Función cognitiva en pacientes diabéticos tipo-2 con dolor neuropático diabético. Su relación con trastornos afectivos, de ansiedad y del sueño

Abstract

Objetivos: El objetivo general de esta Tesis fue evaluar la función cognitiva en pacientes con Diabetes mellitus tipo 2 (DMT2) con Dolor neuropático diabético (DND) y realizar un análisis comparativo con aquellos pacientes que no tenían dolor neuropático, así como analizar el efecto de la ansiedad, la depresión y los trastornos del sueño sobre la función cognitiva en los pacientes con DND.

Como primer paso en la Tesis, realizamos una revisión sistemática de la literatura y un metaanálisis para analizar la función cognitiva en pacientes con DMT1 o DMT2 con Neuropatía diabética periférica (NDP) y ver qué factores se encontraban asociados en esta relación.

En segundo lugar, y a partir de la información obtenida en el estudio de campo realizado en los pacientes con DMT2 con y sin DND, se analizaron las diferencias en la función cognitiva entre los 2 grupos y se investigaron los factores asociados a la misma en los pacientes con DND. Especialmente el efecto de la ansiedad, la depresión y los trastornos del sueño, así como la influencia de las variables relacionadas con la Diabetes mellitus (DM).

En tercer lugar, y a partir de la información obtenida en el anterior trabajo, se comparó la función cognitiva en pacientes con DMT2 y NDP con y sin Dolor neuropático (DN) en función del sexo y se analizó la influencia que tendría la ansiedad, la depresión y los trastornos del sueño sobre la misma en cada uno de estos grupos.

Metodología Para la revisión sistemática y metaanálisis se utilizó la información incluida en cuatro bases de datos (PubMed, Scopus, PsycInfo y Web of Science) hasta noviembre de 2021. Se incluyeron artículos originales publicados en inglés y español realizados en pacientes con DMT1 o DMT2 y NDP, cuyo objetivo principal era analizar su función cognitiva y ver qué otros factores se encontraban asociados. Posteriormente se realizó un metaanálisis en el que se incluyeron cuatro estudios con participantes diagnosticados de DMT2, donde mediante el uso del Mini-Mental State Examination (MMSE) se comparó la función cognitiva de personas con y sin NDP.

Con posterioridad, y para cumplir el objetivo principal de esta Tesis, llevamos a cabo un estudio transversal en 6 centros de atención primaria de la ciudad de Cádiz (España), entre junio de 2017 y marzo de 2020, en el que la población objeto de estudio eran pacientes con DMT2 y NDP. La existencia de NDP se confirmó mediante la exploración del pie con el Test de Monofilamento de 10 g siguiendo el procedimiento estándar.

Para identificar la presencia de DN se utilizó la escala Douleur Neuropatique-4 (DN4), y en función del resultado clasificamos a los pacientes en dos grupos, con o sin DND. Asimismo, se recogieron variables sociodemográficas y clínicas, se midió la intensidad del dolor (EVA), el estado de ánimo (HADS), la calidad del sueño (MOS), el fenotipo del dolor (NPSI), y la calidad de vida (SF-12v2). Finalmente, y como variable más significativa para este trabajo, se midió la función cognitiva mediante el instrumento de evaluación TYM.

Resultados: En la revisión sistemática y metaanálisis realizados, se identificaron un total de 832 artículos, de los que se seleccionaron 19. La presencia de NDP se asoció con un deterioro cognitivo global en personas con DMT1 en dos estudios (p=0,046; p=0,03) y en los pacientes con DMT2 en cuatro (p<0,00; p<0,02; p=0,011; p0,05). En cuanto a las dimensiones específicas de la función cognitiva, esta revisión mostró que las personas con DMT1 y NDP presentaron peor desempeño en velocidad psicomotora, atención, destreza mental, coordinación óculo-motriz y capacidad visoespacial. Asimismo, en las personas con DMT2 y NDP, los peores resultados se observaron en los dominios relacionados con la memoria, retención visual de la información, atención/concentración y velocidad de reacción. De la misma forma, se observó que la depresión se asoció a un deterioro de la función cognitiva en estas personas con diabetes sin especificar si tenían DMT1 o DMT2 (p<0,01). Por último, el metaanálisis mostró que los sujetos con DMT2 y NDP presentaron un rendimiento cognitivo medio más bajo que aquellos sin NDP (Diferencia de Medias Global: -1,0448; IC 95%: -1,93%; -0,16%).

