Hemifacial spasm through the last three decades: From etiology to efficacy and safety of long-term botulinum toxin treatment.

BACKGROUND: Hemifacial spasm (HFS) is an uncommon movement disorder characterized by involuntary contractions of muscles innervated by the facial nerve. The aim of this study is to analyze the etiology of HFS as well as the efficacy and safety of long-term botulinum toxin type A (BTX-A) treatment. METHODS: Retrospective study including 125 patients with HFS treated with BTX-A from 1993 to 2019. Demographic and etiological variables as well as doses, number of sessions of BTX-A, infiltrated muscles, therapeutic response according to Patient Global Impression of Change Scale (PGIC-S), side effects and adjuvant treatments were analyzed. In addition, these variables were compared according to the etiology (idiopathic versus secondary). RESULTS: 92 patients (73.6%) were women and the mean age at diagnosis was 58.63 years (SD 15.4). The etiology was idiopathic in 79 patients (63.2%), 17.6% were secondary to Bell's palsy, 14.4% to vascular compression and 2.4% to tumors. A higher total dose per session was observed in the secondary group. PGIC-S showed a good response in 96% of cases. 16 patients (12.8%) required pharmacological concomitant treatment. 59 patients (47.2%) developed side effects. Transient eyelid ptosis and facial weakness were the most common. CONCLUSIONS: The structural origin of a significant number of cases of HFS makes essential to complete an etiological diagnosis in all patients. In addition, the existence of a secondary cause could be associated with greater doses of BTX-A to achieve a good response. Regardless the etiology, long-term treatment with BTX-A in HFS is safe and effective.

Experiencia clínica en el tratamiento de las fluctuaciones motoras en la enfermedad de Parkinson. Consenso Delphi de un grupo / Clinical experience in the treatment of motor fluctuations in Parkinsons disease. Delphi consensus of a group of experts in movement disorders

INTRODUCCIÓN: Las fluctuaciones motoras son una de las complicaciones más frecuentes en la enfermedad de Parkinson y su tratamiento sigue siendo complejo. Por ello, desde el Grupo de Trastornos del Movimiento de la Asociación Madrileña de Neurología presentamos nuestra experiencia clínica en el tratamiento de estas complicaciones, con la intención de que sea de utilidad en la toma de decisiones en la práctica clínica diaria. DESARROLLO: Se elaboraron 19 preguntas a partir de una revisión bibliográfica y una encuesta abierta respondida por los miembros de dicho grupo. Dichas cuestiones se debatieron en dos fases, utilizando la metodología Delphi. Considerando los resultados de la encuesta, el ajuste de la dosis de levodopa y los agonistas dopaminérgicos son la opción con mejor relación eficacia/tolerabilidad en el tratamiento de las fluctuaciones motoras. La rotigotina es útil en las fluctuaciones motoras asociadas a gastroparesia, y la apomorfina subcutánea intermitente, en pacientes con off impredecible. El efecto adverso más relevante asociado a los agonistas dopaminérgicos es el trastorno del control de impulsos. Los inhibidores de la catecol-O-metiltransferasa son útiles en las fluctuaciones motoras de inicio, especialmente en el wearing off. Los inhibidores de la monoaminooxidasa son fármacos, en general, bien tolerados y útiles en las fluctuaciones motoras. En caso de que estas medidas no resulten eficaces, se deben indicar terapias de segunda línea de manera individualizada. CONCLUSIÓN: El perfil clínico del paciente con enfermedad de Parkinson es primordial para decidir la terapia más adecuada en el tratamiento de las fluctuaciones motora

