Myasthenia gravis. Update on diagnosis and therapy | Medicina Clínica (English Edition)

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Update on diagnosis and therapy" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "119" "paginaFinal" => "127" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Daniel Apolinar García Estévez, Julio Pardo Fernández" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Daniel Apolinar" "apellidos" => "García Estévez" "email" => array:1 [ 0 => "Daniel.apolinar.garcia.estevez@sergas.es" ] "referencia" => array:4 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] 3 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] ] ] 1 => array:3 [ "nombre" => "Julio" "apellidos" => "Pardo Fernández" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "1" "identificador" => "fn0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Neurología, Complexo Hospitalario Universitario de Ourense, Ourense, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Grupo de investigación Neurociencias Clínicas, Instituto de Investigaciones Sanitarias Galicia-Sur, SERGAS-UVIGO, Vigo, Pontevedra, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Unidad de Enfermedades Neuromusculares, Servicio de Neurología, Complexo Hospitalario Universitario de Santiago de Compostela, Facultad de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Miastenia gravis. Actualización diagnóstica y terapéutica" ] ] "textoCompleto" => "IntroductionMyasthenia gravis (MG) is an autoimmune disease caused by the presence of specific antibodies directed against different postsynaptic components of the neuromuscular junction (NMJ), mostly against the nicotinic acetylcholine receptor (AchR). The thymus plays a main role in its aetiopathogenesis and may exhibit pathological alterations such as thymic hyperplasia (65%) or thymoma (10%–15%). Clinically, it is characterised by the presence of fatigable muscle weakness, the neurophysiological correlate of which is a drop in the compound muscle action potential with repetitive nerve stimulation. Treatment is based on the use of reversible acetylcholinesterase inhibitors (pyridostigmine) and various disease-modifying immunosuppressive treatments.Clinical and neurophysiological diagnosis and initial treatment have remained unchanged over the last decades.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2</a> However, our knowledge of the immunological components of NMJ has increased, and new pathogenic antibodies have been identified, which have made it possible to reduce the percentage of MG patients initially classified as seronegative, and to propose a classification of patients into subgroups of clinical and therapeutic interest.<a class="elsevierStyleCrossRefs" href="#bib0015">3–13</a> In addition, we have seen the development of new treatments aimed at managing patients with drug-resistant forms of the disease. These clinical and therapeutic advances will be the focus of this review.EpidemiologyIn terms of incidence and prevalence rates, there is a wide range of figures according to different studies. Two systematic reviews have reported incidence rates of up to 30 cases per 1,000,000 person-years, and a maximum prevalence of 179 cases per 1,000,000 person-years.<a class="elsevierStyleCrossRefs" href="#bib0070">14,15</a> The most recent study in Spain, in the ageing province of Ourense, found an incidence rate of 15.4 cases per 1,000,000 person-years and a prevalence of 260 cases per 1,000,000 person-years.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> A review of the epidemiology in the Iberian Peninsula recorded prevalence rates between 86 and 329 cases per 1,000,000 inhabitants.<a class="elsevierStyleCrossRef" href="#bib0085">17</a> MG can occur at any age, from birth to senescence, although juvenile forms are rare (except in Asian countries and South Africa). The incidence of juvenile MG in the Caucasian population is less than 2 cases per 1,000,000 person-years.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Epidemiological studies consistently show a bimodal incidence in females, with a peak between the age of 20 and 40 and another between the age of 60 and 80, while in males there is a steady increase from 60 years of age onwards.<a class="elsevierStyleCrossRefs" href="#bib0075">15,16</a> Furthermore, there has been an increase in the incidence and prevalence figures in recent years, particularly affecting the elderly population.<a class="elsevierStyleCrossRefs" href="#bib0080">16,19,20</a>Clinical features and classificationThe clinical presentation of MG will depend on the muscles affected. The most common symptoms are: eyelid ptosis, diplopia, dysarthria (slurred-nasalised speech), dysphagia with nasal regurgitation of liquids, head ptosis (neck extensor muscles), and in the proximal muscles of the upper or lower limbs, patients may develop fatigability with repetitive movements.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,8,21–24</a> Muscle weakness is fluctuating, least on waking in the morning; it improves with rest and worsens with physical activity and throughout the day (mainly in the evenings). Most patients will have ocular symptoms at onset (85%), but 80% will develop generalised MG (GMG) within 2–3 years of diagnosis. If symptoms remain localised at the ocular level for one year, it is very likely that the symptoms will not progress, representing the purely ocular form (OMG).<a class="elsevierStyleCrossRefs" href="#bib0105">21,24</a> MG is a heterogeneous disease, not only in terms of clinical features and pathogenic autoantibodies, but also in terms of genetic predisposition.<a class="elsevierStyleCrossRefs" href="#bib0125">25,26</a>The clinical classification currently used is the Myasthenia Gravis Foundation of America (MGFA) Clinical Classification,<a class="elsevierStyleCrossRef" href="#bib0135">27</a> which considers both the location of the affected muscles (oculomotor, oropharyngeal and limb) and the severity of the symptoms (mild-moderate-severe), and an additional class (class V) is represented by myasthenic crisis, which is a clinical exacerbation involving the respiratory muscles and requires the support of invasive mechanical ventilation (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). It is a clinical classification that replaces the classic Osserman classification, which classified patients according to the maximum severity of the affected muscles, and this maximum represents the reference for assessing the response to treatment, which in turn is quantified with the MGFA Post-intervention Status scale.<a class="elsevierStyleCrossRef" href="#bib0135">27</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>MG can be classified according to age at clinical onset into a transient neonatal form that is triggered by passive transfer of maternal pathogenic antibodies to the foetus and affects 10%–20% of newborns<a class="elsevierStyleCrossRef" href="#bib0140">28</a>; a juvenile-onset form (≤18 years)<a class="elsevierStyleCrossRef" href="#bib0090">18</a>; an early-onset form (<50 years), and a late-onset form (≥50 years). The clinical presentation of juvenile MG is similar to that of adults and ocular forms are the most common; anti-AchR antibodies are the most commonly detected, but the percentage of seronegative results is higher than in adults. Puberty has a clear influence on gender prevalence and the likelihood of generalisation, and the differential diagnosis is broader in this age group.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> Early presentation of MG is more prevalent in females, is usually associated with thymic pathology and HLA-B8 and DR3 markers are detected in 60% of cases. In late-onset forms there is a male prevalence, thymic atrophy is common, and an association with HLA-B7 and DR2 markers has been detected. In the late presentation, patients have a higher percentage of positive results for anti-AchR antibodies and OMG is more prevalent than in the early-onset form, and despite having a greater number of medical comorbidities,<a class="elsevierStyleCrossRef" href="#bib0145">29</a> they do not differ in therapeutic management or prognosis.<a class="elsevierStyleCrossRefs" href="#bib0150">30,31</a> Patients with MG diagnosed at an age older than 65 years are the most prevalent, and can be considered a separate clinical subgroup, whose clinical features are similar to those of the late-onset group, but in which the presence of thymoma is very rare, and although MG may begin with severe symptoms, in clinical practice patients usually require a lower degree of immunosuppression for the control of clinical manifestations.<a class="elsevierStyleCrossRefs" href="#bib0100">20,32</a>Autoantibodies in myasthenia gravisAutoantibodies in MG are specific and pathogenic and allow a classification with clinical and therapeutic implications (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRefs" href="#bib0035">7,32,33</a> Fifty percent of OMG and 85% of GMG are positive for anti-AchR antibodies. AchR is a glycoprotein composed of five subunits (2, α, β, δ, ε), that functions as an ion channel, the activation of which results in the influx of Na that generates the depolarising potential at the motor endplate. These autoantibodies exert their pathogenic action through several mechanisms: 1) they belong to the IgG1 and IgG3 subclass with the ability to activate the complement pathway and produce AchR degradation at postsynaptic level; 2) by means of a cross-linking reaction they can result in internalisation of the receptor by increasing endocytosis, and 3) by blocking the receptor preventing its physiological postsynaptic action. Patients in whom these autoantibodies are not detected are termed seronegative. It has been reported that up to 50% of these negative results are due to the presence of low affinity anti-AchR autoantibodies. For this purpose, a diagnostic test based on embryonic kidney cells has been developed, which allows the clustering of AchR with the participation of rapsin, increasing the sensitivity and specificity of the test,<a class="elsevierStyleCrossRef" href="#bib0170">34</a> although its availability in routine clinical practice is still very limited. Patients with such low affinity antibodies have similar clinical features to those patients with anti-AchR antibodies measured by radioimmunoassay. Regarding anti-AchR antibodies, the higher the titre, the higher the diagnostic specificity, but the antibody titre is not associated with the severity of the clinical presentation and the usefulness of its quantification in the clinical follow-up of the patient has not been demonstrated. On the other hand, false positives associated with other autoimmune diseases have been reported, mainly when titres are low.<a class="elsevierStyleCrossRef" href="#bib0115">23</a><elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Antibodies directed against muscle-specific tyrosine kinase (anti-MuSK) are detected in 30%–40% of anti-AchR seronegative patients. The MuSK protein is expressed in the postsynaptic muscle membrane and is required to maintain AchR function. Anti-MuSK antibodies belong to the IgG4 class and cannot activate complement. Their mechanism of action consists of interaction with the lipoprotein receptor-related protein 4 (LRP4), resulting in no AchR clustering, and also, through interaction with matrix proteins such as collagen Q, they contribute to the stabilisation of the synapse. MG with anti-MuSK antibodies (MuSK-MG) accounts for approximately 5% of MG cases. It is more common in women, with involvement of the bulbar and cervical muscles being more common, and usually presents with greater clinical severity. Patients report little variation in strength throughout the day, and muscle atrophy and fasciculations may occur in the affected muscles.<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a>LRP4 is a protein expressed in the postsynaptic membrane that behaves as a receptor for the agrin released from the nerve terminal, which results in the activation of the MuSK protein, and is therefore necessary for proper AchR function. Although rare in routine clinical practice, anti-LRP4 antibodies are detected in some series in 2%–27% of patients negative for anti-AchR and anti-MuSK. MG-LRP4 is more prevalent in females, with ocular and generalised presentations of mild intensity accounting for 85% of clinical manifestations at onset, and in terms of progression, 20% of patients remain in an OMG 2 years after onset. One third of patients have thymic hyperplasia but no thymomas have been reported.<a class="elsevierStyleCrossRef" href="#bib0185">37</a>Another antibody that has been identified in a small number of seronegative patients is directed against the agrin protein.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> This protein is important in the development of the NMJ and in the structural maintenance of the mature synapse, and mutations in the agrin gene cause congenital myasthenic syndrome. Agrin is released from the growing axon terminal into the intracellular matrix, leading to the formation of myotubes, and also binds to the LRP4 protein, and this complex in turn to the MuSK protein, leading to its activation, which ultimately results in the clustering of AchRs.<a class="elsevierStyleCrossRef" href="#bib0055">11</a>. However, the possible pathogenic role of agrin in autoimmune myasthenia has not yet been established,<a class="elsevierStyleCrossRef" href="#bib0040">8</a> and, in fact, most MG patients with these antibodies also have antibodies against AchR, MuSK or LRP4.<a class="elsevierStyleCrossRef" href="#bib0190">38</a>In addition, there are non-pathogenic antibodies, so-called striatal antibodies, directed against muscle proteins, titin and the ryanodine receptor (RyR), located outside the synapse. Titin is involved in the flexibility of the cell structure and the RyR is a calcium channel, located in the sarcoplasmic reticulum, which is involved in muscle cell contraction. These antibodies can be found in late-onset forms but have been proposed as a marker of thymoma in patients with early-onset MG (<40 years).<a class="elsevierStyleCrossRefs" href="#bib0040">8,39</a> However, caution should prevail when interpreting the presence of anti-titin antibodies, as their role as a marker of severity in MG has been questioned.<a class="elsevierStyleCrossRef" href="#bib0050">10</a>DiagnosisDiagnostic suspicion will be established when a patient presents with fatigable muscle weakness at ocular, bulbar or limb level.<a class="elsevierStyleCrossRefs" href="#bib0105">21–23</a> Ocular fatigability can be demonstrated by asking the patient to keep the gaze fixed upwards or to the side (occurrence of diplopia or ptosis); dysarthria, by asking the patient to count aloud to 100 uninterruptedly; and proximal limb fatigability, with repeated movements of upper limb abduction or getting up from a chair without assistance. Eyelid ptosis is usually asymmetrical, and raising the eyelid of the eye with greater ptosis causes the eyelid of the contralateral eye to lower (curtain sign), and Cogan’s sign can also be seen, which consists of holding the gaze downwards for 10–15s, and on recovering the primary position of the gaze, the eyelid with ptosis experiences a momentary upward contraction. As per facial muscles, there is hypercontraction of the frontalis muscle (surprised look) as a compensatory mechanism for the ptosis, and when attempting to smile, the weakness of the orbicularis oris muscle produces a facial expression known as the “myasthenic snarl”. If the patient presents with eyelid ptosis, the ice test can be performed in the consultation room, consisting of applying a cold pack to the ptosed eyelid for two minutes, and the response will be positive if an increase in the eyelid opening of more than 2mm<a class="elsevierStyleCrossRefs" href="#bib0115">23,40</a> is achieved, with a sensitivity of 80%–95% and a specificity of 79%–97%.