Primary Enuresis Research Articles

Use of ChatGPT in Urology and its Relevance in Clinical Practice: Is it useful?

One of the many artificial intelligence based tools that has gained popularity is the Chat-Generative Pre-Trained Transformer (ChatGPT). Due to its popularity, incorrect information provided by ChatGPT will have an impact on patient misinformation. Furthermore, it may cause misconduct as ChatGPT can mislead physicians on the decision-making pathway. Therefore, the aim of this study is to evaluate the accuracy and reproducibility of ChatGPT answers regarding urological diagnoses. ChatGPT 3.5 version was used. The questions asked for the program involved Primary Megaureter (pMU), Enuresis and Vesicoureteral Reflux (VUR). There were three queries for each topic. The queries were inserted twice, and both responses were recorded to examine the reproducibility of ChatGPT's answers. Afterwards, both answers were combined. Finally, those rwere evaluated qualitatively by a board of three specialists. A descriptive analysis was performed. ChatGPT simulated general knowledge on the researched topics. Regarding Enuresis, the provided definition was partially correct, as the generic response allowed for misinterpretation. For VUR, the response was considered appropriate. For pMU it was partially correct, lacking essential aspects of its definition such as the diameter of the dilatation of the ureter. Unnecessary exams were suggested, for Enuresis and pMU. Regarding the treatment of the conditions mentioned, it specified treatments for Enuresis that are ineffective, such as bladder training. Therefore, ChatGPT responses present a combination of accurate information, but also incomplete, ambiguous and, occasionally, misleading details.

National Survey on bladder and bowel dysfunctions in Autism Spectrum Disorder population.

To evaluate lower urinary tract symptoms (LUTS) and bowel disorders in a population of young subjects with autism spectrum disorder (ADS) by a national survey and to assess the relationship between the occurrence, frequency, and type of LUTS and the severity of behavioral and neuropsychiatric characteristics. A survey on LUTS and bowel disorders in the ASD population was sent by mail and social media through the main Italian Associations of ASD between February and September 2022. The correlation between LUTS and ASD severity was also assessed. The survey was completed by 502 subjects with a mean age of 16.6 years ± 10 years: male participants were 413 (mean age: 16.5 years ± 9.8 years), while female participants 89 (mean age: 17.2 years ± 10.9 years). ADS severity was found low in 29.9%, moderate in 27.1%, and severe in 43%. LUTS were reported by 77.1%, storage symptoms in 51.4%, and voiding symptoms in 60.6%. Urinary incontinence was reported by 12.5%. Enuresis was reported by 14.3% (72/502) of the respondents: primary enuresis in 70.8% (51/72), secondary in the remaining. Pads were used by 40 subjects with a median of 2.9 pads/day (range, 0-8). A toilet training program was performed by 61 of the respondents, with satisfactory results in 40/61 (65.6%). A significant correlation was found between greater ASD severity and higher LUTS rates. The mean VAS score on the impact of LUTS on family relationships was 2 ± 2.9. Regular bowel function was reported by 57.4% (288/502) of the respondents, while increased daily defecations were present in 11.2% (56/502), constipation in 31.5% (158/502), and fecal incontinence in 7.9% (40/502). This survey demonstrated that LUTS are very common in the young ASD population and that the prevalence of urinary symptoms is related to higher severity of the ASD condition. Bowel disorders are often associated with urinary symptoms and dysfunctions. Urologists should be aware of the frequent occurrence of urological disorders and symptoms in individuals with ASD and should be involved in their clinical management in a multidisciplinary team that cares for these people.

Research Progress on the Pathogenesis of Primary Enuresis in Children

Nocturnal enuresis (NE) is a common disease in children, commonly known as bedwetting. The International Children's Continence Society (ICCS) defines intermittent urinary incontinence during nighttime sleep in children aged 5 and above as enuresis. Enuresis can be divided into two types: primary nocturnal enuresis (PNE) and secondary nocturnal enuresis (SNE). PNE refers to nocturnal urinary control ability that has never been achieved for more than 6 months in children aged 5 and above with enuresis; SNE refers to the recurrence of enuresis symptoms after a period of more than 6 months of continuous nocturnal urinary control ability. SNE is relatively rare in clinical practice and is often caused by sudden stress events or other diseases such as snoring. Its pathogenesis and treatment are different from PNE. PNE is a multifactorial disease related to genetics, and its pathogenesis is not fully understood. There are not many research and review articles on its pathogenesis. In recent years, there has been significant progress in the epidemiology and pathogenesis of PNE. The following is a summary.