En el segundo trabajo, donde se analizan los resultados del estudio transversal, se incluyeron un total de 149 pacientes (71 con DND). Se observó, que los pacientes con y sin DND presentaron puntuaciones medias similares en el TYM (41,46; DE=6,70 vs. 41,97; DE=5,50, respectivamente). Sin embargo, aquellos pacientes con DND tuvieron una frecuencia ligeramente menor de deterioro cognitivo (TYM score 41= 40,8% vs. 43,6%) pero peores resultados en la dimensión de fluidez verbal (media=3,53; DE=0,98 vs. media=3,82; DE=0,66). Las variables que se relacionaron con una menor puntuación en el TYM (peor función cognitiva) en pacientes con DND, fueron la mayor edad (B= 0,258, p = 0,001) y estar bajo tratamiento con insulina (B= 2,919, p = 0,060). Por el contrario, los pacientes que tenían hipertensión (B=3,291, p=0,025), puntuaciones más altas en el componente físico del SF-12v2 (B=0,118, p=0,044) o tenían estudios primarios (B= 4,359, p=0,010) y secundarios o universitarios (B=8,369, p=0,001) versus a los sin estudios, presentaban puntuaciones más altas en el TYM (mejor función cognitiva). Asimismo, tener obesidad (OR=17,277; IC95%: 2,000-149,270) y una mayor duración de la diabetes (OR=1,317; IC95%: 1,001-1,733) se relacionaron con un mayor riesgo de deterioro cognitivo. De igual manera, una mayor puntuación en el índice MOS-9 (peor calidad del sueño) (OR=0,944; IC95%: 0,898-0,992), mayor puntuación en el componente mental del SF-12v2 (mejor calidad de vida) (OR=0,911; IC95%: 0,837-0,992), tener estudios primarios vs. no tener estudios (OR=0,055; IC95%: 0,007-0,431) y tomar medicación para dormir (OR=0,069; IC95%: 0,009-0,541) fueron factores asociados a un menor riesgo de deterioro cognitivo. Finalmente, para la comparación de la función cognitiva en pacientes con DMT2 y NDP con y sin DND en función del sexo, se utilizaron los datos procedentes de los mismos 149 pacientes (66 mujeres) del estudio previo. Entre los resultados obtenidos se destaca que un alto porcentaje de mujeres vs. hombres presentaban deterioro cognitivo (50% vs 36,1%) y puntuaron más bajo en el TYM (media en mujeres=40,77; DE=6,03 vs. media en hombres =42,49; DE=6,05).

En referencia a las dimensiones específicas de la función cognitiva, se observó que las mujeres con DND tenían una menor puntuación en tareas de cálculo que los hombres con DND (3,17 vs. 3,52, p= 0,018). Por otra parte, las puntuaciones de las mujeres sin DND fueron menores que las de los hombres sin DND en memoria retrógrada (2,70 vs. 3,74), función ejecutiva (3,83 vs. 4,25) y similitudes (2,51 vs. 3,12). En cuanto a las variables que se encontraban relacionadas con una menor función cognitiva en función del sexo, resultaron significativas el tener una mayor edad (B=0,181) y presentar factores de riesgo cardiovasculares (B=5,059) en mujeres, mientras que, en los hombres, las variables asociadas a menor función cognitiva fueron una mayor edad (B=0,154), mayor duración de la diabetes (B=0,319) y la presencia de depresión (B=0,363). Por el contrario, el mayor nivel educativo se relacionó con puntuaciones más altas en el TYM tanto en mujeres como en hombres. Finalmente, en hombres, la presencia de hipertensión (B = 2,549), tener puntuaciones más altas en la escala de ansiedad HAD (B = 0,551) y en el componente mental del SF-12v2 (B = 0,181) se relacionaron con una mayor puntuación en la función cognitiva.