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> The classic diagnostic test is the Tensilon test® (edrophonium chloride), a reversible acetylcholinesterase inhibitor administered intravenously, which causes a rapid and short-lasting response, allowing us to observe the recovery of eyelid ptosis, ophthalmoparesis or dysarthria.<a class="elsevierStyleCrossRef" href="#bib0200">40</a> The sensitivity of the test ranges from 60% to 95% for OMG and 72%–95% for GMG, but the specificity of the test is not clear from published data, and the test can be positive in Lambert-Eaton syndrome, botulism, motor neurone disease and other pathologies.<a class="elsevierStyleCrossRefs" href="#bib0005">1,2,40</a> Because of the possibility of severe bradycardia, it should be performed in a hospital setting, and is not usually performed except in cases of diagnostic uncertainty that cannot be resolved by other techniques. Anti-AchR antibodies should be requested initially, and if negative, the immunological study should be extended to anti-MuSK and/or anti-LRP4 antibodies. A neurophysiological study should be performed to detect neuromuscular transmission abnormalities. This can be done by repetitive nerve stimulation (RNS) at low frequency (3Hz), which, after a train of 10 stimuli, will show a drop in the amplitude of the compound muscle action potential of more than 10% in the fourth or fifth stimulus. The test is positive in 85% of patients with GMG, but only in 50% of patients with OMG. In OMG, facial muscles or spinal accessory nerve RNS has a sensitivity of 15%–35% and a specificity of 95%–99%, but because of the low sensitivity it is often necessary to perform a single-fibre electromyography.<a class="elsevierStyleCrossRefs" href="#bib0105">21,23,40</a> This technique assesses the response of a single motor unit muscle fibre to a series of stimuli, and in case of pathology in neuromuscular transmission it will show increased jitter or blocks.<a class="elsevierStyleCrossRefs" href="#bib0010">2,23,40</a> In cases of MuSK-MG, conventional electromyography can detect the presence of acute denervation potentials (fibrillations and positive sharp waves) and fasciculations in tongue, facial and/or cervical muscles. This situation makes it necessary to establish the differential diagnosis with motor neurone diseases because of their prognostic implications.The differential diagnosis should be made primarily with those entities that can cause fluctuating muscle weakness (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>TreatmentAdvances in the treatment of MG in recent decades have considerably improved the functional status of patients, with a significant decrease in morbidity and mortality. However, 10%–15% still have refractory MG, i.e., if the patient’s clinical status remains unchanged or worsens after treatment with glucocorticoids and at least two other immunosuppressants, using effective doses for an adequate time, with persistent symptoms or disabling side effects.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>Since MG is clinically heterogeneous, treatment must be individualised, taking into account the clinical subtype according to age at onset, associated antibodies, thymic pathology and the distribution and intensity of weakness, as well as possible existing comorbidities. There are various international therapeutic guidelines for its management. These are based mainly on expert recommendations, given the scarcity of controlled clinical trials in this pathology.<a class="elsevierStyleCrossRefs" href="#bib0205">41–45</a>In general, there are several therapeutic options available, which can be divided into symptomatic treatment (acetylcholinesterase inhibitors), chronic immunosuppressive treatment (glucocorticoids and non-steroidal immunosuppressants), fast-acting but short-lasting immunomodulatory treatments for severe conditions (intravenous immunoglobulins and plasmapheresis) and surgical treatment (thymectomy). In addition, in recent years, new treatments for MGM, not yet marketed at the time of this review, have been emerging and are included under emerging treatments heading.Before we start describing the course-modifying treatments for MG, we would like to remind the reader that there are certain medications that can exacerbate the weakness of MG patients. These include, at high risk, botulinum toxin, immune checkpoint inhibitors (e.g., pembrolizumab), intravenous magnesium, penicillamine and telithromycin (ketolide antibiotic); at moderate risk, aminoglycoside antibiotics, fluoroquinolones and macrolides; and at low risk, beta-blockers, hydroxychloroquine, interferon alpha, iodinated contrast agents, quinine and statins.<a class="elsevierStyleCrossRefs" href="#bib0115">23,45</a>Symptomatic treatmentThe most commonly used anticholinesterase (acetylcholinesterase inhibitor) is oral pyridostigmine, which increases the availability of acetylcholine in the NMJ as it delays its degradation by acetylcholinesterase.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> It is effective in all subtypes of MG, with the exception of MuSK-MG, where it tends to have a poor clinical response and a greater susceptibility to side effects.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> Pyridostigmine is the initial treatment of choice in MG and some patients remain asymptomatic with anticholinesterase alone, especially those with OMG or mild MGM.Chronic immunosuppressive treatmentIt is indicated in patients with weakness and/or lack of response to symptomatic anticholinesterase therapy in order to achieve at least a minimal manifestation status, i.e. some muscle weakness on examination but no functional disability (MGFA Post-intervention Status),<a class="elsevierStyleCrossRef" href="#bib0185">37</a> and with as few adverse effects as possible.<a class="elsevierStyleCrossRefs" href="#bib0040">8,47</a> These drugs include glucocorticoids and non-steroidal immunosuppressants (azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, rituximab and cyclophosphamide) (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>When an immunosuppressant is to be prescribed, it is necessary to carry out a preliminary study to detect possible contraindications, latent infections, determine the most suitable drug according to the onset of action and adjust the most appropriate dose. The patient’s vaccination coverage should be checked and a series of complementary tests should be requested before starting immunosuppressive treatment, including a blood and urine test, serology for hepatitis B, hepatitis C and HIV, Mantoux and/or IGRA test (interferon gamma release assay) to rule out latent tuberculosis, pregnancy test in women of childbearing age and chest X-ray.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>GlucocorticoidsThey remain the first-line immunosuppressive treatment and are indicated in patients who do not achieve adequate symptomatic control with anticholinesterase drugs or who cannot tolerate such treatment due to its side effects.<a class="elsevierStyleCrossRef" href="#bib0245">49</a>In patients with OMG, several retrospective studies have shown a lower risk of developing GMG in the group of patients who received early glucocorticoids, although this is still a controversial issue given the lack of long-term prospective studies.<a class="elsevierStyleCrossRef" href="#bib0250">50</a>Symptomatic response is rapid, within 2–4 weeks of onset when administered at high doses, with maximum improvement in the first 4–8 weeks. The response rate is 74%. Up to 40% may experience paradoxical symptomatic worsening in the first two weeks of treatment, followed by clinical improvement. Because of side effects, long-term maintenance treatment should be carried out at low doses (below 7.5mg/day).Classically, there are two ways of administering glucocorticoids orally.<a class="elsevierStyleCrossRef" href="#bib0220">44</a> In patients with moderate-severe MGM or in situations of impending myasthenic crisis, where there is an interest in inducing rapid clinical remission, high doses of prednisone (1mg/kg) are used for 4 weeks or until clinical improvement is achieved. Thereafter, it is advisable to administer treatment every other day and progressively reduce the dose. An exception is in patients with diabetes or hypertension, where daily administration of glucocorticoids is preferable to avoid fluctuations in blood pressure or blood glucose. High-dose glucocorticoids require admission, and in cases of bulbar involvement, simultaneous treatment with intravenous human immunoglobulins is recommended to avoid possible worsening caused by glucocorticoids. In these cases, it is also advisable to start a non-steroidal immunosuppressant (glucocorticoid-sparing agent) in order to be able to use the lowest possible dose in maintenance therapy.In cases of mild OMG or GMG, it is usual to start with low doses (10mg/day or 20mg every other day) and progressively increase the dose until clinical improvement is achieved. Subsequently, alternate days should be tried and the dose should be gradually reduced.Non-corticosteroid immunosuppressantsNonsteroidal immunosuppressants, also called glucocorticoid-sparing agents, are used as a first choice in patients who have not responded to anticholinesterases and are contraindicated for steroid therapy, or in patients taking glucocorticoids in order to be able to taper the dose. In patients with diabetes or osteopenia, non-steroidal immunosuppressants could be considered first line.In general, the first choice is usually azathioprine or mycophenolate mofetil, or methotrexate if there is a contraindication or lack of tolerance to the previous two. If the patient’s clinical condition requires a faster onset of action, cyclosporine or tacrolimus may be used. Rituximab is the first choice in anti-MuSK MG when the patient does not respond to glucocorticoids and is increasingly used in refractory anti-AchR MG, although its efficacy is still uncertain in these cases. Cyclophosphamide should be limited to ultra-refractory cases due to its severe side effects.Rapid-onset, short-course immunomodulatory treatmentsBoth plasmapheresis and intravenous human immunoglobulins are indicated in patients with MG who have suffered an acute worsening and require a rapid therapeutic response. They are mainly used in cases of myasthenic crisis (established or imminent), prior to thymectomy or other surgeries if the patient’s clinical condition requires it, to prevent possible worsening in patients with MG who require initiation of high-dose glucocorticotherapy (especially in case of bulbar involvement), and sometimes as periodic treatment in patients who are not satisfactorily controlled with immunosuppressants or have intolerance to them.<a class="elsevierStyleCrossRefs" href="#bib0115">23,46</a> Plasmapheresis removes circulating antibodies, complement and cytokines. Immunoglobulins have multiple effects, including inhibition of complement deposition, activated Fc receptor blocking, and neutralisation of cytokines and antibodies. The efficacy of both treatments is similar, and the choice is based primarily on the patient’s comorbidities, the availability of either treatment and the practitioner’s experience with these treatments. Intravenous human immunoglobulins (2g/kg administered over 5 days) are generally used because of their ease of administration and good tolerability. Possible side effects are usually mild and related to the infusion rate (headache, chills, dizziness, fluid retention). Anaphylaxis, aseptic meningitis, acute renal failure and thrombotic events are much rarer. In case of plasmapheresis, about five refills (3–5l of plasma each) are usually performed over a period of 7–14 days (usually every two days). Side effects include central catheter thrombosis or infection, bleeding, hypotension, cardiac arrhythmias, muscle cramps, and a toxic reaction to citrate. In anti-MuSK MG, plasmapheresis is more effective than immunoglobulins.<a class="elsevierStyleCrossRef" href="#bib0180">36</a>On the treatment of myasthenic crisis and the chronic treatment of MG, the Spanish Society of Neurology, with the participation of the neuromuscular diseases study group, has drawn up diagnostic-therapeutic recommendations specifying the degrees of recommendation and level of evidence for the treatments used in MG, as well as their initiation and termination, which will serve the clinician as pocket clinical practice guidelines.<a class="elsevierStyleCrossRef" href="#bib0255">51</a>ThymectomyIt is indicated in all patients with thymoma. In non-thymomatous MG, a clinical trial comparing thymectomy with prednisone therapy demonstrated it to be effective up to 3 years after surgery in patients younger than 65 years with anti-AchR antibody positive GMG.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> In a post hoc analysis, no significant differences were found between the two cohorts in patients older than 50 years, so the recommendation of thymectomy for GMG without thymoma is limited to 50 years.<a class="elsevierStyleCrossRef" href="#bib0225">45</a> Thymectomy may also be considered in cases of seronegative MG when they do not respond adequately to immunosuppressive therapy or if the adverse effects of treatment are not tolerable, but would not be indicated in anti-MuSK MG, anti-LRP4 MG, or MGO.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>Video assisted thoracoscopic surgery (VATS) is preferred over median sternotomy as a surgical technique, as it has similar clinical outcomes, a lower complication rate and a shorter hospital stay.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>Emerging treatmentsIn recent years, new, more specific molecules have been developed for the treatment of MG, with a rapid onset of action (generally in the first week) and a good safety and tolerance profile, including complement inhibitors and immunoglobulin neonatal Fc receptor (FcRn) antagonists. Some are already approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), although they are not yet marketed in Spain or have not yet been funded for the treatment of GMG, while others are still in phase 2 or 3 clinical trials.<a class="elsevierStyleCrossRef" href="#bib0265">53</a>Complement inhibitorsThey are exclusively indicated in anti-AchR antibody-associated GMG, where complement plays an essential pathophysiological role. The main expected side effect is possible infection with encapsulated bacteria, especially Neisseria meningitidis, so vaccination against meningococcus is essential before starting treatment. This group includes eculizumab, ravulizumab and zilucoplan. Eculizumab is an intravenously administered humanised monoclonal antibody that selectively inhibits complement protein C5.