Effect of vigabatrin on seizure control and safety profile in different subgroups of children with epilepsy.

OBJECTIVE: To evaluate the efficacy and safety of vigabatrin in pediatric epilepsy. METHODS: We retrospectively reviewed patients with epilepsy treated with vigabatrin over a 2-year period at a pediatric tertiary center. We assessed the relationship between seizure frequency, etiology, vigabatrin dose, adverse events, medication discontinuation reasons, and electroencephalography (EEG) characteristics. RESULTS: One hundred three patients followed at Boston Children's Hospital were treated with vigabatrin and had complete medical records. Within the follow-up interval, 69 (67%) of 103 patients had discontinued vigabatrin therapy. Two patients (1.9%) died during therapy for unknown reasons. Median age at vigabatrin initiation was 8 months (interquartile range [IQR] 5-15). Median starting dose was 48.1 mg/kg per day (IQR 29.8-52.3) with a median target of 100 mg/kg (IQR 81.9-107.9). Median treatment duration was 12.1 months (n = 89, IQR 5.0-22.9) overall, and 13.3 months (IQR 5.2-23.2) for patients who discontinued vigabatrin. The most common reasons for discontinuation were controlled seizures in 31 (43.7%) of 71 and unsatisfactory therapeutic effect in 23 (32.4%) of 71. Median percent seizure reduction from baseline to first follow-up was 83.3% (IQR 27.4-99.8) and 96.7% (IQR 43.3-100) to last follow-up. Twenty-four (38.7%) of 62 patients with a follow-up posttreatment remained seizure-free. Four patients who had initially achieved seizure freedom relapsed. Patients with structural/metabolic etiology had greater median percent seizure reduction at first follow-up than patients with genetic etiology (98.7% vs. 61.4%, respectively, p = 0.001). Hypsarrhythmia resolved after therapy in 18 of 20 (90%, 95% confidence interval [CI] 70-97) patients with pretreatment hypsarrhythmia, and 2 patients presented with hypsarrhythmia posttreatment. Risk of having hypsarrhythmia was reduced by 32% (95% CI 14.9-49.1) posttreatment. SIGNIFICANCE: Vigabatrin is efficacious in all seizure types and resolved hypsarrhythmia in most patients. In this series with a median treatment duration of 12.1 months, vigabatrin had a good safety profile with a low rate of discontinuation due to nonophthalmologic and ophthalmologic adverse effects.

Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience.

OBJECTIVE: Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. METHODS: We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline. RESULTS: Three hundred patients with a median age of 9.1 years (range 0.4-29.6 years) were reviewed. Median follow-up was 9 months (range 1-37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3-28 months). SIGNIFICANCE: Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology.

Seizure detection, seizure prediction, and closed-loop warning systems in epilepsy.

Nearly one-third of patients with epilepsy continue to have seizures despite optimal medication management. Systems employed to detect seizures may have the potential to improve outcomes in these patients by allowing more tailored therapies and might, additionally, have a role in accident and SUDEP prevention. Automated seizure detection and prediction require algorithms which employ feature computation and subsequent classification. Over the last few decades, methods have been developed to detect seizures utilizing scalp and intracranial EEG, electrocardiography, accelerometry and motion sensors, electrodermal activity, and audio/video captures. To date, it is unclear which combination of detection technologies yields the best results, and approaches may ultimately need to be individualized. This review presents an overview of seizure detection and related prediction methods and discusses their potential uses in closed-loop warning systems in epilepsy.

Chronopharmacology of anti-convulsive therapy.

Approximately one-third of patients with epilepsy continue to have seizures despite antiepileptic therapy. Many seizures occur in diurnal, sleep/wake, circadian, or even monthly patterns. The relationship between biomarkers and state changes is still being investigated, but early results suggest that some of these patterns may be related to endogenous circadian patterns whereas others may be related to wakefulness and sleep or both. Chronotherapy, the application of treatment at times of greatest seizure susceptibility, is a technique that may optimize seizure control in selected patients. It may be used in the form of differential dosing, as preparations designed to deliver sustained or pulsatile drug delivery or in the form of 'zeitgebers' that shift endogenous rhythms. Early trials in epilepsy suggest that chronopharmacology may provide improved seizure control compared with conventional treatment in some patients. The present article reviews chronopharmacology in the treatment of epilepsy as well as future treatment avenues.

