Acta Neurologica Belgica (2020) 120:59–64

https://doi.org/10.1007/s13760-019-01102-w

ORIGINAL ARTICLE

A study of comorbidities in myasthenia gravis

Usha K. Misra1   · Jayantee Kalita1 · Varun K. Singh1 · Surendra Kumar1

Received: 13 December 2018 / Accepted: 19 February 2019 / Published online: 10 April 2019
© Belgian Neurological Society 2019

Abstract
Management of myasthenia gravis (MG) in the presence of comorbidities may be difficult. We report the effect of comorbidi-
ties in the outcome of MG. The patients with MG during 1991–2016 were included and evaluated including their demographic
variables, clinical findings, Myasthenia Gravis Foundation of America (MGFA) score. The patients were categorized into
early onset (≤ 40 years) and late onset (> 40 years) MG. The comorbidities (autoimmune and miscellaneous) and iatrogenic
complications were compared between early and late onset, and in good and poor outcome groups. Out of 81 patients with
MG, 48 patients had early and 33 late onset. In 71 (88%) patients, comorbidities were present and were autoimmune in 8
(10%) and miscellaneous in all the patients (88%). Iatrogenic complications were present in 54 (67%) patients. Thymectomy
was done in 19 patients; 16 had thymoma and 3 thymic hyperplasia. Myasthenic crisis occurred in 28 patients; 5 (18%)
had autoimmune and all had miscellaneous comorbidities. The patients with poor outcome had ≥ 2 comorbidities, myas-
thenic crisis, leukocytosis, elevated serum bilirubin and creatinine, and increased number of hospital admissions (P < 0.05).
Myasthenia gravis is associated with comorbidities in majority of patients especially in late onset group, and more than two
comorbidities are related to poor outcome.

Keywords  Myasthenia gravis · Comorbidity · Outcome · Autoimmune · Iatrogenic · Drug induced · Myasthenic crisis

Abbreviations thymectomy, and advancement in treatment of infections and

MG Myasthenia gravis intensive care units (ICU). As the patients with MG are liv-
MGFA Myasthenia Gravis Foundation of America ing longer, a number of comorbidities have been noted. The
MuSK Muscle specific kinase patients with MG may be associated with autoimmune as
LRP4 Lipoprotein-related protein 4 well as non-autoimmune comorbidities along with treatment
related complications which may affect the outcome. In the
developing countries, there is higher frequency of infection,
Introduction malnutrition, and many non-communicable diseases such as
diabetes mellitus, hypertension, coronary artery disease and
Myasthenia gravis (MG) is an antibody-complement-medi- stroke, which are more severe and occur in younger patients.
ated T-cell dependent autoimmune disorder characterized by Moreover poor health infrastructure in these countries fur-
fatigable muscle weakness associated with antibodies to ace- ther aggravates the situation. Use of statins, and many anti-
tylcholine receptor (AchR), muscle specific kinase (MuSK), biotics and antihypertensives may affect neuromuscular
lipoprotein-related protein 4 (LRP4) or agrin in the postsyn- transmission leading to aggravation of myasthenic weakness.
aptic membrane of neuromuscular junction (NMJ) [1]. There is paucity of studies on the role of comorbidities in
The incidence of MG is 7–23/million and prevalence is the outcome of MG, and most of the studies have evaluated
70–320/million. The mortality of MG has declined due to the role of immunological comorbidity [2–7]. None of these
discovery of choline esterase inhibitors, immunomodulators, studies comprehensively evaluated the role of different type
of comorbidities in the outcome of MG [1, 8–11]. In the
present study, we report the burden of comorbidities and
* Usha K. Misra their role in the outcome of the patients with MG.
drukmisra@rediffmail.com; ukmisra@sgpgi.ac.in
1
Department of Neurology, Sanjay Gandhi Post Graduate
Institute of Medical Sciences, Raebareily Road, Lucknow,
Uttar Pradesh 226014, India

