Glutamic acid decarboxylase (GAD) antibody-positive paraneoplastic stiff person syndrome associated with mediastinal liposarcoma
- 1 Hematology and Oncology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
- 2 Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Correspondence to Dr Arthi Sridhar; artshri@gmail.com
Abstract
Stiff person syndrome (SPS) is a rare, debilitating neurological illness characterised by rigidity and spasms of the axial muscles, causing severe restrictions to mobility. SPS can be classic, partial or paraneoplastic. We report a case of a young woman who presented with seizures and painful spasms of the thoracolumbar muscles who was subsequently diagnosed with SPS. Serological work revealed glutamic acid decarboxylase (GAD) antibodies and imaging showed a large mediastinal mass. The patient underwent surgical resection of the mediastinal mass and final pathology revealed well-differentiated mediastinal liposarcoma. She received five sessions of plasma exchange and her neurological symptoms gradually improved after surgery. This case highlights a rare case of GAD antibody-positive paraneoplastic SPS associated with mediastinal liposarcoma.
Background
Stiff person syndrome (SPS), also called Moersch-Woltman syndrome, is a rare autoimmune neurological disorder characterised by fluctuating rigidity, spasms and stiffness of the thoracolumbar muscles resulting in severe restrictions to mobility.1 The classic form of SPS is associated with antiglutamic acid decarboxylase (anti-GAD) antibodies, whereas antibodies against amphiphysin are commonly seen in the paraneoplastic form of the disease.2 Patients with the classic form of SPS are usually seropositive for GAD65 antibody and have coexisting autoimmune disorders.3 We report an interesting case of GAD-seropositive SPS in a patient with mediastinal liposarcoma (ML) who had significant improvement in neurological symptoms after treating the underlying malignancy. To our knowledge, this is the first case of anti-GAD-positive SPS associated with ML.
Case presentation
A young woman in her 20s with a history of vitiligo presented with a 2-month history of seizure and painful muscle spasms predominantly affecting the back and axial muscles but sparing the extremities. The spasms were primarily triggered by stress and laughter and relieved by rest and benzodiazepines. Her symptoms progressively worsened and started interfering with her ambulation. She also reported 14 kg weight loss, palpitations, cough, anxiety, mood swings, nausea, vomiting, diarrhoea and muscle weakness. She denied fever, chills, night sweats, chest pain, shortness of breath or haemoptysis. On examination, her vital signs were stable. She had reduced breath sounds on the left side, and her heart sounds were distant. Abdominal examination was unremarkable. Neurological examination revealed intact cranial nerves, spasticity of the upper and lower extremities, 4/5 strength in bilateral hip flexors, and 5/5 strength in the distal extremities. Skin examination revealed vitiligo.
Investigations
Complete blood count, metabolic parameters and coagulation profile were normal. Serum alpha fetoprotein (AFP) was 1.0 ng/mL (reference range 0–11 ng/mL). Cerebrospinal fluid (CSF) analysis revealed normal glucose and protein. CSF protein electrophoresis did not show any evidence of oligoclonal bands. MRI of the cervical and lumbar spine was unremarkable. Thoracic spine MRI revealed a large mass occupying the majority of the left hemithorax measuring 20 cm in craniocaudal dimension. CT of the chest with contrast revealed a large heterogeneous mass containing fat and soft tissue arising from the anterior mediastinum occupying most of the left hemithorax, causing significant mass effect on the adjacent lung and mediastinum without vascular or osseous invasion (figure 1). MRI of the brain showed no pathological parenchymal or leptomeningeal enhancement. Electroencephalogram confirmed seizure activity. The patient underwent excision of the mediastinal mass, and surgical pathology revealed a 19.5×18.5×11 cm fully encapsulated, fluctuant mass with adherent thin membranous adipose tissue. The outer surface of the tumour was grey-pink and smooth, with prominent vasculature and punctate haemorrhage. The cut surface of the specimen revealed white-yellow fibrofatty material (80%) centrally intermixed with pink-tan, firm and granular substance (20%) (please refer to figure 2 for pathology). Immunohistochemistry analysis of the primary tumour showed expression of Murine Double Minute Clone 2 (MDM2) and cyclin-dependent kinase 4 (CDK4). Subsequent Fluorescence In Situ Hybridization (FISH) results showed amplification of MDM2 and CDK4 consistent with well-differentiated liposarcoma. The anti-GAD65 antibody test done in the serum was positive at the time of initial diagnosis. The antibody titre based on the enzyme-linked immunosorbent assay (ELISA) method was >1:4800 (reference range: negative <1:600, borderline 1:600–1:1200, positive >1:1200). Other paraneoplastic antibody tests, such as anti-N-methyl-D-aspartate receptor antibody, AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) antibody, gamma amino butyric acid (GABA) B receptor antibody, anti-Hu, anti-Yo, anti-Ri, anti-CV2/collapsin response mediator protein(CRMP)5 antibody, anti-amphiphysin antibody, anti- Neuronal Nuclear Antibody (ANNA) and anti-SOX1 (anti-glia nuclear) antibody, were negative.
