Editing Myasthenia gravis (section)

==Diagnosis==
Myasthenia gravis can be difficult to diagnose, as the symptoms can be subtle and hard to distinguish from both normal variants and other neurological disorders.<ref name="Scherer2005" />

Three types of myasthenic symptoms in children can be distinguished:<ref>{{Cite book |url=https://books.google.com/books?id=tlGAAgAAQBAJ&pg=PA277 |title=Pediatric Nursing: The Critical Components of Nursing Care |vauthors=Rudd K, Kocisko D |publisher=F.A. Davis |year=2013 |isbn=978-0-8036-4053-5 |archive-url=https://web.archive.org/web/20160603224352/https://books.google.com/books?id=tlGAAgAAQBAJ&pg=PA277 |archive-date=3 June 2016 |url-status=live}}</ref>
# Transient neonatal myasthenia gravis occurs in 10 to 15% of babies born to mothers afflicted with the disorder, and disappears after a few weeks.
# Congenital myasthenia, the rarest form, occurs when genes are present from both parents.
# Juvenile myasthenia gravis is most common in females.

Congenital myasthenias cause muscle weakness and fatigability similar to those of MG.<ref name="EngelShen2015">{{Cite journal |vauthors=Engel AG, Shen XM, Selcen D, Sine SM |date=April 2015 |title=Congenital myasthenic syndromes: pathogenesis, diagnosis, and treatment |journal=The Lancet. Neurology |volume=14 |issue=4 |pages=420–434 |doi=10.1016/S1474-4422(14)70201-7 |pmc=4520251 |pmid=25792100}}</ref>
The signs of congenital myasthenia usually are present in the first years of childhood, although they may not be recognized until adulthood.<ref>{{Cite web |title=Congenital Myasthenia Information Page: National Institute of Neurological Disorders and Stroke (NINDS) |url=http://www.ninds.nih.gov/disorders/congenital_myasthenia/congenital_myasthenia.htm |archive-url=https://web.archive.org/web/20150712234330/http://www.ninds.nih.gov/disorders/congenital_myasthenia/congenital_myasthenia.htm |archive-date=12 July 2015 |access-date=2015-07-11 |website=www.ninds.nih.gov}}</ref>

=== Subgroup classification ===
{| class="wikitable" style = "float: right; margin-left:15px; text-align:center"
|+ '''Myasthenia Gravis Foundation of America Clinical Classification'''<ref>{{Cite book |title=Myasthenia Gravis and Related Disorders |vauthors=Wolfe GI, Barohn RJ |year=2009 |isbn=978-1-58829-852-2 |pages=293–302 |chapter=Myasthenia Gravis: Classification and Outcome Measurements |doi=10.1007/978-1-59745-156-7_18}}</ref>
|-
! Class !! Description
|-
| I || Any eye muscle weakness, possible [[ptosis (eyelid)|ptosis]], no other evidence of muscle weakness elsewhere
|-
| II || Eye muscle weakness of any severity, mild weakness of other muscles
|-
| IIa || Predominantly limb or axial muscles
|-
| IIb || Predominantly bulbar and/or respiratory muscles
|-
| III || Eye muscle weakness of any severity, moderate weakness of other muscles
|-
| IIIa || Predominantly limb or axial muscles
|-
| IIIb || Predominantly bulbar and/or respiratory muscles
|-
| IV || Eye muscle weakness of any severity, severe weakness of other muscles
|-
| IVa || Predominantly limb or axial muscles
|-
| IVb || Predominantly bulbar and/or respiratory muscles
|-
| V || Intubation needed to maintain airway
|}
When diagnosed with MG, patient can be stratified into distinct subgroups based on the clinical features and serological status, e.g. affected muscle group, age of onset, thymic abnormalities, and profile of serum autoantibodies.<ref>{{Cite journal |last1=Meriggioli |first1=Matthew N |last2=Sanders |first2=Donald B |date=May 2009 |title=Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity |journal=The Lancet Neurology |volume=8 |issue=5 |pages=475–490 |doi=10.1016/S1474-4422(09)70063-8 |pmc=2730933 |pmid=19375665}}</ref>

