Multiple Cranial Neuropathies and Pachymeningitis in a Patient With a Pathogenic Nucleotide-Binding Oligomerization Domain 2 Polymorphism

An 11-year-old boy presented with 2 weeks of intermittent headache, right orbital pain, and constant diplopia. Brain MRI showed dural thickening and enhancement of the right lateral cavernous sinus, right orbital apex, and tentorium. Initial cerebral spinal fluid analysis showed only mild pleocytosis, and serum diagnostics were unrevealing.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Multiple Cranial Neuropathies and Pachymeningitis in a Patient With a Pathogenic Nucleotide-Binding Oligomerization Domain 2 Polymorphism Sravanthi Vegunta, MD, John Bohnsack, MD, Alison Crum, MD, Kathleen Digre, MD, Bradley Katz, MD, PhD, Meagan Seay, DO, Edward Quigley, MD, PhD, Sean Kennedy, MD, Nick Mamalis, MD, Judith Warner, MD Abstract: An 11-year-old boy presented with 2 weeks of intermittent headache, right orbital pain, and constant diplopia. Brain MRI showed dural thickening and enhancement of the right lateral cavernous sinus, right orbital apex, and tentorium. Initial cerebral spinal fluid analysis showed only mild pleocytosis, and serum diagnostics were unrevealing. The working diagnosis was Tolosa-Hunt syndrome. His pain and sixth nerve palsy resolved with corticosteroids. Five months after initial presentation, he developed new numbness of the right cheek, complete right ophthalmoplegia, and weakness and numbness of his right hand and leg, all of which were responsive to steroids. Fifteen months later, he returned to the emergency department with 2 weeks of left-sided headaches and acute diplopia. On examination, he had a left cranial nerve 6 palsy. Dural biopsy showed diffuse mononuclear inflammatory cell reaction consisting mostly of lymphocytes with no signs of granuloma formation, nor any epithelioid or giant cells. His clinical course was consistent with an autoinflammatory condition of unknown etiology. Genetic testing with an immunodeficiency panel showed a risk allele in NOD2 (nucleotide-binding oligomerization domain 2) c.3019dup (p.Leu1007Prof*2) that is associated with an increased risk for Crohn disease. His clinical condition had similarities to central nervous system sarcoidosis. Because of the similarities between our patient’s clinical, imaging, and genetic findings and neurosarcoidosis, he was switched to a more targeted therapy—infliximab. His condition has since been stable for nearly 2 years. In conclusion, genetic testing Departments of Ophthalmology (SV, AC, KD, BK, MS, SK, NM, JW), Rheumatology (JB), Neurology (AC, KD, BK, MS, JW), and Radiology and Imaging Sciences (EQ), University of Utah Hospital, Salt Lake City, Utah. Supported in part by a grant to the Department of Ophthalmology and Visual Sciences from Research to Prevent Blindness, Inc., New York, NY. The authors report no conflicts of interest. Address correspondence to Judith Warner, MD, 65 Mario Capecchi Dr, Salt Lake City, UT 84132; E-mail: [e-mail] Vegunta et al: J Neuro-Ophthalmol 2021; 41: 547-552 should be considered in patients with suspected occult autoimmunity. Journal of Neuro-Ophthalmology 2021;41:547–552 doi: 10.1097/WNO.0000000000001342 © 2021 by North American Neuro-Ophthalmology Society Dr. Warner A n 11-year-old previously healthy boy had experienced intermittent headache and right orbital pressure and pain for 2 weeks. One morning, he had diplopia and inward crossing of the right eye upon awakening. He saw a neurologist who ordered an MRI of the brain, which was read as showing a meningioma. One week later, the patient was referred to a pediatric ophthalmologist, who ordered another MRI of the brain and admitted him to the emergency department for lumbar puncture. When he presented to the children’s hospital, his right orbital pain and diplopia had been present for about 2 months. He had had no recent viral illnesses or sick contacts. He had no past medical history. His brother had a history of Kawasaki disease; his paternal grandfather had rheumatoid arthritis; and his father died of a myocardial infarction at age 48. Our patient’s examination was normal, except for the complete inability to abduct the right eye. Brain MRI showed dural thickening and enhancement of the right lateral cavernous sinus, right orbital apex, and tentorium (Fig. 1). His lumbar puncture showed 6 white blood cells and 1 red blood cell; normal protein, glucose, and angiotensin converting enzyme (ACE); and negative oligoclonal bands, gram stain, and cultures. The working diagnosis was Tolosa–Hunt syndrome. He was given 2 days of IV steroids 547 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study followed by an oral corticosteroid taper. His pain resolved after his first dose of intravenous steroids and sixth nerve palsy resolved one week after starting steroids. But his pain returned while tapering steroids from 60 to 40 mg daily. Dr. Quigley The brain MRI delineated the course of both sixth cranial nerves on T2 axial (Fig. 1A). Figure 1B is a postgadolinium fat-saturated T1 coronal scan demonstrating right nodular pachymeningeal enhancement. Figure 1C is an postgadolinium fat-saturated T1 axial scan demonstrating