Clinical differences in a multidisciplinary pediatric pain unit between primary and secondary chronic pain.

INTRODUCTION: Chronic pain affects an important part of the pediatric population in developed countries. secondary chronic pain (SCP) can have a well-defined medical cause, but primary chronic pain (PCP) can have an unknown etiology. In Spain, there is as yet no information on the clinical differences between patients treated in multidisciplinary units. METHODS: Retrospective analysis of the clinical records of patients seen in 2018 at the Children's Chronic Pain Unit in University La Paz Hospital. RESULTS: A total of 92 patients were included, (age between 3 and 19 years), with a mean age of 12.4 (SD = 4.1) years, mostly female (55%), with a mean duration of pain of 11.3 (SD = 10.4) months. A comparison of patients with PCP (n = 31) and SCP (n = 61) showed that both groups, on average, presented intense pain (X = 5.9; SD = 2.2; range = 0-10), with similar duration and functional repercussions, although PCP was less likely to be associated with neuropathic descriptors than SCP (p = 0.040), and was more extensive (p < 0.001). Both groups received similar treatment, based on rehabilitation, psychotherapy, invasive techniques and analgesic medication, although patients in the PCP group received less analgesic medication (gabapentinoids and opioids) than the SCP (p = 0.011). CONCLUSION: Patients treated in a multidisciplinary Child Pain Unit for PCP or SCP present a very similar clinical profile, though with differences in the number and type of analgesic drugs used. This shows the importance of etiologic diagnosis for adequate pharmacological treatment.

Effects of ATLAS 2030 gait exoskeleton on strength and range of motion in children with spinal muscular atrophy II: a case series.

BACKGROUND: Children with spinal muscular atrophy (SMA) present muscle weakness and atrophy that results in a number of complications affecting their mobility, hindering their independence and the development of activities of daily living. Walking has well-recognized physiological and functional benefits. The ATLAS 2030 exoskeleton is a paediatric device that allows gait rehabilitation in children with either neurological or neuromuscular pathologies with gait disorders. The purpose is to assess the effects in range of motion (ROM) and maximal isometric strength in hips, knees and ankles of children with SMA type II after the use of ATLAS 2030 exoskeleton. METHODS: Three children (mean age 5.7 ± 0.6) received nine sessions bi-weekly of 60 min with ATLAS 2030. ROM was assessed by goniometry and strength by hand-held dynamometer. All modes of use of the exoskeleton were tested: stand up and sit down, forward and backward walking, and gait in automatic and active-assisted modes. In addition, different activities were performed during the gait session. A descriptive analysis of all variables was carried out. RESULTS: The average time of use was 53.5 ± 12.0 min in all sessions, and all participants were able to carry out all the proposed activities as well as to complete the study. Regarding isometric strength, all the measurements increased compared to the initial state, obtaining the greatest improvements for the hip flexors (60.2%) and extensors muscles (48.0%). The ROM increased 12.6% in hip and 34.1% in the ankle after the study, while knee ROM remained stable after the study. CONCLUSION: Improvements were showed in ROM and maximal isometric strength in hips, knees and ankles after using ATLAS 2030 paediatric gait exoskeleton in all three children. This research could serve as a preliminary support for future clinical integration of ATLAS 2030 as a part of a long-term rehabilitation of children with SMA. TRIAL REGISTRATION: The approval was obtained (reference 47/370329.9/19) by Comunidad de Madrid Regional Research Ethics Committee with Medical Products and the clinical trial has been registered on Clinical Trials.gov: NCT04837157.

Delphi consensus on recommendations for the treatment of spinal muscular atrophy in Spain (RET-AME consensus).

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a biallelic mutation of the SMN1 gene, located on the long arm of chromosome 5, and predominantly affects the motor neurons of the anterior horn of the spinal cord, causing progressive muscle weakness and atrophy. The development of disease-modifying treatments is significantly changing the natural history of SMA, but uncertainty remains about which patients can benefit from these treatments and how that benefit should be measured. METHODOLOGY: A group of experts specialised in neurology, neuropediatrics, and rehabilitation and representatives of the Spanish association of patients with SMA followed the Delphi method to reach a consensus on 5 issues related to the use of these new treatments: general aspects, treatment objectives, outcome assessment tools, requirements of the treating centres, and regulation of their use. Consensus was considered to be achieved when a response received at least 80% of votes. RESULTS: Treatment protocols are useful for regulating the use of high-impact medications and should guide treatment, but should be updated regularly to take into account the most recent evidence available, and their implementation should be assessed on an individual basis. Age, baseline functional status, and, in the case of children, the type of SMA and the number of copies of SMN2 are characteristics that should be considered when establishing therapeutic objectives, assessment tools, and the use of such treatments. The cost-effectiveness of these treatments in paediatric patients is mainly influenced by early treatment onset; therefore, the implementation of neonatal screening is recommended. CONCLUSIONS: The RET-AME consensus recommendations provide a frame of reference for the appropriate use of disease-modifying treatments in patients with SMA.