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> It is the first complement inhibitor approved by the FDA in the US and by the EMA in Europe for GMG with anti-AchR antibodies. However, due to its cost-effectiveness, the indication in MG is not funded in Spain. Ravulizumab was developed from eculizumab in order to increase the intravenous administration dose to an interval of 8 weeks, instead of the 2 weeks required for eculizumab. It is approved for administration in the United States and Europe, although it is not yet marketed in Spain.<a class="elsevierStyleCrossRef" href="#bib0275">55</a> Zilucoplan is administered subcutaneously. A phase 3 clinical trial has recently been completed with a daily subcutaneous dose of 0.3mg/kg/day in adults with MGG,<a class="elsevierStyleCrossRef" href="#bib0280">56</a> although the data have not yet been published.Neonatal Fc receptor inhibitors (FcRn inhibitors)IgG-FcRn binding on endothelial cells protects IgG from lysosomal degradation and promotes its recycling. Thus, IgG is released back into the bloodstream without being degraded. FcRn inhibitor drugs are monoclonal antibodies that bind to FcRn, preventing the recycling of IgG and causing a drastic decrease of both pathogenic and normal antibody levels in the blood. The result on the level of circulating antibody reduction is similar to that of plasmapheresis, with the advantage that these drugs are better tolerated. Efgartigimod is an intravenously administered monoclonal antibody directed against the FcRn fragment of immunoglobulin G1 (IgG1) that produces a 70% decrease in blood IgG levels.<a class="elsevierStyleCrossRef" href="#bib0285">57</a> It is approved by the FDA and the EMA for the treatment of anti-AchR antibody-positive GMG in adults, although it is not yet marketed in Spain. Other FcRn inhibitors are rozanolixizumab (subcutaneous), nipocalimab (intravenous) and batoclimab (subcutaneous), still awaiting publication of the final results of the various clinical trials.<a class="elsevierStyleCrossRefs" href="#bib0290">58–60</a>Ethical considerationsThis review does not include patient data or research involving human subjects, so no informed consent has been obtained and no Ethics Committee assessment has been requested.FundingNone.Conflict of interestThe authors declare that they have no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1942661" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1673816" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1942660" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1673817" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Epidemiology" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Clinical features and classification" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Autoantibodies in myasthenia gravis" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Diagnosis" ] 9 => array:3 [ "identificador" => "sec0030" "titulo" => "Treatment" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0035" "titulo" => "Symptomatic treatment" ] 1 => array:2 [ "identificador" => "sec0040" "titulo" => "Chronic immunosuppressive treatment" ] 2 => array:2 [ "identificador" => "sec0045" "titulo" => "Glucocorticoids" ] 3 => array:2 [ "identificador" => "sec0050" "titulo" => "Non-corticosteroid immunosuppressants" ] 4 => array:2 [ "identificador" => "sec0055" "titulo" => "Rapid-onset, short-course immunomodulatory treatments" ] 5 => array:2 [ "identificador" => "sec0060" "titulo" => "Thymectomy" ] 6 => array:2 [ "identificador" => "sec0065" "titulo" => "Emerging treatments" ] 7 => array:2 [ "identificador" => "sec0070" "titulo" => "Complement inhibitors" ] 8 => array:2 [ "identificador" => "sec0075" "titulo" => "Neonatal Fc receptor inhibitors (FcRn inhibitors)" ] ] ] 10 => array:2 [ "identificador" => "sec0080" "titulo" => "Ethical considerations" ] 11 => array:2 [ "identificador" => "sec0085" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-02-27" "fechaAceptado" => "2023-04-18" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1673816" "palabras" => array:6 [ 0 => "Myasthenia gravis" 1 => "Autoantibodies" 2 => "Thymus" 3 => "Acetylcholine receptor" 4 => "Neuromuscular junction" 5 => "Immunotherapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1673817" "palabras" => array:6 [ 0 => "Miastenia gravis" 1 => "Autoanticuerpos" 2 => "Timo" 3 => "Receptor de acetilcolina" 4 => "Unión neuromuscular" 5 => "Inmunoterapia" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Myasthenia gravis is an autoimmune disease caused by the presence of specific antibodies targeting different postsynaptic components of the neuromuscular junction, and is clinically characterized by the presence of fatigueable muscle weakness. In the etiopathogenesis plays a central role the thymus and the most frequently detected pathogenic autoantibodies are targeted to the acetylcholine receptor. The increase in the knowledge of the immunological components of the neuromuscular junction in the last two decades has been fundamental to identify new pathogenic antibodies, reduce the percentage of patients with seronegative myasthenia, and propose a classification of patients into subgroups with clinical-therapeutic interest. In addition, in recent years, new drugs have been developed for the treatment of patients with myasthenia gravis that are refractory to conventional immunosuppressive treatment." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La miastenia gravis es una enfermedad autoinmune causada por la presencia de anticuerpos específicos dirigidos a diferentes componentes postsinápticos de la unión neuromuscular, y clínicamente se caracteriza por la presencia de debilidad muscular fatigable. En la etiopatogenia juega un papel central el timo, y los autoanticuerpos patogénicos más frecuentemente detectados están dirigidos al receptor de la acetilcolina. El incremento en el conocimiento de los componentes inmunológicos de la unión neuromuscular en las últimas dos décadas ha sido fundamental para identificar nuevos anticuerpos patogénicos, reducir el porcentaje de pacientes con miastenia seronegativa y proponer una clasificación de los pacientes en subgrupos con interés clínico-terapéutico. Además, en los últimos años hemos asistido al desarrollo de nuevos fármacos destinados al tratamiento de los pacientes con miastenia que muestran refractariedad al tratamiento inmunosupresor convencional." ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "Both authors have contributed equally to the development of the review." "identificador" => "fn0005" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0200" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Class \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Description \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">I</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Any ocular muscle weakness \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May have weakness of eye closure \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">All other muscle strength is normal \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">II</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mild weakness affecting muscles other than ocular muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May also have ocular muscle weakness of any severity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IIa</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weakness predominantly in the limbs and/or axial muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May have less severe involvement of oropharyngeal muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IIb</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weakness predominantly in the oropharyngeal and/or respiratory muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">There may be a lesser or equal degree of involvement of the axial and/or limb muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">III</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Moderate weakness affecting muscles other than ocular muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May also have ocular muscle weakness of any severity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IIIa</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weakness predominantly in the limbs and/or axial muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May have less severe involvement of the oropharyngeal muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IIIb</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weakness predominantly affecting the oropharyngeal and/or respiratory muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">There may be a lesser or equal degree of involvement of the axial and/or limb muscles. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IV</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Severe weakness affecting muscles other than the ocular muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May also have ocular muscle weakness of any severity \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IVa</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weakness predominantly in the limbs and/or axial muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May also have lesser involvement of oropharyngeal muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IVb</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Predominantly affecting the oropharyngeal and/or respiratory muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May also have lesser or equal involvement of the axial and/or limb muscles \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">V \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Defined by the need for orotracheal intubation, with/without mechanical ventilation, except when employed during routine postoperative management. The use of a feeding tube without intubation places the patient in class IVb. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3236449.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Clinical classification according to the Myasthenia Gravis Foundation of America.<a class="elsevierStyleCrossRef" href="#bib0130">26</a>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0205" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "Anti-Kv1.4: anti-voltage-gated potassium channel Kv1.4 antibody; anti-RyR: anti-ryanodine receptor antibodies." "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of GM (IgG subclass) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age at start (years) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sex (F/M) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Predominantly thymic histology \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HLA association (Caucasian) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Other auto-antibodies \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical features \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " colspan="7" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">MG anti-AchR (IgG1, IgG3)</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">Early onset</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle"><50</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">F>M</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">Hyperplasia (>80%)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Haplotype \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle"></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Predominantly GMG. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A1-B8-DR3-DQ2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle">Thymectomy is indicated</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DQA1; rs601006; rs601006 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle">Late onset</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">≥50</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="middle">M>F</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="middle">Thymic atrophy is common</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DRB1*15:01 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-titin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Predominantly ocular onset forms. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DQB1*05:02 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">Anti-R&R</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">High rate of positive anti-AchR autoantibodies. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DRB1*16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increased number of co-morbidities. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DQA1; rs9271871; rs9271871 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Very late-onset (≥65 years): no thymoma \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle">Associated with thymoma</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Any (common 40–60)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="middle">M>F</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="middle">Lymphoepithelioma (60% benign)</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle"></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-titin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">It is a paraneoplastic form of MG (10%–15% of cases). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-R&R \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">Thymectomy is essential</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-Kv1.4 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-actin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle">Anti-MuSK MG (IgG4)</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Any (common<40)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="middle">F>M</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="4" align="left" valign="middle">Normal</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DRB1*14 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle"></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Early bulbar and cervical involvement is common. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DRB1*16 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">There is muscle atrophy. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DQB1*05 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-response to pyridostigmine. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">DQ5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Thymectomy not indicated. Rituximab is effective \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-LRP4 MG (IgG1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Any \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">F>M \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Follicular hyperplasia (30%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symptoms and treatment comparable to MG-anti-AchR \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">Seronegative MG</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Any</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle"></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle"></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle"></td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clustered-AchR (IgG1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle">Symptoms and treatment comparable to MG-anti-AchR</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-agrin (minority) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3236448.