Journal of Autoimmunity xxx (2014) 1e6
Contents lists available at ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
Diagnostic and clinical classification of autoimmune myasthenia gravis Sonia Berrih-Aknin a, b, c, d, *, Mélinée Frenkian-Cuvelier a, b, c, d, Bruno Eymard e a
INSERM U974, Paris, France CNRS FRE3617, Paris, France c Sorbonne Universités, UPMC Univ Paris 06, UM76, Paris, France d AIM, Institut de myologie, Paris, France e Centre de référence de pathologie neuromusculaire Paris Est, Service de Neurologie 2, Institut de Myologie, Hôpital de la Pitié Salpêtrière, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Accepted 13 November 2013
Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are against the acetylcholine receptor (AChR). Recently, other targets have been described such as the MuSK protein (muscle-specific kinase) or the LRP4 (lipoprotein related protein 4). Myasthenia gravis can be classified according to the profile of the autoantibodies, the location of the affected muscles (ocular versus generalized), the age of onset of symptoms and thymic abnormalities. The disease generally begins with ocular symptoms (ptosis and/or diplopia) and extends to other muscles in 80% of cases. Other features that characterize MG include the following: variability, effort induced worsening, successive periods of exacerbation during the course of the disease, severity dependent on respiratory and swallowing impairment (if rapid worsening occurs, a myasthenic crisis is suspected), and an association with thymoma in 20% of patients and with other autoimmune diseases such as hyperthyroidism and Hashimoto’s disease. The diagnosis is based on the clinical features, the benefit of the cholinesterase inhibitors, the detection of specific autoantibodies (anti-AChR, anti-MuSK or anti-LRP4), and significant decrement evidenced by electrophysiological tests. In this review, we briefly describe the history and epidemiology of the disease and the diagnostic and clinical classification. The neonatal form of myasthenia is explained, and finally we discuss the main difficulties of diagnosis. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Myasthenia gravis Acetylcholine receptor MuSK LRP4 Diagnostic
1. Introduction Autoimmune myasthenia gravis (MG) is a neuromuscular disorder characterized by a defective transmission of nerve impulses to muscles. This defect is caused by an autoimmune attack against components of the neuromuscular junction (NMJ) on the postsynaptic membrane of the striated skeletal muscles. In most patients, the autoimmune response is mediated by antibodies against the acetylcholine receptor (AChR). In approximately 5% of MG patients, the autoreactive antibodies are directed against a protein called muscle specific kinase (MuSK) [1], which plays a central role in the clustering of AChRs and other postsynaptic components at the NMJ. Recently, the agrin receptor LRP4 (low-density lipoprotein receptor-related protein 4), a molecule that forms a complex with * Corresponding author. INSERM U974, Hôpital La Pitié Salpêtrière, 105 Bd de l’hôpital, 75013 Paris, France. Tel.: þ33 (0)1 40 77 81 28; fax: þ33 (0)1 40 77 81 29. E-mail address: [email protected] (S. Berrih-Aknin).
MuSK, has been identified as a novel autoantigenic target in a small proportion of MG patients without anti-AChR or -MuSK antibodies [2,3]. Fig. 1 shows a scheme of the NMJ and the targets of autoimmune attack in MG. Several entities can be defined with distinct physiopathological mechanisms. The evolution of MG is unpredictable, but it is generally characterized by the occurrence of relapses, sometimes subsequent to remissions and a worsening trend in the first years. For 85% of MG patients, the maximum severity is reached within less than 3 years [4]. The severity of MG varies markedly from one patient to another and in the same patient from one moment to another. Involvement of the respiratory muscles and severe swallowing disorders characterize the severe forms (20e30% of patients) and can be managed in intensive care units that permit a significant reduction in mortality. In contrast, myasthenia remains mild in 25% of patients. Between these extremes, the disease is intermediate; it is debilitating because of marked fatigue, impaired swallowing, a hypernasal voice and diplopia. Myasthenia gravis may be associated with
0896-8411/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2014.01.003
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
2
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
Motor neuron
Agrin A AChE
AChR
ErbB
MuSK
Muscle end-plate
LRP4
ColQ
l h Acetylcholine
Rapsyn
Fig. 1. Simplified scheme of the neuromuscular junction. AChE ¼ acetylcholine esterase; AChR ¼ acetylcholine receptor; ColQ ¼ collagen-tail subunit of AChE; ErbB ¼ receptors for neuregulins; LRP4 ¼ lipoprotein related protein 4; MuSK ¼ muscle-specific kinase. The gray stars represent the known targets in MG, the main one being the AChR.
other autoimmune diseases. The role of the thymus in the pathogenesis is highlighted by the benefit of thymectomy and the presence of frequent histologic abnormalities such as thymoma and follicular hyperplasia [5]. Fifteen to twenty percent of patients, usually those older than 40, have a thymoma caused by a proliferation of epithelial cells [6]. In 50% of patients younger than 45 years, typically female with the anti-AChR antibody, the thymus is the site of follicular hyperplasia characterized by the presence of germinal centers [7]. The role of thymic B cells in the production of anti-AChR antibodies has been clearly demonstrated [8,9]. 2. History of the disease Myasthenic bulbar symptoms were reported for the first time in 1672 when the physician Willis described a woman who “for some time can speak freely and readily enough, but after she has spoke long, or hastily, or eagerly, she is not able to speak a word”. At the end of the 19th century, Erb and Goldflam established the first description of the following clinical symptoms attributed to MG: frequent ptosis with diplopia, dysphagia, weakness of the neck, and a course of remissions and relapses. The name “Myasthenia Gravis”, composed of myasthenia, which is Greek for muscle weakness, and gravis, which is Latin for severe, was given because of a presumably neuromuscular inhibitor in the circulation of patients [10].
The chemical substance, liberated at the nerve endings, that could initiate contraction in muscle fibers was identified as acetylcholine (ACh) in the 1930s [11]. A major step forward in treatment occurred in 1934 when Mary Walker realized that MG symptoms were similar to those of curare poisoning, which was treated with physostigmine, a cholinesterase inhibitor. She showed that physostigmine improved myasthenic symptoms [12], making anticholinesterase drugs a basic therapy in MG. The presence of thymic tumors or enlargements of the thymus was described by Norris in 1936 in most MG patients [13]. That year, Blalock removed a thymic tumor in a 19-year-old female with severe generalized myasthenia. Significant improvement suggested that thymectomy could be a potential therapy [14]. In 1944, Blalock reported successful operations on 20 patients, of which two had thymus tumors [15]. This step was followed by a large thymectomy series in London and at the Mayo Clinic with successful therapeutic results. The immune origin of MG was suggested in the 1960s by Simpson and was based on the presence of transient MG symptoms in some newborns of myasthenic mothers (neonatal MG) [16]. In 1959, the presence of a circulating factor able to block neuromuscular transmission was suggested by Nastuk et al., in 1959 by applying plasma samples from MG patients to the frog sciatic nerve-Sartorius muscle preparation [17]. The first evidence that the AChR is implicated in the disease was demonstrated by muscle weakness after the immunization of rabbits with the AChR purified from torpedo fish [18]. In 1973, Fambrough confirmed this finding by the observation of a reduced number of AChRs on the muscle endplates of MG patients [19]. The key role of autoantibodies in MG development was confirmed by the emergence of MG-like symptoms in animals into which purified G immunoglobulins (IgGs) from MG patients were transferred and by the degradation of the AChRs on cultured muscle cells after incubation with IgGs from MG patients [20]. The titration of the antibodies in the myasthenic patient’s sera showed that almost 85% of the patients were positive for the anti-AChR antibodies [21,22]. Since the 1970s, numerous studies have explored the events at the neuromuscular junction when the anti-AChR autoantibodies are present [23,24]. The recent discovery of two novel targets (MuSK and LRP4) has reduced the percentage of patients without known antibodies [1e3], although there are still some seronegative MG patients. 3. Epidemiology MG occurs at any age and in either gender. In the review of Carr et al. summarizing 44 epidemiological studies on MG, the incidence rate varies between 1.7 and 21.3 per million inhabitants, depending on the localization of the study, and the prevalence is between 15
Table 1 Classification of MG patients according to the nature of the autoantibodies.