enhancement of the dura on the right extending along the tentorium to the orbital apex (Fig. 1D). This enhancement corresponds to the patient’s right cranial nerve 6 palsy. The broad differential diagnosis includes Tolosa–Hunt syndrome, neurosarcoidosis, IgG4 disease, tuberculosis, granulomatous disease, lymphoma, systemic lupus erythematosis, and varicella zoster, among others causes of pachymeningitis. Dr. Warner Five months after the initial presentation and after tapering off corticosteroids, he developed new right midfacial numbness in the V2 distribution, complete right ophthalmoplegia, and weakness and numbness of his right hand and leg. These symptoms were also responsive to steroids. MRI of the cervical, thoracic, and lumbar spine with contrast were normal. Further workup showed elevated erythrocyte sedimentation rate (44 mm/hour), C-reactive protein (4.7 mg/dL), and complement-4 (37 mg/dL) while on oral corticosteroids. He was hepatitis immune. ACE, IgG4, vitamin B12, rheumatoid factor (RF), antinuclear antibody (ANA) by immunofluoresence assay, Quantiferon gold, varicella zoster virus IgM, and peripheral blood lymphocyte subsets by flow cytometry were normal or negative. Repeat MRI brain during this episode showed significantly decreased dural thickening along the right lateral cavernous sinus. While taking oral corticosteroids, he developed elevated intraocular pressures (IOPs) of 58 mm Hg in the right eye and 60 mm Hg in the left eye. IOPs were initially controlled with topical timolol and accelerated FIG. 1. A. (Top left) MRI brain T2 axial image demonstrates location of right cranial nerve 6. B. (Top right) Postcontrast fatsaturated T1 coronal image of nodular right pachymeningeal enhancement. C. (Bottom left) Postcontrast fat-saturated T1 axial enhancement of dura on right extending along tentorium. D. (Bottom right) Postcontrast fat-saturated T1 coronal image demonstrating enhancement of the right orbital apex (Will label images with A, B, C, D labels). 548 Vegunta et al: J Neuro-Ophthalmol 2021; 41: 547-552 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study corticosteroid taper. His neurological symptoms resolved, and he was able to taper off steroids with resolution of his ocular hypertension. He was asymptomatic, with a normal examination, for 15 months. His working diagnosis remained Tolosa–Hunt Syndrome. the prior scan (Fig. 2). The patient also exhibited new right middle cranial fossa pachymeningitis. The differential again was similar to prior for pachymeningitis. Dr. Quigley Extensive serum and cerebral spinal fluid (CSF) work up for autoimmune and infectious etiologies were negative. Testing included serum electrophoresis, CSF Lyme, coccidioides, and aspergillus antibodies, meningitis and encephalitis polymerase chain reaction panels, CSF ACE, gram stain, culture, cytology, and cytometry, serum ANA, double-stranded DNA, RF, lysozyme, IgG4, and Quantiferon gold. He had slightly elevated Vitamin D1, 25 (81.5 pg/mL [19.9–79.3]). Differential at that time included neurosarcoidosis, lymphoma, histiocytosis, granulomatosis with polyangiitis, polyarteritis nodosa, IgG4 disease, rheumatoid arthritis-related pachymeningitis, and recurrent Tolosa–Hunt syndrome. Although chest x-ray was unremarkable, suspicion for neurosarcoidosis was high. PET scan was performed to evaluate for a multisystem disease, including sites amenable for biopsy. The scan showed only small calcifications in the left hilum, likely related to prior granulomatous disease. Dural biopsy was thus performed before re-initiating immunosuppressive treatment. He was then started on intravenous corticosteroids, which again addressed his headache initially, but symptoms again recurred during oral corticosteroid taper. He was hospitalized 2 additional times for intravenous corticosteroid administration. He developed hypertension, a forty-pound weight gain, and The subsequent MRI brain postcontrast fat-saturated T1 axial scan (Fig. 2) demonstrated resolution of both the dural thickening and the right lateral cavernous sinus enhancement. The left cavernous sinus and right middle cranial fossa meninges were normal. Dr. Warner Fifteen months later, he returned to the children’s hospital emergency department with 2 weeks of left-sided headaches and acute diplopia. On examination, he now exhibited contralateral complete left sixth nerve palsy. He also reported pain in his knees and ankles, with mild joint effusions on examination. Another MRI of the brain with contrast was obtained. Dr. Quigley The subsequent MRI brain postcontrast fat-saturated axial scan (Fig. 3) demonstrated subtle enlargement of the left cavernous sinus, particularly apparent when compared with FIG. 2. MRI brain postcontrast fat-saturated axial image demonstrates resolution of dural thickening and resolution of the right lateral cavernous sinus enhancement. Vegunta et al: J Neuro-Ophthalmol 2021; 41: 547-552 Dr. Warner FIG. 3. MRI brain postcontrast fat-saturated axial image showed new hypertrophic pachymeningitis isolated to the right middle cranial fossa with slight extension superiorly overlying the lateral sulcus and frontal parietal junction. 