Prevalence of sleep disorders in children and adolescents with primary monosymptomatic enuresis

Prevalence of sleep disorders in children and adolescents with primary monosymptomatic enuresis

Treating asthma in patients with enuresis: repercussions on urinary symptoms.

Children presenting enuresis are more likely to be asthmatics. The association between enuresis and sleep-disordered breathing has already been demonstrated and several studies have shown at least partial improvement of two thirds or more of the cases of enuresis adenoidectomy. Studies have already described associations between enuresis and allergies but do not assess the repercussions of allergy treatment in enuretics. This study aims to evaluated whether asthma treatment alters the course of enuresis and whether there is any predictive factor associated with this improvement. Twenty patients (5 - 12 years old) with uncontrolled enuresis and asthma, received treatment for asthma. Children were also assessed for the presence of rhinitis and other allergies. The control of asthma was confirmed by a validated questionnaire and primary enuresis by clinical history and wet night diaries. Patients received only asthma treatment. At least partial improvement of enuresis was observed in 55% of the patients with an increase in 64.4% in the number of dry nights at the end of the study (p=0.01). The "presence of other allergies" and "obstruction seen in nasal endoscopy" positively influenced the improvement of urinary symptoms (OR = 3.350; CI 0.844-13.306) and (OR=1.272; CI 0.480-3.370), respectively. Until now, only patients presenting upper airway obstruction were known to benefit from the improvement of urinary symptoms when undergoing treatment for their respiratory problems. In our study, we found at least partial improvement in enuresis in 55% of our patients, with only clinical asthma treatment. Controlling asthma in children with primary enuresis resulted in a significant increase in dry nights.

Comparison between Levels of Vitamin D in Primary Mono-Symptomatic Nocturnal Enuresis and Non-Enuretic Children

Background Enuresis (synonymous with intermittent nocturnal incontinence) refers to discrete episodes of urinary incontinence during sleep in children 25 years of age. Enuresis can be divided into primary enuresis (PE) and secondary enuresis (SE). A child who has never been dry is considered to have PE; a child who has been continent for at least 6 months before the onset of the bedwetting is considered to have SE. The pathogenesis of PE is similar to that of SE. Aim of the Study To compare between the levels of Vitamin D - as an important factor in growth and development - in primary monosymptomatic enuretic and non-enuretic children. Patients and Methods This is a case control study was performed in Ain Shams University Hospitals, Damanhour National Medical Institute. The study started on February 2020. The study included 60 children with primary mono-symptomatic nocturnal enuresis selected randomly and 60 healthy children age and sex matched children as a control group. Results We found that 61.7% of cases in the NE group had low Vit.D level (<20ng/ml) compared with 40% in the control group and this difference is statistically significant Conclusion Our study indicates that there • is a significant relationship between primary monosymptomatic nocturnal enuresis and serum vitamin D deficiency.

Comparison of the Efficacy of Tolterodine versus Oxybutynin in the Treatment of Children with Desmopressin-Resistant Enuresis: A Randomized Controlled Clinical Trial.

Enuresis, defined as involuntary nocturnal urination without any underlying organic disorder in a child expected to control urination, poses a common problem. This study evaluated the effectiveness of Tolterodine and Oxybutynin in children presenting with primary desmopressin-resistant enuresis. A randomized clinical trial was undertaken involving 68 participants aged between 5 and 16 years, all suffering from primary enuresis. These patients were randomly assigned to one of two treatment groups for a three-month period: Group 1, treated with Oxybutynin and Desmopressin, and Group 2, treated with Tolterodine and Desmopressin. Data on demographics, clinical and laboratory findings, and subjective responses to treatment were gathered. The response was measured based on the frequency of wetting incidents per night and week and compared with pre-treatment data. Patients were divided into two groups (30 patients in Group 1 and 38 patients in Group 2). The mean age of the patients was 88.97±27.09 months. In the first treatment group, 6 out of 30 patients (20%) experienced a complete treatment response, as did 5 out of 38 patients (13.2%) in the second treatment group. This difference between the groups was not statistically significant. Seven patients (23%) in the Oxybutynin group and 13 patients (34%) in the Tolterodine group reported a lack of response to treatment, a difference that also lacked statistical significance. For patients resistant to Desmopressin, the addition of anticholinergic drugs elicited a significant response in over half of the patients. However, no benefit was observed in using either Oxybutynin or Tolterodine in the treatment of Desmopressin-resistant enuresis.