Percentage of patients Targeted populations Severity grade Pathogenicity Isotypes Role of complement Thymic pathology Correlation of ab titre with disease grade
Solubilized AChR
MuSK
LRP4
Clustered AChR
85% Early onset: F > M Late onset: F ¼ M All severity grades: ocular and generalized forms In vitro and in vivo IgG1, IgG3 Yes Early onset: follicular hyperplasia Late onset: thymoma No
w5% Young females
w2% Young females
w5% Similar to solubilized AChR
Mainly severe form In vitro and in vivo IgG4 No No
Mainly mild form In vitro IgG1 Likely ?
Ocular and generalized forms In vitro IgG1 Likely Mild follicular hyperplasia
Yes
?
?
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6 Table 2 Main features of neonatal and fetal myasthenia gravis. Neonatal Frequency myasthenia Onset Duration Sequels Symptoms
10e20% of children from myasthenic mothers At birth or few hours after birth Few days to 3 months None Hypotonia, impaired sucking, swallowing and breathing, positive effect of anti-cholinesterase drugs In severe cases Tube feedings and ventilatory support Time for elimination 1e5 months of the antibodies in children Correlation with No maternal MG Correlation with the If anti-AChR 100 nM, TNM probable, if anti-AChR 10 nM, TNM rare [28] level of antibodies in the mother Fetal Frequency Very rare myasthenia Symptoms Reduced fetal mobility, polyhydramnios, arthrogryposis, severe myasthenic syndrome at birth, facial/bulbar deficit and atrophy Grade Very severe (risk of fetal death) Cause Transfer of maternal anti-fetal AChR antibodies to the fetus [48] Sequels Facial atrophy and diparesia, nasal voice [46,49]
and 179 per million inhabitants [25]. In the USA, the prevalence has been estimated at approximately 200 per million inhabitants [26]. The MG population can be classified according to the age of onset. Before the age of 50, studies on large series of patients showed that early-onset MG (EOMG) is characterized by female predominance (60e70%), whereas between the age of 50 and 60, there is no gender difference [25]. A very late onset MG, appearing after the age of 60, has been described since 20 years ago. This form is characterized by a clear male predominance [27]. Because immune disorders are augmented with age, the incidence of this form has grown substantially for several years, which may be because of increased longevity. Juvenile MG is uncommon in Europe and North America, representing 10e15% of MG patients in Caucasians [28], whereas in Asia it is much more frequent and represents 50% of MG patients in China, with ocular symptoms occurring before the age of 15 [29]. 4. Clinical classification Because the clinical manifestations of MG vary according to the age of onset, the antibody implicated and the presence of thymic pathology, the disease forms are generally divided in several subgroups according to the presence of autoantibodies (Table 1). 4.1. Pure ocular form Approximately 15% of MG patients present only ocular symptoms all along the disease. Due to the high proportion of patients with initial ocular manifestations in the first year after onset, a minimal delay of two years without generalization is required to classify a patient as having a pure ocular form. One-half of these patients present antibodies not detectable by a classical assay but often detectable in a cell-based assay, in which AChR is clustered [30]. 4.2. Generalized form with anti-AChR antibodies Approximately 85% of the MG population displays this form of the disease. There is not a clear correlation between the level of
3
antibodies and the severity of the disease, although such a correlation has been described at the individual level [31]. Thymic abnormalities are frequently found in these patients, and the highest titers of antibodies are seen in patients with thymic follicular hyperplasia [32]. The anti-AChR antibodies belong to the IgG1 and IgG3 subclasses that do bind to the complement [33]. The patients with anti-AChR antibodies can be subdivided into the following two sub-groups. 4.2.1. Early onset myasthenia gravis (onset of the disease before the age of 50 (EOMG)) The ratio of female/male patients presents a female predominance (ratio 3/1). The histology of the thymus in this group is predominantly thymic follicular hyperplasia that is found mainly in women [34]. The sex hormones may play a role in this form. Recently, a deregulation of the estrogen receptor expression in thymic cells has been demonstrated, which supports this hypothesis [35]. Other autoimmune diseases can be associated with MG in these patients including thyroid disorders (Hashimoto’s or Basedow diseases) [36]. Concerning the genetic background of this population, a genome wide association (GWAS) on EOMG has shown a very strong association with TNFAIP3-interacting protein 1 (TNIP1) and convincingly localized the major MHC association to the class I HLA-B locus [37]. 4.2.2. Late onset myasthenia gravis (onset of the disease after the age of 50 (LOMG)) This late form is frequently associated with the presence of a thymoma, a tumor of the thymic epithelial cells [6]. Other autoantibodies such as the anti-ryanodine antibodies, the anti-titin antibodies or the anti-striated muscle antibodies are frequently found (50%) in those patients, notably in patients with thymoma [38]. Most patients present generalized and severe symptoms such as bulbar involvement [39]. 4.3. The forms without classical anti-AChR antibodies 4.3.1. The form with anti-anti-MuSK antibodies Approximately 5% of the MG population has this antibody type [40]. MuSK positive patients are typically female, and they have a severe form of the disease with common muscular atrophy. The facial, bulbar, and respiratory muscles are frequently affected, whereas ocular symptoms and thymic abnormalities are rare [40,41]. Interestingly, both presynaptic and postsynaptic components of the NMJ are affected in MuSK-MG disease (Review in Ref. [42]). There is a clear correlation between the disease severity and the antibody titer [43]. The anti-MuSK antibodies belong to the IgG4 subclass that does not bind to the complement [44]. 4.3.2. The form with anti-LRP4 antibodies Approximately 12e50% of the seronegative population presents antibodies to LRP4 [2]. These antibodies were discovered in a subgroup of patients who were double seronegative for AChR and MuSK [3,45]. The clinical phenotype of the patients presenting antiLRP4 antibodies is not well defined. 4.3.3. The form with clustered AChR antibodies Approximately 5% of the MG population has no known antibodies. The antibodies to AChR that are not detectable by the classical method (Radio immunoassay) can be detected by a cellbased assay, in which AChRs are clustered. Recent studies have shown that approximately 50% of seronegative patients have these antibodies [30]. The clinical pattern is close to MG with classical anti-AChR antibodies including ocular and generalized forms; thymic hyperplasia may be present [30].
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
4
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
4.4. Neonatal MG The occurrence of pregnancy is not unusual because of the high incidence of myasthenia gravis in young women whose fertility is not affected by the disease. There is a risk of exacerbation of the myasthenic symptoms in 20e40% of females during the first 3 months, but much more in the first weeks following delivery. In 10e20% of the cases, the newborn will display a transient neonatal myasthenia (TNM) that could last a few days to 3 months. This disease is because of the passive transfer of the antibodies of the mother, especially the anti-AChR antibodies [46]. In the case of MuSK-MG, TNM is very rare [47]. There is no correlation between the severity of the disease in the mother and the onset and severity of the disease in the infant. In some rare cases, the fetus could be affected because of antiAChR antibodies that recognize the fetal form of the AChR [48]. The major features of neonatal myasthenia are summarized in Table 2.