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Materials and methods post-prandial blood sugar ≥ 200  mg/dl or HbA1C more

than 6.5 [15]. Transient hyperglycemia during corticoster-
The patients with MG during 2016–2018 were included in oid treatment, which returned to normal after reduction of
the present study. Many patients were in follow up since corticosteroid was not considered as diabetes mellitus.
1991; however, their comorbidities and complications to
treatment in the last 2 years were noted. The diagnosis of Hyperlipidemia
MG was based on low rate repetitive nerve stimulation
(RNS), acetyl choline receptor antibody or muscle specific Patient on anti hyperlipidemic treatment or those with low
kinase (MuSK) antibody and prostigmine test. The patients density lipoprotein more than 100  mg/dl, triglyceride
were included if two out of three tests were positive. Their ≥ 150 mg/dl, and high-density lipoprotein < 40 mg/dl in men
demographic details, age at onset of MG, severity of MG, and < 50 mg/dl in women were considered to have hyper-
and systemic symptoms were noted. The duration and lipidemia [16].
dose of acetyl choline esterase inhibitors (AchEI), predni-
solone, azathioprine, plasmapheresis or IVIg were noted. Chronic obstructive lung disease
The patients were divided into early onset (≤ 40 years) and
late onset (> 40 years) MG [12]. The severity of MG was Cough and dyspnea with winter exacerbation for 2 years or
assessed using Myasthenia Gravis Foundation of America more [17].
Clinical Classification into I–V [13]. Presence of thymoma
was noted. Information about thymectomy, time of surgery, Iatrogenic complications
and complications were noted. The presence of comorbidi-
ties was noted and divided into autoimmune and miscellane- The iatrogenic complications were those which followed
ous groups. Iatrogenic complications as well as infections the treatment of MG and were likely to be due to a specific
and myasthenic crisis were noted. treatment.
Infections and myasthenic crisis during the study period
Definition of comorbidities were also noted.

Autoimmune comorbidities Exclusion criteria

The autoimmune comorbidities were those disorders which Unsupported MG diagnosis, incomplete data or medical
were likely to have an immune-mediated mechanism and follow-up of less than 6 months.
preceded, accompanied or followed the diagnosis of MG.
Presence of systemic lupus erythematosus; autoimmune Categorization of patients
thyroid disorder, rheumatoid arthritis, pernicious anemia,
psoriasis, systemic vasculitis, etc., were noted. The patients with MG were categorized into MG with or
without comorbidities. The patients with comorbidities were
further categorized into autoimmune or miscellaneous. The
Miscellaneous comorbidities patients who developed complications due to treatment of
MG such as steroid induced transient hyperglycemia and
The miscellaneous comorbidities were those which were weight gain, dyslipidemia, osteoporotic fracture, cataract
preceded or accompanied the diagnosis of MG and unlikely were categorized as iatrogenic complication.
to be due to therapy of MG or have an immune-mediated
mechanism. Outcome

Hypertension Outcome was defined at 6 months on the basis of MGFA as

good (MGFA class I and II) or poor outcome (MGFA class
History of documented hypertension, on antihypertensive III–V). The number of deterioration needing hospitalization
therapy or blood pressure above 140/90 mmHg [14]. or emergency medical consultation was also noted.

Diabetes mellitus Statistical analysis

History of documented diabetes, on insulin or oral hypo- The comorbidity in the patients with early onset MG
glycemic drugs or fasting blood sugar ≥ 126  mg/dl and (≤ 40 years) was compared with late onset MG (> 40 years)
using X2 or Fisher exact for categorical and Student t test or

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Acta Neurologica Belgica (2020) 120:59–64 61