INTRODUCTION. Motor fluctuations are one of the most common complications of Parkinsons disease and their treatment is still a complex matter. Therefore, from the Neurology Movement Disorders Group we present our clinical experience in the treatment of these complications, with the intention of it being useful in decision-making in daily clinical practice. DEVELOPMENT. Nineteen questions were developed based on a literature review and an open survey answered by members of this group. These issues were discussed in two phases, using the Delphi methodology. Considering the results of the survey, levodopa dose adjustment and dopamine agonists are the option with the best efficacy/tolerability ratio in the treatment of motor fluctuations. Rotigotine is useful in the motor fluctuations associated with gastroparesis, and intermittent subcutaneous apomorphine has positive effects in patients with unpredictable off periods. The most relevant adverse effect associated with dopamine agonists is impulse control disorder. Catechol-O-methyltransferase inhibitors are useful in the initial stages of motor fluctuations, especially in wearing off. Monoamine oxidase inhibitors are generally drugs that are well-tolerated and useful in motor fluctuations. If these measures are not effective, second-line treatments should be indicated on a case-by-case basis. CONCLUSION. The clinical profile of patients with Parkinson's disease is paramount in deciding the most appropriate therapy for the treatment of motor fluctuations

Efficacy and Safety of Long-Term Therapy with Type A Botulinum Toxin in Patients with Blepharospasm.

Blepharospasm (BPS) is one of the most frequent types of facial dystonia and, at the same time, one of the most disabling, being able to trigger functional blindness if not treated. Our aim with this work was to evaluate the efficacy and safety of long-term onabotulinum A toxin (BAT) treatment in a cohort of patients with BPS. The retrospective study was conducted on consecutive patients with BPS treated with subcutaneous BAT. The selection of muscles and dose was made based on each patient's needs. The clinical and demographic characteristics, number of sessions, dose, duration and effectiveness of treatment, and adverse events were analysed. 130 patients were included in the study. The median (95% confidence interval) length of follow-up was 14 (13-15.6) years with an average of 20.5 sessions (range from 10 to 57). Regarding the efficacy of the treatment, 114 (87.7%) experienced satisfactory results with functional and aesthetics recovery. Patient evaluation of global response suggested a clear improvement without adverse events in 72 (55.4%) patients. Adverse events developed at least once during the treatment in 39% of patients, with transient ptosis and haematoma the most common reported both by physician and patient. The results of our study suggest that botulin toxin A is a safe and effective long-term treatment for blepharospasm with mild, transient and well-tolerated side effects when they appear.

On the interaction between the imidazolium cation and aromatic amino acids. A computational study.

Complexes formed by the imidazolium cation and the aromatic amino acids, phenylalanine, tyrosine, tryptophan, and histidine have been studied by using computational methods. Complexation energies estimated at the MP2.X level amount to -123.3, -124.6, -131.5 and -145.5 kJ mol(-1) for Phe, Tyr, Trp and His, respectively. The results obtained for Phe, Tyr and Trp complexes are similar, with the most stable minima corresponding to structures with the imidazolium cation stacked over the rings. The cation forms hydrogen bonds with the amino acid while establishing cationπ contacts with the aromatic rings. Extended structures with the amino acids in zwitterionic form are almost equally stable, though. The interaction is controlled by electrostatics and induction, though the preference for the stacked minima is due to larger contributions from induction and dispersion despite the energy cost of folding the amino acid. His complexes exhibit a totally different behaviour, and no structures displaying cationπ interactions are found among the most stable minima. Most favourable complexes of His show the cation hydrogen bonded to the amino acid in extended zwitterionic form. Overall, Phe, Tyr and Trp complexes can show parallel structures in competition with similarly stable zwitterionic ones, while His only shows zwitterionic minima, with a stability even larger than any of the other aromatic amino acids, though lacking participation of the π cloud in the interaction.

Aromatic Amino Acids-Guanidinium Complexes through Cation-π Interactions.

Continuing with our interest in the guanidinium group and the different interactions than can establish, we have carried out a theoretical study of the complexes formed by this cation and the aromatic amino acids (phenylalanine, histidine, tryptophan and tyrosine) using DFT methods and PCM-water solvation. Both hydrogen bonds and cation-π interactions have been found upon complexation. These interactions have been characterized by means of the analysis of the molecular electron density using the Atoms-in-Molecules approach as well as the orbital interactions using the Natural Bond Orbital methodology. Finally, the effect that the cation-π and hydrogen bond interactions exert on the aromaticity of the corresponding amino acids has been evaluated by calculating the theoretical NICS values, finding that the aromatic character was not heavily modified upon complexation.

