53.4% of patients and 30.4% of healthy blood donors; HHV-6A was found in 20.4% of patients and 4.4% of controls, and HHV-6B was found in 33.0% vs 26.1%, respectively. Mean viral load in both groups was 7.4 copies of HHV-6 per microgram of DNA (range, 1-15 copies). Analysis of serum samples showed that none of the healthy blood donors were positive for HHV-6, although 14.6% of patients were positive for the virus, specifically the HHV-6A variant. There was no difference between patients during remission or relapse. Mean viral load was 26.3 copies/microg microgram of DNA (range, 1-86 copies). CONCLUSIONS: Despite the low viral load and the lack of clinical correlation, and given the biological characteristics of the virus, our results suggest that there was active HHV-6A infection in 14.6% of patients with MS. Further quantitative real-time polymerase chain reaction studies will help us understand the clinical significance of such a low viral load.

Determinación de genomas de virus de la familia herpesviridae en enfermos de esclerosis múltiple, por la reacción en cadena de la polimerasa (pcr) / Determination of the genomes of viruses of the Herpesviridae family in patients with multiple sclerosis by polymerase chain reaction (PCR)

Fundamentos: La esclerosis múltiple parece ser el fruto de la conjunción de una predisposición genética y un factor ambiental desconocido, que originarían una alteración de tipo autoinmune, que sería la causante de la inflamación y desmielinización propias de la enfermedad. Con el objetivo de determinar este posible factor ambiental hemos estudiado la presencia de virus de la familia Herpesviridae en enfermos de esclerosis múltiple. Métodos: Se estudiaron 204 muestras de sangre: 102 de enfermos de esclerosis múltiple recurrente-remitente, (43 estaban bajo tratamiento con interferón ß), y 102 de donantes de sangre, con las mismas características de edad y sexo que los pacientes de esclerosis múltiple. De estas muestras extrajimos el ADN total, y lo analizamos mediante la reacción en cadena de la polimerasa (PCR) con el fin de detectar la presencia de virus del herpes simple, virus de la varicela zoster, virus de Epstein-Barr, citomegalovirus, herpesvirus humano 6, herpesvirus humano 7 y herpesvirus humano 8. Resultados: a) Tan solo encontramos diferencias estadísticamente significativas (p = 0,0001) para herpesvirus humano 6: un 21,5 por ciento de muestras positivas en donantes (22/102), frente a un 49,02 por ciento de positividad en enfermos de esclerosis múltiple (50/102); b) no encontramos diferencias estadísticamente significativas para ninguno de los virus estudiados entre los pacientes que recibieron interferón ß y los que no lo recibieron. Conclusiones: Estos resultados nos hacen pensar que el herpesvirus humano 6, en enfermos de esclerosis múltiple, puede establecer una infección sistémica, si bien desconocemos cómo actúa en esta enfermedad. El tratamiento con interferón ß no afecta a las prevalencias de ADN de ninguno de los virus estudiados (AU)