Mann–Whitney test for continuous variables. The number of Myasthenic crisis occurred in 28 patients; 16 in early onset
hospitalization in the MG with comorbidity was compared and 12 patients in late onset MG group.
with those without comorbidity using Mann–Whitney test.
The statistical analysis was done by Statistical Package for Effect of age of onset of MG on comorbidities
Social Sciences (SPSS) version 18 (IBM). A variable hav- and iatrogenic complications
ing two tailed P value of < 0.05 was considered significant.
The autoimmune diseases were insignificantly commoner
in early onset MG compared to late (3 vs 5; P = 0.19). Mis-
Results cellaneous comorbidities such as diabetes mellitus (0 vs 9;
P = 0.001), hypertension (5 vs 11; P = 0.01), coronary artery
Our results are based on 81 patients with MG, 34 (42%) of disease (0 vs 4; P = 0.04) and metabolic syndrome (8 vs 16;
them were females. The median age of the patients was 42 P = 0.02) were commoner in late onset MG (Table 1).
(7–75) years. At the time of presentation, 9 patients were in Iatrogenic complications such as transient hyperglyce-
MGFA class 1, 23 in class II, 26 in class III, 17 in class IV mia, drug induced weight gain, dyslipidemia, osteoporotic
and 6 in class V. Repetitive nerve stimulation test was posi- fractures, and cataract were similar between early and late
tive in 78 (96%) patients, AchR antibodies in 70 (86%), anti- onset MG groups.
Musk antibodies in 4 (5%) and prostigmine test was positive
in 78 (96%) patients. Forty-eight (59%) patients had early Myasthenic crisis and comorbidities
onset MG and 33 (41%) late. Comorbidities were present in
71 (88%) patients and included autoimmune in 8 and miscel- 28 (35%) patients had myasthenic crisis which was pre-
laneous in all the 71 patients while iatrogenic complications cipitated by infections in 20, under dosing of drugs in
were present in 54 (67%) patients. Thymic enlargement on five, offending drugs in three, drug default in one, extreme
CT thorax was present in 27 patients and was considered weather in two, thymectomy in two and myocardial infarc-
thymoma in 19 and hyperplasia in 8 patients radiologically. tion in one patient (Table 2). 19 patients needed mechanical
Nineteen (23%) patients underwent thymectomy. Histo- ventilation and 22 received Bilevel Positive Airway Pressure
pathological examination revealed thymic hyperplasia in 3 support. Patients with comorbidities needed more frequent
and thymoma in 16 patients. There was no significant differ- hospitalization (median 2, range 0–11) compared to those
ence between prevalence of either of the thymic abnormality without comorbidities (0).
between early and late onset group. Early onset MG was
more common in female than males (P = 0.002). Outcome
Autoimmune comorbidities were present in eight patients;
autoimmune thyroiditis in two, rheumatoid arthritis in one Sixty-eight (84%) patients had good and 13 (16%) had had
and other autoimmune diseases including SLE in five poor outcome including death in eight patients. The patients
patients. These patients had clinical symptoms and signs of with good outcome had lower frequency of myasthenic crisis
respective autoantibodies. However, in another ten patients, and less frequent intensive care unit admission. Patients with
autoantibodies were present without any clinical evidence anti-musk antibodies and > 2 comorbidities had significantly
of respective immunological disorder. These antibodies poorer outcome compared to fewer comorbidities (Table 3).
included ANA in seven, anti-ds-DNA in one, anti-thyroid
peroxidase antibodies in two, and rheumatoid factor in one
patient. Neither the autoimmune disorder nor the distribution Discussion
of autoantibodies differs significantly between the early and
late onset myasthenia gravis. In this study, comorbidities were present in 88% patients
MUSK positive MG: Out of four patients with anti- and iatrogenic complications in 67%. The comorbidities
MUSK positive MG, none of them had autoimmune comor- were autoimmune disorders in 10% and miscellaneous in
bidities. Among miscellaneous group, one patient had type-2 88% patients. Amongst the miscellaneous comorbidities,
diabetes mellitus, hypertension, metabolic syndrome and diabetes, hypertension, and coronary artery disease were
coronary artery disease, one had anemia and one patient more common in late onset MG. Patients with comorbidi-
developed ischemic stroke. Regarding iatrogenic complica- ties were also associated with myasthenic crisis and poor
tions, one developed osteoporotic fracture. outcome. This study evaluated association of comorbidi-
All the patients received acetylcholine esterase inhibi- ties and its influence in the outcome of MG. The patients
tors while plasmapheresis was done in 14 (17%) patients, with MG are at greater risk of autoimmune comorbidities
intravenous immunoglobulin was prescribed to 10 (12%) compared to non-myasthenic population with a frequency
patients, and mechanical ventilation to 19 (23%) patients. of 25–78%, especially in females and those with early

