Neuromyelitis Optica in Patients with Myasthenia Gravis Who Underwent Thymectomy

ORIGINAL CONTRIBUTION Neuromyelitis Optica in Patients With Myasthenia Gravis Who Underwent Thymectomy

Ilya Kister, MD; Sandeep Gulati, MD; Cavit Boz, MD; Roberto Bergamaschi, MD; Guiseppe Piccolo, MD; Joel Oger, MD; Michael L. Swerdlow, MD

Background: Myasthenia gravis (MG) and neuromy- Patients: Four patients with MG who underwent elitis optica (NMO, also known as Devic disease) are rare thymectomy. autoimmune disorders, with upper-limit prevalence estimates in the general population of 15 per 100 000 and Interventions: None. 5 per 100 000, respectively. To our knowledge, an association between these diseases has not been previously Results: The prevalence of MG within the published co- reported. hort of patients with NMO is more than 150 times higher than that in the general population. Objectives: To describe 4 patients with MG who de- Conclusion: Dysregulation of B-cell autoimmunity in my- veloped NMO after thymectomy and to analyze possible asthenia, possibly exacerbated by loss of control over au- causes of apparent increased prevalence of NMO among toreactive cells as a result of thymectomy, may predis- patients with MG. pose patients to the development of NMO.

Design: Case series. Arch Neurol. 2006;63:851-856

EUROMYELITIS OPTICA REPORT OF CASES (NMO) is characterized by 1 or more attacks of CASE 1 optic neuritis (ON) and myelitis. It can be dif- An African American woman with mild ferentiatedN from multiple sclerosis (MS) asthma, distant history of smoking and with the aid of magnetic resonance imag- cocaine snorting, and family history of ing (MRI),1-3 cerebrospinal fluid anal- MS in her mother developed symptoms ysis4-8 and NMO-IgG antibody.9 The of ocular myasthenia at age 38 years. The lesions in NMO differ from those of MS diagnosis was confirmed by neostigmine with respect to patterns of immunoglob- test and an elevated anti–acetylcholine ulin and complement deposition and receptor (anti-AChR) antibodies titer. 10,11 Author Affiliations: populations of inflammatory cells. That same year, her thymus was excised, Departments of Neurology, Patients with NMO often have coexisting and histologic examination revealed Albert Einstein College of autoimmune disorders, such as systemic hyperplasia. The symptoms resolved and Medicine, Bronx, NY lupus erythematosus, Sjo¨gren syndrome, pyridostigmine bromide therapy was (Drs Kister and Swerdlow), and and pernicious anemia.12,13 Ours is the tapered. Long Island Jewish Medical first case series, to our knowledge, of A year after the surgery, she experi- Center, New Hyde Park, NY coexisting MG and NMO. All 4 of our enced acute-onset visual loss in her right (Dr Gulati); Multiple Sclerosis patients were diagnosed as having MG, eye, followed by visual loss in the left eye Clinic, University of British underwent thymectomy, and subse- 10 days later. Her clinical picture and vi- Columbia, Vancouver (Drs Boz and Oger); and Multiple quently developed NMO. We discuss the sual evoked potentials were typical of ON. Sclerosis Center, Neurological evidence for B-cell dysregulation in Magnetic resonance imaging of the brain Institute “C. Mondino,” Pavia, NMO and for the possible role of thy- disclosed a questionable increased T2 sig- Italy (Drs Bergamaschi and mectomy in potentiating the emergence nal in the right optic nerve and a few non- Piccolo). of autoimmune disease. enhancing scattered subcortical foci of in-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 bar ON. Brain MRI was normal, and increased T2 signal was seen in the left optic nerve. Visual acuity did not improve with time. At age 42 years, she was admitted to the hospital with swelling and pain in the forearms precipitated by vigor- ous clapping. Her urine was dark red, and her creatine kinase level was 25 000 U/L. Rhabdomyolysis resolved with aggressive hydration. At age 43 years, she developed leg paresthesias and midthoracic back pain. She had profound sensory dysfunction in all modalities below T8 level, symmetric hy- perreflexia of the legs, and bilateral extensor plantar responses. Magnetic resonance imaging demonstrated abnormal cord signal from the lower cervical spine to T9 and enhancement in T2 through T4. An MRI of the brain was normal, as were rheumatologic and infectious sero- logic test results, except for a mildly elevated antinuclear