Carla Freeman

I Lewis

J M Heckmann

English

Crossref

ARTICLE
50    SAJP  -   July 2014  Vol. 20  No. 2 
Neuropsychiatric symptoms in patients with thymoma- 
associated and non-thymoma myasthenia gravis
C Freeman,1 MB ChB, FCPsych (SA), MMed (Psych); I Lewis,1 BSc, MB ChB, FCPsych (SA); J M Heckmann,2 MB BCh, FCPNeurol (SA), PhD
1 Department of Psychiatry and Mental Health, Faculty of Health Sciences, University of Cape Town, South Africa
2 Division of Neurology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
Corresponding author: C Freeman (frmcar002@myuct.ac.za)
Background. Around 10 - 15% of patients with myasthenia gravis (MG) have a thymoma, and non-motor symptoms are more frequent in 
these patients. We hypothesised that neuropsychiatric symptoms would also be more frequent. 
Methods. A cross-sectional study of 30 consecutive MG patients attending a clinic at Groote Schuur Hospital, Cape Town, South Africa, 
was done over a 6-month period in 2010. Each patient underwent a series of single-blinded neuropsychiatric assessments, including the 
16-item, self-reported Flanagan Quality of Life (QOL) scale, the Beck Depression Inventory second version, the Young Mania Rating Scale, 
the Hamilton Anxiety Rating Scale and the Brief Psychiatric Rating Scale (BPRS).  
Results. The frequency and nature of neuropsychiatric symptoms were similar between thymoma (n=9) and non-thymoma (n=21) MG 
patients. Symptoms of moderate or severe depression and anxiety were present in around 30%. The severity of depression symptoms 
correlated with MG severity. Prednisone dosing was not associated with neuropsychiatric symptoms or QOL scores. Those with longer 
duration of MG were more likely to have higher scores on the BPRS and anxiety scales. Those with younger-onset MG had higher BPRS 
scores and a tendency to suicidal behaviour. 
Conclusion. Although no association with thyoma was found, this study shows that neuropsychiatric conditions may be underdiagnosed 
in patients with MG. Systematic depression screening should be done at outpatient clinics, particularly for those who developed symptoms 
at a young age, those with severe disease and those with a long duration of illness. 
S Afr J Psych 2014;20(2):50-53. DOI:10.7196/SAJP.519
ARTICLE
 July 2014  Vol. 20  No. 2     -  SAJP    51
Myasthenia gravis (MG) is characterised by muscle 
fatigability, which may be chronic and debilitating.[1] 
In patients who are positive for acetylcholine receptor 
antibodies, 10 - 15% have a thymoma. Thymomas are 
removed surgically, but the associated MG usually per-
sists independently. Patients with thymoma-associated MG often have 
more severe disease than non-thymoma-associated patients, and may 
have additional non-motor symptoms and frequently require long-
term treatment.[2] Psychiatric symptoms have been reported in MG 
patients,[3,4] although little is known about their frequency or their 
rela tion to thymoma MG. The only published report documents three 
cases of psychosis in which psychotic symptoms persisted despite 
thymectomy.[5] 
We hypothesised that a patient with thymoma-associated MG 
will display a higher frequency of neuropsychiatric symptoms than 
patients with no thymoma. Here we report the findings of a pilot 
study in which both thymoma and non-thymoma MG patients were 
assessed using several neuropsychiatric questionnaires by inves-
tigators who were blind to thymoma status. 
Methods
A cross-sectional study was done of 30 consecutive thymoma and non-
thymoma MG patients attending a clinic at Groote Schuur Hosp ital, 
Cape Town, South Africa, over a 6-month period in 2010. Written 
informed consent was obtained and the University of Cape Town Health 
Sciences Human Research Ethics Committee approved the study.
Study population
All participants had MG and followed a standard treatment protocol 
that has been described elsewhere.[1] Patients with thymoma MG were 
stabilised on immunosuppressive therapy and a thymectomy was 
done at the earliest possible opportunity. Thymectomies are offered 