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62 Acta Neurologica Belgica (2020) 120:59–64

Table 1  Distribution Total number Early onset (N = 48) Late onset (N = 33) P value
of comorbidities and of patients
complications in early and late
onset myasthenia gravis Comorbidities 71(88%) 41(85%) 30 (91%) 0.46
 (A) Autoimmune 8 (10%) 3 (6%) 5 (15%) 0.19
  Rheumatoid 1 1/17 0(16) 0.16
  Systemic lupus erythematosus 5 1/29 4/15 0.26
  Thyroid peroxidase antibodies 2 1/16 1/15 0.58
 (B) Miscellaneous 71 (88%) 40 (83%) 31 (94%) 0.46
  Diabetes 16 4 12 0.002
  Hypertension 16 5 11 0.01
  Coronary artery disease 4 0 4 0.04
  Metabolic syndrome 24 8 16 0.02
  Hypothyroidism 2 1 1 0.78
  Tuberculosis 8 3 5 0.79
  Asthma 2 1 1 0.58
  Restless leg syndrome 2 0 2 0.08
  Migraine 2 1 1 0.79
  Anemia 15 10 5 0.67
  Stroke 2 1 1 0.79
 Two or more comorbidities 56 (69%) 30 (62%) 26 (79%) 0.12
 Iatrogenic complications 54 (67%) 30 (63%) 24 (73%) 0.34
  Transient hyperglycemia 6 4 2 0.70
  Osteoporotic fracture 2 1 1 0.79
  Drug induced weight gain 48 30 18 0.47
  Dyslipidemia 27 12 15 0.055
  Cataract 2 1 1 0.79

SLE systemic lupus erythematous, VAP ventilator associated pneumonia, TPO thyroid peroxidase, MUSK
muscle specific kinase antibodies

Table 2  Various precipitating factors of myasthenic crisis MG. The patients with early onset MG have much higher
Precipitation of crisis Number
frequency of autoimmune comorbidities compared to late
of patients onset. Although the latter subgroup also has higher fre-
(N = 28/81) quency of comorbidities compared to general population.
Autoimmune thyroid disorder is the most common auto-
Infections 20
immune comorbidity with MG and in up to 10% in early
Underdosing 5
onset MG [6]. In our study, there was only one patient
Drug default 1
with autoimmune thyroiditis in early onset group and
Thymectomy 2
one patient with rheumatoid arthritis, which is reported
Warm weather 2
in other studies as well [6, 19]. In a study on 75 patients
Contrast toxicity 1
with MG, autoimmune comorbidities were present in 21
Cholinergic crisis 2
(28%) and included autoimmune thyroid disorders in 16%,
Myocardial infarction 1
rheumatoid arthritis in 4%, systemic lupus erythematosus
Offending drug 3
in 2.6% and Lambert–Eaton myasthenic syndrome in 1.3%.
In ten patients, the diagnosis of autoimmune disorder was
established before MG [3]. In our study, autoantibodies
onset MG [18, 19]. In other studies, the frequency of sec- were present in 17 (21%) patients; rheumatoid factor in 1,
ond autoimmune disorder in MG patients ranged from 13 antinuclear antibody in 12, anti-ds-DNA in 6 and anti-TPO
to 14% [6, 7]. Amongst the autoimmune disorders, autoim- antibody in 4. Autoantibodies can be found in MG without
mune thyroiditis is the commonest followed by rheumatoid clinical evidence of respective autoimmune disorder and
arthritis and systemic lupus erythematosus [18, 20]. The may be marker of a later autoimmune disorder in some
autoimmune comorbidities vary in different subgroups of patients. We, however, did not do a long term follow up to