Conclusiones: A la vista de los resultados obtenidos, se pueden extraer las siguientes conclusiones: - Aunque la revisión sistemática muestra una importante variabilidad de instrumentos y metodologías empleadas en los estudios, la presencia de NDP se asoció con deterioro cognitivo en pacientes con DMT1 y DMT2. Específicamente, los pacientes con DMT1 y NDP, mostraron deterioro en la atención/concentración, flexibilidad mental y velocidad psicomotora, y los pacientes con DMT2 y NDP tenían afectadas las dimensiones relacionadas con la función ejecutiva, la memoria y el tiempo de reacción. Asimismo, un estado de ánimo deprimido se asoció con un rendimiento cognitivo más bajo en pacientes diabéticos con NDP.

- El metaanálisis confirmó que los pacientes con DMT2 y NDP tenían un rendimiento cognitivo más bajo que los pacientes con DMT2 sin NDP.

- En el análisis de los resultados obtenidos en el estudio llevado a cabo en los pacientes DMT2 con y sin DND, se observó que las puntuaciones medias de la función cognitiva global valoradas con el TYM fueron ligeramente inferiores al punto de corte establecido por el autor de la escala, pero fueron similares en pacientes con y sin DND. Sin embargo, Los pacientes con DND tuvieron puntuaciones más bajas en la fluidez verbal (dimensión del TYM) que los pacientes sin DND.

- Factores relacionados con la diabetes como el tratamiento con insulina, la obesidad y una mayor duración de la enfermedad se asociaron con un mayor riesgo de deterioro cognitivo en pacientes con DND. De igual manera, la presencia de depresión se relacionó con un mayor riesgo de deterioro cognitivo. Por el contrario, y en contra de lo esperado, una peor calidad del sueño se relacionó con una mejor función cognitiva.

- Las mujeres con DMT2 con y sin DND presentaban peor función cognitiva que los hombres tanto en la función cognitiva global, como en las diferentes dimensiones. Sin embargo, se hallaron más diferencias en dimensiones de la función cognitiva en aquellos hombres y mujeres con DMT2 sin DND, que en aquellos que si tenían dolor. Por lo que se puede pensar que el dolor tuvo un mayor impacto en la función cognitiva en los hombres.

- La presencia de factores de riesgo cardiovascular fue la variable que más se asociaba con un deterioro de la función cognitiva en las mujeres. Por el contrario, la duración de la DMT2 y la presencia de depresión fueron más importantes en los hombres.

Los resultados obtenidos aportan evidencias sobre la necesidad de abordar a los pacientes con DM y DND desde un enfoque multidisciplinar, con el objetivo de obtener mejores resultados clínicos que ayuden a mantener el buen funcionamiento cognitivo de estos pacientes, así como tener en cuenta los factores asociados a cada sexo.