High Prevalence of Dysplastic Development of Sacral Vertebral Arches in Pediatric Enuresis.

This is the first report to compare 3-dimensional computed tomography (3D-CT) images between pediatric patients with enuresis and children without lower urinary tract symptoms who underwent pelvic CT for other reasons. Forty-seven children (33 boys and 14 girls) with primary enuresis underwent 3D-CT of sacrococcygeal bones. The control group consisted of 138 children (78 boys and 60 girls) who underwent pelvic CT for other reasons. First, we determined the presence or absence of unfused sacral arches at the L4-S3 levels in both cohorts. Subsequently, we compared the fusion of sacral arches in age- and sex-matched children from these 2 groups. Dysplastic sacral arches, characterized by lack of fusion at 1 or more levels of the S1-3 arches, were observed in nearly all patients in the enuresis group. In the control group (n=138), 54 of 79 children over 10 years old (68%) exhibited fused sacral arches at 3 S1-3 levels. All 11 control children under 4 years old displayed at least 2 unfused sacral arches at the S1-3 levels. In a comparative study of age- and sex-matched patients with enuresis and control children aged 5 to 13 years (n=32 for each group, with 21 boys and 11 girls; mean age, 8.0±2.2 years [range, 5-13 years]), only 1 patient (3%) in the enuresis group exhibited fusion of all S1-3 arches. In contrast, 20 of 32 control group participants (63%) had 3 fused sacral arches (P<0.0001). Sacral vertebral arches typically fuse by the age of 10 years. However, in this study, children with enuresis exhibited a significantly elevated prevalence of unfused sacral arches, suggesting that dysplastic development of sacral vertebral arches may play a pathological role in enuresis.

Clinical observation on the efficacy of Tongdu Tuina manipulation in the treatment of primary enuresis in children.

The objective was to explore the efficacy of Tongdu Tuina manipulation in the treatment of primary single-symptom enuresis in children. A total of 102 children aged 5-16 with primary single-symptom enuresis were included in this study and randomly assigned to the Tuina group, the medication group and the control group, with 34 children in each group. The Tongdu Tuina group included manipulation of the Guanyuan, Qihai, Zhongji, Mingmen, kidney, Baihui, Sishencong and bladder acupoints, five times a week, the medication group was treated with 0.1 mg desmopressin acetate every night, and in the control group, the patients were given foods with high water content and underwent water deprivation 2 h before bedtime every night. The intervention time of each group was 1 month. The participants were followed up on Day 1 following treatment, as well as half a month, 1 month and 3 months after the implementation of the intervention measures, and the effective rate, the incidence of enuresis per week and the recurrence rate were calculated. As a result baseline demographic characteristics were comparable among 102 patients. Overall, 32 patients in the Tongdu Tuina group, 30 patients in the medication group and 34 patients in the control group completed the intervention. After half a month of treatment, there was no significant difference in the therapeutic efficacy among the three groups (P = 0.158), but each treatment could effectively reduce the frequency of weekly enuresis. The frequency of weekly enuresis in the Tongdu Tuina group was 3.8 ± 1.1 times, while that in the medication group was 4.0 ± 2.0 times. The frequency of weekly enuresis in the control group was 4.7 ± 1.8 times, and the difference was statistically significant (P = 0.016). After 1 month of treatment, the effective rates of the Tongdu Tuina group and the medication group were significantly increased (87.5% vs 83.33%, P < 0.0001), which was not the case with the control group. The frequency of enuresis was 1.9 ± 2.1 times per week in the Tongdu Tuina group, 2.4 ± 1.8 times per week in the medication group and 4.0 ± 0.9 times per week in the control group after 1 month of treatment. The difference between the three groups was statistically significant (P = 0.021), and there was a difference between the Tongdu Tuina group and the medication group (P < 0.0001). There was no significant difference between recurrence rate and the incidence of adverse events (P = 0.837, P = 0.856). In conclusion, both Tuina manipulation and desmopressin treatment can effectively improve children's primary single-symptom enuresis with safety. However, Tongdu Tuina therapy may be superior to desmopressin treatment.