Based on the affected muscle group, patients can be sub-grouped into ocular MG or generalized MG. Ocular MG is characterized by exclusively ocular symptoms, droopy eyelids, or double vision. Generalized MG has muscle weakness with a variable combination of the bulbar, axial, or limb and respiratory muscles.<ref>{{Cite journal |last1=Gilhus |first1=Nils Erik |last2=Verschuuren |first2=Jan J |date=October 2015 |title=Myasthenia gravis: subgroup classification and therapeutic strategies |url=https://doi.org/10.1016/S1474-4422(15)00145-3 |journal=The Lancet Neurology |volume=14 |issue=10 |pages=1023–1036 |doi=10.1016/s1474-4422(15)00145-3 |issn=1474-4422 |pmid=26376969}}</ref>

Patients can also be sub-grouped by the age of onset: juvenile-onset MG (onset age ≤ 18 years of age), early-onset MG (EOMG; 19–50 years of age), late-onset MG (LOMG; onset > 50 years of age), and very late-onset (VLOMG; onset age ≥ 65 years of age).<ref>{{Cite journal |last1=Punga |first1=Anna Rostedt |last2=Maddison |first2=Paul |last3=Heckmann |first3=Jeannine M |last4=Guptill |first4=Jeffrey T |last5=Evoli |first5=Amelia |date=February 2022 |title=Epidemiology, diagnostics, and biomarkers of autoimmune neuromuscular junction disorders |url=https://linkinghub.elsevier.com/retrieve/pii/S1474442221002970 |journal=The Lancet Neurology |volume=21 |issue=2 |pages=176–188 |doi=10.1016/S1474-4422(21)00297-0 |pmid=35065040}}</ref>

The subgroup of the autoantibody profile includes AChR seropositive, MuSK seropositive, LRP4 seropositive, and agrin seropositive.<ref>{{Cite journal |last1=Koneczny |first1=Inga |last2=Herbst |first2=Ruth |date=2019-07-02 |title=Myasthenia Gravis: Pathogenic Effects of Autoantibodies on Neuromuscular Architecture |journal=Cells |volume=8 |issue=7 |pages=671 |doi=10.3390/cells8070671 |issn=2073-4409 |pmc=6678492 |pmid=31269763 |doi-access=free}}</ref>

===Physical examination===
During a physical examination to check for MG, a doctor might ask the person to perform repetitive movements. For instance, the doctor may ask one to look at a fixed point for 30 seconds and to relax the muscles of the forehead, because a person with MG and ptosis of the eyes might be involuntarily using the forehead muscles to compensate for the weakness in the eyelids.<ref name="Scherer2005" /> The clinical examiner might also try to elicit the "curtain sign" in a person by holding one of the person's eyes open, which in the case of MG will lead the other eye to close.<ref name="Scherer2005" />

===Blood tests===
If the diagnosis is suspected, [[serology]] can be performed:
* One test is for antibodies against the acetylcholine receptor;<ref name="Scherer2005" /> the test has a reasonable [[Sensitivity (tests)|sensitivity]] of 80–96%, but in ocular myasthenia, the sensitivity falls to 50%.
* A proportion of the people without antibodies against the acetylcholine receptor have antibodies against the MuSK protein.<ref name="pmid18515870">{{Cite journal |display-authors=6 |vauthors=Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, Beeson D, Willcox N, Vincent A |date=July 2008 |title=IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis |journal=Brain |volume=131 |issue=Pt 7 |pages=1940–52 |doi=10.1093/brain/awn092 |pmc=2442426 |pmid=18515870}}</ref>
* In specific situations, testing is performed for [[Lambert-Eaton syndrome]].<ref>{{MedlinePlusEncyclopedia|000710|Lambert-Eaton syndrome}}</ref>

===Electrodiagnostics===
[[File:Tumor Thymoma1.JPG|thumb|A chest CT-scan showing a thymoma (red circle)]]
[[File:Myasthenia gravis ptosis reversal.jpg|thumb|Photograph of a person showing right partial ptosis (left picture), the left lid shows compensatory pseudo lid retraction because of equal innervation of the m. levator palpabrae superioris ([[Hering's law of equal innervation]]): Right picture: after an edrophonium test, note the improvement in ptosis.]]