Aims The general aim of this Thesis was to evaluate the cognitive function in patients with diabetes mellitus type 2 (DMT2) and to compare patients with and without diabetic neuropathic pain (NP). In addition, to know the effect of anxiety, depression and sleep disorders over cognitive function in patients with NP. As a first step in the thesis, we carried out a systematic review of the literature and a metaanalysis to analyse the cognitive function and factors related in patients with diabetes mellitus type 1 (DMT1) or DMT2 with peripheral diabetic neuropathy (DPN). Secondly, from the information obtained in patients with DMT2 with and without neuropathic pain, the differences in the cognitive function between the 2 groups, and the factors related to it in neuropathic pain patients were analysed. We specially focused on the effect of anxiety, depression and sleep disorders, as well as the influence of variables related to diabetes mellitus (DM). Thirdly, and from the information obtained in the previous work, the cognitive function in patients with DMT2 and DPN with and without NP was compared depending on the sex. The influence of anxiety, depression and sleep disorders on cognitive function was also analysed in each group. Methods For the systematic review and meta-analysis, we used publications included in four databases (PubMed, Scopus, PsycInfo and Web of Science) until November 2021. We included original studies, published in English or Spanish, on patients with DMT1 or DMT2 and DPN, whose main objective were to analyse their cognitive function and factors related. Subsequently, a meta-analysis was varied out including four studies with DMT2 patients, comparing the cognitive function (measured by the Mini-Mental State Examination (MMSE)) in people with and without DPN. Subsequently, to fulfill the main objective of this Thesis, we carried out a multicenter cross-sectional study in six primary care centers in Cádiz (Spain), between June 2017 and March 2020, in which the population under study were patients with DMT2 and DPN. The presence of DPN was confirmed by a clinical foot examination using the monofilament test 10g following the standard procedure. The presence of DP was assessed using the “Douleur Neuropathique 4 (DN4)” scale, and according to the result it was classified patients into two groups, with and without diabetic neuropathic pain (DNP). Likewise, we recorded sociodemographic and clinical variables, pain intensity, mood disorders (HADS), sleep quality (MOS), pain phenotype (NPSI) and quality of life (SF-12v2). Finally, the cognitive function, the most significant construct in our work, was measured using the TYM assessment instrument. Results In the systematic review and meta-analysis conducted, a total of 832 articles were initially identified, with a final selection of 19. The presence of DPN was associated with a global cognitive impairment in people with DMT1 in two studies (p=0.046; p=0.03) and in patients with DMT2 in four (p<0.00; p<0.02; p=0.011; p≤0.05). Regarding the specific dimensions of cognitive function, our study showed that people with DMT1 and DPN performed worse in psychomotor speed, attention, mental agility, hand-eye coordination, and visual perception–organization. Likewise, in people with DMT2 and DPN, the worst results were observed in domains related to the memory, visual retention of information, attention/concentration, and reaction speed. Similarly, it was observed that depression was associated with impaired cognitive function in these people with diabetes (p<0,01). Lastly, the meta-analysis showed that subjects with T2DM and DPN had lower mean cognitive performance than those without DPN (Global mean differences: -1,0448; 95% CI: -1,93%; -0,16%). The second work, where the results of the cross-sectional study were analysed, included 149 patients (71 with DNP). It was observed that patients with and without DNP had similar scores on the TYM (mean=41.46; SD=6.70 vs. mean=41.97; SD=5.50). However, those patients with DNP had a slightly lower frequency of cognitive impairment (TYM score ≤41= 40,8% vs. 43,6%), but worse results in the verbal fluency dimension (mean=3,53; SD=0,98 vs. mean=3,82, SD=0,66). The variables associated with a lower TYM score (worse cognitive function) in patients with DNP were older age (B= − 0,258, p = 0,001) and being under insulin treatment (B=−2,919, p=0,060). On the contrary, patients who had hypertension (B=3.291, p=0.025), higher scores in the physical component of the SF-12v2 (B=0.118, p=0.044) or had primary (B= 4.359, p=0.010) and secondary or university studies (B=8.369, p=0.001) (compared to those without studies), had higher scores on the TYM (better cognitive function). Likewise, having obesity (OR=17,277; 95% CI: 2,000-149,270) and a longer duration of diabetes (OR=1,317; 95% CI: 1,001-1,733) were related to a greater risk of cognitive impairment. Similarly, higher scores on the MOS-9 index (worse sleep quality) (OR=0.944; 95%CI: 0.898-0.992), higher scores in the mental component of the SF-12 (better quality of life) (OR=0.911; 95%CI: 0.837-0.992), having primary education vs. not having studies (OR=0.055; 95%CI: 0.007-0.431), and taking sleeping medication (OR=0.069; 95%CI: 0.009-0.541) were factors associated with a lower risk of cognitive impairment. Finally, for the comparison of cognitive function in patients with T2DM and DPN with and without DNP according to sex, the data from the 149 patients (66 women) from the previous study were used. Among the results obtained, we highlight that a higher percentage of women had cognitive impairment (50% vs. 36,1% in men) and scored lower on the TYM (mean in women=40,77; SD=6,03 vs. mean in men=42,49; SD=6,05). Regarding the specific dimensions of cognitive function, it was observed that women with DNP had a lower score in calculation tasks (3,17 vs. 3,52 in men, p=0,018). On the other hand, the scores of the women without DNP were lower than the men without DNP in retrograde memory (2,70 vs. 3,74), executive function (3,83 vs. 4,25) and similarities (2,51 vs. 3,12). The variables significantly related to a lower cognitive function according to sex were older age (B=−0,181) and having cardiovascular risk factors (B=−5,059) in women, while, in men, the variables associated with lower cognitive function were an older age (B=−0,154), a longer duration of diabetes (B=−0,319) and the presence of depression (B=−0,363). In contrast, a higher educational level was associated with higher TYM scores in both women and men. Finally, in men, the presence of hypertension (B = 2.549), higher scores on the HAD anxiety scale (B=0.551) and on the mental component of the SF-12v2 (B = 0.181) were related to better cognitive function.