Is Allergic Rhinitis Associated With Enuresis Nocturna In Childhood ?

Introduction&#x0D; Allergic rhinitis is the most common form of non-infectious rhinitis and is manifested with the symptoms of nasal congestion, sneezing, nasal discharge, and itching. Primary enuresis nocturna is involuntary urination while asleep after five years, at which bladder control usually begins. Our objective was to evaluate the relationship between allergic rhinitis and primary enuresis nocturna in childhood in this research.&#x0D; Methods:&#x0D; We included 300 children with allergic rhinitis and 300 control cases between the age of 5 and 17 years. With allergic rhinitis cases, age, gender, body mass index percentile, other allergic disorders, allergic rhinitis diagnosis age, allergic rhinitis severity and distribution, presence of primary enuresis nocturna, and presence of primary enuresis nocturna in the family were recorded. Subjects with disorders causing enuresis were excluded from the study.&#x0D; Results:&#x0D; The mean age in the allergic rhinitis and control groups was 9,6±3,4 vs. 10,0±3,1 years, respectively (p=0,15). There was no statistical difference between the two groups in terms of gender, age, body mass index percentile, and primary enuresis nocturna presence in the family (p=0.29, p=0.15, p=0.46, p=0.17; respectively). Primary enuresis nocturna was significantly higher in allergic rhinitis cases (p=0.02). Primary enuresis nocturna was significantly higher in boys than in girls (p=0.007). There is a significant difference in age and gender between those with and without primary enuresis nocturna in allergic rhinitis groups (p=0,001, p=0.01, respectively).&#x0D; Conclusion:&#x0D; We conclude that as allergic rhinitis increases the incidence of primary enuresis nocturna and worsens the quality of life, its treatment should not be neglected.

Parasacral transcutaneous electrical neural stimulation versusurotherapy in primary monosymptomatic enuresis: A prospective randomized clinical trial.

To evaluate the clinical response of parasacral transcutaneous electrical neural stimulation (parasacral TENS) associated with urotherapy in children with primary monosymptomatic nocturnal enuresis(PMNE) compared to urotherapy alone. This prospective controlled clinical trial enrolled 72 children over 5 years of age with PMNE. Children were randomly divided into twogroups, control group (CG), treated with urotherapy and scapular stimulation, and experimental group (EG), treated with urotherapy and parasacral TENS. In both groups, 20 sessions were performed, 3 times weekly, for 20 min each, with 10 Hz frequency, 700 μS pulse width and intesity determinated by the patient threshold. The percentages of dry nights were analyzed for 14 days before treatment (T0), after the 20th session (T1), 15 (T2), 30 (T3), 60 (T4), and 90 (T5) days after the end of the sessions. Patients of both groups were followed with intervals of 2 weeks in the first month and monthly for threeconsecutive months. Twenty-eight enuretic children, 14 girls (50%) with a mean age of 9.09 ± 2.23 years completed the study. There was no difference in mean age between groups. Mean percentage of dry nights in EG at T0 was 36%, at T1 49%, at T2 54%, at T3 54%, at T4 54%, and 57% at T5; while in CG, these percentages were 28%, 39%, 37%, 35%, 36%, and 36%, respectively. Parasacral TENS associated with urotherapy improves the percentage of dry nights in children with PMNE, although no patient had complete resolution of symptoms in this study.

A Single blind clinical study to access the role of homoeopathic constitutional remedies in primary enuresis in age group of 5-15 years.

Background: Enuresis is one of the most common problems in children hampering daily lives and studies. Homoeopathy can be used in enuresis, however not much research has been done regarding this. This study was aimed to investigate whether homoeopathic medicines have effect in the treatment of patients with primary enuresis. &#x0D; Method: It is a randomized, single blind placebo control study, conducted at the outpatient department of Bharati Vidyapeeth (deemed to be university) Homeopathic college and research Centre, Pune. Total 45 patients enrolled, out of which 5 were dropped out and 40 completed trials with follow-ups. Outcome assessment was checked according to Likert scale and intensity of symptoms were recorded. &#x0D; Result: The final outcome was reduction in number of wet nights per week, decreased in no of wet nights per day, decreased in associated symptoms of enuresis along with behavioural change in patients with primary enuresis after 12 -14 weeks of outpatient care. Analysis was done using student paired “t” tests and one sample “t” test. A significant improvement was observed after treatment and patients showed symptomatic relief as well. Mean reduction in intensity of symptoms in experimental group is 23.80, in control group was 9.05 after completion of study. &#x0D; Conclusion: Constitutional Homoeopathic medicines produced significant effect in improving primary enuresis. Further studies with larger sample size and control group can provide a greater resource for proving that constitutional homoeopathic medicines have an effect in treatment in primary enuresis.