Chest X-ray showed a large mass occupying the left hemithorax mainly in the region of the left lower lobe (A). CT of the chest showed a very large heterogeneous mass occupying the majority of the left hemithorax measuring 16.3×11.7×17.8 cm. This mass appears to have arisen from the anterior mediastinum and there is a left to right mass effect on the heart and the entire mediastinum. This mass abuts the aortic arch, the main pulmonary artery and the left main pulmonary artery, as well as the superior and inferior left pulmonary veins (B) and left atrium (C).
Under the microscope, an adipose neoplasm with delicate vasculature is appreciated (A). Unlike the usual lipoma, the adipocytes have different sizes and various shapes (B). The nuclei are plump and enlarged as compared with the usual lipoma (C).
Differential diagnosis
The differential diagnosis of SPS includes ankylosing spondylitis (AS), Parkinson’s disease (PD), tetanus and axial dystonia. In AS, the stiffness is usually worse in the morning and improves with exercise and physical activity. SPS is often misdiagnosed as PD and other movement disorders. The short shuffling gait and extrapyramidal symptoms seen in PD may mimic SPS; however, as in our patient, there is improvement in neurological symptoms with benzodiazepines and this is an important clue to differentiate SPS from PD. It can be extremely challenging to differentiate SPS from axial dystonia, but GAD antibody is an important serological marker pointing towards SPS. Progressive encephalopathy with rigidity and myoclonus (PERM) syndrome should also be considered in the differential diagnosis of SPS. However, our patient’s mental status was intact and there was no myoclonus, hence effectively ruling out PERM.
In a patient presenting with an anterior mediastinal mass, other possibilities such as thymoma, thymic carcinoma, lymphoma, germ cell tumour, substernal thyroid, lipoma and fibrosarcoma were considered. Thymic tumours can present with paraneoplastic syndromes and the most common example is myasthenia gravis. Serum AFP, beta human chorionic gonadotropin and lactate dehydrogenase should be checked in patients with suspected mediastinal germ cell tumours. Patients presenting with fever, night sweats and weight loss should be evaluated for lymphoma. Liposarcoma is a rare mesenchymal tumour that accounts for fewer than 1% of mediastinal tumours.
Treatment
Our patient underwent a median sternotomy with resection of her massive anterior mediastinal mass and total thymectomy. The tumour was noted to be very well circumscribed without pericardial invasion. The patient did not receive any adjuvant radiation or chemotherapy. She also received five sessions of plasma exchange (PLEX).
Outcome and follow-up
The patient’s neurological symptoms significantly improved after surgery and PLEX. Seizures were well controlled on levetiracetam and diazepam. The GAD antibody titres were not rechecked during follow-up as there is no clinical correlation with severity of SPS. Her overall performance status improved with outpatient physical and occupational therapy, and she is now independent with her activities of daily living; however, she does have some residual ataxia and remains on diazepam. The most recent CT of the chest, done in December 2021, showed no evidence of recurrent liposarcoma. She remains on active surveillance and continues to have close outpatient follow-up with neurology and oncology.
