Progressive encephalomyelitis with rigidity and myoclonus initially diagnosed as an anxiety disorder associated with anti-glycine receptor antibodies: A case report

Abstract

Progressive encephalomyelitis with rigidity and myoclonus is a rare neurological disorder predominantly associated with anti-glycine receptor antibodies. It is characterized by rigidity, painful muscle spasms, sensory disturbances, brainstem and spinal cord involvement, autonomic dysfunction, respiratory distress, and sudden, spontaneous, or stimulus-induced myoclonus. A Chinese woman in her early 50s was admitted with acute-onset dysphagia, dysarthria, and stiffness in both lower limbs. Her initial symptoms included anxiety, recurrent myoclonic episodes, swallowing difficulties, and lower limb rigidity. The condition was initially diagnosed as an anxiety disorder, but the diagnosis was reconsidered after the patient’s symptoms progressed despite adequate treatment for almost a year. Diagnostic workup on admission revealed anti-glycine receptor antibodies in the serum, which, along with the clinical presentation, confirmed the diagnosis of progressive encephalomyelitis with rigidity and myoclonus. The patient demonstrated improvement and clinical stabilization after treatment with intravenous immunoglobulin and immunotherapy. This case represents a rare instance of anti-glycine receptor antibody–positive progressive encephalomyelitis with rigidity and myoclonus that initially manifested as an anxiety disorder, later progressing to seizures, myoclonus, brainstem and spinal cord involvement, and autonomic dysfunction. We aim to raise awareness of the psychiatric clinical presentations of progressive encephalomyelitis with rigidity and myoclonus.

Background

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a life-threatening autoimmune disorder characterized by rigidity, painful muscle spasms, sensory disturbances, brainstem and spinal cord involvement, autonomic dysfunction, respiratory difficulties, and spontaneous or stimulus-induced myoclonus.^1,2 PERM may present with an acute, subacute, or insidious onset, with a disease course ranging from weeks to years, and may exhibit relapsing, remitting, or progressive patterns.^2–4 In addition to sharing core symptoms with stiff person spectrum disorder (SPSD), PERM is more severe and often fatal than the classical form of SPSD. It accounts for approximately 0.1% of SPSD cases, with fewer than 100 cases reported in the literature. ⁵ PERM patients often present with prominent autonomic dysfunction, brainstem symptoms, myoclonus, and an exaggerated startle reflex.^2,4,6 It is often misdiagnosed as epilepsy or anxiety disorders, leading to delayed treatment, particularly in primary care settings.^4,7 Here, we report a case of PERM that was initially diagnosed as an anxiety disorder.

Case presentation

A woman in her early 50s was admitted to the Department of Neurology at Quzhou People’s Hospital (Quzhou, Zhejiang Province, China) in early 2022. During the first year of her illness, her symptoms were purely psychiatric and sleep-related (insomnia, emotional tension, and irritability), without any overt neurological signs. During this initial period, she was diagnosed with an anxiety disorder. Approximately 1 week prior to admission, she developed new-onset neurological symptoms, including dysarthria, dysphagia, and limb rigidity, which indicated disease progression and prompted a neurological referral. The patient had experienced insomnia over the past year, primarily characterized by difficulty falling asleep, accompanied by symptoms of emotional tension and irritability. She was diagnosed with an anxiety disorder at local hospitals and psychiatric clinics and was treated with sertraline, venlafaxine, and lorazepam to stabilize her mood and improve her sleep. However, these treatments provided no symptomatic relief. Approximately 2 weeks before admission, she experienced episodes of profuse sweating, limb stiffness, and occasional falls, which gradually resolved within 1–2 min. She fell three times within 1 week, with each episode triggered by emotional stress or external stimuli. These episodes were accompanied by palpitations, rapid breathing, and subsequent altered consciousness. She was unable to walk, and muscle spasms affected both her limbs and trunk, occasionally progressing to tremors lasting several minutes. Myoclonus movements subsided during sleep.

The patient had a 10-year history of a thymic mass. In 2020, she underwent resection of a mediastinal mass and a right lower-lung sublobectomy. Pathology revealed a metastatic type B2 thymoma in the chest wall involving the adjacent lung tissue.