Muscle fibers of people with MG are easily fatigued, which the [[repetitive nerve stimulation]] test can help diagnose. In single-fiber [[electromyography]], which is considered to be the most sensitive (although not the most specific) test for MG,<ref name="Scherer2005" /> a thin needle electrode is inserted into different areas of a particular muscle to record the action potentials from several samplings of different individual muscle fibers. Two muscle fibers belonging to the same motor unit are identified, and the temporal variability in their firing patterns is measured. Frequency and proportion of particular abnormal action potential patterns, called "jitter" and "blocking", are diagnostic. Jitter refers to the abnormal variation in the time interval between action potentials of adjacent muscle fibers in the same motor unit. Blocking refers to the failure of nerve impulses to elicit action potentials in adjacent muscle fibers of the same motor unit.<ref name="Selvan">{{Cite journal |vauthors=Selvan VA |date=January 2011 |title=Single-fiber EMG: A review |journal=Annals of Indian Academy of Neurology |volume=14 |issue=1 |pages=64–67 |doi=10.4103/0972-2327.78058 |pmc=3108086 |pmid=21654930 |doi-access=free}}</ref>

===Ice test===
Applying ice for 2–5 minutes to the muscles reportedly has a [[sensitivity and specificity]] of 76.9% and 98.3%, respectively, for the identification of MG. [[Acetylcholinesterase]] is thought to be inhibited at the lower temperature, which is the basis for this diagnostic test. This generally is performed on the eyelids when ptosis is present and is deemed positive if a ≥2-mm rise in the eyelid occurs after the ice is removed.<ref>{{Cite journal |vauthors=Kearsey C, Fernando P, D'Costa D, Ferdinand P |date=June 2010 |title=The use of the ice pack test in myasthenia gravis |journal=JRSM Short Reports |volume=1 |issue=1 |page=14 |doi=10.1258/shorts.2009.090037 |pmc=2984327 |pmid=21103106}}</ref>

===Edrophonium test===
This test requires the [[intravenous]] administration of [[edrophonium|edrophonium chloride]] or neostigmine, drugs that block the breakdown of acetylcholine by [[cholinesterase]] (acetylcholinesterase inhibitors).<ref>{{MedlinePlusEncyclopedia|003930|Tensilon test}}</ref> This test is no longer typically performed, as its use can lead to life-threatening [[bradycardia]] (slow heart rate) which requires immediate emergency attention.<ref name=":2">{{Cite journal |vauthors=Spillane J, Higham E, Kullmann DM |date=December 2012 |title=Myasthenia gravis |journal=BMJ |volume=345 |issue=dec21 3 |pages=e8497 |doi=10.1136/bmj.e8497 |pmid=23261848 |s2cid=13911967}}</ref> Production of edrophonium was discontinued in 2008.<ref name="Rosen2014" />

===Imaging===
A [[chest X-ray]] may identify widening of the [[mediastinum]] suggestive of thymoma, but [[computed tomography]] or [[magnetic resonance imaging]] (MRI) are more sensitive ways to identify thymomas and are generally done for this reason.<ref name="Kraker">{{Cite journal |vauthors=de Kraker M, Kluin J, Renken N, Maat AP, Bogers AJ |date=June 2005 |title=CT and myasthenia gravis: correlation between mediastinal imaging and histopathological findings |journal=Interactive Cardiovascular and Thoracic Surgery |volume=4 |issue=3 |pages=267–271 |doi=10.1510/icvts.2004.097246 |pmid=17670406 |doi-access=free}}</ref> MRI of the cranium and orbits may also be performed to exclude compressive and inflammatory lesions of the cranial nerves and ocular muscles.<ref>Allan H. Ropper, Robert H. Brown ''Adams and Victor's Principles of Neurology'' McGraw-Hill Professional; 8 edition (2005)</ref>