Multiple red blood cell transfusions and iron overload in very low birthweight infants.

BACKGROUND AND OBJECTIVES: To estimate the risk of iron overload in very low birthweight (VLBW) infants who receive more than two red blood cell (RBC) transfusions, in comparison with those who receive two or less during their hospital stay. MATERIALS AND METHODS: Prospective open cohort study in VLBW infants with >2 (exposed) and ≤2 (non-exposed) RBC transfusions. Ferritin, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured at birth and after each RBC transfusion. The incidence of iron overload was determined. Risk factors were analysed using a logistic regression model. RBC transfusion volume correlations with ferritin, ALT and AST were calculated with Spearman's rank correlation coefficient, as well as correlations between ferritin and aminotransferases. RESULTS: A total of 63 patients were enrolled, 18 of which were exposed and 45 non-exposed. Twelve patients developed severe iron overload, eight exposed (44·5%) vs. four (8·8%) non-exposed (RR: 5, 95% CI: 1·7-14·6). Multivariate analysis showed that the number of transfusions increased the risk of iron overload (OR: 2·07, 95% CI: 1·36-2·14) while a higher one-minute Apgar score was associated with a lower risk (OR: 0·56, 95% CI: 0·32-0·99). Severe iron overload mainly occurred with a transfusion volume higher than 120 ml/kg. There was a positive correlation between ferritin and transfusion (r = 0·53; P < 0·001). CONCLUSION: There was a higher risk of iron overload in exposed infants in comparison with non-exposed infants. Severe iron overload in VLBW infants may occur with a total transfusion volume >120 ml/kg.

[Clinical guidelines for infantile-onset Pompe disease]. / Guia clinica de la enfermedad de Pompe infantil.

Infantile-onset Pompe disease has a fatal prognosis in the short term unless it is diagnosed at an early stage and enzyme replacement therapy is not started as soon as possible. A group of specialists from different disciplines involved in this disease have reviewed the current scientific evidence and have drawn up an agreed series of recommendations on the diagnosis, treatment and follow-up of patients. We recommend establishing enzyme treatment in any patient with symptomatic Pompe disease with onset within the first year of life, with a clinical and enzymatic diagnosis, and once the CRIM (cross-reactive immunological material) status is known.

TITLE: Guia clinica de la enfermedad de Pompe infantil.La enfermedad de Pompe infantil tiene un pronostico fatal a corto plazo si no se diagnostica precozmente ni se inicia un tratamiento enzimatico sustitutivo lo antes posible. Un grupo de especialistas de las diferentes disciplinas involucradas en esta enfermedad ha revisado la evidencia cientifica actual y ha elaborado por consenso una serie de recomendaciones para el diagnostico, el tratamiento y el seguimiento de los pacientes. Se recomienda instaurar tratamiento enzimatico en todo paciente con enfermedad de Pompe sintomatica de comienzo en el primer año de vida, con diagnostico clinico y enzimatico, y una vez conocido el estado CRIM (material inmunologico con reactividad cruzada).

Diazoxide enhances excitotoxicity-induced neurogenesis and attenuates neurodegeneration in the rat non-neurogenic hippocampus.

Diazoxide, a well-known mitochondrial KATP channel opener with neuroprotective effects, has been proposed for the effective and safe treatment of neuroinflammation. To test whether diazoxide affects the neurogenesis associated with excitotoxicity in brain injury, we induced lesions by injecting excitotoxic N-methyl-d-aspartate (NMDA) into the rat hippocampus and analyzed the effects of a daily oral administration of diazoxide on the induced lesion. Specific glial and neuronal staining showed that NMDA elicited a strong glial reaction associated with progressive neuronal loss in the whole hippocampal formation. Doublecortin immunohistochemistry and bromo-deoxyuridine (BrdU)-NeuN double immunohistochemistry revealed that NMDA also induced cell proliferation and neurogenesis in the lesioned non-neurogenic hippocampus. Furthermore, glial fibrillary acidic protein (GFAP)-positive cells in the injured hippocampus expressed transcription factor Sp8 indicating that the excitotoxic lesion elicited the migration of progenitors from the subventricular zone and/or the reprograming of reactive astrocytes. Diazoxide treatment attenuated the NMDA-induced hippocampal injury in rats, as demonstrated by decreases in the size of the lesion, neuronal loss and microglial reaction. Diazoxide also increased the number of BrdU/NeuN double-stained cells and elevated the number of Sp8-positive cells in the lesioned hippocampus. These results indicate a role for KATP channel activation in regulating excitotoxicity-induced neurogenesis in brain injury.