Antiphospholipid antibodies correlate with stroke severity and outcome in patients with antiphospholipid syndrome.

BACKGROUND: Our goal was to analyze the association of the level of antiphospholipid antibodies (aPLs) with stroke severity and outcome in patients with antiphospholipid syndrome (APS). METHODS: Observational study included consecutive patients with ischemic stroke younger than 55 years (2007-2012). We analyzed serum levels of aPLs, including anticardiolipin (aCL) antibodies, anti-ß2-glycoprotein I antibodies (anti-ß2GPI) and antiprothrombin antibodies (aPS/PT) within the first 48 h after admission, and again, in the case of a positive result, at least 12 weeks after the first measurement. Stroke severity was measured by the National Institutes of Health Stroke Scale (NIHSS), and the three-month stroke outcome by the modified Rankin Scale (mRS). Multiple linear regression models were used to analyze the correlation between the aPLs and stroke severity and outcome. RESULTS: Overall 255 stroke patients were included, 22 (8.6%) with APS. Among them, a positive correlation was found between immunoglobulin M (IgM) aCL levels within 48 h and NIHSS (rho = 0.471; p = 0.027), as well as a tendency toward a positive correlation between immunoglobulin G (IgG) anti-ß2GPI levels within 48 h and three-month mRS (rho = 0.364; p = 0.096). Multiple linear regression analyses showed a positive correlation between levels of IgM aCL < 48 h and the NIHSS (ß-coefficient [standard error; SE] = 0.127 [0.044]), as well as the levels of IgG anti-ß2GPIwithin 48 h and the three-month mRS (ß-coefficient [SE] = 0.034 [0.011]). CONCLUSIONS: In young stroke patients with APS, serum levels of IgM aCL within 48 h are correlated with stroke severity and levels of IgG anti-ß2GPI within 48 h are correlated with three-month outcomes.

Interaction between the guanidinium cation and aromatic amino acids.

The interaction of the guanidinium cation with phenylalanine, tyrosine and tryptophan has been studied using a variety of computational methods. Benchmark values for the interaction have been estimated using the CCSD(T) method extrapolated to the complete basis set limit, indicating that the complexation energy amounts to -123.0, -124.4 and -134.2 kJ mol(-1) for Phe, Tyr and Trp, respectively. Most stable minima correspond to neutral folded amino acids, with the cation interacting simultaneously with the carboxyl oxygen, the amino nitrogen and the aromatic ring. However, complexes with the amino acids as zwitterions are as stable as neutral ones. The final relative stability of the different structures results from a complex balance among different contributions to the complexation energy. Extended neutral structures are favored by larger electrostatic and smaller repulsion contributions, as well as by smaller deformation costs for bringing the amino acid to its final geometry into the complex. Zwitterions show large electrostatic and induction contributions that cancel out the huge deformation cost needed to transfer the proton to the amino group. The presence of the cation···π contact in folded minima introduces larger contributions from induction and dispersion (also as a consequence of the bulky guanidinium cation) that are able to overcome other effects, making folded minima the most stable together with zwitterionic ones.

Acute ischemic stroke patients with diabetes should not be excluded from intravenous thrombolysis.

The benefit of intravenous thrombolysis (IVT) has been questioned for patients with diabetes mellitus (DM) in cases of acute ischemic stroke (IS). Our objective was to analyze the differences in outcome according to prior diagnosis of DM and the use or not of IVT. Observational study with inclusion of consecutive IS patients admitted to an stroke unit. Demographic data, vascular risk factors, comorbidity, stroke severity and 3-month follow-up outcome (modified Rankin Scale) were compared according to prior diagnosis of DM and the use or not of IVT. A total of 1,139 IS patients were admitted; 283 (24.8%) patients had a diagnosis of DM, and 261 were IVT treated (23.2% of the group without DM and 21.9% of the DM group). The IVT-treated patients with DM were older, had more comorbidities and had higher glucose levels on admission than those without DM and than IVT-treated patients. No significant differences in stroke severity, hemorrhagic transformation, in-hospital mortality or outcome at 3 months were found. The logistic regression analysis showed that stroke severity was associated with a higher risk of a poor outcome in IVT-treated patients, with no significant effect from DM after adjustment for confounders. Moreover, IVT was independently associated with a lower risk of poor outcome in DM patients (OR 0.49; 95% CI 0.31-0.76; P = .002). DM patients should not be excluded from IVT, because DM is not associated with a poor outcome after IVT and this treatment is clearly beneficial for DM patients as compared with DM patients not treated with IVT.