===Pulmonary function test===
The forced [[vital capacity]] may be monitored at intervals to detect increasing muscular weakness. Acutely, [[negative inspiratory force]] may be used to determine adequacy of ventilation; it is performed on those individuals with MG.<ref>{{MedlinePlusEncyclopedia|003853|Pulmonary function tests}}</ref><ref>{{EMedicine|article|793136|Emergent Management of Myasthenia Gravis}}</ref>

=== Differential diagnoses ===
The muscle weakness that worsens with activity (abnormal [[muscle fatigue]]) in myasthenia gravis<ref name=":0">{{Cite journal |last=Gilhus |first=Nils Erik |date=2021-03-01 |title=Physical training and exercise in myasthenia gravis |url=https://www.sciencedirect.com/science/article/pii/S0960896620306982 |journal=Neuromuscular Disorders |volume=31 |issue=3 |pages=169–173 |doi=10.1016/j.nmd.2020.12.004 |issn=0960-8966 |pmid=33461846 |s2cid=229372884 |hdl-access=free |hdl=11250/2767222}}</ref> is a symptom shared by other neuromuscular diseases. Most of the [[Metabolic myopathy|metabolic myopathies]], such as McArdle disease (GSD-V), have abnormal muscle fatigue rather than fixed muscle weakness.<ref>{{Cite journal |last1=Darras |first1=B. T. |last2=Friedman |first2=N. R. |date=February 2000 |title=Metabolic myopathies: a clinical approach; part I |url=https://pubmed.ncbi.nlm.nih.gov/10738913/ |url-status=live |journal=Pediatric Neurology |volume=22 |issue=2 |pages=87–97 |doi=10.1016/s0887-8994(99)00133-2 |issn=0887-8994 |pmid=10738913 |archive-url=https://web.archive.org/web/20230524221141/https://pubmed.ncbi.nlm.nih.gov/10738913/ |archive-date=24 May 2023 |access-date=24 November 2023}}</ref><ref>{{Cite journal |last=Tobon |first=Alejandro |date=December 2013 |title=Metabolic myopathies |journal=Continuum (Minneapolis, Minn.) |volume=19 |issue=6 Muscle Disease |pages=1571–1597 |doi=10.1212/01.CON.0000440660.41675.06 |issn=1538-6899 |pmc=10563931 |pmid=24305448}}</ref> Also, like myasthenia gravis,<ref name=":0" /> exercise intolerance in [[McArdle disease]] improves with regular physical activity (performed safely using activity adaptations such as getting into [[Second wind#Pathology|second wind]], the "30 for 80 rule," and "six second rule").<ref>{{Cite book |last=Wakelin |first=A. |url=https://www.iamgsd.org/_files/ugd/c951b2_91a5802caa2144d5aedbb0489c1cf543.pdf |title=Living with McArdle Disease |publisher=IamGSD |year=2017 |access-date=24 November 2023 |archive-url=https://web.archive.org/web/20230305215516/https://www.iamgsd.org/_files/ugd/c951b2_91a5802caa2144d5aedbb0489c1cf543.pdf |archive-date=5 March 2023 |url-status=live}}</ref><ref>{{Cite journal |last1=Reason |first1=S. L. |last2=Voermans |first2=N. |last3=Lucia |first3=A. |last4=Vissing |first4=J. |last5=Quinlivan |first5=R. |last6=Bhai |first6=S. |last7=Wakelin |first7=A. |date=July 2023 |title=Development of Continuum of Care for McArdle disease: A practical tool for clinicians and patients |journal=Neuromuscular Disorders |volume=33 |issue=7 |pages=575–579 |doi=10.1016/j.nmd.2023.05.006 |issn=1873-2364 |pmid=37354872 |s2cid=259141690 |doi-access=free}}</ref> A small minority of patients with McArdle disease also have the comorbidity of ptosis (drooping upper eyelid).<ref>{{Cite journal |last1=Scalco |first1=Renata S. |last2=Lucia |first2=Alejandro |last3=Santalla |first3=Alfredo |last4=Martinuzzi |first4=Andrea |last5=Vavla |first5=Marinela |last6=Reni |first6=Gianluigi |last7=Toscano |first7=Antonio |last8=Musumeci |first8=Olimpia |last9=Voermans |first9=Nicol C. |last10=Kouwenberg |first10=Carlyn V. |last11=Laforêt |first11=Pascal |last12=San-Millán |first12=Beatriz |last13=Vieitez |first13=Irene |last14=Siciliano |first14=Gabriele |last15=Kühnle |first15=Enrico |date=2020-11-24 |title=Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) |journal=Orphanet Journal of Rare Diseases |volume=15 |issue=1 |pages=330 |doi=10.1186/s13023-020-01562-x |issn=1750-1172 |pmc=7687836 |pmid=33234167 |doi-access=free}}</ref> Late-onset GSD-II ([[Pompe disease]]) and GSD-XV also have muscle weakness or fatigue with comorbidities of ptosis and ophthalmoplegia; as do many of the [[Mitochondrial myopathy|mitochondrial myopathies]].<ref name=":3">{{Cite journal |last1=Urtizberea |first1=Jon Andoni |last2=Severa |first2=Gianmarco |last3=Malfatti |first3=Edoardo |date=May 2023 |title=Metabolic Myopathies in the Era of Next-Generation Sequencing |journal=Genes |volume=14 |issue=5 |pages=954 |doi=10.3390/genes14050954 |issn=2073-4425 |pmc=10217901 |pmid=37239314 |doi-access=free}}</ref>