549 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study again high IOPs. He underwent XEN gel stent placement in the left eye. Steroid-sparing therapy with rituximab was scheduled. Dr. Mamalis The specimen received at the Moran Eye Center was reported to be a 0.7 · 0.6 · 0.2 cm irregular unfixed portion of pink-tan soft tissue. Microscopic examination with hematoxylin and eosin (H&E) staining showed a dense regular connective tissue consistent with dura. There was a diffuse mononuclear inflammatory cell reaction consisting mostly of lymphocytes with some scattered plasma cells, no signs of granuloma formation, and no epithelioid or giant cells (Fig. 4 H&E stain ·200 magnification). The cells themselves did not show any signs of cellular atypia. Acidfast bacilli, Grocott methenamine silver, and Gram stains were negative for organisms. IgG4 was not increased when compared with IgG immunohistochemical stain. No definitive CD1a positive histiocytes were seen. Smooth muscle actin and S100 stains highlighted scattered spindle cells. Anaplastic lymphoma kinase 1 stain was negative. This chronic nonspecific inflammation of the dura could be associated with Tolosa–Hunt. The final diagnosis is nonspecific chronic inflammatory cell infiltrate of the dural biopsy. He was started on rituximab. Dr. Bohnsack By this point in our patient’s course, he had suffered multiple episodes of neurological and neuro-ophthalmological symptoms that were responsive to corticosteroids, and ophthalmic complications of steroid use. As he continued to be dependent on steroids for recurrent symptoms, it was apparent that he would need a steroid-sparing agent. Targeted therapy was not feasible since the histological specimen did not reveal a diagnosis. As he was not suffering from recur- rent infections, it was unlikely that he had a primary immunodeficiency. Over the past decade, with the advent of genetic testing, we have come to understand that primary immunodeficiencies can result in autoimmune syndromes, involving dysregulation of either the acquired or innate immune system responses. Clinically these patients were thought to have distinct diseases, as patients with primary immunodeficiencies often have recurrent infections that is, common variable immunodeficiency and ataxia telangiectasia, whereas patients with autoinflammatory conditions present with autoimmune signs without any prior inciting infectious exposure that is, familial Mediterranean fever and Crohn disease (1). Autoimmune and autoinflammatory conditions fall along the same spectrum of disease and can result from different mutations in the same gene. Genetic testing has helped in identifying primary immunodeficiencies that can present as autoinflammatory conditions. Thus, we search for polymorphisms that result in immune dysregulation and then apply targeted immunomodulatory therapies based on the component of the immune system that is dysregulated. It seemed possible that our patient had an autoinflammatory condition of unknown etiology. Thus, the next step for our patient was to perform broad genetic screening using an immunodeficiency panel. Our patient underwent testing using Invitae’s (San Francisco, CA) Primary Immunodeficiency Panel of 207 genes. This panel included tests for variants that cause a monogenic autoimmunity and autoinflammatory diseases. Our patient was found to possess a risk allele in NOD2 (nucleotide-binding oligomerization domain 2) c.3019dup (p.Leu1007Prof*2). This variant was a truncating variant at the C-terminus, which is associated with 3.8-fold increased risk for Crohn disease. Variants in other parts of NOD2 have resulted in Blau syndrome and early-onset sarcoidosis (EOS). This variant is present in population databases (rs2066847, ExAC 2.0%), including multiple homozygous individuals. Experimental studies have shown that this truncating variant conveys reduced production of cytokines upon bacterial exposure but is capable of inducing T-cell polarization (2). Blau syndrome and EOS are both rare conditions. The use of genetic testing to help with the diagnosis of an autoinflammatory cause of a neuro-ophthalmic condition has not previously been reported. Final Diagnosis NOD2-associated autoinflammatory syndrome with Pachymeningitis and multiple cranial neuropathies. FIG. 4. Dural biopsy hematoxylin and eosin stain at ·200 magnification demonstrating mononuclear inflammatory cells throughout, mostly lymphocytes with some scattered plasma cells, no signs of granuloma formation, and no epithelioid or giant cells. 