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification of myasthenia gravis by autoantibody subgroups." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0210" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CMAP: compound muscle action potential; CSF: cerebrospinal fluid; EMG: electromyography; IDU: injecting drug users; RA: rheumatoid arthritis; RNS: repetitive nerve stimulation; SCLC: small cell lung carcinoma; SLE: systemic lupus erythematosus." "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle">Lambert-Eaton myasthenic syndrome</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proximal limb weakness, predominantly in the lower limbs. Hypo-areflexia. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysautonomia: dry mouth, dry eye, constipation, orthostatic hypotension. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presynaptic myasthenic syndrome: 50% paraneoplastic (SCLC). Antibodies against calcium channels. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EMG: low amplitude CMAP. RNS: post-tetanic facilitation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Congenital myasthenic syndromes</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Onset in childhood. Family history may exist. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Myopathic features. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absence of MG autoantibodies. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genetic test — myasthenic syndromes \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Botulism</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presynaptic myasthenic syndrome. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aetiology: Clostridium botulinum. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Source of infection: contaminated canned food, infected wounds, IDU. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Clinical: digestive symptoms, mydriasis, ophthalmoparesis, muscle weakness, respiratory insufficiency. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="middle">Mitochondrial myopathies</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gradual onset. Maternal inheritance. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Symmetrical, chronic, non-fluctuating ptosis. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Chronic progressive external ophthalmoparesis without diplopia. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Migraine, deafness, retinopathy, cramps. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Muscle biopsy: mitochondrial proliferation, ragged-red fibres. Study of the mitochondrial respiratory chain. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle">Oculopharyngeal muscular dystrophy</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Age >50 years. Symmetrical, chronic, non-fluctuating ptosis. Complete ophthalmoparesis without diplopia. Dysphagia. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Biopsy: dystrophic muscle. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Genetic test: mutation in poly(A)2-binding protein on chromosome 14q11.2-13 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Drug-induced myasthenic syndrome</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">D-penicillamine: cystinuria, RA, Wilson’s disease. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hydroxychloroquine: SLE, RA, antimalarials \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle">Brainstem pathology (stroke, neoplasm)</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Acute onset in stroke. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Neighbourhood signs: facial paresis, Horner, dysmetria. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Encephalic MRI needed for diagnosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Miller-Fisher syndrome</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ophthalmoparesis. Ataxia. Areflexia. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-ganglioside antibodies: GQ1b \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle">Amyotrophic lateral sclerosis (bulbar)</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">First motor neuron symptoms (hyperreflexia, spasticity, Babinski). Cramps. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-fluctuating weakness. No diplopia. No ptosis. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">May have partial response to pyridostigmine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="middle">Lyme disease (neuroborreliosis)</td><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Borrelia burgdorferi (tick-borne). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Epidemiology: geographical areas. Seasonal: summer. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cranial mononeuritis multiplex. Radiculopathies. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CSF: lymphocytic meningitis. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Treatment: ceftriaxone \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3236450.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Differential diagnosis of myasthenia gravis." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0215" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "HBP: high blood pressure; PML: progressive multifocal leukoencephalopathy. TPMT: thiopurine methyltransferase." "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="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Starting dose \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Maintenance dose \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Onset of action \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adverse effects \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Monitoring \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comments \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pyridostigmine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30mg, 3 times/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60−120mg 4 times daily not disturbing sleep. Adjust according to tolerance and side effects \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30−60min \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Abdominal cramps, diarrhoea, nausea, increased bronchial secretions and salivation, bradycardia, fasciculations, cramps \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monitor for increased secretions in patients with bulbar involvement. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Give 30min before meal if dysphagia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prednisone \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20–60mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">20−60mg with slow tapering, if possible, every other day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10−20 days \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Weight gain, hyperglycaemia, HBP, cataracts, osteoporosis, gastric ulcer, insomnia, mood swings, risk of infection, cushingoid facies \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Periodic haemoglobin A1C and BP control, annual densitometry, annual eye check-up \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monitor diet, calcium and vitamin D supplementation, gastric protector. Bisphosphonates if osteopenia or postmenopausal women. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Azathioprine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">150mg/day or 2−3mg/kg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6−18 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Idiosyncratic flu-like reaction, abdominal discomfort, hepatotoxicity, pancreatitis, myelosuppression, risk of skin cancer and lymphoma. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blood tests every 15 days for the first month, then monthly for 6 months, and then every 3 months. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Can be given in 1–3 doses, with meals. Avoid sun exposure. Prior determination of TPMT activity or genetic study to detect possible no or low enzyme activity. Reduce dose in case of concomitant treatment with allopurinol or sulfasalazine. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mycophenolate mofetil \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">500mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">500–1500mg every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3−12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Teratogenic. Nausea and vomiting, diarrhoea, myelosuppression, risk of skin cancer and rarely lymphoma and PML (rare). \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blood tests every 2 weeks for the first month, then monthly for 6 months, then every 3 months. Contraceptive measures in women of childbearing age \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraception if used in women of childbearing age. Administer one hour before or two hours after meals. Adjust dose if taking cholestyramine. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Methotrexate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.5mg/week \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15–25mg/weekly \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6–12 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hepatotoxicity, stomatitis, nausea and vomiting, pulmonary toxicity, teratogenicity, photosensitivity. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monthly blood tests, then every 3 months. Intermittent check for interstitial lung disease. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraindicated in pregnancy. Folic acid supplementation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclosporine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50−100mg every 12h \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3−5mg/kg/day, in two doses. Try to reduce to 2mg/kg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1−3 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">HBP, nephrotoxicity, hepatotoxicity, neuropathy, tremor, skin cancer, lymphopenia, myalgias, hypertrichosis, hyperkalaemia, common drug interactions \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monthly blood tests for the first 3 months, then every 3 months. Monitor renal function \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blood levels between 100–150ng/ml. For a 70kg person, the usual dose is 100mg every 12h. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tacrolimus \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 mg/day \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3mg/day, in two doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1−6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hyperglycaemia, hypomagnesaemia, diarrhoea, lymphopenia, nephrotoxicity, tremor, myelosuppression, rare cancer risk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monthly blood tests for the first 3 months, then periodically thereafter \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Maintain levels of 2−9ng/ml. Take on an empty stomach. Less nephrotoxicity than cyclosporine. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rituximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1g every two weeks (2 doses) or 375mg/m2 weekly for a total of 4 doses \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Repeat cycles every 6 months if necessary \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1−3 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hypogammaglobulinemia, Myelosuppression, infusion reaction, PML rarely \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Periodic blood tests, CD19 lymphocyte counts \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">A minimum of two cycles of treatment is usually required. Cannot be combined with complement-acting drugs. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cyclophosphamide \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5–1.5g/m2 i.v. or 50−100mg/day oral \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0.5−1g/m2 monthly or 50−100mg/day orally \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1−6 months \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Teratogeny. Infertility. Nausea, alopecia, myelosuppression, haemorrhagic cystitis, cancer risk, cardiac, pulmonary and renal toxicity. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monthly blood and urine tests \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Contraception. Premedication with hydration and antiemetics. Monitoring of haematuria. Short-lasting efficacy. 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Myasthenia gravis. Update on diagnosis and therapy

Miastenia gravis. Actualización diagnóstica y terapéutica

Daniel Apolinar García Estéveza,b,

,1, Julio Pardo Fernándezc,1

a Servicio de Neurología, Complexo Hospitalario Universitario de Ourense, Ourense, Spain

b Grupo de investigación Neurociencias Clínicas, Instituto de Investigaciones Sanitarias Galicia-Sur, SERGAS-UVIGO, Vigo, Pontevedra, Spain

c Unidad de Enfermedades Neuromusculares, Servicio de Neurología, Complexo Hospitalario Universitario de Santiago de Compostela, Facultad de Medicina, Universidad de Santiago de Compostela, Santiago de Compostela, A Coruña, Spain

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    "cabecera" => "<span class="elsevierStyleTextfn">Review</span>"
    "titulo" => "Myasthenia gravis&#46; Update on diagnosis and therapy"
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        "autoresLista" => "Daniel Apolinar Garc&#237;a Est&#233;vez, Julio Pardo Fern&#225;ndez"
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    "titulosAlternativos" => array:1 [