antibody titer (1:80). She was started on azathioprine therapy. Later that year, she was readmitted for progressive stiff- ness and spasms of all extremities. The clinical picture suggested stiff-person syndrome. Her serum anti– glutamic acid decarboxylase antibody titer was 2 U/mL (reference threshold, Ͻ1.0 U/mL). A course of intravenous immunoglobulin and methylprednisolone acetate Figure 1. Axial fluid-attenuated inversion recovery magnetic resonance imaging sequence of the brain of patient 1 shows a few nonenhancing yielded a substantial improvement of her spasticity. scattered subcortical foci of increased T2 signal. At age 44 years, she had a milder relapse of myelitis. An MRI showed cord edema and enhancement from T3 through T5 and abnormal T2 signal at C5-C6. She again creased T2 signal (Figure 1). These were unchanged responded well to a short course of intravenous immu- after several years of follow-up. noglobulin and methylprednisolone. During the next 5 years the patient experienced 7 relapses of ON. Four years after the initial attack, she was CASE 3 given a brief trial of interferon beta-1a (Avonex) but soon developed progressive left-sided weakness. She was admitted to the hospital with a partial Brown-Se´quard syn- A 17-year-old white girl complained of fluctuating diffi- drome and T7 sensory level. An eccentric lesion extend- culties with speech and chewing. She exhibited nasal ing from C2 to T1 was seen on MRI. She was diagnosed voice and facial, tongue, and neck weakness that wors- as having NMO and began azathioprine therapy. Dur- ened with exercise. Decrementing response on repetitive ing the next 2 years she experienced 2 relapses of ON stimulation test, elevated anti-AChR antibodies, and and 2 relapses of myelitis. At last follow-up, she had only positive response to neostigmine confirmed the diagno- shade perception and ambulated with assistance. Re- sis of MG. Good control of symptoms was achieved with sults of an extensive rheumatologic and infectious workup pyrostigmine. Her thymus was resected and revealed were unremarkable. Table 1 and Table 2 summarize hyperplasia. the essential clinical, radiological, and laboratory data, At age 19 years, she sustained acute severe loss of vi- including NMO-IgG antibody status and cerebrospinal sion in both eyes. Visual evoked response was absent on fluid analysis for all of our patients. Figures 2, 3, 4, the right and of low amplitude and delayed P100 la- and 5 show representative MRI views of spinal cord dur- tency on the left. She was diagnosed as having bilateral ing myelitis attack for each of our 4 patients. ON. During the subsequent 5 months, she had 3 relapses of ON leading to blindness in the right eye and CASE 2 severely impaired vision in the left. At age 33 years, she developed leg weakness and sen- A healthy 36-year-old African American woman pre- sory loss below the thorax. A large swollen lesion ex- sented with ocular symptoms of MG and was found to tending from C8 to T3 was seen on MRI. During 10 years have an elevated anti-AChR antibodies titer, decrement- of follow-up, she experienced 9 relapses of myelitis and ing responses on repetitive stimulation, and positive 1 of ON. At last follow-up, she had a sensory T2 level response to neostigmine. She was treated with pyri- and required a cane for walking because of moderate para- dostigmine therapy and thymectomy, with excellent paresis. During the relapses, a cervical-dorsal lesion was response. Thymus hyperplasia was seen on histologic always detected on MRI, variable in size from 3 to 5 spi- examination. nal segments. On 2 occasions the lesion was enhanced At age 41 years, she acutely lost vision in the right with gadolinium. Brain MRI continued to show normal eye. The examination results were consistent with bul- findings.

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Age at Event, y

Patient No./ Onset Onset First Attack No. of ON No. of Myelitis MRI Lesion at First Other Medical Sex/ Race of MG Thymectomy of NMO of NMO Relapses Relapses Myelitis Attack Problems 1/F/AA 38 38 39 ON 7 3 C6-T1 HTN, asthma 2/F/AA 36 37 42 ON 1 2 C7-T9 Asthma, SPS 3/F/white 17 17 19 ON 6 9 C8-T3 None 4/F/Asian 27 28 38 ON/M 2 2 C2, C4-6 None

Abbreviations: AA, African American; HTN, hypertension; M, myelitis; MRI, magnetic resonance imaging; NMO, neuromyelitis optica; ON, optic neuritis; SPS, stiff-person syndrome.