to patients with moderately severe generalised seropositive MG (<45 
years), even in the absence of thymoma. 
Interviews and tools
Interviews were done on the day of patients’ clinic visit by a psychia-
trist, blinded to thymic status. Assessments included the following: 
16-item self-reported Flanagan Quality of Life (QOL) scale, the Beck 
Depression Inventory second version (BDI-II), Young Mania Rating 
Scale (YMRS), the Hamilton Anxiety Rating Scale (HAM-A), and the 
Brief Psychiatric Rating Scale (BPRS) (Table 1). We defined suicidal 
behaviour as current suicidal ideation or one or more previous suicide 
attempts.
Demographic data and psychiatric history were also obtained 
during the interview. The quantified MG score, recent thyroid studies, 
comorbid conditions and current treatment were subsequently 
obtained by folder review. Age at symptom onset, age at diagnosis and 
thymic histology were obtained from an MG database.[1] Participants 
were referred for further psychiatric management if indicated.
Statistical analysis
Data are presented as means and standard deviations (SDs), although 
skewed and ordinal data are presented as medians and interquartile 
ranges (IQRs). The Student t-test or Mann-Whitney U-test was used 
as appropriate and the Spearman rank-order correlation coefficient 
for ordinal data. Fisher’s exact test was used for categorical data. A 
p-value (two-tailed) <0.05 was considered significant (Statistica 10 
(Statsoft)).
Results
Of the participants, 21 (70%) had non-thymoma MG and 9 (30%) 
had thymoma MG. Age and gender distributions, duration of MG 
disease and symptoms before diagnosis, as well as distribution of MG 
symptoms and disease severity between the two groups, were similar. 
As expected, the quantified MG scores correlated with prednisone 
dosing (rs=0.39, p=0.034). Although all patients were receiving 
steroid-sparing agents, at least two-thirds of both groups were also on 
prednisone (76%, non-thymoma MG; 66%, thymoma MG, p=0.76). 
The average dose of prednisone was similar in the two groups (non-
thymoma MG 16.3 mg/day; thymoma MG 17.2 mg/day, p=0.86). 
Eight of nine subjects with thymoma MG had already undergone 
thymectomy. 
When neuropsychiatric symptoms across the non-thymoma and 
thymoma MG groups were compared, no statistical difference was 
seen in the frequency or severity of depression, anxiety or manic 
symptoms (Table 1). However, 33% of the total sample had moderate 
to severe symptoms of depression (thymoma n=2; non-thymoma 
n=8) and anxiety (thymoma n=3; non-thymoma n=5), which was 
associated with lower Flanagan QOL scores (rs=−0.69, p=0.0001). 
Although symptoms of depression and anxiety did not always co-occur 
in the same patient, there was substantial overlap between the two 
as measured by the BDI-II and HAM-A scores (rs=0.56, p=0.001). 
Higher MG severity scores were associated with higher BDI-II scores 
(rs=0.51, p=0.004) and worse Flanagan QOL scores (rs=−0.51, p=0.004), 
but not more severe anxiety symptoms (rs=0.08, p=0.69). 
Only four subjects with non-thymoma MG (amitriptyline n=1; 
fluoxetine n=3) and two with thymoma MG (amitriptyline n=2) 
were on antidepressant therapy at the time of the interview (p=0.37). 
Patients with higher BDI-II scores were more likely to have been 
diagnosed with depression and started on antidepressant therapy; 
however, despite this intervention, these patients still had high scores 
on the BDI-II, which was associated with suicidal behaviour (rs=0.68, 
p=≤0.0001). Four subjects were newly identified with moderate to 
severe depression at the time of the interview (thymoma n=1; non-
thymoma n=3).
In our sample, higher doses of prednisone were less frequent in 
those with symptoms of depression (rs=0.28, p=0.14) or anxiety 
(rs=−0.08, p=0.66). Interestingly, five patients met the criteria for 
hypomania, although these features were negatively associated with 
prednisone dose (rs=−0.38, p=0.034). 
Overall, a longer duration of MG (based on symptom duration) 
was associated with both symptoms of anxiety (rs=0.38, p=0.035) and 