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        "titulo" => "Miastenia gravis&#46; Actualizaci&#243;n diagn&#243;stica y terap&#233;utica"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Myasthenia gravis &#40;MG&#41; is an autoimmune disease caused by the presence of specific antibodies directed against different postsynaptic components of the neuromuscular junction &#40;NMJ&#41;&#44; mostly against the nicotinic acetylcholine receptor &#40;AchR&#41;&#46; The thymus plays a main role in its aetiopathogenesis and may exhibit pathological alterations such as thymic hyperplasia &#40;65&#37;&#41; or thymoma &#40;10&#37;&#8211;15&#37;&#41;&#46; Clinically&#44; it is characterised by the presence of fatigable muscle weakness&#44; the neurophysiological correlate of which is a drop in the compound muscle action potential with repetitive nerve stimulation&#46; Treatment is based on the use of reversible acetylcholinesterase inhibitors &#40;pyridostigmine&#41; and various disease-modifying immunosuppressive treatments&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Clinical and neurophysiological diagnosis and initial treatment have remained unchanged over the last decades&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> However&#44; our knowledge of the immunological components of NMJ has increased&#44; and new pathogenic antibodies have been identified&#44; which have made it possible to reduce the percentage of MG patients initially classified as seronegative&#44; and to propose a classification of patients into subgroups of clinical and therapeutic interest&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;13</span></a> In addition&#44; we have seen the development of new treatments aimed at managing patients with drug-resistant forms of the disease&#46; These clinical and therapeutic advances will be the focus of this review&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">In terms of incidence and prevalence rates&#44; there is a wide range of figures according to different studies&#46; Two systematic reviews have reported incidence rates of up to 30 cases per 1&#44;000&#44;000 person-years&#44; and a maximum prevalence of 179 cases per 1&#44;000&#44;000 person-years&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a> The most recent study in Spain&#44; in the ageing province of Ourense&#44; found an incidence rate of 15&#46;4 cases per 1&#44;000&#44;000 person-years and a prevalence of 260 cases per 1&#44;000&#44;000 person-years&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> A review of the epidemiology in the Iberian Peninsula recorded prevalence rates between 86 and 329 cases per 1&#44;000&#44;000 inhabitants&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> MG can occur at any age&#44; from birth to senescence&#44; although juvenile forms are rare &#40;except in Asian countries and South Africa&#41;&#46; The incidence of juvenile MG in the Caucasian population is less than 2 cases per 1&#44;000&#44;000 person-years&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Epidemiological studies consistently show a bimodal incidence in females&#44; with a peak between the age of 20 and 40 and another between the age of 60 and 80&#44; while in males there is a steady increase from 60 years of age onwards&#46;<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;16</span></a> Furthermore&#44; there has been an increase in the incidence and prevalence figures in recent years&#44; particularly affecting the elderly population&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;19&#44;20</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Clinical features and classification</span><p id="par0020" class="elsevierStylePara elsevierViewall">The clinical presentation of MG will depend on the muscles affected&#46; The most common symptoms are&#58; eyelid ptosis&#44; diplopia&#44; dysarthria &#40;slurred-nasalised speech&#41;&#44; dysphagia with nasal regurgitation of liquids&#44; head ptosis &#40;neck extensor muscles&#41;&#44; and in the proximal muscles of the upper or lower limbs&#44; patients may develop fatigability with repetitive movements&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;8&#44;21&#8211;24</span></a> Muscle weakness is fluctuating&#44; least on waking in the morning&#59; it improves with rest and worsens with physical activity and throughout the day &#40;mainly in the evenings&#41;&#46; Most patients will have ocular symptoms at onset &#40;85&#37;&#41;&#44; but 80&#37; will develop generalised MG &#40;GMG&#41; within 2&#8211;3 years of diagnosis&#46; If symptoms remain localised at the ocular level for one year&#44; it is very likely that the symptoms will not progress&#44; representing the purely ocular form &#40;OMG&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;24</span></a> MG is a heterogeneous disease&#44; not only in terms of clinical features and pathogenic autoantibodies&#44; but also in terms of genetic predisposition&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">The clinical classification currently used is the Myasthenia Gravis Foundation of America &#40;MGFA&#41; Clinical Classification&#44;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> which considers both the location of the affected muscles &#40;oculomotor&#44; oropharyngeal and limb&#41; and the severity of the symptoms &#40;mild-moderate-severe&#41;&#44; and an additional class &#40;class V&#41; is represented by myasthenic crisis&#44; which is a clinical exacerbation involving the respiratory muscles and requires the support of invasive mechanical ventilation &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; It is a clinical classification that replaces the classic Osserman classification&#44; which classified patients according to the maximum severity of the affected muscles&#44; and this maximum represents the reference for assessing the response to treatment&#44; which in turn is quantified with the <span class="elsevierStyleItalic">MGFA Post-intervention Status</span> scale&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">MG can be classified according to age at clinical onset into a transient neonatal form that is triggered by passive transfer of maternal pathogenic antibodies to the foetus and affects 10&#37;&#8211;20&#37; of newborns<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a>&#59; a juvenile-onset form &#40;&#8804;18 years&#41;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#59; an early-onset form &#40;&#60;50 years&#41;&#44; and a late-onset form &#40;&#8805;50 years&#41;&#46; The clinical presentation of juvenile MG is similar to that of adults and ocular forms are the most common&#59; anti-AchR antibodies are the most commonly detected&#44; but the percentage of seronegative results is higher than in adults&#46; Puberty has a clear influence on gender prevalence and the likelihood of generalisation&#44; and the differential diagnosis is broader in this age group&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Early presentation of MG is more prevalent in females&#44; is usually associated with thymic pathology and HLA-B8 and DR3 markers are detected in 60&#37; of cases&#46; In late-onset forms there is a male prevalence&#44; thymic atrophy is common&#44; and an association with HLA-B7 and DR2 markers has been detected&#46; In the late presentation&#44; patients have a higher percentage of positive results for anti-AchR antibodies and OMG is more prevalent than in the early-onset form&#44; and despite having a greater number of medical comorbidities&#44;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> they do not differ in therapeutic management or prognosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a> Patients with MG diagnosed at an age older than 65 years are the most prevalent&#44; and can be considered a separate clinical subgroup&#44; whose clinical features are similar to those of the late-onset group&#44; but in which the presence of thymoma is very rare&#44; and although MG may begin with severe symptoms&#44; in clinical practice patients usually require a lower degree of immunosuppression for the control of clinical manifestations&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;32</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Autoantibodies in myasthenia gravis</span><p id="par0035" class="elsevierStylePara elsevierViewall">Autoantibodies in MG are specific and pathogenic and allow a classification with clinical and therapeutic implications &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;32&#44;33</span></a> Fifty percent of OMG and 85&#37; of GMG are positive for anti-AchR antibodies&#46; AchR is a glycoprotein composed of five subunits &#40;2&#44; &#945;&#44; &#946;&#44; &#948;&#44; &#949;&#41;&#44; that functions as an ion channel&#44; the activation of which results in the influx of Na that generates the depolarising potential at the motor endplate&#46; These autoantibodies exert their pathogenic action through several mechanisms&#58; 1&#41; they belong to the IgG1 and IgG3 subclass with the ability to activate the complement pathway and produce AchR degradation at postsynaptic level&#59; 2&#41; by means of a <span class="elsevierStyleItalic">cross-linking</span> reaction they can result in internalisation of the receptor by increasing endocytosis&#44; and 3&#41; by blocking the receptor preventing its physiological postsynaptic action&#46; Patients in whom these autoantibodies are not detected are termed seronegative&#46; It has been reported that up to 50&#37; of these negative results are due to the presence of low affinity anti-AchR autoantibodies&#46; For this purpose&#44; a diagnostic test based on embryonic kidney cells has been developed&#44; which allows the clustering of AchR with the participation of rapsin&#44; increasing the sensitivity and specificity of the test&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> although its availability in routine clinical practice is still very limited&#46; Patients with such low affinity antibodies have similar clinical features to those patients with anti-AchR antibodies measured by radioimmunoassay&#46; Regarding anti-AchR antibodies&#44; the higher the titre&#44; the higher the diagnostic specificity&#44; but the antibody titre is not associated with the severity of the clinical presentation and the usefulness of its quantification in the clinical follow-up of the patient has not been demonstrated&#46; On the other hand&#44; false positives associated with other autoimmune diseases have been reported&#44; mainly when titres are low&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Antibodies directed against muscle-specific tyrosine kinase &#40;anti-MuSK&#41; are detected in 30&#37;&#8211;40&#37; of anti-AchR seronegative patients&#46; The MuSK protein is expressed in the postsynaptic muscle membrane and is required to maintain AchR function&#46; Anti-MuSK antibodies belong to the IgG4 class and cannot activate complement&#46; Their mechanism of action consists of interaction with the lipoprotein receptor-related protein 4 &#40;LRP4&#41;&#44; resulting in no AchR clustering&#44; and also&#44; through interaction with matrix proteins such as collagen Q&#44; they contribute to the stabilisation of the synapse&#46; MG with anti-MuSK antibodies &#40;MuSK-MG&#41; accounts for approximately 5&#37; of MG cases&#46; It is more common in women&#44; with involvement of the bulbar and cervical muscles being more common&#44; and usually presents with greater clinical severity&#46; Patients report little variation in strength throughout the day&#44; and muscle atrophy and fasciculations may occur in the affected muscles&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">LRP4 is a protein expressed in the postsynaptic membrane that behaves as a receptor for the agrin released from the nerve terminal&#44; which results in the activation of the MuSK protein&#44; and is therefore necessary for proper AchR function&#46; Although rare in routine clinical practice&#44; anti-LRP4 antibodies are detected in some series in 2&#37;&#8211;27&#37; of patients negative for anti-AchR and anti-MuSK&#46; MG-LRP4 is more prevalent in females&#44; with ocular and generalised presentations of mild intensity accounting for 85&#37; of clinical manifestations at onset&#44; and in terms of progression&#44; 20&#37; of patients remain in an OMG 2 years after onset&#46; One third of patients have thymic hyperplasia but no thymomas have been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Another antibody that has been identified in a small number of seronegative patients is directed against the agrin protein&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> This protein is important in the development of the NMJ and in the structural maintenance of the mature synapse&#44; and mutations in the agrin gene cause congenital myasthenic syndrome&#46; Agrin is released from the growing axon terminal into the intracellular matrix&#44; leading to the formation of myotubes&#44; and also binds to the LRP4 protein&#44; and this complex in turn to the MuSK protein&#44; leading to its activation&#44; which ultimately results in the clustering of AchRs&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>&#46; However&#44; the possible pathogenic role of agrin in autoimmune myasthenia has not yet been established&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and&#44; in fact&#44; most MG patients with these antibodies also have antibodies against AchR&#44; MuSK or LRP4&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In addition&#44; there are non-pathogenic antibodies&#44; so-called striatal antibodies&#44; directed against muscle proteins&#44; titin and the ryanodine receptor &#40;RyR&#41;&#44; located outside the synapse&#46; Titin is involved in the flexibility of the cell structure and the RyR is a calcium channel&#44; located in the sarcoplasmic reticulum&#44; which is involved in muscle cell contraction&#46; These antibodies can be found in late-onset forms but have been proposed as a marker of thymoma in patients with early-onset MG &#40;&#60;40 years&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;39</span></a> However&#44; caution should prevail when interpreting the presence of anti-titin antibodies&#44; as their role as a marker of severity in MG has been questioned&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diagnosis</span><p id="par0060" class="elsevierStylePara elsevierViewall">Diagnostic suspicion will be established when a patient presents with fatigable muscle weakness at ocular&#44; bulbar or limb level&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#8211;23</span></a> Ocular fatigability can be demonstrated by asking the patient to keep the gaze fixed upwards or to the side &#40;occurrence of diplopia or ptosis&#41;&#59; dysarthria&#44; by asking the patient to count aloud to 100 uninterruptedly&#59; and proximal limb fatigability&#44; with repeated movements of upper limb abduction or getting up from a chair without assistance&#46; Eyelid ptosis is usually asymmetrical&#44; and raising the eyelid of the eye with greater ptosis causes the eyelid of the contralateral eye to lower &#40;curtain sign&#41;&#44; and Cogan&#8217;s sign can also be seen&#44; which consists of holding the gaze downwards for 10&#8211;15<span class="elsevierStyleHsp" style=""></span>s&#44; and on recovering the primary position of the gaze&#44; the eyelid with ptosis experiences a momentary upward contraction&#46; As per facial muscles&#44; there is hypercontraction of the frontalis muscle &#40;surprised look&#41; as a compensatory mechanism for the ptosis&#44; and when attempting to smile&#44; the weakness of the orbicularis oris muscle produces a facial expression known as the &#8220;myasthenic snarl&#8221;&#46; If the patient presents with eyelid ptosis&#44; the ice test can be performed in the consultation room&#44; consisting of applying a cold pack to the ptosed eyelid for two minutes&#44; and the response will be positive if an increase in the eyelid opening of more than 2<span class="elsevierStyleHsp" style=""></span>mm<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;40</span></a> is achieved&#44; with a sensitivity of 80&#37;&#8211;95&#37; and a specificity of 79&#37;&#8211;97&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The classic diagnostic test is the Tensilon test&#174; &#40;edrophonium chloride&#41;&#44; a reversible acetylcholinesterase inhibitor administered intravenously&#44; which causes a rapid and short-lasting response&#44; allowing us to observe the recovery of eyelid ptosis&#44; ophthalmoparesis or dysarthria&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> The sensitivity of the test ranges from 60&#37; to 95&#37; for OMG and 72&#37;&#8211;95&#37; for GMG&#44; but the specificity of the test is not clear from published data&#44; and the test can be positive in Lambert-Eaton syndrome&#44; botulism&#44; motor neurone disease and other pathologies&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;40</span></a> Because of the possibility of severe bradycardia&#44; it should be performed in a hospital setting&#44; and