Morvan Fibrillary Chorea Associated with Monoclonal B Cell Lymphocytosis

Introduction

Morvan fibrillary chorea (Morvan syndrome) is an exceptionally rare disorder characterized by a constellation of neurological symptoms, consisting of peripheral nerve excitability, neuromyotonia, autonomic instability, memory impairment, and delirium [1]. The prevalence of Morvan syndrome is <1 person per 1 000 000 [2]. The mechanism of Morvan syndrome is suspected to occur through autoantibodies directed against voltage gated potassium channels (VGKC), and has been linked with several autoimmune diseases, hematologic malignancies, and post-viral infections [3,4]. The contactin-associated protein-like 2 IgG (CASPR) antibody is classically associated with Morvan’s pathogenesis. CASPR is a membrane protein expressed in the central and peripheral nervous system, which is essential for localization of VGKCs [5]. We present a case of Morvan syndrome in association with monoclonal B cell lymphocytosis. Upon our literature review, we believe this to be the first documented case of Morvan syndrome associated with monoclonal B cell lymphocytosis.

Case Report

INVESTIGATIONS:

Initial laboratory evaluations included a complete blood count (CBC), showing white blood cells 5.5 thousand/uL, hemoglobin 15.1 g/dL, platelets 274 000/uL, absolute neutrophils 3333 cells/uL, and absolute lymphocytes 1452 cells/uL. Creatine kinase (CK) and erythrocyte sedimentation rate (ESR) were elevated at 263 U/L and 117 mm, respectively. During hospitalization, the patient underwent imaging, including a CT (computed tomography scan) chest/abdomen/pelvis, which noted mild splenomegaly at 14.7 cm, and an MRI (magnetic resonance imaging) brain (Figure 1) showed non-specific enhancement of the canalicular and labyrinthine segments of his left 7th cranial nerve and the anterior genu. MRI lumbar spine revealed multi-level degenerative changes without severe canal or neural foraminal stenosis, and no suspicious mass lesions. A subsequent lumbar puncture showed mildly elevated protein and glucose, at 74 mg/dL and 71 mg/dL, respectively. Cerebrospinal fluid (CSF) cytology and work-up for viral, bacterial, fungal, parasitic etiology was negative. Electromyography (EMG) was performed in 5 upper- and 5 lower-extremity muscles and showed no evidence of radiculopathy, myopathy, or neuropathy. However, a comprehensive serum rheumatological work-up was performed, uncovering a contactin-associated protein-like 2 IgG (CASPR2) at 1: 100 dilution (reference range: negative), as well as a voltage gated K+ channel antibody present in serum at 0.21 nmol/L (reference range: <0.02 nmol/L). Leucine-rich glioma 1 (LGl1-IgG) was negative. EEG and nerve conduction studies were within normal limits.

Subsequent evaluation for the underlying cause included a PET/ CT (Figure 2), which revealed numerous prominent lymph nodes (subcarinal conglomerate: 3.2×1.2 cm with SUV max 5.1, right hilar conglomerate: 2.2×1.7 cm with SUV max 5.1, left inguinal: 2×0.9 cm with SUV max 3.2, right common iliac: 2×0.9 cm with SUV max 3.8), as well as splenomegaly of 15 cm, which was concerning for a possible underlying lymphoproliferative disorder. Peripheral blood flow cytometry showed a small population of abnormal lambda-restricted B cells, 0.97% of leukocytes, expressing CD20 (Dim), CD22 (Dim), CD5, CD43, CD23, CD79B (Variable), CD81, and CD20, with an inverted CD4: CD8 ratio (11.9: 1). Following flow cytometry, a bone marrow biopsy was obtained that was slightly hypercellular, and showed a similar, small CD5+ B cell population with a chronic lymphocytic leukemia (CLL) immunophenotype consistent with the population found in peripheral blood. Due to his positive PET CT findings, he underwent a mediastinoscopy and excisional biopsy. Pathology from the right lower paratracheal lymph node (R4) lymph node revealed the same population of monoclonal B cells.

DIFFERENTIAL DIAGNOSIS:

On initial presentation, given the patient’s left anterolateral thigh numbness and tingling, he was diagnosed with meralgia paresthetica. However, after developing additional neuropathic pain in his hands and feet, confusion, insomnia, asynchronous muscle fasciculations, weight loss, and severe bouts of sweating, further investigation was pursued. After an exhaustive work-up, it was discovered that our patient had positive CASPR2 antibodies, consistent with a diagnosis of Morvan syndrome. While evaluating for the underlying cause, he was noted to have an abnormal circulating B cell population consistent with a CLL/SLL immunophenotype; however, he did not meet all the requirements for CLL or SLL as he did not have an absolute B lymphocyte count in the peripheral blood ≥5000/ microL for at least 3 months, flow cytometry demonstrating immunoglobulin light chain restriction, or lymphoma documented on excisional biopsy. He did have significant B symptoms, including weight loss, night sweats, and splenomegaly to 14.7 cm, and thus was classified as having monoclonal B cell lymphocytosis.

