Original article
Myoclonic epilepsy in Down syndrome and Alzheimer disease
Epilepsia mioclónica en el síndrome de Down y en la enfermedad de Alzheimer
J.S. Aller-Alvareza,
, M. Menéndez-Gonzálezb, R. Ribacoba-Monteroc, M. Salvadoa, V. Vegab, R. Suárez-Morod, M. Sueirase, M. Toledoa, J. Salas-Puiga, J. Álvarez-Sabina
Corresponding author
a Servicio de Neurología, Hospital Universitari Vall d’Hebron, Barcelona, Spain
b Unidad de Neurología, Hospital Alvarez Buylla, Mieres, Asturias, Spain
c Servicio de Neurología, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
d Servicio de Neurología, Hospital de Cabueñes, Gijón, Asturias, Spain
e Servicio de Neurofisiología, Hospital Universitari Vall d’Hebron, Barcelona, Spain
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Such other factors as oestrogens, APOE alleles, and prion protein (PRNP) gene polymorphisms are also involved.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Epilepsy was believed to be a typically late-onset phenomenon in the course of AD. However, Lozsadi and Larner<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a> report that up to 6.8% of the patients with a new diagnosis of clinically probable AD will present epilepsy and need antiepileptic treatment. In 3.4% of these cases, epileptic seizure onset coincides with onset of cognitive impairment.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Myoclonic seizures have been described in DS patients in the context of AD dementia; these seizures are progressive and coincide with a significant acceleration of cognitive decline and increased level of dependence. The entity was first described in 1994 by Genton and Paglia.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">5</span></a> It is characterised by myoclonus occurring predominantly in the morning hours and affecting the upper limbs most of all. They are associated with generalised discharges of polyspike-wave complexes in EEG studies.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Our study describes a series of patients with DS or AD and myoclonus and generalised tonic–clonic seizures in order to better understand these symptoms and improve management of these patients.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Method</span><p id="par0030" class="elsevierStylePara elsevierViewall">This descriptive study is based on a retrospective review of a series of patients from 3 hospitals in Asturias (Hospital Alvarez Buylla, Hospital Valle del Nalón, and Hospital Universitario Central de Asturias) and a hospital in Barcelona (Hospital Universitari Vall d’Hebron). We selected patients diagnosed with DS (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8) or AD (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3) who had also developed myoclonic seizures. The most common means of access to neurologists for these patients was through the emergency department after suffering an epileptic seizure. We obtained each patient's medical data related to clinical follow-up, neuroimaging studies (CT and/or cranial MRI), and EEG study.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><p id="par0035" class="elsevierStylePara elsevierViewall">Patients’ demographic and clinical characteristics as well as data from complementary tests are included in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. In the DS patient group, ages ranged from 21 to 65 years; 75% were women. Mean age (x¯) at seizure onset was 45.1 years. Three patients (patients 5, 6, and 8) were already dependent for activities of daily living before epileptic symptoms manifested. Two of them (5 and 8) had a history of cognitive decline in addition to their intellectual deficits (DS), and they were diagnosed with probable AD.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">In the AD patient group (patients 9, 10, and 11), ages at time of data collection were 68, 74, and 78; 2 were women. Their APOE genotypes were 3.3, 3.4, and 4.4, respectively. We excluded mutations in PS1, PS2, and APP genes. These 3 patients were already dependent for instrumental activities before epilepsy manifested; GDS was 4 for all 3 cases.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Seizure semiology mainly consisted of tonic–clonic seizures and myoclonus, although one patient initially presented complex partial seizures years before experiencing myoclonus. Patients 4 and 6 had a history of epilepsy before onset of myoclonus; myoclonus (after menopause in patient 4 and at age 53 in patient 6) was accompanied by cognitive impairment, and seizures became refractory to antiepileptic treatment.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Cranial CT scan showed predominantly cortical brain atrophy in all patients. EEGs revealed a slowing of background activity in all patients. In addition, we observed generalised polyspike-wave paroxysms in 8 patients.