is not usually performed except in cases of diagnostic uncertainty that cannot be resolved by other techniques&#46; Anti-AchR antibodies should be requested initially&#44; and if negative&#44; the immunological study should be extended to anti-MuSK and&#47;or anti-LRP4 antibodies&#46; A neurophysiological study should be performed to detect neuromuscular transmission abnormalities&#46; This can be done by repetitive nerve stimulation &#40;RNS&#41; at low frequency &#40;3<span class="elsevierStyleHsp" style=""></span>Hz&#41;&#44; which&#44; after a train of 10 stimuli&#44; will show a drop in the amplitude of the compound muscle action potential of more than 10&#37; in the fourth or fifth stimulus&#46; The test is positive in 85&#37; of patients with GMG&#44; but only in 50&#37; of patients with OMG&#46; In OMG&#44; facial muscles or spinal accessory nerve RNS has a sensitivity of 15&#37;&#8211;35&#37; and a specificity of 95&#37;&#8211;99&#37;&#44; but because of the low sensitivity it is often necessary to perform a single-fibre electromyography&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21&#44;23&#44;40</span></a> This technique assesses the response of a single motor unit muscle fibre to a series of stimuli&#44; and in case of pathology in neuromuscular transmission it will show increased jitter or blocks&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;23&#44;40</span></a> In cases of MuSK-MG&#44; conventional electromyography can detect the presence of acute denervation potentials &#40;fibrillations and positive sharp waves&#41; and fasciculations in tongue&#44; facial and&#47;or cervical muscles&#46; This situation makes it necessary to establish the differential diagnosis with motor neurone diseases because of their prognostic implications&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">The differential diagnosis should be made primarily with those entities that can cause fluctuating muscle weakness &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Treatment</span><p id="par0070" class="elsevierStylePara elsevierViewall">Advances in the treatment of MG in recent decades have considerably improved the functional status of patients&#44; with a significant decrease in morbidity and mortality&#46; However&#44; 10&#37;&#8211;15&#37; still have refractory MG&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; if the patient&#8217;s clinical status remains unchanged or worsens after treatment with glucocorticoids and at least two other immunosuppressants&#44; using effective doses for an adequate time&#44; with persistent symptoms or disabling side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Since MG is clinically heterogeneous&#44; treatment must be individualised&#44; taking into account the clinical subtype according to age at onset&#44; associated antibodies&#44; thymic pathology and the distribution and intensity of weakness&#44; as well as possible existing comorbidities&#46; There are various international therapeutic guidelines for its management&#46; These are based mainly on expert recommendations&#44; given the scarcity of controlled clinical trials in this pathology&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#8211;45</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In general&#44; there are several therapeutic options available&#44; which can be divided into symptomatic treatment &#40;acetylcholinesterase inhibitors&#41;&#44; chronic immunosuppressive treatment &#40;glucocorticoids and non-steroidal immunosuppressants&#41;&#44; fast-acting but short-lasting immunomodulatory treatments for severe conditions &#40;intravenous immunoglobulins and plasmapheresis&#41; and surgical treatment &#40;thymectomy&#41;&#46; In addition&#44; in recent years&#44; new treatments for MGM&#44; not yet marketed at the time of this review&#44; have been emerging and are included under emerging treatments heading&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">Before we start describing the course-modifying treatments for MG&#44; we would like to remind the reader that there are certain medications that can exacerbate the weakness of MG patients&#46; These include&#44; at high risk&#44; botulinum toxin&#44; immune checkpoint inhibitors &#40;<span class="elsevierStyleItalic">e&#46;g&#46;</span>&#44; pembrolizumab&#41;&#44; intravenous magnesium&#44; penicillamine and telithromycin &#40;ketolide antibiotic&#41;&#59; at moderate risk&#44; aminoglycoside antibiotics&#44; fluoroquinolones and macrolides&#59; and at low risk&#44; beta-blockers&#44; hydroxychloroquine&#44; interferon alpha&#44; iodinated contrast agents&#44; quinine and statins&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;45</span></a></p><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Symptomatic treatment</span><p id="par0090" class="elsevierStylePara elsevierViewall">The most commonly used anticholinesterase &#40;acetylcholinesterase inhibitor&#41; is oral pyridostigmine&#44; which increases the availability of acetylcholine in the NMJ as it delays its degradation by acetylcholinesterase&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> It is effective in all subtypes of MG&#44; with the exception of MuSK-MG&#44; where it tends to have a poor clinical response and a greater susceptibility to side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Pyridostigmine is the initial treatment of choice in MG and some patients remain asymptomatic with anticholinesterase alone&#44; especially those with OMG or mild MGM&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Chronic immunosuppressive treatment</span><p id="par0095" class="elsevierStylePara elsevierViewall">It is indicated in patients with weakness and&#47;or lack of response to symptomatic anticholinesterase therapy in order to achieve at least a minimal manifestation status&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span> some muscle weakness on examination but no functional disability <span class="elsevierStyleItalic">&#40;MGFA Post-intervention Status&#41;</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> and with as few adverse effects as possible&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;47</span></a> These drugs include glucocorticoids and non-steroidal immunosuppressants &#40;azathioprine&#44; mycophenolate mofetil&#44; methotrexate&#44; cyclosporine&#44; tacrolimus&#44; rituximab and cyclophosphamide&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">When an immunosuppressant is to be prescribed&#44; it is necessary to carry out a preliminary study to detect possible contraindications&#44; latent infections&#44; determine the most suitable drug according to the onset of action and adjust the most appropriate dose&#46; The patient&#8217;s vaccination coverage should be checked and a series of complementary tests should be requested before starting immunosuppressive treatment&#44; including a blood and urine test&#44; serology for hepatitis B&#44; hepatitis C and HIV&#44; Mantoux and&#47;or IGRA test &#40;interferon gamma release assay&#41; to rule out latent tuberculosis&#44; pregnancy test in women of childbearing age and chest X-ray&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Glucocorticoids</span><p id="par0105" class="elsevierStylePara elsevierViewall">They remain the first-line immunosuppressive treatment and are indicated in patients who do not achieve adequate symptomatic control with anticholinesterase drugs or who cannot tolerate such treatment due to its side effects&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">In patients with OMG&#44; several retrospective studies have shown a lower risk of developing GMG in the group of patients who received early glucocorticoids&#44; although this is still a controversial issue given the lack of long-term prospective studies&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Symptomatic response is rapid&#44; within 2&#8211;4 weeks of onset when administered at high doses&#44; with maximum improvement in the first 4&#8211;8 weeks&#46; The response rate is 74&#37;&#46; Up to 40&#37; may experience paradoxical symptomatic worsening in the first two weeks of treatment&#44; followed by clinical improvement&#46; Because of side effects&#44; long-term maintenance treatment should be carried out at low doses &#40;below 7&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Classically&#44; there are two ways of administering glucocorticoids orally&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> In patients with moderate-severe MGM or in situations of impending myasthenic crisis&#44; where there is an interest in inducing rapid clinical remission&#44; high doses of prednisone &#40;1<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#41; are used for 4 weeks or until clinical improvement is achieved&#46; Thereafter&#44; it is advisable to administer treatment every other day and progressively reduce the dose&#46; An exception is in patients with diabetes or hypertension&#44; where daily administration of glucocorticoids is preferable to avoid fluctuations in blood pressure or blood glucose&#46; High-dose glucocorticoids require admission&#44; and in cases of bulbar involvement&#44; simultaneous treatment with intravenous human immunoglobulins is recommended to avoid possible worsening caused by glucocorticoids&#46; In these cases&#44; it is also advisable to start a non-steroidal immunosuppressant &#40;glucocorticoid-sparing agent&#41; in order to be able to use the lowest possible dose in maintenance therapy&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In cases of mild OMG or GMG&#44; it is usual to start with low doses &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;day or 20<span class="elsevierStyleHsp" style=""></span>mg every other day&#41; and progressively increase the dose until clinical improvement is achieved&#46; Subsequently&#44; alternate days should be tried and the dose should be gradually reduced&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Non-corticosteroid immunosuppressants</span><p id="par0130" class="elsevierStylePara elsevierViewall">Nonsteroidal immunosuppressants&#44; also called glucocorticoid-sparing agents&#44; are used as a first choice in patients who have not responded to anticholinesterases and are contraindicated for steroid therapy&#44; or in patients taking glucocorticoids in order to be able to taper the dose&#46; In patients with diabetes or osteopenia&#44; non-steroidal immunosuppressants could be considered first line&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In general&#44; the first choice is usually azathioprine or mycophenolate mofetil&#44; or methotrexate if there is a contraindication or lack of tolerance to the previous two&#46; If the patient&#8217;s clinical condition requires a faster onset of action&#44; cyclosporine or tacrolimus may be used&#46; Rituximab is the first choice in anti-MuSK MG when the patient does not respond to glucocorticoids and is increasingly used in refractory anti-AchR MG&#44; although its efficacy is still uncertain in these cases&#46; Cyclophosphamide should be limited to ultra-refractory cases due to its severe side effects&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Rapid-onset&#44; short-course immunomodulatory treatments</span><p id="par0140" class="elsevierStylePara elsevierViewall">Both plasmapheresis and intravenous human immunoglobulins are indicated in patients with MG who have suffered an acute worsening and require a rapid therapeutic response&#46; They are mainly used in cases of myasthenic crisis &#40;established or imminent&#41;&#44; prior to thymectomy or other surgeries if the patient&#8217;s clinical condition requires it&#44; to prevent possible worsening in patients with MG who require initiation of high-dose glucocorticotherapy &#40;especially in case of bulbar involvement&#41;&#44; and sometimes as periodic treatment in patients who are not satisfactorily controlled with immunosuppressants or have intolerance to them&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;46</span></a> Plasmapheresis removes circulating antibodies&#44; complement and cytokines&#46; Immunoglobulins have multiple effects&#44; including inhibition of complement deposition&#44; activated Fc receptor blocking&#44; and neutralisation of cytokines and antibodies&#46; The efficacy of both treatments is similar&#44; and the choice is based primarily on the patient&#8217;s comorbidities&#44; the availability of either treatment and the practitioner&#8217;s experience with these treatments&#46; Intravenous human immunoglobulins &#40;2<span class="elsevierStyleHsp" style=""></span>g&#47;kg administered over 5 days&#41; are generally used because of their ease of administration and good tolerability&#46; Possible side effects are usually mild and related to the infusion rate &#40;headache&#44; chills&#44; dizziness&#44; fluid retention&#41;&#46; Anaphylaxis&#44; aseptic meningitis&#44; acute renal failure and thrombotic events are much rarer&#46; In case of plasmapheresis&#44; about five refills &#40;3&#8211;5<span class="elsevierStyleHsp" style=""></span>l of plasma each&#41; are usually performed over a period of 7&#8211;14 days &#40;usually every two days&#41;&#46; Side effects include central catheter thrombosis or infection&#44; bleeding&#44; hypotension&#44; cardiac arrhythmias&#44; muscle cramps&#44; and a toxic reaction to citrate&#46; In anti-MuSK MG&#44; plasmapheresis is more effective than immunoglobulins&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">On the treatment of myasthenic crisis and the chronic treatment of MG&#44; the Spanish Society of Neurology&#44; with the participation of the neuromuscular diseases study group&#44; has drawn up diagnostic-therapeutic recommendations specifying the degrees of recommendation and level of evidence for the treatments used in MG&#44; as well as their initiation and termination&#44; which will serve the clinician as pocket clinical practice guidelines&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Thymectomy</span><p id="par0150" class="elsevierStylePara elsevierViewall">It is indicated in all patients with thymoma&#46; In non-thymomatous MG&#44; a clinical trial comparing thymectomy with prednisone therapy demonstrated it to be effective up to 3 years after surgery in patients younger than 65 years with anti-AchR antibody positive GMG&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> In a <span class="elsevierStyleItalic">post hoc</span> analysis&#44; no significant differences were found between the two cohorts in patients older than 50 years&#44; so the recommendation of thymectomy for GMG without thymoma is limited to 50 years&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Thymectomy may also be considered in cases of seronegative MG when they do not respond adequately to immunosuppressive therapy or if the adverse effects of treatment are not tolerable&#44; but would not be indicated in anti-MuSK MG&#44; anti-LRP4 MG&#44; or MGO&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Video assisted thoracoscopic surgery <span class="elsevierStyleItalic">&#40;</span>VATS&#41; is preferred over median sternotomy as a surgical technique&#44; as it has similar clinical outcomes&#44; a lower complication rate and a shorter hospital stay&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Emerging treatments</span><p id="par0160" class="elsevierStylePara