Transcranial direct current stimulation (tDCS) in the management of epilepsy: A systematic review.

PURPOSE: Current therapies for the management of epilepsy are still suboptimal for several patients due to inefficacy, major adverse events, and unavailability. Transcranial direct current stimulation (tDCS), an emergent non-invasive neuromodulation technique, has been tested in epilepsy samples over the past two decades to reduce either seizure frequency or electroencephalogram (EEG) epileptiform discharges. METHODS: A systematic review was performed in accordance with PRISMA guidelines (PROSPERO record CRD42020160292). A thorough electronic search was completed in MEDLINE, EMBASE, CENTRAL and Scopus databases for trials that applied tDCS interventions to children and adults with epilepsy of any cause, from inception to April 30, 2020. RESULTS: Twenty-seven studies fulfilled eligibility criteria, including nine sham-controlled and 18 uncontrolled trials or case reports/series. Samples consisted mainly of drug-resistant focal epilepsy patients that received cathodal tDCS stimulation targeted at the site with maximal EEG abnormalities. At follow-up, 84 % (21/25) of the included studies reported a reduction in seizure frequency and in 43 % (6/14) a decline in EEG epileptiform discharge rate was observed. No serious adverse events were reported. CONCLUSIONS: Cathodal tDCS is both a safe and probably effective technique for seizure control in patients with drug-resistant focal epilepsy. However, published trials are heterogeneous regarding samples and methodology. More and larger sham-controlled randomized trials are needed, preferably with mechanistic informed stimulation protocols, to further advance tDCS therapy in the management of epilepsy.

Executive dysfunction in children and adolescents with temporal lobe epilepsy: is the Wisconsin Card Sorting Test enough?

The Wisconsin Card Sorting Test (WCST) is the gold standard in the evaluation of executive dysfunction (ED) in patients with temporal lobe epilepsy (TLE). We evaluated 35 children with TLE and 25 healthy controls with the WCST and with a more comprehensive battery. Among the children with TLE, 77.14% showed impairment on the WCST. On other tests (Wechsler Intelligence Scale for Children-Digit Forward, Matching Familiar Figures Test, Trail Making Test, Word Fluency, Finger Windows, and Number-Letter Memory), impairment was demonstrated in 94.29%. The authors concluded that the WCST is a good paradigm to measure executive impairment in children with TLE; however, it may be not enough. Evaluation performed only with the WCST not only underestimated the number of patients with ED, but also missed relevant information regarding the type of ED.

Interictal EEG in temporal lobe epilepsy in childhood.

The authors clarified the value of interictal discharges and verified which extratemporal regions may also show epileptiform activity in temporal lobe epilepsy (TLE) in childhood. Thirty consecutive patients aged 3 to 18 years (mean age = 12.16 years; 16 male) with TLE associated with hippocampal atrophy were studied. Each patient had 1 to 15 interictal EEG recordings (mean: 5.6; total = 192 EEGs). Video-EEG monitoring was performed in 20 patients. All patients had MRI. The findings were compared with a control group of 53 consecutive TLE adult outpatients with hippocampal atrophy. Each adult patient underwent 3 to 21 routine EEGs (mean: 10.67; total = 566). Interictal EEGs of children with TLE showed extratemporal epileptiform discharges more frequently than EEGs of adults with TLE. Frontal, parietal, and occipital discharges were more frequently seen in children (P < 0.05). These results suggest a close interaction between temporal and other cerebral regions in children with epilepsy and provide further evidence of the existence of neural networks.

Temporal lobe epilepsy in childhood: comprehensive neuropsychological assessment.