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Treatment was successful in decreasing the number of seizures and the risk of falling in 36.4% of the patients; the most widely used antiepileptic drugs were valproate (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6) and levetiracetam (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4). In patients with a good response to antiepileptic treatment, monotherapy with levetiracetam was sufficient for seizure control (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4). Doses of levetiracetam in our patients were between 500 and 2000<span class="elsevierStyleHsp" style=""></span>mg/day. Caring for patients became easier with seizure treatment.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Regarding progression, significant cognitive and functional decline accompanied epileptic seizures in all patients. The 3 patients with AD obtained GDS scores of 5 (previously 4). Seven patients died within 5 years of onset of myoclonus, with a mean survival of 3 years (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The main cause of death was infectious complications, with the most frequent being aspiration-related pulmonary infection.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">In our series, late-onset myoclonic epilepsy (LOMEDS) constitutes a turning point in the course of the disease; impairment of cognitive functions and functional capacity starts or exacerbates with epilepsy onset. Clinical characteristics of our patients are similar to those in other published series.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">6,7</span></a> Regarding treatment, the number of epileptic seizures can be reduced in many patients by using new antiepileptic drugs, such as levetiracetam. This is the only drug demonstrated to decrease seizure frequency in mouse models with overexpression of human APP, with the possibility of improvement at the behavioural and cognitive levels.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">8</span></a> The role of valproate in AD remains controversial; despite having potentially neurotoxic effects and accelerating brain volume loss, it is not associated with significant changes in AD patients’ scores on cognitive assessment scales.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">9</span></a> It would be reasonable to avoid valproate in elderly patients due to its adverse effects.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">10</span></a> It is important to remember that some antiepileptic drugs that act on the sodium channel, such as phenytoin or carbamazepine, could exacerbate myoclonic seizures.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">As mentioned previously, all subjects with DS and mild cognitive impairment show anatomopathological changes compatible with AD, although not all patients develop dementia symptoms.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">2</span></a> This observation has sparked a growing interest in the pathophysiology of AD in this population. In light of this interest, the 2012 neuropathological criteria of the National Institute on Ageing and the Alzheimer's Association<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">12</span></a> clearly established that a clinical diagnosis of AD is not required to assign a neuropathological diagnosis of this disease. This criterion is compatible with the new diagnostic criteria for AD established in 2011,<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">13</span></a> and which introduced the idea of biomarkers that may be correlated with neuropathological lesions, a situation that would foster the possibility of early diagnosis.</p><p id="par0075" class="elsevierStylePara elsevierViewall">At one time, epilepsy was thought to be secondary to the neurodegeneration caused by deposition of Aβ protein. Nevertheless, in recent years, neurotransmitter alterations in the excitatory-inhibitory balance have been reported not only to provoke epileptic seizures but also to contribute to cognitive impairment.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">14</span></a> In addition, Aβ peptide may cause synaptic dysfunction, which would occur before neuronal loss.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">15</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Degeneration of cholinergic and glutaminergic systems is a well-established process in AD, although the gamma-aminobutyric acid system seems to be preserved.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">16</span></a> Similarly, a Na<span class="elsevierStyleSup">+</span> channel (Nav1.1) was found to be potentially relevant for both epileptogenesis and cognitive impairment in APP mice.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">15</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Tau protein (an axonal microtubule-associated protein whose main function is to stabilise microtubules) is another factor that may play a fundamental role in epileptogenesis: mice with AD-type dementia show reduced intensity and frequency of epileptic seizures when tau protein also decreases.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">17</span></a> Lastly, late-onset epilepsy may manifest in autosomal dominant AD related to a presenilin 1 (PSEN1) gene mutation,<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">18</span></a> although the aetiopathogenesis has not been studied sufficiently considering the wide variety of phenotypes of this mutation.