Table 3 Other myasthenic syndromes. LamberteEaton syndrome - Autoimmune, presynaptic, anti-calcium channels antibodies - Clinical features: lower limb weakness at foreground, dysautonomic symptoms (mouth, eye dryness), small cell lung carcinoma (50% of patients, mostly, male, smokers), associated paraneoplasic syndrome (cerebellar ataxia) - Electrophysiology: decreased CMAP amplitude, 3 Hz decrement and 40 Hz frequency/post-exercise increment - P/Q type voltage-gated calcium channels (VGCC) antibodies Toxic/iatrogenic myasthenic syndromes - Botulism from clostridium botulinum toxin. Context: ingestion of spoiled canned food - Abdominal symptoms, poorly reactive mydriasis, mouth dryness - D-penicillamine, chloroquine, hydroxychloroquine Congenital myasthenic syndromes (CMS) - Early onset (birth, infancy) - Myopathic features - Family history (inconstant) - Electrophysiological features: double motor response after single stimulation in slow-channel CMS - Molecular testing: 15 genes
5. Diagnostic The diagnosis of myasthenia gravis is based on a series of clinical and paraclinical arguments.
perform. It must be limited to difficult cases (a negative EMG, in particular in ocular myasthenia) [11].
5.1. Clinical features
5.1.4. Autoantibodies The anti-AChR antibodies are highly specific for MG. If they are negative, it is important to search for the anti-MuSK, LRP4 or clustered AChR (see above).
5.1.1. Primary symptoms 1) The presence of suggestive signs and symptoms such as diplopia, ptosis, without pupillary abnormalities, bulbar disorders, weakness and fatigue of member and cervical muscles 2) The evocative combination of the following symptoms: ptosis þ facial paresis þ dysphonia þ neck weakness 3) A purely muscular damage with no sensory or central nervous system alterations 4) Exacerbation by exercise 5) A typical variability in the symptoms: a) short duration variation during the daytime with worsened symptoms in the evening, during menstruation or during the occurrence of fatigue, and b) relapses corresponding to worsening of the disease over a period of several weeks to several months. Ptosis is particularly helpful in the diagnosis, because it may vary or alternate in a few minutes and worsens after sustained upward gaze. If there is a significant ptosis, the ice test (ice cubes applied on the side of ptosis for 1 min) corrects the drop lid for a few seconds. The use of photographs is useful to validate an alternating ptosis.
5.1.2. Favorable effect of cholinesterase inhibitors The injection of 0.5 mg neostigmine subcutaneously or intramuscularly has a significant effect on the deficit signs (ptosis, hypernasal voice, limb weakness) from 15 min and persisting for 2 h. The slow intravenous injection of hydrophonium or edrophonium at 2 and then 10 mg has a brief response of 3e5 min. The test of oral cholinesterase over a few weeks is quite justifiable to assess the functional status in daily life and over time. 5.1.3. Electromyography The presence of an EMG decrement is essential and must be investigated in several proximal and distal nerveemuscle pairs and if possible after 12 h interruption of AChE inhibitors. The single fiber analysis that reveals an elongated jitter (the time between the potentials of two muscle fibers of the same motor unit) is more sensitive but less specific than the classical EMG and is difficult to
5.1.5. CT scan The CT scan explores the potential presence of a thymoma. If the patient presents with a generalized form of MG with anti-AChR antibodies, it is justifiable to control the thymus every 5 years if the patient was not thymectomized. Overall, the negativity of these features does not cause the diagnosis to be discarded. It is essential to examine the patient if a symptom appears and to repeat the measurement of specific antibodies a few months after the first dosage because the antibodies can become positive when the disease worsens. 5.2. Screening for signs of severity The occurrence in a few days of respiratory congestion, shortness of breath, ineffective cough, choking, and rapid motor deterioration predicts a myasthenic crisis that could be life-threatening. These severe symptoms indicate an emergency case requiring immediate hospitalization in intensive care. It is not always easy to distinguish a myasthenic crisis from a cholinergic crisis caused by an anticholinesterase overdose. Both crisis conditions share rapid motor and respiratory deterioration. A cholinergic crisis is distinguished by signs of cholinergic overdose such as abundant fasciculations, gastrointestinal symptoms (nausea, vomiting, diarrhea), excessive salivation, bronchial hypersecretion, sweating, tearing, pallor, miosis, and bradycardia. The most common development is confusion between the two complications. When a patient worsens rapidly, the common mistake is to increase the anticholinesterase drugs that induce uncontrollable bronchial congestion and exacerbate muscle weakness. In practice, when a patient has worrying symptoms, intensive care is required in order to stop anticholinesterase drugs if needed. 5.3. Difficulties of diagnosis Diagnosis is frequently difficult in the beginning of the disease. If the ocular damage is isolated and unilateral, brain imaging (CT or
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
MRI) to exclude a cerebral tumor (meningioma of the cavernous sinus) or arterial aneurysm is recommended. If there is a subacute limb or face weakness, possibly associated with swallowing or eye muscle disorders, the diagnosis of GuillaineBarré can be discussed. The diagnosis will be rectified if other symptoms appear including the following: the presence of sensory disorders, neurogenic damage with slow conduction velocities in the EMG, and elevated protein level (sometimes initially absent). If bulbar disorders are central, the following diagnoses are frequently mentioned: a stroke, if the onset is sudden and the patient is elderly or an amyotrophic lateral sclerosis (ALS) if the disease is progressive. Muscle atrophy, fasciculations, pyramidal signs, a monotone dysarthria, and denervation in the EMG members and mouth floor support the latter diagnosis. A misleading decrement is possible in ALS. In case of doubt, clinical and electromyography monitoring will help to conclude the diagnosis. In case of an initial diplopia in a young adult, multiple sclerosis (MS) is frequently mentioned. The concept of visual loss leading to optic neuritis; the presence of sensory signs; the vestibular, cerebellar, and pyramidal syndrome; and evidence of hypersignals on the brain MRI are strong arguments in favor of MS. In the case of seronegative myasthenic syndrome, autoimmune MG cannot be ruled out, but other diseases affecting neurotransmission should be suspected (see Table 3). If a chronic progressive course without fluctuation is observed, ocular myopathies should be hypothesized. Oculopharyngeal myopathy is suspected if the onset is after 50 years of age. It displays an autosomal transmission and there is no systemic involvement. Mitochondrial myopathies are suspected if other multisystemic features are involved (deafness, pigmentary retinopathy, atrioventricular bloc), and muscle biopsy is mandatory for diagnosis. 6. Conclusion Most MG patients have antibodies directed at proteins of the neuromuscular junction. The number of patients with unknown antibodies is less than 5%. The autoantibodies against AChR, MuSK and LRP4 alter differentially neuromuscular transmission, and MG could be classified according to the nature of the antibodies. The management of patients should be adapted accordingly. Many clinical tools and biological assays are useful for diagnosing MG. There are some cases that are difficult to diagnose, and a careful clinical examination should help in making the correct diagnosis. Acknowledgments This work was funded by a grant from the European Community (FIGHT-MG/HEALTH-2009-242-210). References [1] Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Autoantibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001;7:365e8. [2] Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to lowdensity lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011;69:418e22. [3] Pevzner A, Schoser B, Peters K, Cosma NC, Karakatsani A, Schalke B, et al. AntiLRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 2012;259:427e35. [4] Grob D, Brunner NG, Namba T. The natural course of myasthenia gravis and effect of therapeutic measures. Ann N Y Acad Sci 1981;377:652e69. [5] Le Panse R, Bismuth J, Cizeron-Clairac G, Weiss JM, Cufi P, Dartevelle P, et al. Thymic remodeling associated with hyperplasia in myasthenia gravis. Autoimmunity 2010;43:401e12. [6] Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Strobel P. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 2013;12:875e84.
