Exploring Telitacicept for Neurological Autoimmune Disorders: A Case Study on Morvan Syndrome

Introduction

Morvan syndrome is a rare and complex disorder characterized by the overlap of various symptoms of the peripheral nervous system (PNS) and central nervous system (CNS), including cerebral symptoms (cognition and epilepsy), cerebellar symptoms, insomnia, peripheral nerve hyperexcitability, autonomic dysfunction, neuropathic pain, and weight loss [1,2]. Current evidence supports an autoimmune basis for Morvan syndrome, characterized by an association between thymomas and antibodies against the voltage-gated potassium channel (VGKC) complex, with contactin-associated protein-like 2 (Caspr2) antibodies being more common than leucine-rich, glioma-inactivated 1 (LGI1) antibodies [3,4].

To date, no standardized treatment protocol for Morvan syndrome has been established. Current therapeutic approaches primarily rely on case reports and experiences from other autoimmune diseases. For instance, Zhang et al documented a female patient with Morvan syndrome who tested positive for both the CASPR2 and LGI1 antibodies [5]. This patient presented with symptoms such as bilateral leg pain, widespread myokymia, memory disturbance, seizures, hyperhidrosis, and insomnia. While intravenous immunoglobulin (IVIG) therapy showed limited efficacy in this case, corticosteroid treatment led to near-complete remission. On the other hand, Ma et al reported 3 cases of Morvan syndrome with positive serum Caspr2 antibodies [6]. All 3 patients experienced disease recurrence following glucocorticoid treatment. Patients 1 and 2 exhibited some symptom relief after IVIG administration, but their conditions relapsed and worsened upon treatment discontinuation. These reports underscore the heterogeneous nature of Morvan syndrome immunotherapy responses. The most common treatments for Morvan syndrome include corticosteroids, plasma exchange, and IVIG. As first-line therapy, corticosteroids are often preferred for their anti-inflammatory and immunosuppressive properties [2]. However, their effectiveness can vary significantly among patients. Plasma exchange, while effective in some cases due to its ability to rapidly remove circulating autoantibodies, is an invasive procedure requiring multiple sessions. IVIG, which provides passive immunization, has demonstrated efficacy in certain patients, but its high cost and potential adverse effects restrict its widespread application.

Growing evidence of the role of B cells and humoral immunity in the pathogenesis of neurological autoimmune diseases has made targeting B cells, cytokines, and chemokines involved in B-cell-mediated pathogenesis an active area of treatment research. Recently, effective treatment with B-cell depletion therapy has been demonstrated in patients with refractory Morvan syndrome [7]. The cytokines B-cell activating factor (BAFF; also known as BLyS) and a proliferation-inducing ligand (APRIL) work synergistically to maintain and regulate B-cell homeostasis and humoral immunity by promoting B-cell differentiation, maturation, and plasma cell antibody secretion [8,9]. Telitacicept, a novel humanized recombinant transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI)-Fc fusion protein that simultaneously binds both BAFF and APRIL [10,11]. It has been approved in China for the treatment of systemic lupus erythematosus [12]. Clinical trials and case reports have demonstrated its potential therapeutic effects in multiple autoimmune conditions. In addition to systemic lupus erythematosus, telitacicept has been investigated for its efficacy in diseases such as myasthenia gravis [13], anti-neurofascin-155 autoimmune nodopathy [14], myelin oligodendrocyte glycoprotein antibody disease [15], IgA nephropathy [16], primary Sjögren syndrome [17], and neuromyelitis optica spectrum disorders [18], among others. This report describes a 54-year-old man presenting with peripheral nerve hyperexcitability and sleep disturbance due to Morvan syndrome, which responded to treatment with telitacicept.

Case Report

A 54-year-old male patient presented with weakness, muscle cramps, burning sensation, pain in both lower limbs, and walking instability in September 2023. Additionally, the patient had severe sleep disturbance, manifesting as difficulty falling asleep, disturbance in sleep duration, and screaming during sleep. Within 2 months of onset, he also had cognitive impairment, difficulty concentrating, restlessness, and depression. After the onset of the illness, he had hyperhidrosis, frequent urination, and his weight decreased by approximately 15 kg.