The neuropsychological features of children with temporal lobe epilepsy are not yet well defined. The aim of this study was to identify the neuropsychological deficits in children with temporal lobe epilepsy. We evaluated 25 patients and compared them with 25 normal children. All children underwent a comprehensive neuropsychological assessment. We found a significant difference in favor of the control group in the following measures: IQ; forward digit; Trail Making Test for Children B; Wisconsin Card Sorting Test; block design; Boston naming test, verbal fluency; and Wide Range Assessment of Memory and Learning verbal learning, visual learning, verbal memory, visual memory, delayed recall of verbal learning, delayed recall of stories, and recognition of stories. Our findings show that children with temporal lobe epilepsy present with several neuropsychological deficits, despite normal IQ. These findings point to a dysfunction of cerebral areas other than temporal lobe, particularly the frontal lobes.

Frontal lobe dysfunction in children with temporal lobe epilepsy.

There is evidence that adults with temporal lobe epilepsy present executive impairments. However, there is limited information in children, especially when using a comprehensive neuropsychologic battery. We aimed to: 1) investigate the presence and severity of executive dysfunctions in children with temporal lobe epilepsy, and 2) determine the implications of clinical variables (including etiology) in the occurrence and severity of executive dysfunction, using eight paradigms. Thirty-one children with temporal lobe epilepsy were evaluated and compared with 21 age-matched controls. Patients with temporal lobe epilepsy had significantly worse performance than controls. Intragroup analysis indicated that patients with symptomatic epilepsy were more impaired than those with cryptogenic epilepsy. In the former group, patients with mesial lesions performed worse than those with lateral lesions. Regarding the severity of executive dysfunction, 83.87% manifested severe to moderate executive impairment. Early age of onset, longer duration of epilepsy, and use of polytherapy were correlated with worse executive dysfunction. These findings indicated the presence of frontal lobe dysfunction in children with temporal lobe epilepsy, with worse performance in those with mesial temporal lobe epilepsy, early onset, longer duration of disease, and use of polytherapy. Our study corroborates the hypothesis that temporal lobe epileptogenic activity affects the extratemporal regions that mediate attentional and executive functions.

Clobazam higher-evening differential dosing as an add-on therapy in refractory epilepsy.

PURPOSE: Clobazam treatment tailored to the timing of patient's seizures may improve seizure control. We aim to describe the safety and efficacy of higher-evening differential dose of clobazam as add-on therapy in patients with night-time/early morning seizures. METHOD: Differential dosing with higher evening dosing was started based on a high proportion of seizures (>80%) at nighttime (6p.m. to 6a.m.). Differential dosing was defined as providing more than 50% of the total daily dose of clobazam after 6p.m. RESULTS: Twenty-seven patients were treated with clobazam differential dosing as an add-on therapy. The median age was 9.1 years, with 11 (40.7%) females and median of the first follow-up was 2.7 months. Patients with differential dosing tolerated a higher median total clobazam dose of 0.8mg/kg/d at first follow-up, as compared to 0.6mg/kg/d in controls. In differential dose, the median percentage of the total clobazam dose administered in the evening was 66.7%. Differential dose patients exhibited a median seizure reduction of 75% as compared to 50% in controls (p<0.005). Patients with generalized seizures benefited the most from differential dosing with a 77.5% median seizure reduction, as compared to 50% in controls (p=0.017). CONCLUSION: Higher-evening differential dose of clobazam improved seizure control in patients with predominantly nighttime and early-morning seizures. Chronotherapy tailored to the patients' seizure susceptibility patterns may improve care in epilepsy patients as differential dosing may allow for higher overall treatment doses at times of greatest seizure susceptibility without increased side effects at other times.

Real-time multi-channel monitoring of burst-suppression using neural network technology during pediatric status epilepticus treatment.