5
[7] Berrih-Aknin S, Ragheb S, Le Panse R, Lisak RP. Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis. Autoimmun Rev 2013;12:885e 93. [8] Leprince C, Cohen-Kaminsky S, Berrih-Aknin S, Vernet-Der Garabedian B, Treton D, Galanaud P, et al. Thymic B cells from myasthenia gravis patients are activated B cells. Phenotypic and functional analysis. J Immunol 1990;145: 2115e22. [9] Aissaoui A, Klingel-Schmitt I, Couderc J, Chateau D, Romagne F, Jambou F, et al. Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis. Ann Neurol 1999;46:559e67. [10] Jolly F. Ueber myasthenia gravis pseudoparalytica. Berl Klin Wochenschr 1895;32:1e7. [11] Dale H. Pharmacology and nerve-endings (Walter Ernest Dixon Memorial Lecture): (Section of Therapeutics and Pharmacology). Proc R Soc Med 1935;28:319e32. [12] Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet 1934;1:1200e1. [13] Norris EH. The thymoma and thymic hyperplasia in myasthenia gravis with observations on the general pathology. Am J Cancer 1936;27:421e33. [14] Blalock A, Mason MF, Morgan HJ, Riven SS. Myasthenia gravis and tumors of the thymic region: report of a case in which the tumor was removed. Ann Surg 1939;110:544e61. [15] Blalock A. Thymectomy in the treatment of myasthenia gravis, report of 20 cases. J Thorac Surg 1944;13:316e39. [16] Simpson JA. Myasthenia gravis: a new hypothesis. Scott Med J 1960;5:419e 36. [17] Nastuk WL, Strauss AJ, Osserman KE. Search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis. Am J Med 1959;26: 394e409. [18] Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science 1973;180:871e2. [19] Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science 1973;182: 293e5. [20] Toyka KV, Brachman DB, Pestronk A, Kao I. Myasthenia gravis: passive transfer from man to mouse. Science 1975;190:397e9. [21] Aharonov A, Abramsky O, Tarrab-Hazdai R, Fuchs S. Humoral antibodies to acetylcholine receptor in patients with myasthenia gravis. Lancet 1975;2: 340e2. [22] Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976;26:1054e9. [23] Guyon T, Levasseur P, Truffault F, Cottin C, Gaud C, Berrih-Aknin S. Regulation of acetylcholine receptor alpha subunit variants in human myasthenia gravis. Quantification of steady-state levels of messenger RNA in muscle biopsy using the polymerase chain reaction. J Clin Invest 1994;94:16e24. [24] Guyon T, Wakkach A, Poea S, Mouly V, Klingel-Schmitt I, Levasseur P, et al. Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss. J Clin Invest 1998;102:249e63. [25] Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol 2010;10:46. [26] Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 2009;8:475e90. [27] Alkhawajah NM, Oger J. Late onset myasthenia gravis: a review when incidence in the older adults keeps increasing. Muscle Nerve 2013;48:705e10. [28] Eymard B, Vernet-der Garabedian B, Berrih-Aknin S, Pannier C, Bach JF, Morel E. Anti-acetylcholine receptor antibodies in neonatal myasthenia gravis: heterogeneity and pathogenic significance. J Autoimmun 1991;4:185e95. [29] Zhang X, Yang M, Xu J, Zhang M, Lang B, Wang W, et al. Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry 2007;78:386e90. [30] Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008;131:1940e52. [31] Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985;48:1246e52. [32] Berrih S, Morel E, Gaud C, Raimond F, Le Brigand H, Bach JF. Anti-AChR antibodies, thymic histology, and T cell subsets in myasthenia gravis. Neurology 1984;34:66e71. [33] Verschuuren JJ, Huijbers MG, Plomp JJ, Niks EH, Molenaar PC, MartinezMartinez P, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev 2013;12:918e23. [34] Eymard B, Berrih-Aknin S. Role of the thymus in the physiopathology of myasthenia. Rev Neurol 1995;151:6e15. [35] Nancy P, Berrih-Aknin S. Differential estrogen receptor expression in autoimmune myasthenia gravis. Endocrinology 2005;146:2345e53. [36] Klein R, Marx A, Strobel P, Schalke B, Nix W, Willcox N. Autoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. Hum Immunol 2013;74: 1184e93.
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
6
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
[37] Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, et al. Risk for myasthenia gravis maps to a (151) Pro/Ala change in TNIP1 and to human leukocyte antigen-B*08. Ann Neurol 2012;72:927e35. [38] Suzuki S, Utsugisawa K, Nagane Y, Suzuki N. Three types of striational antibodies in myasthenia gravis. Autoimmune Dis 2011;2011. 740583. [39] Romi F, Aarli JA, Gilhus NE. Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features. Eur J Neurol 2007;14:617e 20. [40] Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003;126:2304e11. [41] Leite MI, Strobel P, Jones M, Micklem K, Moritz R, Gold R, et al. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol 2005;57:444e8. [42] Le Panse R, Berrih-Aknin S. Autoimmune myasthenia gravis: autoantibody mechanisms and new developments on immune regulation. Curr Opin Neurol 2013;26:569e76. [43] Bartoccioni E, Scuderi F, Minicuci GM, Marino M, Ciaraffa F, Evoli A. AntiMuSK antibodies: correlation with myasthenia gravis severity. Neurology 2006;67:505e7.
[44] McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004;55:580e4. [45] Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, et al. Autoantibodies to lipoprotein-related protein 4 in patients with doubleseronegative myasthenia gravis. Arch Neurol 2012;69:445e51. [46] Morel E, Eymard B, Vernetdergarabedian B, Pannier C, Dulac O, Bach JF. Neonatal myasthenia-gravis e a new clinical and immunological appraisal on 30 cases. Neurology 1988;38:138e42. [47] Behin A, Mayer M, Kassis-Makhoul B, Jugie M, Espil-Taris C, Ferrer X, et al. Severe neonatal myasthenia due to maternal anti-MuSK antibodies. Neuromuscul Disord 2008;18:443e6. [48] Vincent A, Newland C, Brueton L, Beeson D, Riemersma S, Huson SM, et al. Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen. Lancet 1995;346:24e5. [49] Jeannet PY, Marcoz JP, Kuntzer T, Roulet-Perez E. Isolated facial and bulbar paresis: a persistent manifestation of neonatal myasthenia gravis. Neurology 2008;70:237e8.