Other diseases that involve abnormal muscle fatigue (which may be described as exercise-induced muscle weakness, reversible muscle weakness, or muscle weakness that improves with rest) include: endocrine myopathies (such as [[Hoffmann syndrome|Hoffman syndrome]]), Tubular aggregate myopathy (TAM), [[ischemia]] (such as [[intermittent claudication]], [[popliteal artery entrapment syndrome]], and [[chronic venous insufficiency]]), and poor diet or malabsorption diseases that lead to [[vitamin D deficiency]] (osteomalic myopathy). Although limb-girdle muscular dystrophies (LGMDs) involve fixed muscle weakness, LGMDR8 also involves muscle fatigue;<ref>{{Cite web |title=MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 8; LGMDR8 |url=https://www.omim.org/entry/254110 |url-status=live |archive-url=https://web.archive.org/web/20240531123356/https://www.omim.org/entry/254110 |archive-date=31 May 2024 |access-date=2023-11-24 |website=www.omim.org }}</ref> as do some limb-girdle muscular dystrophy-dystroglycanopathies such as MDDGC3 (a.k.a. LGMDR15 and LGMD2O).<ref name=":3" /><ref>{{Cite web |title=MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (LIMB-GIRDLE), TYPE C, 3; MDDGC3 |url=https://www.omim.org/entry/613157 |url-status=live |archive-url=https://web.archive.org/web/20230609063352/https://omim.org/entry/613157 |archive-date=9 June 2023 |access-date=2023-11-24 |website=www.omim.org }}</ref> Myofibrillar myopathy 10,<ref>{{Cite web |title=MYOFIBRILLAR MYOPATHY 10; MFM10 |url=https://www.omim.org/entry/619040 |url-status=live |archive-url=https://web.archive.org/web/20240421111521/https://omim.org/entry/619040 |archive-date=21 April 2024 |access-date=2023-11-24 |website=www.omim.org }}</ref> dimethylglycine dehydrogenase deficiency,<ref>{{Cite web |title=DIMETHYLGLYCINE DEHYDROGENASE DEFICIENCY; DMGDHD |url=https://www.omim.org/entry/605850 |url-status=live |archive-url=https://web.archive.org/web/20221014230504/https://omim.org/entry/605850 |archive-date=14 October 2022 |access-date=2023-11-24 |website=www.omim.org }}</ref> erythrocyte lactate transporter defect,<ref>{{Cite web |title=ERYTHROCYTE LACTATE TRANSPORTER DEFECT |url=https://www.omim.org/entry/245340 |url-status=live |archive-url=https://web.archive.org/web/20240513063740/https://www.omim.org/entry/245340 |archive-date=13 May 2024 |access-date=2023-11-24 |website=www.omim.org }}</ref> and myopathy with myalgia, increased serum creatine kinase, with or without episodic rhabdomyolysis (MMCKR)<ref>{{Cite web |title=MYOPATHY WITH MYALGIA, INCREASED SERUM CREATINE KINASE, AND WITH OR WITHOUT EPISODIC RHABDOMYOLYSIS; MMCKR |url=https://www.omim.org/entry/620138 |url-status=live |archive-url=https://web.archive.org/web/20240603103141/https://www.omim.org/entry/620138 |archive-date=3 June 2024 |access-date=2023-11-24 |website=www.omim.org }}</ref> also include muscle fatigue.