Aims The general aim of this Thesis was to evaluate the cognitive function in patients with diabetes mellitus type 2 (DMT2) and to compare patients with and without diabetic neuropathic pain (NP). In addition, to know the effect of anxiety, depression and sleep disorders over cognitive function in patients with NP. As a first step in the thesis, we carried out a systematic review of the literature and a metaanalysis to analyse the cognitive function and factors related in patients with diabetes mellitus type 1 (DMT1) or DMT2 with peripheral diabetic neuropathy (DPN). Secondly, from the information obtained in patients with DMT2 with and without neuropathic pain, the differences in the cognitive function between the 2 groups, and the factors related to it in neuropathic pain patients were analysed. We specially focused on the effect of anxiety, depression and sleep disorders, as well as the influence of variables related to diabetes mellitus (DM). Thirdly, and from the information obtained in the previous work, the cognitive function in patients with DMT2 and DPN with and without NP was compared depending on the sex. The influence of anxiety, depression and sleep disorders on cognitive function was also analysed in each group. Methods For the systematic review and meta-analysis, we used publications included in four databases (PubMed, Scopus, PsycInfo and Web of Science) until November 2021. We included original studies, published in English or Spanish, on patients with DMT1 or DMT2 and DPN, whose main objective were to analyse their cognitive function and factors related. Subsequently, a meta-analysis was varied out including four studies with DMT2 patients, comparing the cognitive function (measured by the Mini-Mental State Examination (MMSE)) in people with and without DPN. Subsequently, to fulfill the main objective of this Thesis, we carried out a multicenter cross-sectional study in six primary care centers in Cádiz (Spain), between June 2017 and March 2020, in which the population under study were patients with DMT2 and DPN. The presence of DPN was confirmed by a clinical foot examination using the monofilament test 10g following the standard procedure. The presence of DP was assessed using the “Douleur Neuropathique 4 (DN4)” scale, and according to the result it was classified patients into two groups, with and without diabetic neuropathic pain (DNP). Likewise, we recorded sociodemographic and clinical variables, pain intensity, mood disorders (HADS), sleep quality (MOS), pain phenotype (NPSI) and quality of life (SF-12v2). Finally, the cognitive function, the most significant construct in our work, was measured using the TYM assessment instrument. Results In the systematic review and meta-analysis conducted, a total of 832 articles were initially identified, with a final selection of 19. The presence of DPN was associated with a global cognitive impairment in people with DMT1 in two studies (p=0.046; p=0.03) and in patients with DMT2 in four (p<0.00; p<0.02; p=0.011; p≤0.05). Regarding the specific dimensions of cognitive function, our study showed that people with DMT1 and DPN performed worse in psychomotor speed, attention, mental agility, hand-eye coordination, and visual perception–organization. Likewise, in people with DMT2 and DPN, the worst results were observed in domains related to the memory, visual retention of information, attention/concentration, and reaction speed. Similarly, it was observed that depression was associated with impaired cognitive function in these people with diabetes (p<0,01). Lastly, the meta-analysis showed that subjects with T2DM and DPN had lower mean cognitive performance than those without DPN (Global mean differences: -1,0448; 95% CI: -1,93%; -0,16%). The second work, where the results of the cross-sectional study were analysed, included 149 patients (71 with DNP). It was observed that patients with and without DNP had similar scores on the TYM (mean=41.46; SD=6.70 vs. mean=41.97; SD=5.50). However, those patients with DNP had a slightly lower frequency of cognitive impairment (TYM score ≤41= 40,8% vs. 43,6%), but worse results in the verbal fluency dimension (mean=3,53; SD=0,98 vs. mean=3,82, SD=0,66). The variables associated with a lower TYM score (worse cognitive function) in patients with DNP were older age (B= − 0,258, p = 0,001) and being under insulin treatment (B=−2,919, p=0,060). On the contrary, patients who had hypertension (B=3.291, p=0.025), higher scores in the physical component of the SF-12v2 (B=0.118, p=0.044) or had primary (B= 4.359, p=0.010) and secondary or university