Discussion
SPS is a rare heterogeneous movement disorder predominantly seen in women. SPS is a spectrum of disorders and includes several key variants such as stiff limb syndrome, jerking SPS and PERM. SPS can be broadly classified into classic, partial and paraneoplastic variants.2 Classic SPS is believed to be autoantibody-mediated and commonly seen in association with autoimmune disorders such as type 1 diabetes, Hashimoto thyroiditis, pernicious anaemia and vitiligo. The key symptoms of classic SPS include spasms and rigidity primarily affecting the truncal muscles, resulting in lumbar hyperlordosis and postural instability. Also, there is heightened sensitivity to various external or emotional stimuli.1 2 Approximately 60%–80% of patients with classic SPS have autoantibodies against GAD, which is a key enzyme involved in the synthesis of the inhibitory neurotransmitter GABA.3 Subsequent reduction in GABA in the nervous system causes simultaneous contraction of the agonist and antagonistic muscles, leading to painful muscle spasms. Although GAD autoantibodies are seen in majority of classic SPS cases, there is no convincing evidence that GAD antibodies are directly pathogenic as there is no correlation between antibody titre and disease activity.4 5
Partial SPS is seen in 10%–15% of patients and is characterised by stiffness and impaired mobility affecting one limb or extremity, and the trunk is often spared.2 Patients with partial SPS are usually GAD65-seronegative, rarely in association with autoimmunity, but have a higher incidence of malignancy.
Paraneoplastic SPS is a rare (1%–2% of cases) antibody-mediated neurological disorder seen in patients with malignancy. In contrast to classic SPS, the paraneoplastic type is usually anti-GAD antibody-negative, but patients instead have anti-amphiphysin (AA) antibodies.6 In preclinical studies, it was observed that the injection of IgG AA antibodies into rats caused stiffness mimicking SPS in humans, thus supporting the pathogenic role of these autoantibodies.7 AA antibody-associated SPS is usually seen in elderly women (age >60 years) and is frequently associated with cervical region stiffness and breast cancer.7 Additional neuronal antibodies are present in the overwhelming majority (80%) of AA-seropositive patients with small cell lung cancer, whereas in breast and other cancer types AA antibodies appear alone.6 8
Table 1 shows various autoantibodies seen in paraneoplastic SPS and the associated malignancy. The type of antibody is an important prognostic marker, with GAD-seropositive patients having the worst outcome.9 There have also been reports of paraneoplastic SPS associated with Hodgkin’s lymphoma and colon cancer with no detectable autoantibodies.10 11 In addition to the movement disorder, patients with the paraneoplastic variant of SPS tend to have anorexia, weight loss and other symptoms related to underlying malignancy. Hence, it is reasonable to screen for malignancy in patients presenting with features of SPS.
Autoantibodies seen in paraneoplastic stiff person syndrome
| Autoantibodies | Malignancy | Reference | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| GAD, glutamic acid decarboxylase. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Anti-amphiphysin | Breast | 15–17 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Anti-GAD | Thymoma | 18–20 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Breast cancer | 21–23 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Multiple myeloma | 24 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Renal cell carcinoma | 25 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Lung adenocarcinoma | 26 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Carcinoid tumour | 27 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pancreatic adenocarcinoma | 28 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Anti-Ri | Lung adenocarcinoma | 29 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Small cell carcinoma of the bladder | 30 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Ethics statements
Patient consent for publication
Acknowledgments
The authors would like to thank Ms Virginia Mohlere for editorial assistance and Dr Bihong Zhao for providing the pathology images.
Footnotes
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Contributors BY: conception, design and drafting of the manuscript. AS: acquisition, analysis and review of the manuscript critically for important intellectual content. JJK: data collection and critical review of the manuscript for intellectual content. SHJ: served as senior faculty and revised the manuscript for important intellectual content.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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