The patient had a 7-year history of hypertension. Six months prior to symptom onset, the patient was diagnosed with type 2 diabetes mellitus. After treatment, the patient’s blood glucose levels were suboptimal. Presenting with the aforementioned symptoms, the patient initially sought medical attention at the Department of Endocrinology. Upon admission, the patient’s fasting blood glucose level was 11.2 mmol/L, and the glycated hemoglobin level was 10.5%. Following the correction of the glycemic disorder, the patient was transferred to the Department of Neurology. There was no other significant medical history, and no family history of hereditary diseases was noted.

Physical examination revealed a heart rate of 124 beats/min. Obvious and persistent muscle fasciculation, myokymia, and occasional stiffness were observed in both limbs, predominantly in the lower extremities. The subankle sensation was decreased. In addition, the patient had sensory ataxia. Neurocognitive and psychological testing revealed a Mini-Mental State Examination score of 24/30, Montreal Cognitive Assessment score of 22/30, Hamilton Depression Scale score of 28, and Hamilton Anxiety Scale score of 30. In ancillary examinations, routine serological tests, cerebrospinal fluid, and investigations for tumors and autosystemic immune diseases were normal. Chest computed tomography scans were normal. F-waves were unrecognized in all limbs because of peripheral nerve hyperexcitability (Figure 1A1, A2). Needle electromyography revealed frequent myokymic discharges, mostly in the muscles of the lower limbs. Head magnetic resonance imaging showed spotted ischemic lesions in the left radiative crown and central hemispherical oval region, without remarkable signals on enhanced brain imaging (Figure 1B1, B2). During dynamic video electroencephalogram monitoring, the patient was observed to shout abnormally or dream murmurs during nighttime sleep, without any abnormal discharges detected on the synchronized electroencephalogram or epileptic discharges (Figure 1C). The anti-Caspr2 autoantibodies were detected in the serum (1: 30, cell-based assay, Wuhan Kingmed Medical Laboratory Co, Ltd) but not in the cerebrospinal fluid (Figure 1D1, D2). Anti-LGI 1autoantibodies were negative.

In conclusion, the patient was a middle-aged man presenting with symptoms of peripheral nerve hyperexcitability (muscle fasciculation, myotonia), autonomic nervous system dysfunction (hyperhidrosis, arrhythmia, weight loss, frequent urination), severe sleep disturbance, and CNS symptoms (cognitive impairment, emotional disorder). In addition, needle electromyography revealed frequent myokymic discharges, and the anti-Caspr2 antibodies were positive in serum. The patient met the diagnostic criteria for Morvan syndrome. Through the above typical symptoms, differential diagnoses, such as limbic encephalitis, Isaacs syndrome, and Guillain-Barré syndrome, were excluded, and the final diagnosis was Morvan syndrome.

Currently, there is no standard immunotherapy regimen for Morvan syndrome. Commonly used treatments include corticosteroid pulse therapy, IVIG, plasma exchange, and rituximab (B-cell depletion therapy). Given the patient’s blood glucose issues, he declined high-dose corticosteroid pulse therapy. Ultimately, the corticosteroid dosage administered was 200 mg/day for 3 days. Subsequently, the dosage was gradually tapered every 3 days, and then maintained at 40 mg/day until discharge. Other treatment options, including IVIG, plasma exchange, and rituximab, were discussed with the patient. However, after being fully informed, the patient elected to receive telitacicept treatment. Telitacicept was administered by subcutaneous injection at a dose of 160 mg once a week. Other symptomatic therapies, such as gabapentin, were also used.

Clinical improvement occurred in the second week after telitacicept treatment. The patient showed improvements in clinical muscular myokymia and neuropathic pain, and the sleep disturbances were alleviated. After discharge, the patient continued to receive weekly subcutaneous injections of telitacicept and tapered doses of steroids. At the 1-month follow-up after discharge, the myokymia and neuropathic pain had completely disappeared. By then, the patient could sleep throughout the night without experiencing nighttime talking or shouting. Follow-up electrocardiography showed a return to a normal heart rate. Additionally, there was a significant improvement in the patient’s emotional and cognitive functions, compared with admission (Mini-Mental State Examination score, 30; Montreal Cognitive Assessment score, 28; Hamilton Depression Scale score, 12; and Hamilton Anxiety Scale score, 8), leading to a substantial enhancement in the patient’s quality of life. The patient had withdrawn oral steroids at the 2-month follow-up, when repeated electrophysiological tests displayed normality in the nerve conduction study, and no more peripheral nerve hyperexcitability or myokymia was observed. At the third follow-up visit, all symptoms had resolved completely. The patient persistently continued with the telitacicept treatment. Throughout the follow-up period of nearly 6 months, the patient did not experience any infections or other adverse effects. The patient showed good tolerance to the treatment. Recently, the patient withdrew telitacicept for personal reasons, and tacrolimus was used to prevent recurrence (Figures 2, 3).

