Egad!

The serum GAD65 antibody level was greater than 265,000 × 10³ IU/µL (normal <5,000), and the CSF level was 11.2 nmol/L (normal: ≤0.02). Serum amphiphysin antibody testing was negative.

Significantly elevated serum and CSF anti-GAD65 antibody levels are highly suggestive of SPS. Stiff person syndrome with rapidly progressive clinical symptoms raises the concern of a paraneoplastic neurologic syndrome. Although anti-amphiphysin antibody – the antibody classically associated with breast cancer and SPS – was negative, anti-GAD65 antibody has been implicated in paraneoplastic SPS with thymoma, lymphoma, and thyroid carcinoma. Paraneoplastic neurologic syndrome can predate a detectable malignancy by several years. As SPS and lymphoma are associated with pruritus and lymphocytosis, imaging is indicated to search for malignancy. Antiglycine receptor antibody, associated with PERM, is not routinely available commercially.

Computed tomography of the chest, abdomen, and pelvis with intravenous contrast revealed a 3.9 × 8.0 × 7.0 cm anterior mediastinal mass (Figure 1, Panel A). Biopsy of the mass demonstrated a thymoma. Given that the patient exhibited no further signs of CNS involvement, her initial transiently altered mental status was attributed to opioids and steroids. As she did not meet the clinical criteria for PERM, testing of antiglycine antibodies was not pursued.

She received scheduled baclofen and diazepam with as needed cyclobenzaprine for continued muscle spasms. Over the next several days, her stiffness, spasms, and myoclonic jerks slowly improved, and she was able to attempt physical therapy (Appendix Video 1; https://youtu.be/d0gLpTgqaCs). She subsequently received intravenous immunoglobulin (IVIG) with further improvement. After five months of scheduled diazepam and baclofen, she was able to ambulate with minimal assistance (Appendix Video 2; https://youtu.be/I00i638u00o). Given the absence of safe tissue planes for resection, the patient received neoadjuvant chemotherapy with four cycles of cyclophosphamide, doxorubicin, and cisplatin. Tumor size decreased to 1.7 × 6.5 × 5.2 cm (Figure 1, Panel B), and she subsequently underwent resection (Figure 2). Pathological analysis demonstrated a type B1 thymoma.

SPS is a condition of muscle stiffness and spasticity. Diagnosis is difficult and often delayed due to its rarity, with an approximate prevalence of one to two cases per million people.¹ SPS typically occurs in middle age, and women are diagnosed twice as often as men. Classic SPS is characterized by axial and limb muscle stiffness, episodic spasms precipitated by tactile or auditory stimuli, continuous motor unit activity in agonist and antagonist muscles on EMG, high-titer antibody to GAD65 or amphiphysin, and the absence of an alternate diagnosis.² Variant syndromes have been described, including a milder variant limited to the limbs, a severe variant with brainstem and spinal cord involvement, and a paraneoplastic variant.³ This patient’s clinical presentation, EMG findings, and extraordinarily high anti-GAD titers in the serum and CSF were diagnostic of SPS.

The pathophysiology of SPS is associated with autoantibodies targeting proteins such as GAD65, amphiphysin, gephyrin, and GABA_A receptor-associated protein (GABARAP). These proteins are critical to gamma-aminobutyric acid (GABA) signaling, the primary inhibitory neurotransmitter pathway in the CNS (Figure 3).⁴ The formation of GABA from glutamate is catalyzed by GAD65. Gamma-aminobutyric acid is loaded into secretory vesicles, and amphiphysin facilitates vesicle recycling from the synaptic space.⁵ In the postsynaptic neuron, GABA binds the GABA_A receptor, leading to neuronal hyperpolarization and resistance to excitation. The GABA_A receptor is clustered on the plasma membrane through a scaffold formed by gephyrin. GABARAP facilitates this clustering, in part by linking GABA_A receptors and gephyrin.⁶ Autoantibodies to these proteins may be pathogenic; however, the direct effects on their targets are unclear. The end result is decreased GABAergic activity, leading to continuous activation of opposing muscle groups. The resulting stiffness is characteristic of this disorder. Colchicine is known to antagonize GABA_A receptor signaling, and this may have brought the underlying diagnosis of SPS to clinical attention.^7,8

Symptomatic treatment of SPS targets the GABAergic system. Typically, high doses of scheduled benzodiazepines⁹ and baclofen¹⁰ are necessary. When symptoms are not controlled by GABAergic drugs, immunosuppression with corticosteroids and IVIG has been used, as have plasmapheresis and rituximab.¹¹ The efficacy of the latter, however, was not supported by a randomized, placebo-controlled trial.¹² This patient experienced significant improvement with benzodiazepines, baclofen, IVIG, and neoadjuvant chemotherapy prior to thymoma resection. The pruritus, paresthesia, and lymphocytosis also resolved with medical therapy. Interestingly, GABA signaling suppresses itch, suggesting that loss of GABA_A signaling may have contributed to the development of pruritus.

SPS occasionally occurs as a paraneoplastic neurologic syndrome. Breast cancer is the most commonly associated malignancy, although associations between thymomas and SPS¹³ with anti-GAD65 antibodies¹⁴ have also been described. The presentation of thymomas is variable, with approximately one-third discovered incidentally on imaging, one-third producing symptoms of local compression, and one-third identified in the setting of another syndrome, most commonly myasthenia gravis. In addition to myasthenia gravis, thymomas have been associated with conditions such as hypogammaglobulinemia, pure red cell aplasia, and agranulocytosis. Stiff person syndrome is a known, albeit infrequently associated, condition.¹⁵

A critical step in arriving at the relevant differential diagnosis requires correctly framing the patient’s case.¹⁶ The treatment team’s initial frame was “a 69-year-old woman with weakness and elevated CK,” which prioritized causes of weakness and myositis. Stiff person syndrome does not cause weakness, but rather impaired movement from marked stiffness and spasms. The patient’s elevated CK was a result of continual muscle contractions. The physical exam and lack of motor deficit on EMG led the treatment team to reframe as “a 69-year-old woman with severe stiffness and spasms.” Egad! This correct frame was the key to diagnosis and confirmed by EMG and GAD65 antibody testing.