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
Contents lists available at ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
Diagnostic and clinical classification of autoimmune myasthenia gravis Sonia Berrih-Aknin a, b, c, d, *, Mélinée Frenkian-Cuvelier a, b, c, d, Bruno Eymard e a
INSERM U974, Paris, France CNRS FRE3617, Paris, France c Sorbonne Universités, UPMC Univ Paris 06, UM76, Paris, France d AIM, Institut de myologie, Paris, France e Centre de référence de pathologie neuromusculaire Paris Est, Service de Neurologie 2, Institut de Myologie, Hôpital de la Pitié Salpêtrière, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 October 2013 Accepted 13 November 2013
Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are against the acetylcholine receptor (AChR). Recently, other targets have been described such as the MuSK protein (muscle-specific kinase) or the LRP4 (lipoprotein related protein 4). Myasthenia gravis can be classified according to the profile of the autoantibodies, the location of the affected muscles (ocular versus generalized), the age of onset of symptoms and thymic abnormalities. The disease generally begins with ocular symptoms (ptosis and/or diplopia) and extends to other muscles in 80% of cases. Other features that characterize MG include the following: variability, effort induced worsening, successive periods of exacerbation during the course of the disease, severity dependent on respiratory and swallowing impairment (if rapid worsening occurs, a myasthenic crisis is suspected), and an association with thymoma in 20% of patients and with other autoimmune diseases such as hyperthyroidism and Hashimoto’s disease. The diagnosis is based on the clinical features, the benefit of the cholinesterase inhibitors, the detection of specific autoantibodies (anti-AChR, anti-MuSK or anti-LRP4), and significant decrement evidenced by electrophysiological tests. In this review, we briefly describe the history and epidemiology of the disease and the diagnostic and clinical classification. The neonatal form of myasthenia is explained, and finally we discuss the main difficulties of diagnosis. Ó 2014 Elsevier Ltd. All rights reserved.
Keywords: Myasthenia gravis Acetylcholine receptor MuSK LRP4 Diagnostic
1. Introduction Autoimmune myasthenia gravis (MG) is a neuromuscular disorder characterized by a defective transmission of nerve impulses to muscles. This defect is caused by an autoimmune attack against components of the neuromuscular junction (NMJ) on the postsynaptic membrane of the striated skeletal muscles. In most patients, the autoimmune response is mediated by antibodies against the acetylcholine receptor (AChR). In approximately 5% of MG patients, the autoreactive antibodies are directed against a protein called muscle specific kinase (MuSK) [1], which plays a central role in the clustering of AChRs and other postsynaptic components at the NMJ. Recently, the agrin receptor LRP4 (low-density lipoprotein receptor-related protein 4), a molecule that forms a complex with * Corresponding author. INSERM U974, Hôpital La Pitié Salpêtrière, 105 Bd de l’hôpital, 75013 Paris, France. Tel.: þ33 (0)1 40 77 81 28; fax: þ33 (0)1 40 77 81 29. E-mail address: [email protected] (S. Berrih-Aknin).
MuSK, has been identified as a novel autoantigenic target in a small proportion of MG patients without anti-AChR or -MuSK antibodies [2,3]. Fig. 1 shows a scheme of the NMJ and the targets of autoimmune attack in MG. Several entities can be defined with distinct physiopathological mechanisms. The evolution of MG is unpredictable, but it is generally characterized by the occurrence of relapses, sometimes subsequent to remissions and a worsening trend in the first years. For 85% of MG patients, the maximum severity is reached within less than 3 years [4]. The severity of MG varies markedly from one patient to another and in the same patient from one moment to another. Involvement of the respiratory muscles and severe swallowing disorders characterize the severe forms (20e30% of patients) and can be managed in intensive care units that permit a significant reduction in mortality. In contrast, myasthenia remains mild in 25% of patients. Between these extremes, the disease is intermediate; it is debilitating because of marked fatigue, impaired swallowing, a hypernasal voice and diplopia. Myasthenia gravis may be associated with
0896-8411/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2014.01.003
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
2
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
Motor neuron
Agrin A AChE
AChR
ErbB
MuSK
Muscle end-plate
LRP4
ColQ
l h Acetylcholine
Rapsyn
Fig. 1. Simplified scheme of the neuromuscular junction. AChE ¼ acetylcholine esterase; AChR ¼ acetylcholine receptor; ColQ ¼ collagen-tail subunit of AChE; ErbB ¼ receptors for neuregulins; LRP4 ¼ lipoprotein related protein 4; MuSK ¼ muscle-specific kinase. The gray stars represent the known targets in MG, the main one being the AChR.
other autoimmune diseases. The role of the thymus in the pathogenesis is highlighted by the benefit of thymectomy and the presence of frequent histologic abnormalities such as thymoma and follicular hyperplasia [5]. Fifteen to twenty percent of patients, usually those older than 40, have a thymoma caused by a proliferation of epithelial cells [6]. In 50% of patients younger than 45 years, typically female with the anti-AChR antibody, the thymus is the site of follicular hyperplasia characterized by the presence of germinal centers [7]. The role of thymic B cells in the production of anti-AChR antibodies has been clearly demonstrated [8,9]. 2. History of the disease Myasthenic bulbar symptoms were reported for the first time in 1672 when the physician Willis described a woman who “for some time can speak freely and readily enough, but after she has spoke long, or hastily, or eagerly, she is not able to speak a word”. At the end of the 19th century, Erb and Goldflam established the first description of the following clinical symptoms attributed to MG: frequent ptosis with diplopia, dysphagia, weakness of the neck, and a course of remissions and relapses. The name “Myasthenia Gravis”, composed of myasthenia, which is Greek for muscle weakness, and gravis, which is Latin for severe, was given because of a presumably neuromuscular inhibitor in the circulation of patients [10].
The chemical substance, liberated at the nerve endings, that could initiate contraction in muscle fibers was identified as acetylcholine (ACh) in the 1930s [11]. A major step forward in treatment occurred in 1934 when Mary Walker realized that MG symptoms were similar to those of curare poisoning, which was treated with physostigmine, a cholinesterase inhibitor. She showed that physostigmine improved myasthenic symptoms [12], making anticholinesterase drugs a basic therapy in MG. The presence of thymic tumors or enlargements of the thymus was described by Norris in 1936 in most MG patients [13]. That year, Blalock removed a thymic tumor in a 19-year-old female with severe generalized myasthenia. Significant improvement suggested that thymectomy could be a potential therapy [14]. In 1944, Blalock reported successful operations on 20 patients, of which two had thymus tumors [15]. This step was followed by a large thymectomy series in London and at the Mayo Clinic with successful therapeutic results. The immune origin of MG was suggested in the 1960s by Simpson and was based on the presence of transient MG symptoms in some newborns of myasthenic mothers (neonatal MG) [16]. In 1959, the presence of a circulating factor able to block neuromuscular transmission was suggested by Nastuk et al., in 1959 by applying plasma samples from MG patients to the frog sciatic nerve-Sartorius muscle preparation [17]. The first evidence that the AChR is implicated in the disease was demonstrated by muscle weakness after the immunization of rabbits with the AChR purified from torpedo fish [18]. In 1973, Fambrough confirmed this finding by the observation of a reduced number of AChRs on the muscle endplates of MG patients [19]. The key role of autoantibodies in MG development was confirmed by the emergence of MG-like symptoms in animals into which purified G immunoglobulins (IgGs) from MG patients were transferred and by the degradation of the AChRs on cultured muscle cells after incubation with IgGs from MG patients [20]. The titration of the antibodies in the myasthenic patient’s sera showed that almost 85% of the patients were positive for the anti-AChR antibodies [21,22]. Since the 1970s, numerous studies have explored the events at the neuromuscular junction when the anti-AChR autoantibodies are present [23,24]. The recent discovery of two novel targets (MuSK and LRP4) has reduced the percentage of patients without known antibodies [1e3], although there are still some seronegative MG patients. 3. Epidemiology MG occurs at any age and in either gender. In the review of Carr et al. summarizing 44 epidemiological studies on MG, the incidence rate varies between 1.7 and 21.3 per million inhabitants, depending on the localization of the study, and the prevalence is between 15
Table 1 Classification of MG patients according to the nature of the autoantibodies.