</p><p id="par0090" class="elsevierStylePara elsevierViewall">Animal model studies featuring secretase inhibitors, immunotherapy, mGluR5 inhibitors, and APP transcription inhibitors are currently underway. However, these drugs are not yet being used as typical treatments, and no biomarkers are available for use in daily practice.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">The past few years have ushered in advances in medical care that have significantly increased the life expectancy of DS patients, many of whom now live longer than 50 years. Furthermore, the mindset of society at large has evolved considerably; patients are now better integrated so that their lives can be as active as possible.</p><p id="par0100" class="elsevierStylePara elsevierViewall">In this context, the work of the neurologist is essential for detecting loss of competence for activities of daily living and increased frequency of epileptic seizures. Appropriate antiepileptic treatment may achieve seizure control, which will facilitate patient care and improve short-term outcomes.</p><p id="par0105" class="elsevierStylePara elsevierViewall">At present, objective aetiopathogenic data is not sufficient to define LOMEDS as an independent nosological entity. When this disease manifests, it is usually accompanied by a marked and rapid cognitive decline; however, this entity may also be a more latent continuous process which becomes more evident in later stages of the disease.</p><p id="par0110" class="elsevierStylePara elsevierViewall">On the other hand, we cannot deny the theoretical relevance of this process and of epileptogenesis in AD; new findings have allowed us to expand our knowledge of the disease and develop new treatment strategies. Studying DS patients, who present a wide variety of phenotypes and a higher incidence of epilepsy than that of the general population, has resulted in important scientific advances in this field.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0115" class="elsevierStylePara elsevierViewall">The lead author of this article, on behalf of himself and of all coauthors, states that there are no potential conflicts of interest related to this study.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres816744" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec813972" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres816743" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec813973" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Method" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Conclusions" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-04-29" "fechaAceptado" => "2014-12-11" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec813972" "palabras" => array:5 [ 0 => "Down syndrome" 1 => "Alzheimer's disease" 2 => "Myoclonic epilepsy" 3 => "Dementia" 4 => "Late-onset myoclonic epilepsy in Down syndrome" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec813973" "palabras" => array:5 [ 0 => "Síndrome de Down" 1 => "Enfermedad de Alzheimer" 2 => "Epilepsia mioclónica" 3 => "Demencia" 4 => "Late-onset myoclonic epilepsy in Down syndrome" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patients with Down syndrome (DS) who exhibit Alzheimer disease (AD) are associated with age. Both diseases with a common neuropathological basis have been associated with late-onset myoclonic epilepsy (LOMEDS). This entity presents electroencephalogram features as generalised polyspike-wave discharges.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Method</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We present a series of 11 patients with the diagnosis of DS or AD who developed myoclonic seizures or generalised tonic–clonic seizures. In all cases, clinical and neuroimaging studies and polygraph EEG monitoring was performed.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">In all cases, cognitive impairment progressed quickly after the onset of epilepsy causing an increase in the degree of dependence. The most common finding in the EEG was a slowing of brain activity with theta and delta rhythms, plus intercritical generalised polyspike-waves were objectified in eight patients. In neuroimaging studies was found cerebral cortical atrophy. The most effective drug in this series was the levetiracetam.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The association of generalised epilepsy with elderly DS represents an epiphenomenon in evolution which is associated with a progressive deterioration of cognitive and motor functions. This epilepsy has some electroclinical characteristics and behaves as progressive myoclonic epilepsy, which is probably related to the structural changes that characterise the evolutionary similarity of DS with AD. Recognition of this syndrome is important, since it has prognostic implications and requires proper treatment.