On admission, the patient was alert and fully oriented. Frequent limb myoclonus was observed during examination. Neurological examination revealed unclear articulation. There was significantly increased muscle tension in both lower extremities, with marked rigidity on the right side. The Babinski sign was positive on the right side and suspiciously positive on the left side. The heel–knee–shin test could not be performed. No sensory deficits were noted. The Mini-Mental State Examination score was 26 points.

Laboratory tests

Electroencephalography and brain magnetic resonance imaging findings were normal. Cerebrospinal fluid analysis, including routine and biochemical examination, showed no abnormalities.

Antibodies to autoimmune encephalitis—including NMDAR (1a, 2a, and 2b), AMPAR1/AMPAR2, LGI1, CASPR2, GABABR, DPPX, IGLON5, GABAAR (α1, β3, and γ2), mGluR, D2R, neurexin 3α, and KCNA4—were negative in the serum. However, anti-GlyR1 immunoglobulin G (IgG) antibodies were positive at a titer of 1:320 (Figure 1). Additionally, serum antibodies to amphiphysin, Yo, Hu, Ri, CV2, Ma2, Ma1, SOX1, Tr (DNER), Zic4, GAD65, PKCγ, and recoverin were negative, whereas IgG antibodies to titin were strongly positive (+++).

Figure 1.

Anti-GlyR1 IgG antibody was positive at a titer of 1:320. The internal control data for this assay are unavailable as the commercial testing laboratory has ceased operations.

Head magnetic resonance imaging, performed with and without contrast, revealed no abnormalities (Figure 2). A 24-h dynamic electroencephalogram showed no significant abnormalities. Chest computed tomography (CT) revealed a right-sided chest wall metastasis from thymoma postsurgery (Figure 3), slight enlargement of lymph nodes in the right lung hilum and mediastinum, and subpleural nodules in the upper lobe of the right lung, which were suspected to be benign.

Figure 2.

T1- and T2-weighted images. (a) A T1-weighted sequence, illustrating normal tissue contrasts: cerebrospinal fluid (CSF) appears hypointense, gray matter demonstrates intermediate signal intensity relative to the hyperintense white matter, and osseous and soft tissue structures of the scalp and skull exhibit signal characteristics congruent with their respective tissue types. (b) A fluid-attenuated inversion recovery sequence, where the CSF signal is nulled, enabling optimized visualization of intraparenchymal abnormalities; in these images, the cerebral parenchyma shows no overt pathological signal alterations.

Figure 3.

CT of the thorax revealed a right-sided chest wall metastasis from thymoma postsurgery. CT: computed tomography.

The patient initially presented with subacute-onset symptoms suggestive of an anxiety disorder, followed by seizures and myoclonus, along with brainstem, spinal cord, and autonomic nervous system symptoms. Based on her medical history and examination findings, she was diagnosed with anti-GlyR antibody–associated PERM.

After the diagnosis of PERM, the patient received first-line immunotherapy in accordance with established international guidelines for autoimmune neurological disorders. ⁸ The treatment regimen included intravenous immunoglobulin (IVIG) administered at a dose of 22 g per day for 5 days. She also underwent intravenous methylprednisolone therapy, starting at a dose of 500 mg/day for 3 days, followed by tapering doses, consistent with standard protocol.^8,9 Oral sertraline was prescribed for emotional regulation, Depakine combined with levetiracetam for seizure control, and clonazepam for muscle spasticity. The patient’s condition gradually improved following this treatment. Two weeks later, immunosuppressive therapy was initiated with oral mycophenolate mofetil (0.5 g twice daily), while oral methylprednisolone was gradually tapered.

Discharged neurological examination

After approximately 1 month, the patient was discharged from the hospital without convulsions or coughing, with fluent speech and the ability to walk with support. During an outpatient follow-up visit 6 months later, a serum autoimmune encephalitis antibody retest revealed that her anti-GlyR1 antibodies were negative, but anti-Titin antibodies remained positive. Currently, the patient remains emotionally stable and seizure-free, with clear articulation, normal muscle tone, no recurrence of limb stiffness, and restored normal mobility.

