TB or Not TB? That is the Question

Since the first English language description by Miller and Smith in 1966 of ischemic optic neuropathy as a distinct ophthalmic syndrome, a long series of studies has refined the clinical profile to what we consider to be accurate today. From the specifics of pathogenesis to the clinical appearance to the effect of therapy, the basic tenets of diagnosis and management have evolved over 5 decades. What we thought we knew about the following topics has changed: location of vasculopathy; incidence; age at onset; optic disc appearance; risk factors for development; natural history; rate of fellow eye involvement; ischemia as an all-or-none phenomenon; and treatment. A look back at these discoveries shows both how far we have come and how far we have to go in managing this disorder.

Clinical-Pathological Case Study Section Editors: Neil R. Miller, MD Janet Rucker, MD "TB or Not TB?" That is the Question Andrew R. Carey, MD, Jose Antonio Bermudez-Magner, MD, Sander R. Dubovy, MD, Norman J. Schatz, MD, Linda L. Sternau, MD, Evelyn M. Sklar, MD, Byron L. Lam, MD Dr. Carey and Dr. Sternau: A 36-year-old man was evaluated in the emergency department with severe headaches, bilateral leg numbness, and bilateral decreased vision. Headaches, neck stiffness, and intermittent blurry vision had begun 6 months earlier, at which time brain magnetic resonance imaging (MRI) with contrast was unremarkable. Symptoms slowly progressed and 1 month before presentation, while on vacation in Ecuador, the patient had a prolonged generalized seizure requiring intubation, after which he was discharged without antiepileptic medication. The patient's medical history was significant for a Bacillus Calmette-Guérin (BCG) vaccination as a child in Ecuador. He emigrated to the United States at age 19 years. In 2005, he had a positive purified protein derivative test for tuberculosis (TB) but a negative chest x-ray. In 2011, he developed pleuritic chest pain and chest radiography showed a 3-cm cavitary lung lesion in the right upper lobe. He was diagnosed with active pulmonary TB and completed treatment in 2013, 4 months before the onset of initial neurological symptoms. On examination, the patient was drowsy but arousable to verbal stimuli and oriented to person, place, and time. Visual acuity was light perception in each eye and pupils reacted sluggishly to light. Ocular versions were full, with an exotropia of 30 prism diopters. Ophthalmoscopy showed bilateral optic disc edema. Strength was reduced in all limbs. There was less response to painful stimuli in the lower extremities than in the upper extremities. Reflexes were 2+ and symmetric with absent Hoffman and Babinski signs. Differential diagnosis included an intracranial mass lesion, vasculitis involving the central nervous system (CNS), encephalopathy of toxic, nutritional, infectious, or inflammatory etiology, or a meningeal process of infectious, inflammatory, or neoplastic etiology. A repeat brain MRI was performed with and without contrast. A lumbar spine MRI also was performed. Department of Ophthalmology (ARC, JAB-M, SRD, NJS, BLL), Bascom Palmer Eye Institute, Miller School of Medicine, University of Miami, Florida; Department of Neurosurgery (LLS), Memorial Regional Hospital, Hollywood, Florida; and Departments of Radiology and Ophthalmology (EMS), Miller School of Medicine, University of Miami, Miami, Florida. The authors report no conflicts of interest. Address correspondence to Andrew R. Carey, MD, 255 Iowa Avenue, Apartment 202, Iowa City, Iowa, 52240; E-mail: [e-mail] Carey et al: J Neuro-Ophthalmol 2016; 36: 197-201 Dr. Schatz: Postcontrast brain MRI shows dilated optic nerve sheaths, protrusion of the optic nerve heads, flattening of the posterior globes (Fig. 1A, B), an empty sella turcica (Fig. 1C), and dilated ventricles (Fig. 1D). Fluid-attenuated inversion recovery (FLAIR) sequences demonstrate hyperintensity of the sulci (Fig. 1B). In addition, there is diffuse enhancement of the leptomeninges most notable in the cerebellar sulci (Fig. 1A) and involvement of the optic chiasm (Fig. 1D) tracking along the optic nerves into the optic canals bilaterally (not shown). MRI of the lumbar spine with contrast demonstrates postcontrast enhancement of the conus without a focal mass (not shown). Dr. Lam: The key feature at this point was the diffuse meningeal enhancement, which has a spectrum of potential causes: infectious etiologies include bacterial, fungal (e.g., cryptococcal), viral, and TB meningitis; inflammatory etiologies include neurosarcoidosis, IgG4-related disease, small-vessel vasculitis such as anti-neutrophil-cytoplasm-antibody-associated vasculitis; idiopathic hypertrophic pachymeningitis, and histiocytic syndromes. Neoplastic etiologies include leptomeningeal carcinomatosis, diffuse meningiomatosis, primary leptomeningeal gliomatosis, lymphoma, and leukemia. Dr. Sternau: Serum white blood cells (WCB) count was elevated to 25,300/mL. Lumbar puncture showed xanthochromia with an opening cerebrospinal fluid (CSF) pressure of 40 cm water. CSF red blood cells (RBC) count was 4,000/mL, WBC was 110/mL with 66% monocytes and 22% bands, protein was elevated to 701 mg/dL (normal: 15-60 mg/dL), and CSF glucose was low at 36 mg/dL (lower limit normal: 40 mg/dL). TB with meningeal involvement was diagnosed and the patient was started on anti-TB medications. However, CSF acid-fast bacilli smears, gram stain, polymerase chain reaction, and cultures were negative for TB and other infectious agents. Dr. Bermudez-Magner: Examination of the CSF cytospin slides demonstrates cells with large marginated nuclei, prominent nucleoli, 197 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Brain