OBJECTIVE: To develop a real-time monitoring system that has the potential to guide the titration of anesthetic agents in the treatment of pediatric status epilepticus (SE). METHODS: We analyzed stored multichannel electroencephalographic (EEG) data collected from 12 pediatric patients with generalized SE. EEG recordings were initially segmented in 500ms time-windows. Features characterizing the power, frequency, and entropy of the signal were extracted from each segment. The segments were annotated as bursts (B), suppressions (S), or artifacts (A) by two electroencephalographers. The EEG features together with the annotations were inputted in a three-layer feed forward neural network (NN). The sensitivity and specificity of NNs with different architectures and training algorithms to classify segments into B, S, or A were estimated. RESULTS: The maximum sensitivity (95.96% for B, 89.25% for S, and 75% for A) and specificity (89.36 for B, 96.26% for S, and 99.8% for A) was observed for the NN with 10 nodes in the hidden layer. By using this NN, we designed a real-time system that estimates the burst-suppression index (BSI). CONCLUSIONS: Our system provides a reliable real-time estimate of multichannel BSI requiring minimal memory and computation time. SIGNIFICANCE: The system has the potential to assist intensive care unit attendants in the continuous EEG monitoring.

Severe epilepsy and pachygyria associated with peculiar facial traits characterize Fryns-Aftimos syndrome.

We describe an 18-year-old boy with a frontofacial syndrome. The presence of severe epilepsy led to a neuroimaging investigation, which revealed a diffuse pachygyric (normal thickness and simplified folding) cortex that was bilateral and affected all supratentorial regions, sparing the medial and inferior aspects of the frontal lobe plus the posterior occipital region. In addition, an unusual skull base presentation with small posterior fossa, narrowed foramen magnum, and low torcular and tentorial insertions was documented. Dysmorphic ventricles and enlarged cavi of the septi pellucidum, vergae, and velum interpositum were also noted. This case shares many similarities with two patients formerly described by Fryns and Aftimos, who were previously classified as having mental retardation and multiple congenital anomalies syndrome. The existence of a new case corroborates the idea of a distinct condition with particular characteristic dysmorphic facial features and the presence of a specific malformation of cortical development associated with severe epilepsy. We believe that epilepsy and pachygyria play a central role in distinguishing this syndrome from others classified as frontofacial or cerebrofrontofacial syndromes, and we propose the term "Fryns-Aftimos syndrome" to name it.

Autonomic changes following generalized tonic clonic seizures: An analysis of adult and pediatric patients with epilepsy.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is the most common cause of mortality directly related to epilepsy. Its incidence is higher in adult patients and its pathophysiology remains poorly understood, but likely involves autonomic dysregulation following generalized tonic clonic seizures (GTCS). In the current study, we aimed to analyze post-ictal autonomic changes following GTCS in adult and pediatric patients. METHODS: Patients admitted to the epilepsy monitoring unit were prospectively recruited, and wore an electrodermal activity (EDA) wrist sensor that continuously measured sympathetic activity while being monitored with EEG and EKG electrodes. Peri-ictal EDA parameters were assessed as a measure of sympathetic activity. Peri-ictal parasympathetic activity was determined through the high frequency component (HF) analysis of heart rate variability (HRV). The duration of post-ictal generalized EEG suppression (PGES) was also documented. RESULTS: Twenty patients with GTCS were included in the study on whom 30 GTCS were recorded. PGES duration strongly correlated with age (r=0.62, p=0.004) and measures of the EDA response. After controlling for PGES duration, we found pediatric patients had greater sympathetic activation measured as log rising portion of the area under the curve of the EDA response (ß=+0.67, p=0.034) and a higher degree of vagal suppression measured as maximal percentage change of HF power (ß=-12.65, p=0.0036). CONCLUSION: Sympathetic activity can be measured in the peri-ictal period, and directly correlates with PGES duration. Age is a significant determinant of the sympathetic and parasympathetic response following a GTCS; given the same PGES duration, pediatric patients demonstrate stronger sympathetic activation and higher vagal suppression. However, the increase in PGES duration with age and the associated autonomic dysregulation may provide clues as to why there is a variable vulnerability to SUDEP across age groups.

Lamotrigine and valproate: efficacy of co-administration in a pediatric population.