Percentage of patients Targeted populations Severity grade Pathogenicity Isotypes Role of complement Thymic pathology Correlation of ab titre with disease grade
Solubilized AChR
MuSK
LRP4
Clustered AChR
85% Early onset: F > M Late onset: F ¼ M All severity grades: ocular and generalized forms In vitro and in vivo IgG1, IgG3 Yes Early onset: follicular hyperplasia Late onset: thymoma No
w5% Young females
w2% Young females
w5% Similar to solubilized AChR
Mainly severe form In vitro and in vivo IgG4 No No
Mainly mild form In vitro IgG1 Likely ?
Ocular and generalized forms In vitro IgG1 Likely Mild follicular hyperplasia
Yes
?
?
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6 Table 2 Main features of neonatal and fetal myasthenia gravis. Neonatal Frequency myasthenia Onset Duration Sequels Symptoms
10e20% of children from myasthenic mothers At birth or few hours after birth Few days to 3 months None Hypotonia, impaired sucking, swallowing and breathing, positive effect of anti-cholinesterase drugs In severe cases Tube feedings and ventilatory support Time for elimination 1e5 months of the antibodies in children Correlation with No maternal MG Correlation with the If anti-AChR 100 nM, TNM probable, if anti-AChR 10 nM, TNM rare [28] level of antibodies in the mother Fetal Frequency Very rare myasthenia Symptoms Reduced fetal mobility, polyhydramnios, arthrogryposis, severe myasthenic syndrome at birth, facial/bulbar deficit and atrophy Grade Very severe (risk of fetal death) Cause Transfer of maternal anti-fetal AChR antibodies to the fetus [48] Sequels Facial atrophy and diparesia, nasal voice [46,49]
and 179 per million inhabitants [25]. In the USA, the prevalence has been estimated at approximately 200 per million inhabitants [26]. The MG population can be classified according to the age of onset. Before the age of 50, studies on large series of patients showed that early-onset MG (EOMG) is characterized by female predominance (60e70%), whereas between the age of 50 and 60, there is no gender difference [25]. A very late onset MG, appearing after the age of 60, has been described since 20 years ago. This form is characterized by a clear male predominance [27]. Because immune disorders are augmented with age, the incidence of this form has grown substantially for several years, which may be because of increased longevity. Juvenile MG is uncommon in Europe and North America, representing 10e15% of MG patients in Caucasians [28], whereas in Asia it is much more frequent and represents 50% of MG patients in China, with ocular symptoms occurring before the age of 15 [29]. 4. Clinical classification Because the clinical manifestations of MG vary according to the age of onset, the antibody implicated and the presence of thymic pathology, the disease forms are generally divided in several subgroups according to the presence of autoantibodies (Table 1). 4.1. Pure ocular form Approximately 15% of MG patients present only ocular symptoms all along the disease. Due to the high proportion of patients with initial ocular manifestations in the first year after onset, a minimal delay of two years without generalization is required to classify a patient as having a pure ocular form. One-half of these patients present antibodies not detectable by a classical assay but often detectable in a cell-based assay, in which AChR is clustered [30]. 4.2. Generalized form with anti-AChR antibodies Approximately 85% of the MG population displays this form of the disease. There is not a clear correlation between the level of
3
antibodies and the severity of the disease, although such a correlation has been described at the individual level [31]. Thymic abnormalities are frequently found in these patients, and the highest titers of antibodies are seen in patients with thymic follicular hyperplasia [32]. The anti-AChR antibodies belong to the IgG1 and IgG3 subclasses that do bind to the complement [33]. The patients with anti-AChR antibodies can be subdivided into the following two sub-groups. 4.2.1. Early onset myasthenia gravis (onset of the disease before the age of 50 (EOMG)) The ratio of female/male patients presents a female predominance (ratio 3/1). The histology of the thymus in this group is predominantly thymic follicular hyperplasia that is found mainly in women [34]. The sex hormones may play a role in this form. Recently, a deregulation of the estrogen receptor expression in thymic cells has been demonstrated, which supports this hypothesis [35]. Other autoimmune diseases can be associated with MG in these patients including thyroid disorders (Hashimoto’s or Basedow diseases) [36]. Concerning the genetic background of this population, a genome wide association (GWAS) on EOMG has shown a very strong association with TNFAIP3-interacting protein 1 (TNIP1) and convincingly localized the major MHC association to the class I HLA-B locus [37]. 4.2.2. Late onset myasthenia gravis (onset of the disease after the age of 50 (LOMG)) This late form is frequently associated with the presence of a thymoma, a tumor of the thymic epithelial cells [6]. Other autoantibodies such as the anti-ryanodine antibodies, the anti-titin antibodies or the anti-striated muscle antibodies are frequently found (50%) in those patients, notably in patients with thymoma [38]. Most patients present generalized and severe symptoms such as bulbar involvement [39]. 4.3. The forms without classical anti-AChR antibodies 4.3.1. The form with anti-anti-MuSK antibodies Approximately 5% of the MG population has this antibody type [40]. MuSK positive patients are typically female, and they have a severe form of the disease with common muscular atrophy. The facial, bulbar, and respiratory muscles are frequently affected, whereas ocular symptoms and thymic abnormalities are rare [40,41]. Interestingly, both presynaptic and postsynaptic components of the NMJ are affected in MuSK-MG disease (Review in Ref. [42]). There is a clear correlation between the disease severity and the antibody titer [43]. The anti-MuSK antibodies belong to the IgG4 subclass that does not bind to the complement [44]. 4.3.2. The form with anti-LRP4 antibodies Approximately 12e50% of the seronegative population presents antibodies to LRP4 [2]. These antibodies were discovered in a subgroup of patients who were double seronegative for AChR and MuSK [3,45]. The clinical phenotype of the patients presenting antiLRP4 antibodies is not well defined. 4.3.3. The form with clustered AChR antibodies Approximately 5% of the MG population has no known antibodies. The antibodies to AChR that are not detectable by the classical method (Radio immunoassay) can be detected by a cellbased assay, in which AChRs are clustered. Recent studies have shown that approximately 50% of seronegative patients have these antibodies [30]. The clinical pattern is close to MG with classical anti-AChR antibodies including ocular and generalized forms; thymic hyperplasia may be present [30].
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
4
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
4.4. Neonatal MG The occurrence of pregnancy is not unusual because of the high incidence of myasthenia gravis in young women whose fertility is not affected by the disease. There is a risk of exacerbation of the myasthenic symptoms in 20e40% of females during the first 3 months, but much more in the first weeks following delivery. In 10e20% of the cases, the newborn will display a transient neonatal myasthenia (TNM) that could last a few days to 3 months. This disease is because of the passive transfer of the antibodies of the mother, especially the anti-AChR antibodies [46]. In the case of MuSK-MG, TNM is very rare [47]. There is no correlation between the severity of the disease in the mother and the onset and severity of the disease in the infant. In some rare cases, the fetus could be affected because of antiAChR antibodies that recognize the fetal form of the AChR [48]. The major features of neonatal myasthenia are summarized in Table 2.