Table 2. Laboratory Findings in 4 Patients With MG and NMO

CSF Analysis Antibodies Patient No./ Sex/ Race WBC Count, Cells/µL Oligoclonal Bands NMO-IgG Anti-AChR Other 1/F/AA 10 None ϩϩ − 2/F/AA 2 None ϩϩAnti-GAD; ANA, 1:80 3/F/white 55 2 − ϩ ANA, 1:1024 4/F/Asian NA NA NA ϩ −

Abbreviations: AA, African American; anti-AChR, anti–acetocholine receptor; ANA, antinuclear antibodies; anti-GAD, anti–glutamic acid decarboxylase antibody; CSF, cerebrospinal fluid; NA, not available; NMO-IgG, neuromyelitis optica–IgG; WBC, white blood cell; ϩ, present; −, absent.

CASE 4 servation that autoimmune disorders are vastly overrep- resented within this subset of patients with NMO. In the A 27-year-old Chinese woman presented with ptosis largest published NMO cohort,1 as many as a third of pa- and diplopia. She was diagnosed as having MG in her tients with relapsing disease, but none in the monopha- native Hong Kong and underwent thymectomy the sic group, had a concomitant autoimmune disorder. same year. There was no evidence of thymoma on Within the published cohort of approximately 200 pathologic examination. Her symptoms were initially cases of NMO,1-3,5,6,8,14-20 there are now 5 patients with a controlled with pyridostigmine and prednisone, but at dual diagnosis of NMO and MG—4 of them are de- age 31 years she was admitted to a Canadian hospital scribed here and 1 by Antoine et al.21 The association be- with worsening diplopia and limb weakness. Her anti- tween the 2 diseases is unlikely to be due to chance be- AChR antibodies titer was elevated. Azathioprine was cause NMO and MG are both rare, with prevalence added to her treatment regimen. Repeat exploration of estimates from 0.4 per 100 000 to 5.4 per 100 000 for her anterior chest was performed in view of a sugges- NMO,22,23 and 15 per 100 000 for MG.18 Although a rig- tion of residual thymic tissue on chest computed orous demonstration of an association between the 2 dis- tomography. eases would require a population-based analysis, the wide At age 37 years, her vision acutely declined in both discrepancy between the prevalence of MG in the pub- eyes and she complained of weakness and abnormal sen- lished NMO cohort (2%-3%) compared with its preva- sation in the arms and urinary retention. Visual evoked lence in the general population (Ͻ0.02%) is quite re- potentials were consistent with ON. Spinal MRI showed markable. Three of our 4 patients in our series are of foci of high signal within the cervical cord, most promi- African or Asian descent—consistent with previous re- nently alongside C4 and C5 but extending to the C2 ports of higher prevalence and greater severity of NMO level. among nonwhite individuals.19,22,23 A year later, her vision deteriorated acutely in both The number of patients with both MG and NMO may eyes. She also complained of paroxysmal tonic spasms, be even higher, if one were to include patients with a sug- which later resolved. Magnetic resonance imaging showed gestive clinical picture but without radiographic confir- T2 signal alongside C4 through C6 and a lesion at the mation, such as a patient with MG and recurrent bilat- level of C2. Brain MRI was unremarkable. eral ON who developed myelitis after thymectomy,24 or the patient with a presumed dual diagnosis who was de- COMMENT scribed by Martikainen et al.25 There are also reports of individuals with MG who underwent thymectomy and Our case series of coexisting MG and relapsing- then developed relapsing-recurrent myelitis26 or bilat- remitting NMO is in line with the well-documented ob- eral ON,27,28 possibly formes frustes of NMO.

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 2. Contrast-enhanced T1-weighted sagittal magnetic resonance image obtained during one of patient 1’s myelitis relapses demonstrates spinal cord swelling and a partially enhancing lesion within spinal cord substance involving the entire cervical and upper thoracic spine.