The Relationship Between Copeptin Level and Enuresis in Children Aged 5 - 15 Years

Background: Enuresis is bedwetting that occurs during sleep in children over five years old. If left untreated, it can lead to social and psychological problems for children and their parents. The role of copeptin in patients with primary monosymptomatic nocturnal enuresis (PMNE) has been reported in several studies. Due to the favorable structural properties of copeptin and the reflection of arginine vasopressin (AVP) concentration, it can be used as an alternative marker for AVP secretion. Objectives: This study aims to compare the levels of copeptin in healthy and enuresis children aged 5 - 15 years. Methods: This case-control study was performed on 42 children with primary monosymptomatic enuresis and 42 children without enuresis who were referred to the clinic of Taleghani hospital in Gorgan in 2020. Copeptin levels were measured by the enzyme-linked immunosorbent assay (ELISA) method. Results: Out of 84 patients, an equal proportion of girls (21 patients) and boys (21 patients) participated in both the case and control groups. The age of the children was 8.05 ± 2.46 years, and there was no statistically significant difference between the two groups (P = 0.16). The mean level of copeptin in the case and control groups were 6.7 ± 4.27 and 6.87 ± 8.52 pg/mL, respectively, significantly lower in the case group (P = 0.03). There was a statistically significant difference in the level of copeptin between the boys in the two groups (P = 0.03). Although the mean level of copeptin in the girls in the patient group was lower than that in the control group, this difference was not statistically significant (P = 0.35). Conclusions: In this study, the mean level of copeptin in PMNE was significantly lower than that in the control group, which suggests it may be considered as a probable biomarker for the prediction of response to treatment with desmopressin, but further study is required to confirm this hypothesis.

Limited caffeine consumption as first-line treatment in managing primary monosymptomatic enuresis in children: how effective is it? A randomised clinical trial

ObjectiveEvidence about the negative caffeine effect on enuresis in children remains understudied or poorly understood. The study aimed to investigate the effect of caffeine restriction on the improvement and severity...

Predictive factors of full response to desmopressin treatment in children with primary monosymptomatic enuresis nocturna

Predictive factors of full response to desmopressin treatment in children with primary monosymptomatic enuresis nocturna

One-day voiding diary in the evaluation of Lower Urinary Tract Symptoms in children.

Voiding diary (VD) is an important tool in the evaluation of children with voiding symptoms. Voiding frequency, maximal voided volume (MVV), average voided volume (AVV) and nocturnal volume (NV) can be extracted and are valuable in diagnosing and monitoring these disorders. Recently, ICCS has reduced the period of data recording on VD from 3 to 2 days.We hypothesized that one day voiding diary would be enough for guiding treatment. Children with overactive bladder (OAB) and primary monosymptomatic enuresis (PMNE) were oriented to fulfill a 3-day VD. Data obtained from VD were evaluated for the first day (1dVD), the first two days (2dVD), and all 3 days (3dVD) and compared according to the MVV, AVV, frequency, NV and expected bladder capacity (EBC). The Friedman, Student's t test and the Fisher's exact was used. ANOVA was used for multiple comparisons. We also used Pearson correlation test. Ninety-eight children were included, 59 had PMNE and 30 OAB. Frequency, AVV and VN were similar regardless how many days the voiding episodes were recorded. Only MVV was higher by a mean of only 32 mL on 3dVD compared to 1dVD. A 1dVD has a sensitivity of 93,9% and a positive likelihood ratio of 2.2. As for the correlation of MVV and EBC it was observed that in 83% of children, MVV was lower than EBC. MVV corresponds to 67% and 69% of EBC in children with PMNE and OAB, respectively. We believe that 1dVD is sufficient to assess these children. It has a high sensitivity and good correlation to 3dVD in evaluating these children. Bladder capacity in this population, evaluated by maximum voided volume, was close to 68% of that obtained by the EBC.