Table 3 Other myasthenic syndromes. LamberteEaton syndrome - Autoimmune, presynaptic, anti-calcium channels antibodies - Clinical features: lower limb weakness at foreground, dysautonomic symptoms (mouth, eye dryness), small cell lung carcinoma (50% of patients, mostly, male, smokers), associated paraneoplasic syndrome (cerebellar ataxia) - Electrophysiology: decreased CMAP amplitude, 3 Hz decrement and 40 Hz frequency/post-exercise increment - P/Q type voltage-gated calcium channels (VGCC) antibodies Toxic/iatrogenic myasthenic syndromes - Botulism from clostridium botulinum toxin. Context: ingestion of spoiled canned food - Abdominal symptoms, poorly reactive mydriasis, mouth dryness - D-penicillamine, chloroquine, hydroxychloroquine Congenital myasthenic syndromes (CMS) - Early onset (birth, infancy) - Myopathic features - Family history (inconstant) - Electrophysiological features: double motor response after single stimulation in slow-channel CMS - Molecular testing: 15 genes
5. Diagnostic The diagnosis of myasthenia gravis is based on a series of clinical and paraclinical arguments.
perform. It must be limited to difficult cases (a negative EMG, in particular in ocular myasthenia) [11].
5.1. Clinical features
5.1.4. Autoantibodies The anti-AChR antibodies are highly specific for MG. If they are negative, it is important to search for the anti-MuSK, LRP4 or clustered AChR (see above).
5.1.1. Primary symptoms 1) The presence of suggestive signs and symptoms such as diplopia, ptosis, without pupillary abnormalities, bulbar disorders, weakness and fatigue of member and cervical muscles 2) The evocative combination of the following symptoms: ptosis þ facial paresis þ dysphonia þ neck weakness 3) A purely muscular damage with no sensory or central nervous system alterations 4) Exacerbation by exercise 5) A typical variability in the symptoms: a) short duration variation during the daytime with worsened symptoms in the evening, during menstruation or during the occurrence of fatigue, and b) relapses corresponding to worsening of the disease over a period of several weeks to several months. Ptosis is particularly helpful in the diagnosis, because it may vary or alternate in a few minutes and worsens after sustained upward gaze. If there is a significant ptosis, the ice test (ice cubes applied on the side of ptosis for 1 min) corrects the drop lid for a few seconds. The use of photographs is useful to validate an alternating ptosis.
5.1.2. Favorable effect of cholinesterase inhibitors The injection of 0.5 mg neostigmine subcutaneously or intramuscularly has a significant effect on the deficit signs (ptosis, hypernasal voice, limb weakness) from 15 min and persisting for 2 h. The slow intravenous injection of hydrophonium or edrophonium at 2 and then 10 mg has a brief response of 3e5 min. The test of oral cholinesterase over a few weeks is quite justifiable to assess the functional status in daily life and over time. 5.1.3. Electromyography The presence of an EMG decrement is essential and must be investigated in several proximal and distal nerveemuscle pairs and if possible after 12 h interruption of AChE inhibitors. The single fiber analysis that reveals an elongated jitter (the time between the potentials of two muscle fibers of the same motor unit) is more sensitive but less specific than the classical EMG and is difficult to
5.1.5. CT scan The CT scan explores the potential presence of a thymoma. If the patient presents with a generalized form of MG with anti-AChR antibodies, it is justifiable to control the thymus every 5 years if the patient was not thymectomized. Overall, the negativity of these features does not cause the diagnosis to be discarded. It is essential to examine the patient if a symptom appears and to repeat the measurement of specific antibodies a few months after the first dosage because the antibodies can become positive when the disease worsens. 5.2. Screening for signs of severity The occurrence in a few days of respiratory congestion, shortness of breath, ineffective cough, choking, and rapid motor deterioration predicts a myasthenic crisis that could be life-threatening. These severe symptoms indicate an emergency case requiring immediate hospitalization in intensive care. It is not always easy to distinguish a myasthenic crisis from a cholinergic crisis caused by an anticholinesterase overdose. Both crisis conditions share rapid motor and respiratory deterioration. A cholinergic crisis is distinguished by signs of cholinergic overdose such as abundant fasciculations, gastrointestinal symptoms (nausea, vomiting, diarrhea), excessive salivation, bronchial hypersecretion, sweating, tearing, pallor, miosis, and bradycardia. The most common development is confusion between the two complications. When a patient worsens rapidly, the common mistake is to increase the anticholinesterase drugs that induce uncontrollable bronchial congestion and exacerbate muscle weakness. In practice, when a patient has worrying symptoms, intensive care is required in order to stop anticholinesterase drugs if needed. 5.3. Difficulties of diagnosis Diagnosis is frequently difficult in the beginning of the disease. If the ocular damage is isolated and unilateral, brain imaging (CT or
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
MRI) to exclude a cerebral tumor (meningioma of the cavernous sinus) or arterial aneurysm is recommended. If there is a subacute limb or face weakness, possibly associated with swallowing or eye muscle disorders, the diagnosis of GuillaineBarré can be discussed. The diagnosis will be rectified if other symptoms appear including the following: the presence of sensory disorders, neurogenic damage with slow conduction velocities in the EMG, and elevated protein level (sometimes initially absent). If bulbar disorders are central, the following diagnoses are frequently mentioned: a stroke, if the onset is sudden and the patient is elderly or an amyotrophic lateral sclerosis (ALS) if the disease is progressive. Muscle atrophy, fasciculations, pyramidal signs, a monotone dysarthria, and denervation in the EMG members and mouth floor support the latter diagnosis. A misleading decrement is possible in ALS. In case of doubt, clinical and electromyography monitoring will help to conclude the diagnosis. In case of an initial diplopia in a young adult, multiple sclerosis (MS) is frequently mentioned. The concept of visual loss leading to optic neuritis; the presence of sensory signs; the vestibular, cerebellar, and pyramidal syndrome; and evidence of hypersignals on the brain MRI are strong arguments in favor of MS. In the case of seronegative myasthenic syndrome, autoimmune MG cannot be ruled out, but other diseases affecting neurotransmission should be suspected (see Table 3). If a chronic progressive course without fluctuation is observed, ocular myopathies should be hypothesized. Oculopharyngeal myopathy is suspected if the onset is after 50 years of age. It displays an autosomal transmission and there is no systemic involvement. Mitochondrial myopathies are suspected if other multisystemic features are involved (deafness, pigmentary retinopathy, atrioventricular bloc), and muscle biopsy is mandatory for diagnosis. 6. Conclusion Most MG patients have antibodies directed at proteins of the neuromuscular junction. The number of patients with unknown antibodies is less than 5%. The autoantibodies against AChR, MuSK and LRP4 alter differentially neuromuscular transmission, and MG could be classified according to the nature of the antibodies. The management of patients should be adapted accordingly. Many clinical tools and biological assays are useful for diagnosing MG. There are some cases that are difficult to diagnose, and a careful clinical examination should help in making the correct diagnosis. Acknowledgments This work was funded by a grant from the European Community (FIGHT-MG/HEALTH-2009-242-210). References [1] Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Autoantibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001;7:365e8. [2] Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to lowdensity lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011;69:418e22. [3] Pevzner A, Schoser B, Peters K, Cosma NC, Karakatsani A, Schalke B, et al. AntiLRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 2012;259:427e35. [4] Grob D, Brunner NG, Namba T. The natural course of myasthenia gravis and effect of therapeutic measures. Ann N Y Acad Sci 1981;377:652e69. [5] Le Panse R, Bismuth J, Cizeron-Clairac G, Weiss JM, Cufi P, Dartevelle P, et al. Thymic remodeling associated with hyperplasia in myasthenia gravis. Autoimmunity 2010;43:401e12. [6] Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Strobel P. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 2013;12:875e84.