elsevierViewall">In recent years&#44; new&#44; more specific molecules have been developed for the treatment of MG&#44; with a rapid onset of action &#40;generally in the first week&#41; and a good safety and tolerance profile&#44; including complement inhibitors and immunoglobulin neonatal Fc receptor &#40;FcRn&#41; antagonists&#46; Some are already approved by the <span class="elsevierStyleItalic">Food and Drug Administration</span> &#40;FDA&#41; and the European Medicines Agency &#40;EMA&#41;&#44; although they are not yet marketed in Spain or have not yet been funded for the treatment of GMG&#44; while others are still in phase 2 or 3 clinical trials&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Complement inhibitors</span><p id="par0165" class="elsevierStylePara elsevierViewall">They are exclusively indicated in anti-AchR antibody-associated GMG&#44; where complement plays an essential pathophysiological role&#46; The main expected side effect is possible infection with encapsulated bacteria&#44; especially <span class="elsevierStyleItalic">Neisseria meningitidis</span>&#44; so vaccination against meningococcus is essential before starting treatment&#46; This group includes eculizumab&#44; ravulizumab and zilucoplan&#46; Eculizumab is an intravenously administered humanised monoclonal antibody that selectively inhibits complement protein C5&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> It is the first complement inhibitor approved by the FDA in the US and by the EMA in Europe for GMG with anti-AchR antibodies&#46; However&#44; due to its cost-effectiveness&#44; the indication in MG is not funded in Spain&#46; Ravulizumab was developed from eculizumab in order to increase the intravenous administration dose to an interval of 8 weeks&#44; instead of the 2 weeks required for eculizumab&#46; It is approved for administration in the United States and Europe&#44; although it is not yet marketed in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> Zilucoplan is administered subcutaneously&#46; A phase 3 clinical trial has recently been completed with a daily subcutaneous dose of 0&#46;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day in adults with MGG&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> although the data have not yet been published&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Neonatal Fc receptor inhibitors &#40;FcRn inhibitors&#41;</span><p id="par0170" class="elsevierStylePara elsevierViewall">IgG-FcRn binding on endothelial cells protects IgG from lysosomal degradation and promotes its recycling&#46; Thus&#44; IgG is released back into the bloodstream without being degraded&#46; FcRn inhibitor drugs are monoclonal antibodies that bind to FcRn&#44; preventing the recycling of IgG and causing a drastic decrease of both pathogenic and normal antibody levels in the blood&#46; The result on the level of circulating antibody reduction is similar to that of plasmapheresis&#44; with the advantage that these drugs are better tolerated&#46; Efgartigimod is an intravenously administered monoclonal antibody directed against the FcRn fragment of immunoglobulin G1 &#40;IgG1&#41; that produces a 70&#37; decrease in blood IgG levels&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> It is approved by the FDA and the EMA for the treatment of anti-AchR antibody-positive GMG in adults&#44; although it is not yet marketed in Spain&#46; Other FcRn inhibitors are rozanolixizumab &#40;subcutaneous&#41;&#44; nipocalimab &#40;intravenous&#41; and batoclimab &#40;subcutaneous&#41;&#44; still awaiting publication of the final results of the various clinical trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">58&#8211;60</span></a></p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Ethical considerations</span><p id="par0175" class="elsevierStylePara elsevierViewall">This review does not include patient data or research involving human subjects&#44; so no informed consent has been obtained and no Ethics Committee assessment has been requested&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Funding</span><p id="par0180" class="elsevierStylePara elsevierViewall">None&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Conflict of interest</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest&#46;</p></span></span>"
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          "titulo" => "Autoantibodies in myasthenia gravis"
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              "titulo" => "Rapid-onset&#44; short-course immunomodulatory treatments"
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              "titulo" => "Thymectomy"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Myasthenia gravis is an autoimmune disease caused by the presence of specific antibodies targeting different postsynaptic components of the neuromuscular junction&#44; and is clinically characterized by the presence of fatigueable muscle weakness&#46; In the etiopathogenesis plays a central role the thymus and the most frequently detected pathogenic autoantibodies are targeted to the acetylcholine receptor&#46; The increase in the knowledge of the immunological components of the neuromuscular junction in the last two decades has been fundamental to identify new pathogenic antibodies&#44; reduce the percentage of patients with seronegative myasthenia&#44; and propose a classification of patients into subgroups with clinical-therapeutic interest&#46; In addition&#44; in recent years&#44; new drugs have been developed for the treatment of patients with myasthenia gravis that are refractory to conventional immunosuppressive treatment&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">La miastenia gravis es una enfermedad autoinmune causada por la presencia de anticuerpos espec&#237;ficos dirigidos a diferentes componentes postsin&#225;pticos de la uni&#243;n neuromuscular&#44; y cl&#237;nicamente se caracteriza por la presencia de debilidad muscular fatigable&#46; En la etiopatogenia juega un papel central el timo&#44; y los autoanticuerpos patog&#233;nicos m&#225;s frecuentemente detectados est&#225;n dirigidos al receptor de la acetilcolina&#46; El incremento en el conocimiento de los componentes inmunol&#243;gicos de la uni&#243;n neuromuscular en las &#250;ltimas dos d&#233;cadas ha sido fundamental para identificar nuevos anticuerpos patog&#233;nicos&#44; reducir el porcentaje de pacientes con miastenia seronegativa y proponer una clasificaci&#243;n de los pacientes en subgrupos con inter&#233;s cl&#237;nico-terap&#233;utico&#46; Adem&#225;s&#44; en los &#250;ltimos a&#241;os hemos asistido al desarrollo de nuevos f&#225;rmacos destinados al tratamiento de los pacientes con miastenia que muestran refractariedad al tratamiento inmunosupresor convencional&#46;</p></span>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Class&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Description&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle">I</td><td class="td-with-role" title="\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Any ocular muscle weakness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May have weakness of eye closure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">All other muscle strength is normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">II</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild weakness affecting muscles other than ocular muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May also have ocular muscle weakness of any severity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>IIa</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weakness predominantly in the limbs and&#47;or axial muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May have less severe involvement of oropharyngeal muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>IIb</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weakness predominantly in the oropharyngeal and&#47;or respiratory muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">There may be a lesser or equal degree of involvement of the axial and&#47;or limb muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">III</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Moderate weakness affecting muscles other than ocular muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May also have ocular muscle weakness of any severity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>IIIa</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weakness predominantly in the limbs and&#47;or axial muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May have less severe involvement of the oropharyngeal muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>IIIb</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weakness predominantly affecting the oropharyngeal and&#47;or respiratory muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">There may be a lesser or equal degree of involvement of the axial and&#47;or limb muscles&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle">IV</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Severe weakness affecting muscles other than the ocular muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May also have ocular muscle weakness of any severity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>IVa</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weakness predominantly in the limbs and&#47;or axial muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May also have lesser involvement of oropharyngeal muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>IVb</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Predominantly affecting the oropharyngeal and&#47;or respiratory muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May also have lesser or equal involvement of the axial and&#47;or limb muscles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">V&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Defined by the need for orotracheal intubation&#44; with&#47;without mechanical ventilation&#44; except when employed during routine postoperative management&#46; The use of a feeding tube without intubation places the patient in class IVb&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Clinical classification according to the <span class="elsevierStyleItalic">Myasthenia Gravis Foundation of America&#46;</span><a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Anti-Kv1&#46;4&#58; anti-voltage-gated potassium channel Kv1&#46;4 antibody&#59; anti-RyR&#58; anti-ryanodine receptor antibodies&#46;</p>"
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              "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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Type of GM &#40;IgG subclass&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Age at start &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sex &#40;F&#47;M&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Predominantly thymic histology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">HLA association &#40;Caucasian&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Other auto-antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical features&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="7" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">MG anti-AchR &#40;IgG1&#44; IgG3&#41;</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>Early onset</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle">&#60;50</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="middle">F<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>M</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="middle">Hyperplasia &#40;&#62;80&#37;&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Haplotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Predominantly GMG&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A1-B8-DR3-DQ2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="middle">Thymectomy is indicated</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DQA1&#59; rs601006&#59; rs601006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>Late onset</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">&#8805;50</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="middle">M<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>F</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="middle">Thymic atrophy is common</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DRB1&#42;15&#58;01&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-titin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Predominantly ocular onset forms&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DQB1&#42;05&#58;02&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="middle">Anti-R&#38;R</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">High rate of positive anti-AchR autoantibodies&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DRB1&#42;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increased number of co-morbidities&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DQA1&#59; rs9271871&#59; rs9271871&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Very late-onset &#40;&#8805;65 years&#41;&#58; no thymoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle"><span class="elsevierStyleHsp" style=""></span>Associated with thymoma</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Any &#40;common 40&#8211;60&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="middle">M<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>F</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="middle">Lymphoepithelioma &#40;60&#37; benign&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-titin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">It is a paraneoplastic form of MG &#40;10&#37;&#8211;15&#37; of cases&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-R&#38;R&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="middle">Thymectomy is essential</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-Kv1&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-actin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle"><span class="elsevierStyleItalic">Anti-MuSK MG &#40;IgG4&#41;</span></td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Any &#40;common<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>40&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="middle">F<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>M</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="4" align="left" valign="middle">Normal</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DRB1&#42;14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Early bulbar and cervical involvement is common&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DRB1&#42;16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">There is muscle atrophy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DQB1&#42;05&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-response to pyridostigmine&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DQ5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thymectomy not indicated&#46; Rituximab is effective&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Anti-LRP4 MG &#40;IgG1&#41;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Any&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">F<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>M&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Follicular