550 Dr. Bohnsack NOD2 is located on chromosome 16 and is primarily expressed in peripheral leukocytes as a cytoplasmic intracellular sensor of bacterial muramyl dipeptide and plays a role in Vegunta et al: J Neuro-Ophthalmol 2021; 41: 547-552 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study cell sensing of viral single stranded RNA. NOD2 upregulates NFKB protein, which activates hundreds of other genes involved in immune response. Gene variants can contribute to a variety of autoinflammatory conditions such as Blau syndrome, early-onset sarcoidosis, Crohn disease, or NOD2-associated Inflammatory Disease (NAID or Yao syndrome) (3). Blau syndrome, initially described in 1985, is granulomatous condition classically characterized by the triad of uveitis, dermatitis, and arthritis. Blau initially described this condition in a family later discovered to have a NOD2 polymorphism. EOS has similar clinical manifestations to Blau and is caused by a sporadic mutation of the NOD2 gene (4). NAID is a polygenic disease characterized by periodic fever, dermatitis, arthritis, extremity swelling, and gastrointestinal and sicca-like symptoms. It is associated with specific NOD2 variants—intervening sequence IVS 81158 or R702W variant (5,6). Our patient’s clinical symptoms were construed to be within the range of clinical findings in previously described NOD2 autoinflammatory conditions, but his genetic testing was not diagnostic of any of the specific entities above. Our patient’s family members were also tested with the Invitae (San Francisco, CA) immunodeficiency panel. His mother and 2 brothers have the same variant. His youngest brother has developed rashes at age 10. Although our patient and his family members did not have symptoms of Crohn disease, his genetic testing was concerning for a gain-of-function or loss-of-function mutation that could result in a granulomatous inflammatory condition such as central nervous system sarcoidosis or EOS. We did not perform additional functional studies to help to confirm the association between the clinical phenotype and his genetic variant. Drs. Warner and Bohnsack Genetic testing led to a better understanding of the origin of his relapsing pachymeningitis. It became apparent that he would need long-term immunosuppression over years. His clinical condition had similarities to central nervous system (CNS) sarcoidosis. Neurologic involvement occurs in less than 1% of adult sarcoidosis cases and is isolated in only 17% of neurosarcoidosis cases (7). Isolated pediatric neurosarcoidosis is even rarer, but the incidence is unknown because of the small number of cases reported in the literature. The diagnosis is further complicated by the variety of presentations among children, often without pulmonary involvement (7). EOS typically presents with the clinical triad of uveitis, arthritis, and dermatitis; rare neurological manifestations include headache, seizures, cranial neuropathy, optic neuritis, and hypothalamic and/or pituitary dysfunction (4). Diagnostic criteria for pediatric neurosarcoidosis have not been established, although most use the Zajicek et al (9) classification schema, ranging from possible to definitive, based on clinical criteria with confirmatory radiologic, serologic, spinal fluid, or histolVegunta et al: J Neuro-Ophthalmol 2021; 41: 547-552 ogy studies (10). In isolated cases such as this, brain or dural biopsies to establish a diagnosis of definite neurosarcoidosis may not be possible or are deemed too high risk. With clinical presentation and radiological findings alone, the diagnosis is no more than “possible.” In all cases, it is important to rule out diseases that present similarly such as tuberculosis, berylliosis, malignancies, and Sjogren syndrome. The most characteristic MRI findings in adults are leptomeningeal contrast enhancement on postgadolinium T1 images (11). Now, genetic testing for autoinflammatory disease susceptibility variants may be a helpful tool in the neuro-ophthalmologist’s repertoire, building diagnostic certainty from “possible” neurosarcoidosis to NOD2-associated autoinflammation. Genetic testing also clarified that this patient will likely need life-long immunomodulatory therapy. Because of the similarities between our patient’s clinical and imaging findings and neurosarcoidosis, supported by the information of propensity to granulomatous disease provided by the NOD2 mutation, his therapy was adjusted to target a different pro-inflammatory pathway—infliximab (chimeric mouse-human monoclonal anti-TNF-a antibody), rather than a more general B cell inhibitor. TNFa is produced by epithelioid and giant cells in human sarcoidosis granulomas. Infliximab was chosen because it has been shown to be effective for patients with CNS sarcoidosis (12,13). Infliximab is also used to treat Crohn disease. He is currently taking this medication in addition to methotrexate. The addition of methotrexate to infliximab increases the lifetime efficacy of the biologic by reducing the production of neutralizing antibodies against infliximab. His condition has been stable for 21 months. In conclusion, genetic testing should be considered in patients with suspected autoinflammatory conditions without a known cause. It should be considered in patients with pediatric neurosarcoidosis as well, to help establish genetic and clinical correlations. Our case was particularly challenging because of the inconclusive imaging and histological findings and negative serologic work up. The additional information provided by genetic testing clarified his diagnosis and guided his therapy. This is all the more reason to expand the neuro-ophthalmologist’s tool kit to include genetic testing with the help of the rheumatologist, immunologist, or medical geneticist. REFERENCES 1. McCusker C, Upton J, Warrington R. 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