A possible association between MG, an antibody- mediated autoimmune disease, and NMO is intriguing in view of the considerable body of evidence implicat- ing dysfunction of humoral immunity in the patho- Figure 3. Sagittal T2-weighted spine magnetic resonance image from patient genesis of NMO. Especially noteworthy is a recent 2 shows extensive, abnormal high-T2 signal from the C6 to T9 level. finding9 of NMO autoantibody marker, which reacts against a self-antigen localized at the blood-brain barrier and has a reported sensitivity and specificity of gence of NMO: In that case, only antibodies from the pa- 73% and 91%, respectively, for this disease. Others29 tient’s serum taken early in the course of NMO stained showed that serum of patients with NMO reacts with rat’s central nervous system tissues, whereas serum taken myelin oligodendrocyte glycoprotein antigen. This is either before or 10 days after onset did not. in agreement with an experimental model of myelin oli- The role of humoral immunity in NMO is highlighted godendrocyte glycoprotein–induced allergic encephalo- by immunohistopathological studies11 suggesting that ac- myelitis in rats in which 39% of the rats exhibited tivation of the classical complement pathway and recruit- “NMO-type illness” with an appearance of major lesions ment of macrophages in NMO lesions may be triggered in optic nerve and spinal cord.30 The index of IgG1 in by a specific antibody found in the blood-brain barrier. This the cerebrospinal fluid of patients with NMO was not idea has been corroborated by the recent discovery of an significantly elevated, in contrast to the index in NMO-IgG autoantibody against aquaporin 4.9 patients with MS,7 suggesting that IgG1-associated, cell- It is of considerable interest that, in all 5 patients mediated response is relatively unimportant in NMO with MG and NMO, thymectomy preceded develop- and possibly explaining the absence of oligoclonal ment of NMO by months to years. By contrast, in the bands, mostly composed of IgG1 subclass, in most MS/MG cohort, MG anticipated MS in only half of the patients with NMO. cases.18 The fact that NMO followed thymectomy may The case report21 of NMO in an individual with MG not be a mere coincidence. A long-term study31 of thy- and a thymoma provides the most direct evidence for a mectomized patients showed that 12.5% of them devel- temporal, if not necessarily causal, relationship be- oped autoimmune diseases and more than 60% had at tween production of aberrant autoantibodies and emer- least 1 expansion within the CD8 and CD4 T-cell reper-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Figure 4. An abnormal high-T2 signal extending throughout the cervical cord is seen on a sagittal T2-weighted magnetic resonance image of patient 3.

toire, compared with less than 15% of control subjects. Patients who underwent thymectomy also had signifi- cant increase in total IgM, anti-cardiolipin, and anti– double-stranded DNA and high-titer antinuclear antibodies compared with patients with MG who had not undergone operation and healthy controls.31 These data suggested that suppressor T cells in the adult thymus may be necessary to keep in check autoreactive cells Figure 5. On a sagittal T2-weighted magnetic resonance image of patient 4, 31 an abnormal high-T2 signal is seen throughout the cervical cord but is and to prevent the emergence of autoimmune disease. especially prominent at the C3 through C5 levels. Gerli et al31 also cited numerous extant reports of autoimmune disease after thymectomy (references 7-23 in that article). It is interesting to note that 2 of our 4 patients tested positive for non-MG autoantibodies and 1 patient developed stiff-person syndrome. A paradoxi- Accepted for Publication: January 24, 2006. cal role of thymus in protecting against some autoim- Correspondence: Michael L. Swerdlow, MD, Depart- mune conditions, while potentiating others, was dem- ment of Neurology, Albert Einstein College of Medi- onstrated in animal models.32 cine, 111 E 210th St, Bronx, NY 10467. The present article describes 4 patients with MG and Author Contributions: Study concept and design: Kister NMO, 2 rare and seemingly unrelated autoimmune dis- and Swerdlow. Acquisition of data: Kister, Gulati, Boz, Ber- orders. The 150-fold increase in prevalence of MG gamaschi, Piccolo, and Oger. Analysis and interpretation within the published cohort of patients with NMO com- of data: Kister and Bergamaschi. Drafting of the manu- pared with the general population suggests that this as- script: Kister, Gulati, Boz, and Bergamaschi. Critical re- sociation is not random. We speculate that dysregula- vision of the manuscript for important intellectual content: tion of B-cell autoimmunity seen in MG and possibly Kister, Gulati, Bergamaschi, Piccolo, Oger, and Swerd- exacerbated by loss of control over autoreactive cells as low. Administrative, technical, and material support: Kister a result of thymectomy predisposed our patients to de- and Gulati. Study supervision: Bergamaschi and Swerd- velopment of NMO. Future research is required to es- low. tablish whether there is indeed a small long-term excess Acknowledgment: We thank Richard Lipton, MD, for risk of developing autoimmune disease in individuals critical review of the manuscript and Todd Miller, MD, with MG who undergo thymectomy. for technical assistance.

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Correction

Error in Byline: In the Original Contribution by Kister et al titled “Neuromyelitis Optica in Patients With Myasthenia Gravis Who Underwent Thymectomy,” published in the June issue of the ARCHIVES (2006;63:851- 856), an error occurred on page 851. In the byline, the full name of Dr Piccolo should have appeared as “Giovanni Piccolo, MD.”

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