This study aimed to assess the risks and benefits of the co-administration of lamotrigine and valproate in a pediatric population with refractory epilepsy. Twenty-eight children who received lamotrigine and valproate during co-medication were evaluated. Outcome measurements were established according to efficacy in seizure control, adverse effects, and tolerability. Treatment was considered effective when >50% frequency reduction was obtained. Adverse effects were also analyzed and in patients who presented them the mode of administration was compared with those who did not to verify the importance of this factor. Association of lamotrigine and valproate was considered effective in 64.3% of all patients, regardless of the seizure type. Seizure-free status was obtained in six patients. Drop attacks and secondary generalized tonic-clonic seizures were reduced in five patients, who remained under treatment despite less than the satisfactory (<50%) seizure decrease. Tremor occurred in six patients; urinary incontinence and ataxia in one. Skin rash also occurred, as an early manifestation, in two patients, both with a previous history of hypersensitivity to antiepileptic drugs. Causes for discontinuation were inefficacy of treatment in six patients and presence of adverse effects in two. In our series, seizure control was obtained in most children with refractory epilepsy, some of whom had a previous history of unsatisfactory response to lamotrigine and valproate, either in monotherapy or polytherapy. Adverse effects were uncommon, but skin rash was observed in higher proportions than in other series with lamotrigine or valproate. Nevertheless, these risks may be lessened with slow introduction and by exclusion of patients with a previous history of hypersensitivity.

Clobazam: effect on frequency of seizures and safety profile in different subgroups of children with epilepsy.

BACKGROUND: Clobazam has been used in clinical practice as an adjunctive treatment for diverse seizure types and epilepsy syndromes. We evaluated the efficacy and safety of clobazam in a large sample of patients with refractory epilepsy at a tertiary pediatric center. METHODS: We retrospectively reviewed patients treated with clobazam between January 2001 and July 2013 who had a follow-up visit at least one month after starting clobazam. Response was defined as ≥50% reduction in seizure frequency compared with baseline seizure frequency during the 3 months before the introduction of clobazam. We examined the relationship between dose range and response rate. RESULTS: Four-hundred twenty-five patients were prescribed clobazam, of whom 300 (median age 9.1 years, interquartile range 4.7-13.3 years) had follow-up data greater than 1 month. Median follow-up was 5 months (interquartile range 3-11 months). Response to treatment with clobazam was observed in 203 of 300 (67.7%) patients, of whom 84 (28%) became seizure-free. The median starting dose was 0.2 (interquartile range 0.13-0.33) mg/kg/day with a target dose of 0.48 (0.26-0.80) mg/kg/day. Twenty-seven (9%) patients discontinued clobazam, 16 (59.3%) because adverse effects, 10 (37%) because of a lack of efficacy, and one (3.7%) because of a combination of adverse effects and lack of efficacy. The most common adverse effects were tiredness in 44 of 300 (14.6%) and mood or behavioral changes in 23 (7.7%). CONCLUSIONS: Clobazam is a well-tolerated antiepileptic drug with good response rates in pediatric patients with refractory epilepsy.

Valproate and lamotrigine in pediatric patients with refractory epilepsy: after the first year.

The combination of lamotrigine and valproate/divalproex sodium has been shown to be effective in the treatment of refractory epilepsy. This study aims to evaluate the pharmacologic properties of using this combination in a pediatric population refractory to antiepileptic drugs, with an extended follow-up. We studied a group of 51 patients, ranging from 4 to 16 years of age. Sixteen patients (31.4%) had generalized epilepsy and 35 (69.6%) had focal epilepsy. The combination was effective in 39 patients (76.5%) in the first year of follow-up and in 36 patients (70.6%) in the second year, with a reduction in drop attacks observed in 22 (88.5%). Adverse effects included rash, leading to discontinuation in four patients (7.8%). Slower introduction of lamotrigine minimizes adverse effects, thereby improving quality of life and adherence to treatment. In addition, therapeutic efficacy is maintained with lower doses of lamotrigine, even after the first year of treatment.

Late adverse effects of the coadministration of valproate and lamotrigine.