X-linked episodic muscle weakness (EMWX) includes general muscle weakness, ptosis, and fluctuations in strength. In some individuals, fatiguability was demonstrable, the phenotype having features comparable to congenital myasthenic syndromes and [[Channelopathy|channelopathies]].<ref>{{Cite web |title=EPISODIC MUSCLE WEAKNESS, X-LINKED; EMWX |url=https://www.omim.org/entry/300211 |url-status=live |archive-url=https://web.archive.org/web/20240703204110/https://www.omim.org/entry/300211 |archive-date=3 July 2024 |access-date=2023-11-24 |website=www.omim.org }}</ref>

Signs and symptoms of myasthenia presenting from infancy or childhood may be one of the [[congenital myasthenic syndrome]]s, which can be inherited in either an autosomal dominant or recessive manner. There are currently over two dozen types of congenital myasthenic syndromes.<ref>{{Cite web |title=Phenotypic Series - PS601462, PS610542 - Congenital myasthenic syndromes - OMIM |url=https://www.omim.org/phenotypicSeries/PS610542,PS601462 |url-status=live |archive-url=https://web.archive.org/web/20240703204110/https://www.omim.org/phenotypicSeries/PS610542,PS601462 |archive-date=3 July 2024 |access-date=2023-11-24 |website=www.omim.org}}</ref>

Limb–girdle myasthenia gravis is a distinct condition from myasthenia gravis. It is an adult-onset, autoimmune condition affecting the neuromuscular junction. However, it lacks eye abnormalities and is associated with autoimmune conditions such as systemic lupus erythematosus, Hashimoto's thyroiditis, and thymoma.<ref>{{Cite web |title=159400 - MYASTHENIA, LIMB-GIRDLE, AUTOIMMUNE - OMIM |url=https://www.omim.org/entry/159400 |url-status=live |archive-url=https://web.archive.org/web/20230602162212/https://omim.org/entry/159400 |archive-date=2 June 2023 |access-date=2024-02-29 |website=www.omim.org }}</ref>

[[Lambert–Eaton myasthenic syndrome]] (LEMS) is an autoimmune condition that attacks the neuromuscular junction, either as a paraneoplastic syndrome (typically older patients) or associated with a non-cancerous primary autoimmune condition (typically younger patients). It usually involves lower limb weakness and exercise-induced fatiguability, although the upper limbs and eyes may also be involved. Lambert's sign is the unusual improvement of grip strength that follows after squeezing the hand at maximum intensity for 2–3 seconds.<ref>{{Cite journal |last1=Pascuzzi |first1=Robert M. |last2=Bodkin |first2=Cynthia L. |date=2022 |title=Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome: New Developments in Diagnosis and Treatment |journal=Neuropsychiatric Disease and Treatment |volume=18 |pages=3001–3022 |doi=10.2147/NDT.S296714 |issn=1176-6328 |pmc=9792103 |pmid=36578903 |doi-access=free}}</ref>