Neuromyelitis Optica Spectrum Disorder in Castleman Disease

Neuromyelitis optica spectrum disorder (NMOSD) is a rare, often debilitating autoimmune disorder that preferentially affects the spinal cord and optic nerve. Relapses may lead to permanent neurologic deficits.¹

This inflammatory condition of the central nervous system (CNS) involves complex pathophysiologic processes that are not fully understood. Circulating immunoglobulin G1 antibodies targeting the astrocyte water channel aquaporin-4 (AQP4) have been found almost exclusively in people with NMOSD.¹ The incidence of NMOSD is between 0.039 and 0.73/100,000 person-years with a higher prevalence among women and a mean age at onset of 40 years.²

Castleman disease (CD) encompasses a heterogeneous group of lymphoproliferative disorders that have no sex predilection and a bimodal distribution, with peaks in the age at disease diagnosis occurring during the third and seventh decades.³ According to data from case reports and cohort studies, it’s estimated that the incidence of CD in the United States is between 5 and 16 per million person-years. Although CD is rare, its incidence is increasing. CD has an association with human immunodeficiency virus (HIV) and human herpesvirus 8 (HHV-8) infection.^3,4

1. There are 2 common clinical presentations of CD:

2. The localized or unicentric variant, the most common form of CD, is confined to a single lymph node.

The systemic or multicentric variant involves multiple lymph nodes and frequently is accompanied by systemic manifestations, such as fever, weight loss, cytopenia, and hepatomegaly.^3,5

Neurologic manifestations of CD are rare, with peripheral neuropathy being the most common presentation; optic neuropathy has been described in a few cases.⁴

Case Presentation

AR, age late 70s, with a history of Sjögren syndrome and hypertension, presented to the emergency department with sudden onset of chest pain radiating to the upper extremity with a negative workup for acute coronary syndrome.

Chest radiograph demonstrated interstitial infiltrate, and chest CT scans showed multiple nodular opacities in the lower lung fields with mediastinal lymph nodes. Serum testing revealed lymphocytosis. HIV testing produced negative results. Biopsy of the lung lesions and lymphoid nodules demonstrated an increased number of plasma cells and dense lymphoid infiltrate, with an immunohistochemistry profile that showed positive markers for CD20, CD10, CD23, and CD38. These findings were compatible with CD of the plasma cell variant with aberrant multicentric CD56 expression. AR was discharged from the emergency department with instructions to follow up with a hematologist.

Three months later, AR returned to the clinic with a painless, unilateral loss of visual acuity in the left eye, which developed over 2 days. On examination, a left relative afferent pupillary defect and visual acuity of 20/100 were found, which is consistent with optic neuropathy. Optic nerve MRI revealed a T2-hyperintense lesion and a T1-weighted gadolinium-enhancing lesion extending over more than half of the optic nerve length, without compromising optic chiasm. Brain MRI showed nonspecific white matter lesions, and spinal cord MRI revealed no lesions.

AR received pulse corticosteroid therapy for 5 days with mild improvement in visual acuity documented. A demyelinating disease of the CNS was suspected, and a directed workup was performed, with subsequent confirmation of positive anti-AQP4 antibodies (AQP4+) by cell-based assay. Since that time, AR has been treated with azathioprine 50 mg every 12 hours, without any new relapses of neurologic symptoms. A year after first visual symptoms, optical coherence tomography testing revealed left eye retinal nerve fiber layer and ganglion cell layer thinning, consistent with optic atrophy (Figure and Table).

Discussion

We present a case of biopsy-proven multicentric CD with lymph node and pulmonary involvement associated with left optic neuropathy and AQP4+ status.