Written informed consent was obtained from the patient for treatment, use of clinical data for research, and publication of individual medical details and accompanying images. We have deidentified all patient details in the report. The reporting of this study conforms to the Case Report (CARE) guidelines. ¹⁰

Discussion and conclusions

Although PERM is classified as an autoimmune disease, its underlying mechanism remains incompletely understood. Although psychiatric manifestations are recognized comorbidities in SPSD, their occurrence as the initial and isolated presentation of anti-GlyR antibody–positive PERM is exceedingly rare and often underrecognized.^9,11 This often leads to considerable diagnostic delay, as illustrated by the present case. In this case, a purely psychiatric phenotype, refractory to conventional anxiolytics, preceded the onset of neurological signs by approximately 1 year. This case highlights that a treatment-resistant anxiety disorder may serve as the sole harbinger of PERM and underscores the need to consider autoimmune etiologies in atypical presentations to ensure timely diagnosis and intervention. Clinically, patients with PERM typically present with muscle spasms and stiffness, along with symptoms involving the brainstem and spinal cord, such as dysarthria, difficulty swallowing, and eye movement disorders. Additionally, autonomic nervous system symptoms such as sweating, pupil dilation, tachycardia, rapid breathing, elevated body temperature, and abdominal pain may occur. The patient in this case exhibited these typical clinical manifestations. Imaging and other auxiliary investigations typically reveal no obvious abnormalities in PERM but are often used for differential diagnosis. ¹² Although the patient’s electromyography findings were normal, some experts consider continuous motor unit activity in electromyography a key diagnostic criterion. ¹³ Most PERM patients test positive for GlyR antibodies, ¹⁴ as observed in this case. Given its diverse clinical manifestations, early diagnosis of PERM remains challenging. The patient had typical clinical symptoms, and no other neurological disease or cognitive impairment could explain the stiffness and other symptoms. This case fulfilled four primary criteria and one secondary criterion for PERM, as proposed by Newsome and Johnson. ¹⁵ These findings are consistent with the characteristics of PERM and the pattern of disease evolution reported in the literature. Therefore, we established a diagnosis of PERM.

The patient in this case exhibited psychiatric symptoms 1 year before the onset of motor symptoms, leading to a delayed diagnosis. Currently, psychiatric symptoms in SPSD are receiving increasing attention. In 2023, Nasri et al. ⁷ reviewed 239 SPSD patients with comorbid psychiatric symptoms, including 18 PERM patients. ¹⁶ Psychological symptoms may appear before, after, or simultaneously with motor symptoms, with anxiety being among the most common clinical manifestations. ⁷ Statistical data indicate that autoimmune diseases are the most common cause of SPSD associated with psychiatric manifestations. ⁷ Among the 18 PERM patients, autoimmune reasons accounted for 89% (16/18) of the cases, consistent with the findings in the current case. Psychological symptoms were previously considered a secondary response to motor symptoms in SPSD patients. However, in this case, psychiatric symptoms manifested 1 year before the onset of motor symptoms, contradicting this viewpoint.

The literature indicates that the primary antibodies associated with PERM are anti-GlyR antibodies, followed by antibodies against glutamic acid decarboxylase (GAD). ¹⁴ Gamma-aminobutyric acid (GABA), the predominant inhibitory neurotransmitter in the central nervous system, exerts its effects by binding to specific postsynaptic receptors and opening chloride ion channels. GlyRs are primarily located in the caudal brainstem, cerebellum, and spinal cord. Antibodies against GlyR disrupt the inhibitory mechanism of glycine, leading to sustained, exaggerated startle responses. ¹³ Scholars have confirmed that certain autoantibodies reduce the release of GABA in specific regions, leading to anxiety-like phenotypes in rats. ¹⁷ Therefore, some scholars believe that autoantibodies such as anti-GAD and anti-GlyR may serve as pathogenic factors contributing to psychiatric disorders in SPSD patients. ⁷ In this case, the patient’s psychiatric symptoms were not effectively treated with antianxiety drugs but were completely relieved after receiving immunosuppressive therapy, which seems to confirm the abovementioned hypothesis.