depression (rs=0.37, p=0.045), but not with suicidal ideation (rs=0.10, 
p=0.59). A younger age at MG onset revealed a trend toward suicidal 
ideation or behaviour (p=0.07); these subjects had higher scores 
on the multiple domain psychopathology measurement (rs=−0.48, 
p=0.007), but neither higher depression or anxiety scores nor lower 
Flanagan QOL (p=0.05). Taken together, almost half (46%) of the 
participants interviewed required further psychiatric evaluation and 
management, in particular who developed MG symptoms at a young 
age.
ARTICLE
52    SAJP  -   July 2014  Vol. 20  No. 2 
Discussion
A cross-sectional neuropsychiatric evaluation of a sample of 30 MG 
patients revealed prominent psychiatric symptoms. Although we did 
not find a difference in the frequency of neuropsychiatric symptoms 
between thymoma and non-thymoma MG patients as anticipated, 
one-third overall were found to be either clinically depressed or 
experiencing moderate to severe anxiety symptoms. In addition, 
one-third reported one or more past suicide attempts or exhibited 
suicidal ideation at the time of interview, and almost half of the 
sample required additional psychiatric evaluation and management, 
particularly those with a younger age of MG onset. Although 20% 
were taking antidepressants, they reported ongoing symptoms of 
depression and/or anxiety. Three of these subjects were taking 
25 mg amitriptyline daily, a dose considered subtherapeutic for the 
Table 1. Clinical and demographic characteristics of MG patients with or without thymoma, on the day of psychiatric interview
Total (N=30) Non-thymoma MG (n=21) Thymoma MG (n=9) p-value
Male/female 8/22 5/16 3/6 0.61
Age, years, mean (SD) 44.9 (14.9) 45.0 (16.9) 44.7 (9.8) 0.89
Age at MG symptom onset, years
Mean (SD) 32.1 (18.2) 30.9 (18.9) 34.9 (17.2) 0.59
Median (IQR) 32 (16, 44) 25 (16, 43) 39 (29, 44) 0.50
Months of MG symptoms prediagnosis, median (IQR) 5.5 (2, 10) 6.0 (3, 10) 3.0 (2, 6) 0.39
Duration of MG since diagnosis, months, median (IQR) 85 (24, 132) 89 (49, 154) 36 (13, 18) 0.14
Marital status, n (%) 0.23
Married/partner 13 (43) 7 (33) 6 (66)
Single 10 (33) 8 (38) 2 (22)
Divorced 7 (23) 6 (28) 1 (11)
Educational level, n (%) 0.20
Primary school 4 (13) 2 (9) 2 (22)
Secondary school 14 (47) 12 (57) 2 (22)
Tertiary study 12 (40) 7 (33) 5 (55)
Additional autoimmune disease, n (%) 5 (17) 3 (14)* 2 (22)† 0.62
MG symptoms, n (%)‡ 0.47
Bulbar 13 (43) 11 (52) 2 (22)
Respiratory 7 (23) 5 (24) 2 (22)
Ocular 16 (53) 12 (57) 4 (44)
Limbs 17 (57) 10 (48) 7 (78)
QMGS, median (IQR)‡ 9 (4, 11) 8 (5, 11) 10 (4, 11) 0.76
Prednisone, n (%) 22 (73) 16 (76) 6 (66) 0.61
Daily dose (mg/day), mean (SD) 16.6 (16.6) 16.3 (16.7) 17.2 (17.2) 0.86
Thymectomy, n (%) 18 (60) 10 (48) 8 (88) 0.043
Antidepressant therapy, n (%) 6 (20) 4 (19) 2 (22) 0.37
Fluoxetine 20 mg daily, n (%) 3 (10) 3 (10) -
Amitriptyline 25 mg daily, n (%) 3 (10) 1 (3) 2 (7)
Neuropsychiatric assessments
BDI-II score, mean (SD) 16 (9) 18 (10) 13 (6) 0.16
HAM-A score, mean (SD) 14 (9) 14 (9) 13 (9) 0.67
BPRS score, mean (SD) 12 (7) 13 (7) 10 (6) 0.30
YMRS score, mean (SD) 4 (4) 4 (4) 4 (4) 0.87
Suicidal ideation, n (%) 9 (30) 7 (33) 2 (22) 0.65
Psychiatric referral, n (%) 14 (46) 11 (52) 3 (33) 0.42
MG = myasthenia gravis; SD = standard deviation; IQR = interquartile range; QMGS = quantified myasthenia gravis score; BDI-II = Beck Depression Inventory (≤13 = minimal; 14 - 19 = mild; 
20 - 28 = moderate); HAM-A = Hamilton Anxiety Rating Scale (14 - 17 = mild; 18 - 24 = moderate); BPRS = Brief Psychiatric Rating Scale (0 - 31 = mildly ill); YMRS = Young Mania Rating Scale 
(8 - 12 = hypomania). 
* Included biochemically controlled thyroid disease (n=2), vitiligo and coeliac disease. 
† Included one patient with neuromyotonia and one with polymyositis.
‡ Outcome at the time of interview. 
ARTICLE
 July 2014  Vol. 20  No. 2     -  SAJP    53
treatment of depression and potentially contributing to ongoing 
symptoms. Medication adherence was not assessed in this study, 
but should be considered in cases of subclinical treatment response. 