5
[7] Berrih-Aknin S, Ragheb S, Le Panse R, Lisak RP. Ectopic germinal centers, BAFF and anti-B-cell therapy in myasthenia gravis. Autoimmun Rev 2013;12:885e 93. [8] Leprince C, Cohen-Kaminsky S, Berrih-Aknin S, Vernet-Der Garabedian B, Treton D, Galanaud P, et al. Thymic B cells from myasthenia gravis patients are activated B cells. Phenotypic and functional analysis. J Immunol 1990;145: 2115e22. [9] Aissaoui A, Klingel-Schmitt I, Couderc J, Chateau D, Romagne F, Jambou F, et al. Prevention of autoimmune attack by targeting specific T-cell receptors in a severe combined immunodeficiency mouse model of myasthenia gravis. Ann Neurol 1999;46:559e67. [10] Jolly F. Ueber myasthenia gravis pseudoparalytica. Berl Klin Wochenschr 1895;32:1e7. [11] Dale H. Pharmacology and nerve-endings (Walter Ernest Dixon Memorial Lecture): (Section of Therapeutics and Pharmacology). Proc R Soc Med 1935;28:319e32. [12] Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet 1934;1:1200e1. [13] Norris EH. The thymoma and thymic hyperplasia in myasthenia gravis with observations on the general pathology. Am J Cancer 1936;27:421e33. [14] Blalock A, Mason MF, Morgan HJ, Riven SS. Myasthenia gravis and tumors of the thymic region: report of a case in which the tumor was removed. Ann Surg 1939;110:544e61. [15] Blalock A. Thymectomy in the treatment of myasthenia gravis, report of 20 cases. J Thorac Surg 1944;13:316e39. [16] Simpson JA. Myasthenia gravis: a new hypothesis. Scott Med J 1960;5:419e 36. [17] Nastuk WL, Strauss AJ, Osserman KE. Search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis. Am J Med 1959;26: 394e409. [18] Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science 1973;180:871e2. [19] Fambrough DM, Drachman DB, Satyamurti S. Neuromuscular junction in myasthenia gravis: decreased acetylcholine receptors. Science 1973;182: 293e5. [20] Toyka KV, Brachman DB, Pestronk A, Kao I. Myasthenia gravis: passive transfer from man to mouse. Science 1975;190:397e9. [21] Aharonov A, Abramsky O, Tarrab-Hazdai R, Fuchs S. Humoral antibodies to acetylcholine receptor in patients with myasthenia gravis. Lancet 1975;2: 340e2. [22] Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976;26:1054e9. [23] Guyon T, Levasseur P, Truffault F, Cottin C, Gaud C, Berrih-Aknin S. Regulation of acetylcholine receptor alpha subunit variants in human myasthenia gravis. Quantification of steady-state levels of messenger RNA in muscle biopsy using the polymerase chain reaction. J Clin Invest 1994;94:16e24. [24] Guyon T, Wakkach A, Poea S, Mouly V, Klingel-Schmitt I, Levasseur P, et al. Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss. J Clin Invest 1998;102:249e63. [25] Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol 2010;10:46. [26] Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 2009;8:475e90. [27] Alkhawajah NM, Oger J. Late onset myasthenia gravis: a review when incidence in the older adults keeps increasing. Muscle Nerve 2013;48:705e10. [28] Eymard B, Vernet-der Garabedian B, Berrih-Aknin S, Pannier C, Bach JF, Morel E. Anti-acetylcholine receptor antibodies in neonatal myasthenia gravis: heterogeneity and pathogenic significance. J Autoimmun 1991;4:185e95. [29] Zhang X, Yang M, Xu J, Zhang M, Lang B, Wang W, et al. Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry 2007;78:386e90. [30] Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008;131:1940e52. [31] Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985;48:1246e52. [32] Berrih S, Morel E, Gaud C, Raimond F, Le Brigand H, Bach JF. Anti-AChR antibodies, thymic histology, and T cell subsets in myasthenia gravis. Neurology 1984;34:66e71. [33] Verschuuren JJ, Huijbers MG, Plomp JJ, Niks EH, Molenaar PC, MartinezMartinez P, et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev 2013;12:918e23. [34] Eymard B, Berrih-Aknin S. Role of the thymus in the physiopathology of myasthenia. Rev Neurol 1995;151:6e15. [35] Nancy P, Berrih-Aknin S. Differential estrogen receptor expression in autoimmune myasthenia gravis. Endocrinology 2005;146:2345e53. [36] Klein R, Marx A, Strobel P, Schalke B, Nix W, Willcox N. Autoimmune associations and autoantibody screening show focused recognition in patient subgroups with generalized myasthenia gravis. Hum Immunol 2013;74: 1184e93.
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
6
S. Berrih-Aknin et al. / Journal of Autoimmunity xxx (2014) 1e6
[37] Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, et al. Risk for myasthenia gravis maps to a (151) Pro/Ala change in TNIP1 and to human leukocyte antigen-B*08. Ann Neurol 2012;72:927e35. [38] Suzuki S, Utsugisawa K, Nagane Y, Suzuki N. Three types of striational antibodies in myasthenia gravis. Autoimmune Dis 2011;2011. 740583. [39] Romi F, Aarli JA, Gilhus NE. Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features. Eur J Neurol 2007;14:617e 20. [40] Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003;126:2304e11. [41] Leite MI, Strobel P, Jones M, Micklem K, Moritz R, Gold R, et al. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol 2005;57:444e8. [42] Le Panse R, Berrih-Aknin S. Autoimmune myasthenia gravis: autoantibody mechanisms and new developments on immune regulation. Curr Opin Neurol 2013;26:569e76. [43] Bartoccioni E, Scuderi F, Minicuci GM, Marino M, Ciaraffa F, Evoli A. AntiMuSK antibodies: correlation with myasthenia gravis severity. Neurology 2006;67:505e7.
[44] McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004;55:580e4. [45] Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, et al. Autoantibodies to lipoprotein-related protein 4 in patients with doubleseronegative myasthenia gravis. Arch Neurol 2012;69:445e51. [46] Morel E, Eymard B, Vernetdergarabedian B, Pannier C, Dulac O, Bach JF. Neonatal myasthenia-gravis e a new clinical and immunological appraisal on 30 cases. Neurology 1988;38:138e42. [47] Behin A, Mayer M, Kassis-Makhoul B, Jugie M, Espil-Taris C, Ferrer X, et al. Severe neonatal myasthenia due to maternal anti-MuSK antibodies. Neuromuscul Disord 2008;18:443e6. [48] Vincent A, Newland C, Brueton L, Beeson D, Riemersma S, Huson SM, et al. Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen. Lancet 1995;346:24e5. [49] Jeannet PY, Marcoz JP, Kuntzer T, Roulet-Perez E. Isolated facial and bulbar paresis: a persistent manifestation of neonatal myasthenia gravis. Neurology 2008;70:237e8.
Please cite this article in press as: Berrih-Aknin S, et al., Diagnostic and clinical classification of autoimmune myasthenia gravis, Journal of Autoimmunity (2014), http://dx.doi.org/10.1016/j.jaut.2014.01.003