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Method" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Los pacientes con síndrome de Down (SD) presentan una demencia tipo Alzheimer (EA) asociada a la edad. Ambas patologías, con una base neuropatológica común, han sido asociadas a la epilepsia mioclónica de inicio tardío (LOMEDS). Esta entidad presenta alteraciones electroencefalográficas características en forma de descargas generalizadas de polipunta-onda.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Método</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Presentamos una serie de 11 pacientes con el diagnóstico de SD o EA que desarrollaron crisis epilépticas mioclónicas o tónico-clónicas generalizadas. En todos ellos, se realizó un seguimiento clínico y estudios de neuroimagen y poligrafía EEG.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">En todos los casos, el deterioro cognitivo avanzó rápidamente tras el comienzo de la epilepsia, produciendo un incremento en el grado de dependencia. El hallazgo más común en el EEG fue un enlentecimiento de la actividad cerebral con ritmos theta y delta; además, en 8 pacientes se objetivaron descargas intercríticas generalizadas de polipunta-onda. En los estudios de neuroimagen se encontró atrofia cerebral cortical. El fármaco más eficaz en esta serie fue el levetiracetam.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La asociación de epilepsia generalizada al SD de edad avanzada supone un epifenómeno en la evolución que marca un agravamiento rápidamente progresivo de las funciones cognitivas y motoras. Presenta unas características electroclínicas bien definidas y se comporta como una epilepsia mioclónica progresiva, que probablemente se relaciona con los cambios estructurales que caracterizan el parecido evolutivo del SD con la enfermedad de Alzheimer. El reconocimiento de este síndrome es importante, dado que tiene repercusiones pronósticas y requiere un tratamiento adecuado.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Método" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:2 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Aller-Alvarez JS, Menéndez-González M, Ribacoba-Montero R, Salvado M, Vega V, Suárez-Moro R, et al. Epilepsia mioclónica en el síndrome de Down y en la enfermedad de Alzheimer. Neurología. 2017;32:69–73.</p>" ] 1 => array:2 [ "etiqueta" => "☆☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Three patients in this series were mentioned in the oral communication “Myoclonic epilepsy in Down syndrome and Alzheimer disease”, presented during the 64th Annual Meeting of the Spanish Society of Neurology (Barcelona), November 2012.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">–: not available; CBZ: carbamazepine; CPS: complex partial seizures; GTCS: generalised tonic–clonic seizures; CZP: clonazepam; AD: Alzheimer disease; F: frontal; FT: frontotemporal; LEV: levetiracetam; LTG: lamotrigine; MYOCL: myoclonus; PSW: poly-spike wave; DS: Down syndrome; VPA: valproic acid.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Patient \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Sex \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Seizure onset<br>(age) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Seizure symptoms \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">EEG \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Cranial CT/MRI scan \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Seizure control \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Death (age) \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Slowing<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Anterior atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor control (despite dosage increases) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Posterior atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LTG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor control (VPA) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">52 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">41 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Normal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor control (LEV) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL (at menopause) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Posterior atrophy (dilation of the posterior horns) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">CBZ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor control (combination therapy including LEV) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">FT atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">6 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">47 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised slowing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse cortical-subcortical atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor control (LEV) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">56 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">7 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised slowing \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse cortical atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VPA<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>LEV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Good control (LEV only) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">53 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DS \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised slowing<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>Left FT irritative zone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse cortical atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LEV<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>CZP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Good control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">65 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse cortical atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">VPA \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Poor control (despite higher doses) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">10 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Female \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">72 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse cortical atrophy<br>(more pronounced in the medial regions of the temporal lobes) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LEV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Good control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">74 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="char" valign="top">11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Male \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AD \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">76 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">GTCS<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>MYOCL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Generalised PSW \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse cortical atrophy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">LEV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Good control \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1372574.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Patients’ demographic and clinical characteristics and complementary test results.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:18 [ 0 => array:3 [ "identificador" => "bib0095" "etiqueta" => "1" "referencia" => array:1 [ 0 => 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 4 | 11 |
| 2024 October | 42 | 12 | 54 |
| 2024 September | 72 | 7 | 79 |
| 2024 August | 66 | 13 | 79 |
| 2024 July | 70 | 14 | 84 |
| 2024 June | 55 | 7 | 62 |
| 2024 May | 57 | 12 | 69 |
| 2024 April | 62 | 2 | 64 |
| 2024 March | 80 | 9 | 89 |
| 2024 February | 95 | 11 | 106 |
| 2024 January | 120 | 6 | 126 |
| 2023 December | 99 | 14 | 113 |
| 2023 November | 68 | 13 | 81 |
| 2023 October | 124 | 17 | 141 |
| 2023 September | 71 | 14 | 85 |
| 2023 August | 85 | 7 | 92 |
| 2023 July | 87 | 14 | 101 |
| 2023 June | 104 | 10 | 114 |
| 2023 May | 151 | 14 | 165 |
| 2023 April | 117 | 4 | 121 |
| 2023 March | 127 | 14 | 141 |
| 2023 February | 64 | 13 | 77 |
| 2023 January | 56 | 8 | 64 |
| 2022 December | 61 | 4 | 65 |
| 2022 November | 35 | 7 | 42 |
| 2022 October | 41 | 7 | 48 |
| 2022 September | 54 | 23 | 77 |
| 2022 August | 41 | 14 | 55 |
| 2022 July | 26 | 16 | 42 |
| 2022 June | 32 | 5 | 37 |
| 2022 May | 27 | 11 | 38 |
| 2022 April | 42 | 11 | 53 |
| 2022 March | 27 | 9 | 36 |
| 2022 February | 38 | 6 | 44 |
| 2022 January | 48 | 15 | 63 |
| 2021 December | 42 | 12 | 54 |
| 2021 November | 61 | 18 | 79 |
| 2021 October | 43 | 13 | 56 |
| 2021 September | 62 | 12 | 74 |
| 2021 August | 62 | 14 | 76 |
| 2021 July | 23 | 16 | 39 |
| 2021 June | 38 | 21 | 59 |
| 2021 May | 30 | 16 | 46 |
| 2021 April | 62 | 28 | 90 |
| 2021 March | 41 | 11 | 52 |
| 2021 February | 33 | 8 | 41 |
| 2021 January | 45 | 15 | 60 |
| 2020 December | 39 | 19 | 58 |
| 2020 November | 38 | 17 | 55 |
| 2020 October | 20 | 6 | 26 |
| 2020 September | 38 | 22 | 60 |
| 2020 August | 34 | 18 | 52 |
| 2020 July | 39 | 20 | 59 |
| 2020 June | 49 | 18 | 67 |
| 2020 May | 28 | 19 | 47 |
| 2020 April | 38 | 7 | 45 |
| 2020 March | 44 | 14 | 58 |
| 2020 February | 30 | 16 | 46 |
| 2020 January | 31 | 15 | 46 |
| 2019 December | 22 | 16 | 38 |
| 2019 November | 32 | 17 | 49 |
| 2019 October | 29 | 11 | 40 |
| 2019 September | 32 | 15 | 47 |
| 2019 August | 8 | 7 | 15 |
| 2019 July | 28 | 11 | 39 |
| 2019 June | 45 | 26 | 71 |
| 2019 May | 129 | 18 | 147 |
| 2019 April | 62 | 18 | 80 |
| 2019 March | 13 | 10 | 23 |
| 2019 February | 12 | 9 | 21 |
| 2019 January | 17 | 4 | 21 |
| 2018 December | 22 | 8 | 30 |
| 2018 November | 18 | 11 | 29 |
| 2018 October | 30 | 16 | 46 |
| 2018 September | 9 | 6 | 15 |
| 2018 August | 5 | 7 | 12 |
| 2018 July | 7 | 3 | 10 |
| 2018 June | 8 | 2 | 10 |
| 2018 May | 10 | 6 | 16 |
| 2018 April | 6 | 2 | 8 |
| 2018 March | 11 | 3 | 14 |
| 2018 February | 9 | 5 | 14 |
| 2018 January | 8 | 5 | 13 |
| 2017 December | 11 | 2 | 13 |
| 2017 November | 7 | 10 | 17 |
| 2017 October | 7 | 7 | 14 |
| 2017 September | 13 | 13 | 26 |
| 2017 August | 15 | 4 | 19 |
| 2017 July | 10 | 5 | 15 |
| 2017 June | 18 | 3 | 21 |
| 2017 May | 14 | 4 | 18 |
| 2017 April | 24 | 5 | 29 |
| 2017 March | 22 | 19 | 41 |
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