A proportion of participants found to be depressed had not been 
previously diagnosed.
The high prevalence of psychiatric symptoms found in patients 
with MG, particularly depression and anxiety, correspond with 
previous reports. A similar-sized sample using a structured psychiatric 
interview (MINI-Plus) found 26% to have a depression disorder and 
46% an anxiety disorder.[3] We used the BDI-II to measure depression 
and found higher overall scores compared with two larger cohorts, 
North American and Japanese, who used the same tool. MG patients 
with high scores on the BDI-II were also at greater risk for suicidal 
behaviour.[4,6] In addition, one-third of our sample reported moderate 
to severe anxiety symptoms. However, there was no correlation 
between anxiety and either thymoma status or prednisone dose. In 
contrast, a large Chinese cohort using the same scale, found 46% 
to have high anxiety scores correlating with both the presence of 
thymoma and prednisone dose.[7] 
Our findings revealed a number of factors associated with a 
depressed state in MG: more severe disease, comorbid anxiety 
symptoms, suicidal ideation or behaviour, and concurrent 
antidepressant therapy. In contrast to a previous report, we found 
no association between the current prednisone dose and severity of 
mood or presence of anxiety symptoms.[4] Although not apparent 
in our study, treatment with corticosteroids is well known to 
precipitate dose-dependent psychiatric disturbance, particularly 
affective disorders, and should be considered in the aetiology of 
psychopathology in MG. 
We found five patients with hypomanic features on the YMRS, 
although the reliability of this scale is limited as it does not reflect 
the clinical picture over several days, which is needed to make the 
diagnosis of mania or hypomania. Mania and hypomania are often 
thought to arise as a consequence of corticosteroid therapy, but we 
found no correlation with prednisone dose. Only one of these patients 
was on antidepressants at the time of interview, and two had thymoma 
MG. 
Study limitations
This study had several limitations. The sample size was small, 
increasing the possibility of a statistical type 2 error. Although the 
subjects were outpatients, those with more severe disease would be 
more likely to have frequent follow-up visits, introducing selection 
bias. Owing to limited resources, a battery of validated psychiatric 
rating scales was used in the structured psychiatric interview to 
assess depression, anxiety and manic symptoms based on those 
previously used in MG studies. A detailed psychiatric assessment 
examining broader psychopathology, e.g. cognitive impairment, 
personality disorders and substance abuse, was not undertaken. 
Although we enquired about social and occupational function, we 
omitted a specific tool assessing daily function in MG and did not 
assess socioeconomic status, which could affect psychopathology. 
Conclusion
Neuropsychiatric symptoms did not differ between thymoma and 
non-thymoma MG patients in this sample. A high frequency of 
depression and anxiety was found in this MG cohort. Clinicians 
had overlooked psychiatric symptoms which, if untreated, would 
be likely to impact on the QOL and management of MG. Our 
results highlight the need for systematic depression screening in the 
outpatient clinic, particularly in patients who develop symptoms at a 
young age, those with severe disease and those with a long duration 
of illness. 
Acknowledgements. The authors wish to thank the staff of the 
Division of Neurology, Groote Schuur Hospital, for their assistance 
with this study. Dr C P Freeman is a recipient of a Discovery 
Foundation Academic Award.
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Neuropsychiatric symptoms in patients with thymoma-associated and non-thymoma myasthenia gravis

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Neuropsychiatric symptoms in patients with thymoma-associated and non-thymoma myasthenia gravis

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