It is important to distinguish Isaac syndrome from Morvan syndrome, as they have shared peripheral nerve symptoms, particularly neuromyotonia. The key distinguishing factors lie in the central nervous system pathogenesis of Morvan syndrome, leading patients to display confusion and hallucinations. Our patient demonstrated symptoms affecting both central and peripheral nervous systems with autonomic dysfunction, consistent with the diagnosis of Morvan syndrome.

TREATMENT & OUTCOME:

The patient was treated with IV methylprednisolone 1 g for 5 days and received IVIG 10% injection 30 g for 5 days. Following treatment, he had an immediate improvement in symptoms and resolution of fasciculations and sensory deficits. The patient’s only residual neurologic deficit after treatment was Bell’s palsy. Since discharge, the patient has had a complete neurological recovery, without requiring any further immunosuppression. A follow-up CT chest/abdomen/pelvis at 6 months showed no obvious lymphadenopathy and improvement in spleen size to 12.5 cm. His blood counts remained stable, he has regained much of his lost weight, and he continues to be followed up closely for signs of recurrence.

Discussion

Morvan syndrome is a rare disease characterized by myokymia, dysautonomia, and neuropsychiatric features such as insomnia, confusion, and hallucinations. Epidemiologically, Morvan syndrome is rare and as of 2018 less than 100 cases have been reported in the literature [4]. The syndrome has been reported to occur with a male-to-female ratio of 13: 1, with a mean age at diagnosis of 52 years of age with a range of 18 to 78 years. The average duration of symptoms is estimated to be 12 months from time of diagnosis [6].

The suspected mechanism is related to autoantibodies against CASPR2 limiting the formation of voltage gated potassium channels. CASPR2 is a cellular adhesion molecule that regulates the formation of axons in the nodes of Ranvier. It further has a role as a membrane scaffold allowing potassium voltage gated channels to cluster at the juxtaparanodal region. CASPR2 is widely expressed in both the central and peripheral nervous systems, which may explain the variations in clinical presentation of Morvan syndrome [7].

Morvan syndrome has been noted to occur in association with thymomas, supporting a paraneoplastic etiology. In 2009 El-Bita et al reported a case of Morvan secondary to B cell lymphoma and in 2020 Jiang et al reported the first case of Morvan syndrome associated with diffuse large B cell lymphoma [8,9]. These case reports demonstrate a paraneoplastic association between CASPR2-antibody production and B lymphocyte proliferative disorders.

Serologically, several Morvan cases have had increased serum creatine phosphokinase (CPK), mildly increased lactate dehydrogenase (LDH), and increased immunoglobulin G in the CSF. Increased CSF IgG has been suspected to manifest Morvan syndrome through immune mediated limbic dysfunction [8]. A variant of Morvan syndrome has been described as double-positive, characterized by antibodies against LG1 and CASPR2. Double hit Morvan syndrome is more frequently documented as a paraneoplastic syndrome secondary to underlying thymoma. Double-positive Morvan is an important clinical consideration, as it carries a poorer prognosis [10].

Our patient’s abnormal B cell population was consistent with a CLL/SLL immunophenotype; however, he did not meet all requirements for CLL or SLL and was classified as having monoclonal B cell lymphocytosis. Given that Morvan syndrome can precede the diagnosis of underlying malignancies, our patient continues to be monitored clinically and he has no evidence of CLL or other lymphoma on exam or imaging after 1 year of treatment. Initiation of CLL treatment would have been the medical team’s next step had the patient not improved with steroids and IVIG.

Treatment for Morvan syndrome includes symptomatic and therapeutic care. Unfortunately, symptomatic care for neuropathy has seen limited success and case reports have noted the inefficacy of fentanyl, lorazepam, haloperidol, doxepin, and gabapentin [8], consistent with what our patient experienced, as he did not have any relief with gabapentin. Therapeutic modalities include targeting the underlying antibody production with steroids, IVIG, plasmapheresis, and steroid-sparing agents such as azathioprine and cyclophosphamide. In recent years, several case reports have demonstrated successful treatment of Morvan syndrome with rituximab [10]. To date, there have been approximately 12 case reports that have documented the treatment of Morvan syndrome refractory to steroids and IVIG successfully treated with rituximab [10].

The association between monoclonal B cell lymphocytosis and Morvan syndrome, based on our initial literature review, has not yet been documented. A better understanding of the relationship between B cell lymphocyte proliferative disorders and Morvan will provide insight into pathophysiology and clinical decision making.

Conclusions

Our case demonstrates that there is an association between B cell lymphoproliferative disorders and Morvan syndrome. Although exceptionally rare, Morvan syndrome should be considered as a potential differential in the work-up of neurologic presentations of unknown etiology, especially in the presence of myokymia.