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Table 3  Effect of comorbidities Parameters Good outcome (68) Poor outcome (13) P value
on the outcome of myasthenia
gravis Comorbidities
 Miscellaneous 59 (87%) 12 (92%) 0.16
 Autoimmune 5 (7%) 3 (23%) 0.06
Iatrogenic complications 44 (72%) 10 (92%) 0.53
Crisis (28) 20 (29%) 8 (61%) 0.01
Admission in intensive care unit 22 (32%) 9 (69%) 0.01
Anti-muscle specific kinase antibodies 2/57 (3%) 2/10 (20%) 0.04
Comorbidities 58 (85%) 13 (100%) 0.14
Comorbidities ≥ 2 43 (63%) 13 (100%) 0.01
Total leucocyte count/mm3 mean ± SD 3737 ± 1730 7018 ± 5888 0.003
Serum creatinine (mg/dl) 0.9 ± 0.21 1.1 ± 0.53 0.03
Serum bilirubin (mg/dl) 0.81 ± 0.47 1.2 ± 1.14 0.02
Low dose pyridostigmine 19 (28%) 8 (61%) 0.03

MUSK muscle specific kinase antibodies

document the significance of these autoantibodies. Ocular Limitations

myasthenia has a special link with thyroid disorders [21,
22]. In our study, eight out of nine patients with ocular This study has retrospective design; therefore, the details
MG had comorbidities. Myasthenia associated with auto- of complication may not have been very accurately cap-
immune thyroid disease has a milder clinical course [2]. tured. The study has been conducted in a tertiary care
Myasthenic crisis occurred in 28 patients in our study teaching hospital where advanced or complicated cases
and was associated with infection in 68%. The other trig- are referred; hence, the result of our study may not be
gers such as under dosing or missing of drugs, stress of extrapolated to MG in general. In our hospital, there are
extreme temperature and surgery were present in 35.7%. active super specialty departments of immunology, endo-
In an earlier study on 64 patients with MG, 14 (22%) had crinology, and cardiology, which could have affected the
myasthenic crisis, which was attributed to infection in 6, referral to the respective super specialty department and
surgery in 5, drug withdrawal in 2 and comorbidity in 1 may account for a lower frequency of autoimmune disor-
patient [23]. The reported frequency of myasthenic cri- ders in our study. However, this study comprehensively
sis is 15–20% who require mechanical ventilator [24]. A evaluates the effects of comorbidities in MG. Comorbidi-
higher frequency of myasthenic crisis in the present study ties in MG are common, and attention should be paid in
may be due to a referral bias of a tertiary care hospital managing these comorbidities with appropriate safe drugs
where advance cases are referred. for better outcome.
Miscellaneous comorbidities are important especially in
the patients with late onset MG. Not only diabetes, hyper- Acknowledgements  We thank Mr. Shakti Kumar for secretarial help.
tension and pulmonary disease offer additional risk but
the drugs used in their treatment may worsen MG such as Author contributions  UKM: Writing and drafting of manuscript. JK:
Writing and drafting of manuscript. VKS: Data collection and analysis
antihypertensive and statins. In our study, drugs like levo- of data. SK: Data collection, analysis of data and statistical analysis.
floxacin, clindamycin and verapamil were found to worsen
MG leading to crisis in three patients. Myasthenia gravis Funding None.
patients have higher frequency of diabetes mellitus and
insulin is prescribed three times more than the controls Compliance with ethical standards 
[25].
Iatrogenic complications are important especially in late Ethical approval  This study was approved by Institutional Ethics Com-
onset MG. Prednisolone is the first line immunosuppressive mittee, SGPGIMS, Lucknow INDIA. All the patients or care givers
gave their written informed consent for research, which was conducted
drug and results in frequent side effects such as precipitat- in accordance with the Helsinki Declaration.
ing diabetes, hypertension, weight gain, cushingoid appear-
ance, osteoporosis, and bone fractures. However, there was Conflict of interest  The authors declare that the have no conflict of
no increase in bone fractures in a registry based study [26]. interest.
In our study, one MUSK positive patient had fracture fol-
lowing steroid use.

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