A retrospective study about incontinence and enuresis in the shadow of Covid19 pandemic

Aim: Enuresis and/or incontinence are one of the most common problems that families seek professional help. In this study we wanted to evaluate the patients who applied to pediatric nephrology outpatient clinics with enuresis and/or urinary incontinence during Covid19 pandemic. Methods: We retrospectively evaluated the patients with the ICD diagnoses of “Non-organic enuresis” and “Urinary incontinence”. The data regarding two hundred and four patients were analyzed and compared via dividing them into two groups as Group A (Primary enuresis nocturna) and Group B (other enuresis and incontinence types such as dysfunctional voiding, secondary enuresis, bladder and bowel dysfunction etc.). Results: Mean age was significantly higher in Group A when compared with Group B (9.57 (± 2.78) vs. 8.67 (±3.27), p=0.036). In Group A male/female ratio was 61/43, in Group B male/female ratio was 36/64 (p

Primary enuresis in adults: pathogenesis, clinical course and modern approaches to treatment: A review

The review article presents current data on the epidemiology, classification, pathogenesis, risk factors, diagnosis, and features of the clinical course of primary enuresis in adults. The main methods of treatment of patients with primary enuresis are described in detail. It has been shown that in the treatment of this category of patients, the leading role is given to the use of a synthetic analogue of the antidiuretic hormone desmopressin. A detailed analysis of the pharmacological properties and clinical use of desmopressin in patients with primary enuresis is presented. The advantages of prescribing a sublingual form of desmopressin, which ensures its high efficiency and good tolerability of therapy.

Relationship between primary monosymptomatic enuresis and process toilet training: a case-control.

Primary monosymptomatic nocturnal enuresis (PMNE) is a prevalent condition in childhood, and the pathophysiology is multifactorial. This study investigated the relationship between the toilet training process (TT) and PMNE in children and adolescents. A case-control study was carried out from 2015 to 2020. The presence of PMNE was identified according to International Children's Continence Society criteria. A semi-structured questionnaire was applied to assess TT. The study included 103 children and adolescents with PMNE and 269 participants with normal psychomotor development without PMNE (control group [CG]). Readiness signals were more remembered and less frequent in participants with PMNE (p=0.001) when compared to control group. No differences were found between the groups regarding the onset age of the daytime TT (p= 0.10), the nocturnal TT (p=0.08), the acquisition of daytime continence (p=0.06), and the type of equipment used for the TT (p=0.99). The use of Child-Oriented approach in group of children with enuresis was lower than in controls [87.4% (90/103) versus 94% (250/266)], respectively (OR= 0.44, 95% CI 0.21-0.94, p = 0.039). The age of onset of TT, acquisition of daytime continence, and the type of equipment were not associated with higher occurrence of PMNE. On the other hand, the Child-Oriented approach was a protective factor for the occurrence of PMNE.

Comprehensive Review of Nocturnal Enuresis in Children

Background: Enuresis is a common problem that affects up to 15% of 5‐year‐old children and may have significant psychological, emotional, and social consequences for both the child and their family. Enuresis is the inability of toilet‐trained children to hold urine during the night. It can be classified as primary and secondary. Secondary enuresis occurs in children who have had a dry duration of more than six months; otherwise, it is called primary enuresis. Objectives: This narrative review aims to summarize the available data on the epidemiology, etiology, pathophysiology, evaluation, and treatment of children with enuresis. Methods: This study was conducted through a literature search with the keywords based on Medical Subject Headings (MESH) and were combined with other keywords, including enuresis, pediatric, incontinence, and treatment using PubMed, Embase, Web of Sciences, Scopus, and Cochrane databases. Results: The initial evaluation of enuresis needs a detailed medical history and a careful physical examination with no need for radiology and invasive procedures. The treatment’s mainstay is non‐pharmacological treatments, such as behavioral intervention followed by pharmacotherapy. The appropriate treatment chosen depends on the children's age, midnight voiding patterns, and family and child preferences. Conclusions: Enuresis is a common disorder that affects both the child and the family in many ways. Enuresis's etiology is complex, and it is still not well understood. The child and family must be included in the treatment process, and potential pathophysiological causes must be taken into account.