Although there is currently no optimal treatment for PERM, there is a general consensus to adopt therapeutic strategies similar to those used for autoimmune encephalitis. ¹⁸ These strategies include acute-phase immunotherapy, such as high-dose corticosteroid intravenous infusion, IVIG, and/or plasma exchange, alongside symptomatic treatment. When first-line immunotherapy proves insufficient, B cell–depleting therapy with rituximab—a monoclonal antibody targeting CD20-positive B cells—is frequently considered. It is important to note that the evidence from a randomized placebo-controlled trial did not meet its primary endpoints at the group level. ¹⁹ However, subsequent analyses indicated that a clinically relevant proportion of patients, particularly those with more advanced disease and significant disability, showed notable clinical improvement. ²⁰ This suggests that patient selection based on disease severity may be crucial for identifying individuals most likely to benefit from this treatment approach.^13,19,20 Additionally, thorough screening for potential tumors is essential. Approximately 20% of PERM patients present with comorbidities such as breast cancer, small-cell lung cancer, thymoma, and kidney cancer. In this case, strong positivity for anti-titin antibodies further supported a paraneoplastic etiology associated with her thymoma. ²¹ Recent advances in immunotherapy have highlighted the potential of FcRn antagonists, such as efgartigimod, in treating antibody-mediated neurological disorders. A case report demonstrated rapid symptomatic improvement and safe thymectomy with efgartigimod in thymoma-associated myasthenia gravis.^22,23 This targeted approach accelerates IgG clearance—which is highly relevant—considering our patient’s anti-GlyR and anti-Titin IgG antibodies and her positive response to IVIG. FcRn inhibition may represent a promising strategy for severe or refractory PERM, particularly in cases with persistent antibodies despite conventional immunotherapy. Further studies are warranted to elucidate its role in anti-GlyR antibody–positive neurological syndromes.

Timely treatment of primary tumors can improve prognosis.^14,24 The patient in this case had a 10-year history of thymic tumors. Two years before the onset of PERM, she was diagnosed with thymoma, which was surgically resected. After immunosuppressive therapy, her GlyR1 antibody became negative, and she exhibited no further symptoms of PERM. Follow-up chest CT demonstrated stable lesions without evidence of thymoma activity; however, long-term observation remains necessary.

Early treatment is crucial. Chang et al. ²⁵ reported that patients with a good prognosis received immunotherapy within 2 months of their initial visit. The patient in this case started immunosuppressive therapy 1 year after experiencing anxiety symptoms. Follow-up evaluations demonstrated a significant improvement in both psychiatric and motor symptoms. Despite a delayed diagnosis, she responded well to immunoglobulin and immunosuppressive therapy. Another case described a PERM patient who underwent IVIG combined with hormone immunosuppression and plasma exchange therapy after a delayed diagnosis of 10 years, ultimately achieving optimal outcomes. ²⁶ Beyond conventional immunotherapies and GABAergic drugs, α2-adrenergic agonists such as clonidine may provide rapid symptomatic relief during acute crises, particularly in refractory cases. A recent study demonstrated that intravenous clonidine (150 mcg) promptly resolved severe spasms and rigidity in a patient with anti-GAD antibody–positive SPSD. ²⁷ This finding supports earlier evidence of clonidine’s efficacy in modulating spinal motor neuron hyperexcitability in SPSD, offering a valuable adjunctive treatment option for acute exacerbations. ²⁸ These findings suggest that, despite the difficulty in diagnosing PERM, appropriate treatment should be administered once diagnosed, regardless of delay in diagnosis, which is likely to improve the prognosis.

Although PERM remains a rare condition, its recognition is increasing due to growing awareness and the widespread use of antibody detection techniques. It is advisable that individuals with unexplained encephalitis symptoms undergo timely antibody testing to identify GlyR antibody–associated PERM. A limitation of this study is the detection of anti-GlyR antibodies only in the serum and not in the cerebrospinal fluid. However, the high specificity of serum testing for diagnosing anti-GlyR antibody–associated PERM is well-established in the literature. ¹⁴ The combination of a positive serum result and classic clinical presentation was considered sufficient for diagnosis in this case, a decision partly influenced by the patient’s financial constraints. The patient’s marked clinical response to immunotherapy further corroborates the diagnostic accuracy.

Immunotherapy has demonstrated promising results and effectiveness in managing this condition, emphasizing the importance of recognizing atypical initial manifestations, ensuring early diagnosis, and initiating timely treatment. Even with a prolonged disease course, immunosuppressive therapy can still improve the patient’s prognosis.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605251387911 - Supplemental material for Progressive encephalomyelitis with rigidity and myoclonus initially diagnosed as an anxiety disorder associated with anti-glycine receptor antibodies: A case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605251387911 for Progressive encephalomyelitis with rigidity and myoclonus initially diagnosed as an anxiety disorder associated with anti-glycine receptor antibodies: A case report by Yi Jiang, Chuanliu Wang and Chunya Liu in Journal of International Medical Research