hyperplasia &#40;30&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Symptoms and treatment comparable to MG-anti-AchR&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="middle"><span class="elsevierStyleItalic">Seronegative MG</span></td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Any</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="middle"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="middle"></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clustered-AchR &#40;IgG1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="middle">Symptoms and treatment comparable to MG-anti-AchR</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-agrin &#40;minority&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "leyenda" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">CMAP&#58; compound muscle action potential&#59; CSF&#58; cerebrospinal fluid&#59; EMG&#58; electromyography&#59; IDU&#58; injecting drug users&#59; RA&#58; rheumatoid arthritis&#59; RNS&#58; repetitive nerve stimulation&#59; SCLC&#58; small cell lung carcinoma&#59; SLE&#58; systemic lupus erythematosus&#46;</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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="middle">Lambert-Eaton myasthenic syndrome</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Proximal limb weakness&#44; predominantly in the lower limbs&#46; Hypo-areflexia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysautonomia&#58; dry mouth&#44; dry eye&#44; constipation&#44; orthostatic hypotension&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presynaptic myasthenic syndrome&#58; 50&#37; paraneoplastic &#40;SCLC&#41;&#46; Antibodies against calcium channels&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EMG&#58; low amplitude CMAP&#46; RNS&#58; post-tetanic facilitation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Congenital myasthenic syndromes</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Onset in childhood&#46; Family history may exist&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Myopathic features&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Absence of MG autoantibodies&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Genetic test &#8212; myasthenic syndromes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="4" align="left" valign="middle">Botulism</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presynaptic myasthenic syndrome&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aetiology&#58; <span class="elsevierStyleItalic">Clostridium botulinum</span>&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Source of infection&#58; contaminated canned food&#44; infected wounds&#44; IDU&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Clinical&#58; digestive symptoms&#44; mydriasis&#44; ophthalmoparesis&#44; muscle weakness&#44; respiratory insufficiency&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="middle">Mitochondrial myopathies</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gradual onset&#46; Maternal inheritance&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Symmetrical&#44; chronic&#44; non-fluctuating ptosis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chronic progressive external ophthalmoparesis without diplopia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Migraine&#44; deafness&#44; retinopathy&#44; cramps&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Muscle biopsy&#58; mitochondrial proliferation&#44; ragged-red fibres&#46; Study of the mitochondrial respiratory chain&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle">Oculopharyngeal muscular dystrophy</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#62;50 years&#46; Symmetrical&#44; chronic&#44; non-fluctuating ptosis&#46; Complete ophthalmoparesis without diplopia&#46; Dysphagia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Biopsy&#58; dystrophic muscle&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Genetic test&#58; mutation in poly&#40;A&#41;2-binding protein on chromosome 14q11&#46;2-13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Drug-induced myasthenic syndrome</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D-penicillamine&#58; cystinuria&#44; RA&#44; Wilson&#8217;s disease&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hydroxychloroquine&#58; SLE&#44; RA&#44; antimalarials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle">Brainstem pathology &#40;stroke&#44; neoplasm&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acute onset in stroke&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neighbourhood signs&#58; facial paresis&#44; Horner&#44; dysmetria&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Encephalic MRI needed for diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="middle">Miller-Fisher syndrome</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ophthalmoparesis&#46; Ataxia&#46; Areflexia&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-ganglioside antibodies&#58; GQ1b&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="3" align="left" valign="middle">Amyotrophic lateral sclerosis &#40;bulbar&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">First motor neuron symptoms &#40;hyperreflexia&#44; spasticity&#44; Babinski&#41;&#46; Cramps&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Non-fluctuating weakness&#46; No diplopia&#46; No ptosis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">May have partial response to pyridostigmine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="middle">Lyme disease &#40;neuroborreliosis&#41;</td><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Borrelia burgdorferi</span> &#40;tick-borne&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Epidemiology&#58; geographical areas&#46; Seasonal&#58; summer&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cranial mononeuritis multiplex&#46; Radiculopathies&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CSF&#58; lymphocytic meningitis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Treatment&#58; ceftriaxone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of myasthenia gravis&#46;</p>"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">HBP&#58; high blood pressure&#59; PML&#58; progressive multifocal leukoencephalopathy&#46; TPMT&#58; thiopurine methyltransferase&#46;</p>"
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            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="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Starting dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Maintenance dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Onset of action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Adverse effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Monitoring&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Comments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pyridostigmine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30<span class="elsevierStyleHsp" style=""></span>mg&#44; 3 times&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#8722;120<span class="elsevierStyleHsp" style=""></span>mg 4 times daily not disturbing sleep&#46; Adjust according to tolerance and side effects&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#8722;60<span class="elsevierStyleHsp" style=""></span>min&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Abdominal cramps&#44; diarrhoea&#44; nausea&#44; increased bronchial secretions and salivation&#44; bradycardia&#44; fasciculations&#44; cramps&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monitor for increased secretions in patients with bulbar involvement&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Give 30<span class="elsevierStyleHsp" style=""></span>min before meal if dysphagia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prednisone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#8211;60<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#8722;60<span class="elsevierStyleHsp" style=""></span>mg with slow tapering&#44; if possible&#44; every other day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#8722;20 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Weight gain&#44; hyperglycaemia&#44; HBP&#44; cataracts&#44; osteoporosis&#44; gastric ulcer&#44; insomnia&#44; mood swings&#44; risk of infection&#44; cushingoid facies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Periodic haemoglobin A<span class="elsevierStyleInf">1C</span> and BP control&#44; annual densitometry&#44; annual eye check-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monitor diet&#44; calcium and vitamin D supplementation&#44; gastric protector&#46; Bisphosphonates if osteopenia or postmenopausal women&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Azathioprine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">150<span class="elsevierStyleHsp" style=""></span>mg&#47;day or 2&#8722;3<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#8722;18 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Idiosyncratic flu-like reaction&#44; abdominal discomfort&#44; hepatotoxicity&#44; pancreatitis&#44; myelosuppression&#44; risk of skin cancer and lymphoma&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blood tests every 15 days for the first month&#44; then monthly for 6 months&#44; and then every 3 months&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Can be given in 1&#8211;3 doses&#44; with meals&#46; Avoid sun exposure&#46; Prior determination of TPMT activity or genetic study to detect possible no or low enzyme activity&#46; Reduce dose in case of concomitant treatment with allopurinol or sulfasalazine&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mycophenolate mofetil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">500<span class="elsevierStyleHsp" style=""></span>mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">500&#8211;1500<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#8722;12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Teratogenic&#46; Nausea and vomiting&#44; diarrhoea&#44; myelosuppression&#44; risk of skin cancer and rarely lymphoma and PML &#40;rare&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blood tests every 2 weeks for the first month&#44; then monthly for 6 months&#44; then every 3 months&#46; Contraceptive measures in women of childbearing age&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraception if used in women of childbearing age&#46; Administer one hour before or two hours after meals&#46; Adjust dose if taking cholestyramine&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methotrexate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#8211;25<span class="elsevierStyleHsp" style=""></span>mg&#47;weekly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#8211;12 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hepatotoxicity&#44; stomatitis&#44; nausea and vomiting&#44; pulmonary toxicity&#44; teratogenicity&#44; photosensitivity&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monthly blood tests&#44; then every 3 months&#46; Intermittent check for interstitial lung disease&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicated in pregnancy&#46; Folic acid supplementation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cyclosporine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#8722;100<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&#8722;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; in two doses&#46; Try to reduce to 2<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8722;3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HBP&#44; nephrotoxicity&#44; hepatotoxicity&#44; neuropathy&#44; tremor&#44; skin cancer&#44; lymphopenia&#44; myalgias&#44; hypertrichosis&#44; hyperkalaemia&#44; common drug interactions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monthly blood tests for the first 3 months&#44; then every 3 months&#46; Monitor renal function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blood levels between 100&#8211;150<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46; For a 70<span class="elsevierStyleHsp" style=""></span>kg person&#44; the usual dose is 100<span class="elsevierStyleHsp" style=""></span>mg every 12<span class="elsevierStyleHsp" style=""></span>h&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tacrolimus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1 mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#44; in two doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8722;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hyperglycaemia&#44; hypomagnesaemia&#44; diarrhoea&#44; lymphopenia&#44; nephrotoxicity&#44; tremor&#44; myelosuppression&#44; rare cancer risk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monthly blood tests for the first 3 months&#44; then periodically thereafter&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Maintain levels of 2&#8722;9<span class="elsevierStyleHsp" style=""></span>ng&#47;ml&#46; Take on an empty stomach&#46; Less nephrotoxicity than cyclosporine&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rituximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>g every two weeks &#40;2 doses&#41; or 375<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span> weekly for a total of 4 doses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Repeat cycles every 6 months if necessary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8722;3 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypogammaglobulinemia&#44; Myelosuppression&#44; infusion reaction&#44; PML rarely&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Periodic blood tests&#44; CD19 lymphocyte counts&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A minimum of two cycles of treatment is usually required&#46; Cannot be combined with complement-acting drugs&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cyclophosphamide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&#8211;1&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;m<span class="elsevierStyleSup">2</span> i&#46;v&#46; or 50&#8722;100<span class="elsevierStyleHsp" style=""></span>mg&#47;day oral&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#46;5&#8722;1<span class="elsevierStyleHsp" style=""></span>g&#47;m<span class="elsevierStyleSup">2</span> monthly or 50&#8722;100<span class="elsevierStyleHsp" style=""></span>mg&#47;day orally&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8722;6 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Teratogeny&#46; Infertility&#46; Nausea&#44; alopecia&#44; myelosuppression&#44; haemorrhagic cystitis&#44; cancer risk&#44; cardiac&#44; pulmonary and renal toxicity&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monthly blood and urine tests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraception&#46; Premedication with hydration and antiemetics&#46; Monitoring of haematuria&#46; Short-lasting efficacy&#46; Only indicated in rare cases of refractory myasthenia gravis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Chronic medical treatments in myasthenia gravis&#46;</p>"
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Article information

ISSN: 23870206
Original language: English

DOI:10.1016/j.medcle.2023.04.012

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