Effect of stepwise microhydration on the guanidinium···π interaction.

The characteristics of the interaction of microhydrated guanidinium cation with the aromatic moieties present in the aromatic amino acids side chains have been studied by means of computational methods. The most stable minima found for non-hydrated complexes correspond in all cases to structures with guanidinium oriented toward the ring and interacting by means of N-H···π hydrogen bonds. The interaction becomes stronger when going from benzene (-14 kcal mol⁻¹) to phenol (-17 kcal mol⁻¹) to indole (-21 kcal mol⁻¹). These complexes are held together mainly by electrostatics, but with important contributions from induction and dispersion. The presence of a small number of water molecules significantly affects the characteristics of the complexes. Hydrogen bonds formed by water with the cation, another water molecule, or the aromatic units become more and more similar in intensity as water molecules are included in the complex, leading to a great variety of minima with similar stability but showing very different structural patterns. The behavior is similar with the three aromatic units, the differences in stability mainly being a consequence of the different strength of the cation···π contact.

Cation···π interaction and microhydration effects in complexes formed by pyrrolidinium cation and aromatic species in amino acid side chains.

A computational study has been carried out in complexes formed by pyrrolidinium cation and aromatic units present in amino acid side chains. The interaction is stronger with indole (-21.9 kcal mol(-1) at the CCSD(T) complete basis set level) than with phenol (-17.4 kcal mol(-1)) or benzene (-16.1 kcal mol(-1)). Most stable structures show a N-H···π contact between pyrrolidinium cation and the phenyl ring of the three aromatic species, except in phenol complexes where the most stable minimum shows a N-HO hydrogen bond. In phenol and indole complexes, secondary contacts are established between the C-H groups of the carbon skeleton of pyrrolidinium and the aromatic rings or hydroxyl oxygen, being the main reason for the enhanced stability with respect to benzene, where these contacts are not possible. The interaction is mainly controlled by electrostatics, but contributions from induction and dispersion are also significant, especially the latter in indole complexes. These three attractive contributions increase their intensity when going from benzene to phenol and indole. Microhydration effects have been estimated by including up to three water molecules in the complexes. In monohydrated pyrrolidiniumbenzene complex the most stable structure shows the water molecule coordinated to the cation without interacting with the ring. In phenol and indole, otherwise, the water molecule interacts with both the cation and the aromatic species, forming a cyclic hydrogen bond pattern π(phenyl)···H-N-H···O-H···X (X = π, O). This pattern is also present among the most stable structures found for complexes with two and three water molecules, though a variety of almost isoenergetic minima showing different hydrogen bond patterns have been found. Water molecules remove the stability differences between phenol and indole complexes, which already with two water molecules show similar stabilities, though around 5 kcal mol(-1) larger than benzene ones.

Intravenous thrombolysis in stroke patients under 55 years of age: is there a different effect according to etiology and severity?