Discussion

This case report highlights several key insights into the management of Morvan syndrome. First, it demonstrates the potential efficacy of telitacicept, a novel humanized recombinant TACI-Fc fusion protein targeting BAFF and APRIL, in treating Morvan syndrome. The rapid and sustained clinical improvement observed in the patient suggests that modulating BAFF and APRIL, which are crucial for B-cell differentiation and autoantibody production, can effectively address the autoimmune basis of Morvan syndrome. This finding adds to the growing evidence of the role of B-cell targeted therapies in neurological autoimmune diseases and provides a new treatment avenue for patients for whom conventional immunotherapies fail. Second, the case emphasizes the importance of recognizing the diverse clinical manifestations of Morvan syndrome, including peripheral nerve hyperexcitability, autonomic dysfunction, sleep disturbances, and cognitive impairments. Early identification of these symptoms, along with the detection of anti-Caspr2 antibodies, can facilitate timely diagnosis and initiation of appropriate treatment. Lastly, the successful use of telitacicept in this patient, who had comorbid type 2 diabetes and hypertension, suggests that this therapy can be well-tolerated in patients with multimorbidity, although further studies are needed to confirm its safety and efficacy in different patient populations.

The patient, a 54-year-old man with a history of type 2 diabetes and hypertension, presented with typical symptoms of Morvan syndrome, including peripheral nerve hyperexcitability, autonomic dysfunction, severe sleep disturbances, cognitive impairment, and positive serum anti-Caspr2 antibodies. The presence of these antibodies, which target VGKCs, is a hallmark of Morvan syndrome and contributes to the disease’s pathogenesis [3,4]. The patient’s symptoms were severe and debilitating, yet the rapid improvement observed within weeks of initiating telitacicept treatment is noteworthy. This response suggests that targeting BAFF and APRIL, key cytokines involved in B-cell differentiation and autoantibody production, can effectively modulate the underlying autoimmune process in Morvan syndrome.

The variability of symptoms and presentations in Morvan syndrome is in accordance with the distribution of Caspr2 in both the CNS and PNS. Substantial overlap of symptoms reflects the frequent involvement of both the CNS and PNS and increases the difficulty of diagnosis. For example, the expression of Caspr2 in raphe nuclei and thalamus in the CNS may explain the prominence of sleep disorders. Rich hippocampal and limbic system expression of Caspr2 ensure the vulnerability of these areas to pathogenic autoantibodies, resulting in core cerebral symptoms (amnesia, emotional disorders, delirium, and hallucinations), and even seizures.

Our case exhibits similarities and differences with previous Morvan syndrome reports when considering clinical presentation, diagnosis, and treatment response. In terms of presentation, all cases demonstrated the classic triad of Morvan syndrome: peripheral neuropathy, autonomic dysfunction (notably hyperhidrosis and significant weight loss), and CNS involvement (primarily severe insomnia). In the case report by Zhang et al [5], the patient presented seizures and hallucinations; however, our patient did not experience these symptoms, and cerebrospinal fluid antibody testing was negative. For diagnosis, all cases relied on the Graus criteria, with EMG findings and serum Caspr2 antibodies being critical. Nevertheless, our case differed in antibody profiles from that of Zhang et al [5], which displayed rare dual LGI1/Caspr2 positivity, and lacked the thymoma comorbidity noted by Ma et al [6]. Regarding treatment, all cases showed a rapid response to immunotherapy. Our case aligns with previous reports in the classic presentation and diagnostic criteria for Morvan syndrome but shows variation in symptom severity, antibody status, and treatment response, underscoring the need for personalized therapeutic approaches.

In this report, the patient was administered telitacicept at a dose of 160 mg once weekly via subcutaneous injection. Clinical improvement was observed within the second week of treatment, with significant reductions in muscle myokymia, neuropathic pain, and sleep disturbances. By the end of the first month, the patient’s symptoms had largely resolved, and follow-up assessments showed marked improvements in cognitive function and emotional well-being. The patient achieved complete remission within 2 months of treatment, with no recurrence of symptoms during the 6-month follow-up period. The rapid and sustained response to telitacicept highlights its efficacy in modulating the autoimmune response in Morvan syndrome.