NMOSD is an antibody-mediated inflammatory disease of the CNS. AQP4-Ab channels expressed in the foot processes of astrocytes play an important role in NMOSD pathogenesis. Our understanding of NMOSD has evolved in recent years. Six core clinical syndromes have been identified according to their location, including optic nerve, spinal cord, area postrema of the medulla oblongata, other regions of the brainstem, diencephalon, and cortical region. The most common presenting syndromes are transverse myelitis or optic neuritis, but other symptoms may occur in about 4% of individuals.⁶

Several histologic patterns may be found in CD, including the hyaline vascular variant, plasma cell variant, and mixed forms. HIV infection may be associated with the plasmablastic variant. The proliferation of plasma cells induced by interleukin-6 (IL-6) is one of the pathophysiological mechanisms underlying the HHV-8-associated variant of CD. As a result, targeted therapies have been developed to block this interleukin. Interleukin-1, the RAF pathway, epidermal growth factor receptor, and vascular endothelial growth factor also play a role in the pathophysiology of CD.⁷

Neurologic manifestations of CD are rare. The most common is peripheral demyelinating neuropathy, typically associated with POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes, such as thickening, tightening, hypertrichosis, or hyperhidrosis).³ Involvement of the CNS has been reported in 15% of individuals with CD, mainly caused by infiltration of the leptomeninges.⁸ Cases of immune-mediated cerebellitis, pseudotumor cerebri, myasthenia gravis, and spinal cord compression have also been described.^9,10

Optic nerve involvement is an unusual manifestation of CD, but cases of bilateral optic neuropathy have been reported. One case was described as an initial presentation of CD, and others as variants of the TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly), which is associated with a severe course and a poor outcome.¹¹ There is 1 report of unilateral optic neuropathy with cecocentral scotoma and total dyschromatopsia.¹²

We present an individual diagnosed with seropositive NMOSD and CD plasma cell variant, unrelated to HIV infection. To our knowledge, this is the first case encompassing both entities. A proposed mechanism of the pathophysiology is increased activity of proinflammatory cytokines, such as vascular endothelial growth factor and IL-6—which can be present in HHV-8 infection—in CD. Cases unrelated to HIV or HHV-8, termed idiopathic, are usually associated with other autoimmune diseases, which can be present before or after the diagnosis of CD.¹³

The IL-6 cytokine has pleiotropic actions. It induces constitutional symptoms and proliferation of some cell types, such as B cells and plasmablasts.¹⁴ In NMOSD, IL-6 levels are significantly increased in serum and cerebrospinal fluid, promoting the proliferation of plasmablasts, and, therefore, the production of antibodies, such as those directed against AQP4, which lead to the disruption of the blood–brain barrier and the activation of T cells.¹⁴ This irregular production of IL-6 could be one of the mechanisms that explains the association of CD and NMOSD, but more studies are needed to explain the coexistence of systemic autoimmune disorders and paraneoplastic syndromes with NMOSD.^1,5,14

Immunosuppressive and immunomodulatory therapies are effective in treatment of CD. In the case of unicentric CD, surgery is the first option, with anti-CD20 therapies such as rituximab being the next line of treatment in unresectable cases.¹⁵ For multicentric disease, IL-6 antagonist therapy (Sylvant [siltuximab]; EUSA Pharma, Boston, MA) and IL-6 receptor antagonist therapy (tocilizumab) are the treatments of choice.^3,15 Anti-CD20 therapies are second-line management for refractory disease. These monoclonal antibodies are also particularly effective treatments in NMOSD with evidence that rituximab and tocilizumab decrease the number of annual relapses and improve functional prognosis.¹

Enspryng (satralizumab; Chugai Pharmaceutical, Berkeley Heights, NJ), an IL-6 receptor antagonist used as therapy for individuals with NMOSD, has not been studied in those with CD. Other common immunosuppressive therapies include steroids and bortezomib.³

Conclusion

Optic neuropathy in the setting of CD is rare. To our knowledge, this is the first report of CD with optic neuropathy and AQP4+ status meeting criteria for NMOSD. Similar pathophysiologic underpinnings, including a role for IL-6, may underlie the concurrent presentation.