studies (B=8.369, p=0.001) (compared to those without studies), had higher scores on the TYM (better cognitive function). Likewise, having obesity (OR=17,277; 95% CI: 2,000-149,270) and a longer duration of diabetes (OR=1,317; 95% CI: 1,001-1,733) were related to a greater risk of cognitive impairment. Similarly, higher scores on the MOS-9 index (worse sleep quality) (OR=0.944; 95%CI: 0.898-0.992), higher scores in the mental component of the SF-12 (better quality of life) (OR=0.911; 95%CI: 0.837-0.992), having primary education vs. not having studies (OR=0.055; 95%CI: 0.007-0.431), and taking sleeping medication (OR=0.069; 95%CI: 0.009-0.541) were factors associated with a lower risk of cognitive impairment. Finally, for the comparison of cognitive function in patients with T2DM and DPN with and without DNP according to sex, the data from the 149 patients (66 women) from the previous study were used. Among the results obtained, we highlight that a higher percentage of women had cognitive impairment (50% vs. 36,1% in men) and scored lower on the TYM (mean in women=40,77; SD=6,03 vs. mean in men=42,49; SD=6,05). Regarding the specific dimensions of cognitive function, it was observed that women with DNP had a lower score in calculation tasks (3,17 vs. 3,52 in men, p=0,018). On the other hand, the scores of the women without DNP were lower than the men without DNP in retrograde memory (2,70 vs. 3,74), executive function (3,83 vs. 4,25) and similarities (2,51 vs. 3,12). The variables significantly related to a lower cognitive function according to sex were older age (B=−0,181) and having cardiovascular risk factors (B=−5,059) in women, while, in men, the variables associated with lower cognitive function were an older age (B=−0,154), a longer duration of diabetes (B=−0,319) and the presence of depression (B=−0,363). In contrast, a higher educational level was associated with higher TYM scores in both women and men. Finally, in men, the presence of hypertension (B = 2.549), higher scores on the HAD anxiety scale (B=0.551) and on the mental component of the SF-12v2 (B = 0.181) were related to better cognitive function. Conclusions In view of the results obtained, the following conclusions can be drawn: - Although the systematic review shows a significant variability of instruments and methodologies used in the studies, the presence of DPN was associated with cognitive deterioration in patients with DMT1 and DMT2 in any case. Specifically, patients with DMT1 and DPN showed impaired attention/concentration, mental flexibility, and psychomotor speed, and patients with DMT2 and NDP showed impaired executive function, memory, and reaction time. Likewise, a depressed mood was associated with lower cognitive performance in patients with DPN. - The meta-analysis confirmed that T2DM patients with DPN had lower cognitive performance than T2DM patients without DPN. - In the analysis of the results obtained in the study carried out in DMT2 patients with and without DNP, it was observed that the mean scores of global cognitive functions assessed with the TYM were slightly lower than the cut-off point established by the author of the scale, but they were similar in patients with and without DND. However, patients with DNP had lower scores on verbal fluency (a TYM dimension) than patients without DNP. - Diabetes-related factors such as insulin treatment, obesity, and longer disease duration were associated with increased risk of cognitive impairment in patients with DNP. Similarly, the presence of depression was associated with an increased risk of cognitive impairment. Contrary to expectations, poorer sleep quality was associated with better cognitive function. - Women with DMT2 with and without DNP had worse cognitive function than men, both in global cognitive function and in the different dimensions. However, more differences in dimensions of cognitive function were found between men and women with DMT2 without DNP, than in those with pain. Thus, it can be thought that pain had a greater impact on cognitive function in men. - The presence of cardiovascular risk factors was the factor most strongly associated with impaired cognitive function in women. In contrast, the duration of DMT2 and the presence of depression were more important in men. The results obtained provide evidence of the need to address patients with DM and DNP from a multidisciplinary approach, with the aim of obtaining better clinical results that help maintain the good cognitive functioning of these patients, as well as take into account the factors associated with each sex.