The effect of intravenous thrombolysis (IVT) according to etiology and stroke severity in young patients with ischemic stroke (IS) has not been described previously. To analyze the effect of IVT in young patients with IS according to etiological subtype and stroke severity. Observational study with inclusion of IS patients under 55 years of age (2007-2012). Two groups were compared according to IVT treatment. Favorable outcomes were defined as 3 months modified Rankin Scale ≤2. Multivariate analyses were performed to determine those factors independently associated with favorable outcomes, and subgroup analyses were conducted to assess the effect of IVT according to etiological stroke subtype and severity on admission, adjusted for other prognostic variables. We evaluated 262 patients. 63 (24%) received IVT. The mean age and the sex distribution were similar in the IVT treated and the non-treated groups. Multivariate analyses showed that IVT was associated with a higher probability of favorable outcome (OR, 95% CI: 4.652, 1.294-16.722) whereas artery dissection (OR, 95% CI: 0.191, 0.056-0.654) and NIHSS (OR, 95% CI: 0.727, 0.664-0.797) were associated with a lower probability of a favorable outcome. The subgroup analysis showed that the beneficial effect of IVT on outcomes was significant in moderate-severe strokes (NIHSS ≥8) (OR, 95% CI: 3.782, 1.095-13.069) and in cardioembolism (OR, 95% CI: 41.887, 1.001-1751.596). In IS patients under 55 years of age, those with moderate-severe strokes benefit more from IVT than those with mild strokes. Cardioembolic infarctions may benefit more from IV tPA than other etiologies.

High-density lipoprotein: a novel marker for risk of in-hospital infection in acute ischemic stroke patients?

BACKGROUND: Several studies have shown that high-density lipoprotein (HDL) cholesterol provides protection against bacterial infections. Our aim was to investigate the influence of HDL cholesterol levels on the risk of developing in-hospital infectious complications after an acute ischemic stroke (IS) as well as the possible effect of prestroke statin treatment on this association. METHODS AND RESULTS: Observational study that included consecutive IS patients during a 5-year period (2006-2010). We analyzed vascular risk factors, prestroke treatments (including statins), laboratory data (including HDL cholesterol levels), stroke severity, and the development of infectious complications (pneumonia, urinary tract infection and sepsis). A multivariate analysis that included HDL cholesterol levels, prior statin treatment and the interaction between both variables was performed to identify those factors associated with the presence of infectious complications. A total of 1,385 patients were included, 130 of whom (9.4%) developed in-hospital infections. The receiver operating characteristic curve showed the predictive value of HDL cholesterol with an area under the curve of 0.597 (95% CI, 0.526-0.668; p = 0.006) and pointed to 38.5 mg/dl of HDL cholesterol (65.5% sensitivity and 53.4% specificity) as the optimal cutoff level for developing infectious complications during hospitalization. An HDL cholesterol level ≥38.5 mg/dl was an independent predictive factor for lower risk of infection (OR 0.308; 95% CI 0.119-0.795), whereas prestroke statin treatment was not associated with the development of infection. CONCLUSIONS: An HDL cholesterol level ≥38.5 mg/dl was independently associated with lower risk for developing infectious complications in acute IS patients. Statins do not influence this association.

Effect of stepwise microhydration on the methylammonium···phenol and ammonium···phenol interaction.

A computational study has been performed for studying the characteristics of the interaction of phenol with ammonium and methylammonium cations. The effect of the presence of water molecules has also been considered by microhydrating the clusters with up to three water molecules. Clusters of phenol with ammonium and methylammonium cations present similar characteristics, though ammonium complexes have been found to be more stable than the methylammonium ones. The first water molecule included in the complexes interacts with a N-H group of ammoniun cations and simultaneously with the hydroxyl oxygen atom of phenol (or the aromatic ring). This first water molecule is more tightly bound in the complex, so the stability gain as more water molecules are included drops significantly by 2-3 kcal mol(-1) with respect to the first one. As more water molecules are included, the differences between favorable coordination sites (the cation, the hydroxyl group or a previous water molecule) decrease. As a consequence, several of the most stable complexes located including three water molecules already exhibit hydrogen bonds between the hydroxyl group and one water molecule. The results indicate that a cyclic pattern formed by a series of hydrogen bonds: π···H-N-H···O-H···O-ϕ, is characteristic of the most stable minima, being kept as more water molecules are included in the system. Therefore, this pattern can be expected to be crucial in ammonium cations···phenol interaction if exposed to the solvent to any degree.