In vivo adhesion of malignant B cells to bone marrow microvasculature is regulated by α4ß1 cytoplasmic-binding proteins.

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) cells must attach to the bone marrow (BM) microvasculature before lodging in the BM microenvironment. Using intravital microscopy (IVM) of the BM calvariae we demonstrate that the α4ß1 integrin is required for MM and CLL cell firm arrest onto the BM microvasculature, while endothelial P-selectin and E-selectin mediate cell rolling. Talin, kindlin-3 and ICAP-1 are ß1-integrin-binding partners that regulate ß1-mediated cell adhesion. We show that talin and kindlin-3 cooperatively stimulate high affinity and strength of α4ß1-dependent MM and CLL cell attachment, whereas ICAP-1 negatively regulates this adhesion. A functional connection between talin/kindlin-3 and Rac1 was found to be required for MM cell attachment mediated by α4ß1. Importantly, IVM analyses with talin- and kindlin-3-silenced MM cells indicate that these proteins are needed for cell arrest on the BM microvasculature. Instead, MM cell arrest is repressed by ICAP-1. Moreover, MM cells silenced for talin and kindlin-3, and cultured on α4ß1 ligands showed higher susceptibility to bortezomib-mediated cell apoptosis. Our results highlight the requirement of α4ß1 and selectins for the in vivo attachment of MM and CLL cells to the BM microvasculature, and indicate that talin, kindlin-3 and ICAP-1 differentially control physiological adhesion by regulating α4ß1 activity.

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity.

Under pathological conditions, microglia, the resident CNS immune cells, become reactive and release pro-inflammatory cytokines and neurotoxic factors. We investigated whether this phenotypic switch includes changes in the expression of the L-type voltage-gated calcium channel (VGCC) in a rat model of N-methyl-D-aspartate-induced hippocampal neurodegeneration. Double immunohistochemistry and confocal microscopy evidenced that activated microglia express the L-type VGCC. We then analyzed whether BV2 microglia express functional L-type VGCC, and investigated the latter's role in microglial cytokine release and phagocytic capacity. Activated BV2 microglia express the CaV1.2 and CaV1.3 subunits of the L-type VGCC determined by reverse transcription-polymerase chain reaction, Western blot and immunocytochemistry. Depolarization with KCl induced a Ca2+ entry facilitated by Bay k8644 and partially blocked with nifedipine, which also reduced TNF-α and NO release by 40%. However, no nifedipine effect on BV2 microglia viability or phagocytic capacity was observed. Our results suggest that in CNS inflammatory processes, the L-type VGCC plays a specific role in the control of microglial secretory activity.

[Anterior approach in low cervical fractures prodited by hyperflexion or tear drop]. / Abordaje anterior de las fracturas cervicales bajas por mecanismo de hiperflexión o en gota de lágrima.

Hyperflexion or teardrop fracture of low cervical vertebrae is characterised by ligament affectation of the entire intervertebral segment, the vertebral body, primarily its anteroinferior third and, frequently, spinal medullar affectation. This series presents the clinical symptoms, diagnosis, surgical approach, and post surgical evolution in 30 patients with tear drop fractures. Over the last 30 years, thirty patients with tear drop fractures at the low cervical spine (C3-C7) were admitted to our Neurosurgical Service. Diagnostic studies included simple radiographs, computerised axial tomography (CT), and magnetic resonance imaging (MRI), all of which evidenced the instability of the damaged segment due to osteoligamentous affectation, and a primarily vertebral body fracture. Patients' neurological status was according to the Frankel' scale adapted to the American Spinal Injury Association scale (ASIA). 11 patients were included in grade A, 5 in B, 3 in grade C, 2 in grade D and 9 grade E of neurological affectation. Surgery through an anterior approach was performed, an average of 5 days after placement of halo traction, which had been placed on admission to the hospital. Surgery consisted in vertebral corporectomy and placement of a plate and a graft from the iliac crest. The patients' neurological evolution was favourable in all cases with incomplete medullar lesions. There were 11 patients with complete lesions, or Frankel grade A affectation; two died due to other associated lesions and the other nine showed no neurological improvement after surgery. The degree of arthrodesis was good and only one patient required an a combined anterior-posterior approach. We conclude that teardrop fractures were associated with severe neurological affectation in more than 50% of our patients, and that these fractures provoke instability requiring arthrodesis, generally via an anterior approach.