Individuals treated with combined valproate-lamotrigine rarely present late adverse effects (unrelated to introduction and titration). We describe four patients in whom such effects occurred after continuous, long-term use of valproate-lamotrigine (at 9 months to 2 years after final antiepileptic drug adjustment). The patients presented heterogeneous disturbances, including ataxia, vertigo, and headache, and rare movement disorders, such as tics and abnormal eye movements. Although these effects are heterogeneous in their occurrence and timing, they can alert physicians to the possibility of late neurologic disturbances, and must be considered in order to avoid unnecessary ancillary tests. Treatment discontinuation is unnecessary, given that a small decrease in dose led to remission of these adverse effects.

Droga órfã: surgimento de um novo conceito / Orphan drug: arisement of new concept

INTRODUÇÃO: A partir de 2007, quatro novas drogas anti-epilépticas foram aprovadas, o acetato de eslicarbazepina, lacosamida, rufinamida e estiripentol. Destas drogas, duas aparecem como drogas órfãs, ou seja, drogas desenvolvidas especificamente para o tratamento de uma síndrome-específica, sendo essas, o estiripentol, indicada na Síndrome de Dravet e a rufinamida, na Síndrome de Lennox-Gastaut. OBJETIVO: Revisar a eficácia, tolerabilidade e efeitos adversos das novas drogas, em especial das drogas órfãs. MÉTODO: Estudos foram selecionados de banco de dados eletrônicos. A análise destes estudos averiguou a eficácia, efetividade, efeitos adversos mais comuns, raros e de longo prazo assim como a comparação com os fármacos existentes. CONCLUSÕES: O desenvolvimento de drogas específicas no tratamento das síndromes epilépticas constitui-se na pedra angular do tratamento da epilepsia, minimizando o tempo até o alcance do controle de crises, com consequente menor tempo de exposição aos efeitos deletérios da epilepsia.

INTRODUCTION: Four new antiepileptic drugs have been approved since 2007, eslicarbazepine acetate, lacosamide, rufinamide and stiripentol. Out of these, two drugs are orphan drugs, that is, drugs specifically designed for the treatment of a specific epileptic syndrome, such as stiripentol for Dravet Syndrome and rufinamide for Lennox-Gastaut Syndrome. OBJECTIVE: to review the efficacy, tolerability and adverse effects of the newly released drugs, especially of both orphan drugs. METHODOLOGY: Studies were selected from electronic data base. Analyses of these studies ascertained the most common, rare and long-term adverse effects, efficacy, and effectiveness, as well as comparison with existing drugs. CONCLUSIONS: The development of specific drugs in the treatment of epileptic syndromes constitutes the cornerstone in the treatment of epilepsy, minimizing the time needed to achieve seizure control, with consequent reduced exposure to the deleterious effects of epilepsy.

Risk factors for psychogenic nonepileptic seizures in children and adolescents with epilepsy.

There is evidence that psychogenic nonepileptic seizures (PNES) remain underdiagnosed, especially in children and adolescents. Diagnosis of such events is even more difficult in patients that do have epilepsy, leading to delayed diagnosis and treatment and, consequently, iatrogenic complications. This study aimed to evaluate possible risk factors in children with epilepsy who had PNES. Seizures and epileptic syndromes were classified according to International League Against Epilepsy guidelines. Patients were evaluated with a structured psychiatric anamnesis and classified according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; Classification of Mental and Behavioral Disorders: Diagnostic Criteria for Research; and Schedule for Affective Disorders and Schizophrenia for School-Age Children--Epidemiological Version. Risk factors such as head trauma, physical, sexual and psychological abuse, and psychiatric diagnoses, among others, were investigated. Family history of epilepsy and psychiatric illness were detected by review of medical records and/or follow-up interviews. Gender was not a predictive factor, and although older children had a higher risk for PNES, younger children also presented truly psychogenic events mimicking epileptic seizures. The most common associated psychiatric diagnosis was depression. Family histories for epilepsy and psychiatric illness were a frequent finding. An inadequate family environment was more common than sexual or physical abuse. Current knowledge obtained from adults with PNES has been used to understand children with PNES. However, this study of children with epilepsy revealed some similarities and many differences. These features may help to identify predictive factors in a population in need of adequate diagnosis of and therapy for this long-lasting pathology.