The rapid clinical improvement observed in this patient is consistent with the mechanism of action of telitacicept. By binding to BAFF and APRIL, telitacicept inhibits the survival, differentiation, and antibody production of B cells, which are central to the pathogenesis of Morvan syndrome. The patient’s response underscores the importance of targeting these cytokines in the treatment of autoimmune neurological disorders. This case suggests that telitacicept can be effective in patients with severe symptoms and high levels of pathogenic autoantibodies, such as anti-Caspr2 antibodies. In anti-Caspr2-antibody-associated disease, symptoms including peripheral nerve hyperexcitability, neuropathic pain, and autonomic dysfunction are often seen in the PNS. More than half of the patients with Morvan syndrome have peripheral nerve hyperexcitability. This is consistent with the high expression of Caspr2 in the PNS. Together with contactin-2, Caspr2 forms a transmembrane axonal complex at the tightly defined juxtaparanodes of myelinated axons. In Morvan syndrome, the electrophysiological characteristics of axonal neuropathies can be detected, such as reduced motor and sensory nerve action potential amplitudes, spontaneous muscle fiber activity (fasciculations, myokymia, and neuromyotonic discharges), and large complex motor units with reduced recruitment [1]. In our case, we observed spontaneous muscle fiber activity similar to classical myokymia and fasciculation. However, we did not detect reduced action potential amplitude in either the motor or sensory nerves of the nerve conduction study. However, we observed features similar to those of demyelinated injuries, such as prolonged distal latency and reduced velocity. In fact, “reversible conduction failure” or “slow conduction velocity in the range of demyelination” is also reported in early stages of some axonal neuropathies, owing to transmission obstacles in ion channels or energy restriction [19]. This could explain the electrophysiological characteristics of the present case and the rapid improvement after immunotherapy. If pathogenic factors are not corrected, continuous axonal damage or degeneration can be observed over time.

Currently, there are no immunotherapeutic agents available for the treatment of Morvan syndrome. In addition to conventional immunotherapy, B-cell depletion therapies such as rituximab are reportedly effective in the treatment of patients with refractory Morvan syndrome. Moreover, targeting cytokines and chemokines that are integral to B cell-mediated pathogenic mechanisms has attracted attention in the field of autoimmune diseases. For example, belimumab, a BAFF inhibitor, has demonstrated efficacy in patients with systemic lupus erythematosus [20]. Telitacicept, a novel humanized recombinant TACI-Fc fusion protein that binds both BAFF and APRIL, potentially affecting later B-cell differentiation and inhibiting plasma cell formation and autoantibody secretion, has demonstrated efficacy and safety in various autoimmune diseases [12]. Recently, we found successful experiences and safety in the treatment of refractory myasthenia gravis with subcutaneous telitacicept [13]. Here, we report successful treatment with telitacicept in a patient with Morvan syndrome. In this case, the patient responded rapidly to telitacicept treatment within 2 weeks. At later follow-ups, the patient achieved complete remission after 2 months of treatment. The rapid improvement of symptoms was consistent with a gradual increase in the serum TACI-BLyS complex, peaking around 1 month after treatment [21]. Furthermore, with telitacicept treatment, the patient was administered a lower dose of steroids and achieved a rapid reduction. For patients who are intolerant to steroids or are concerned about their adverse effects, telitacicept treatment is a very good option. During the follow-up period, the patient reported no evident discomfort or symptoms of infection. Notably, telitacicept was well-tolerated by our patient.

This case provides valuable clinical experience regarding the use of telitacicept in Morvan syndrome. The patient’s rapid response and sustained remission highlight the potential of telitacicept as a first-line treatment option, especially for patients who are intolerant to or concerned about the adverse effects of traditional immunotherapies. The use of a weekly 160 mg dose of telitacicept was well-tolerated and effective in this patient, suggesting that this dosing regimen may be appropriate for others with similar presentations. Future studies should focus on confirming these findings in larger patient populations and exploring the optimal dosing and treatment duration for telitacicept in Morvan syndrome. Further randomized controlled therapy trials should be performed in patients with anti-Caspr2-associated Morvan syndrome in the future.

Conclusions

This report has highlighted the approach to diagnosing Morvan syndrome, which can present with peripheral nerve hyperexcitability, and supports the role of immunomodulatory therapy, including telitacicept.