magnetic resonance imaging with gadolinium. Axial T2 (A) and FLAIR (B) images show dilated optic nerve sheaths, protrusion of the optic nerve heads (arrow), and flattening of the posterior globes. There is hyperintensity in the sulci (arrows) on the FLAIR image. C. Postcontrast sagittal T1 image demonstrates an empty sella and leptomeningeal enhancement most prominent in the cerebellar sulci (arrows). D. Postcontrast coronal T1 scan shows dilated lateral ventricles and leptomeningeal enhancement surrounding the optic chiasm (arrows). FLAIR, fluid-attenuated inversion recovery. and high nuclear-to-cytoplasm ratio (Fig. 2). There are scattered atypical cells containing cytoplasmic pigmentation. These findings suggest a possible malignancy of epithelial origin or at least with epithelioid morphology. Dr. Lam: Immunohistochemical testing was inconclusive. A second opinion from Brigham and Women's Hospital (Boston, MA) resulted in a final interpretation of panmelanocyte immunoreactivity, raising the possibility of melanoma but lacking convincing S100 reactivity. Metastatic carcinoma could not be excluded; lymphoma was thought to be highly unlikely. Accordingly, it was decided that a craniotomy for leptomeningeal biopsy should be performed. 198 Dr. Sternau: A right fronto-temporal craniotomy was performed. On reflection of the dura, the leptomeninges were diffusely pigmented (Fig. 3A) throughout the entire field of view. Initial intraoperative impression was that this might represent chronic subdural hemorrhage. However, further dissection under highpower magnification revealed a highly vascularized, subarachnoid-subpial, infiltrating pigmented lesion. The lesion was diffusely involving the subarachnoid space and likely limiting the flow of CSF within the meninges. Four 1-cm biopsies were taken, revealing underlying vascular inflammation with petechial hemorrhage. Dr. Dubovy: There are pigmented cells in the leptomeninges adjacent to foci of unremarkable parenchyma (Fig. 3B). Atypical Carey et al: J Neuro-Ophthalmol 2016; 36: 197-201 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 2. Cerebrospinal fluid cytology. A. Large cells are present with high nuclear to cytoplasm ratio and large, marginated nuclei surrounded by numerous erythrocytes (hematoxylin and eosin, ·400). B. Cytospin specimen demonstrates large cells with a high nuclear to cytoplasm ratio with large nuclei and prominent nucleoli (Giemsa, ·400). pigmented spindle and epithelioid cells are present with mitotic figures (Fig. 3C) with an elevated Ki-67 index. The tumor cells stain positive for melanocyte markers Melanin-A and S-100 (Fig. 3D, E) and are negative for pan-cytokeratin (Fig. 3F). These findings are consistent with leptomeningeal melanomatosis (LMM). Dr. Carey: Genetic testing was negative for BRAF mutations p.V600E and p.V600K. Full-body dermatologic examination was negative for cutaneous melanoma. Ophthalmologic examination showed no abnormal uveo-scleral pigmentation and FIG. 3. Surgical and pathologic findings. A. There is marked and diffuse pigmentation of the frontotemporal subarachnoid space. B. Pigmented leptomeninges are adjacent to normal neural tissue (hematoxylin and eosin, ·15). C. Leptomeninges reveal spindle and epitheliod pigmented cells with mitotic figures and cellular atypia (hematologic and eosin, ·400). D. Melanin-A (red) stains markedly positive in the leptomeninges and negative in neural tissue (·200). E. S100 (red) shows positive staining of the leptomeninges in a background of brown melanin pigment (·200). F. There is negative staining of the leptomeninges for pan-keratin (·200). Carey et al: J Neuro-Ophthalmol 2016; 36: 197-201 199 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study no tumors of the conjunctiva, iris, or choroid. Computed tomographic scans of the chest, abdomen, and pelvis were negative. A positron emission tomography scan was not obtainable during the hospitalization. A lumbar CSF drain and, subsequently, a ventriculoperitoneal shunt were placed, resulting in temporary improvement in vision and level of consciousness. The patient was started on ipilimumab, a monoclonal antibody to increase host immune response to melanoma cells. The patient was discharged to the rehabilitation unit where he self-extubated his tracheostomy, could not be reintubated, and died. An autopsy was not performed. Final Diagnosis Nonsyndromic primary leptomeningeal melanomatosis (LMM). Drs. Carey and Lam: LMM consists of melanoma cell spread along the leptomeninges (1). There are 3 primary etiologies for LMM: distant metastasis (usually cutaneous); seeding from a primary CNS melanoma; and isolated or diffuse involvement of leptomeningeal origin without a focal primary (1-5). Benign variants are called leptomeningeal melanocytosis; however, these lesions may undergo malignant transformation, cause neurologic dysfunction and lead to death, even without histologic evidence of malignancy (3). Of the 3 mechanisms, metastasis is the most common etiology. Primary CNS melanomas may occur with or without syndromic association, including neurocutaneous syndromes such as Nevus of Ota and Sturge-Weber or Dandy-Walker (3,6). These melanomas arise from the intrinsic melanocytes of the leptomeninges (3). A recent genetic study showed that GNAQ was the most common mutation in 37% of primary CNS melanocytic tumors, whereas 1 of 4 melanomas demonstrated a BRAF mutation (7). Peak incidence of primary LMM occurs in the fourth decade of life (8). Presentation of LMM depends on the site of involvement. With CNS involvement, the most common symptoms are headache in 46%, followed by nausea and vomiting in 37%; the most common signs are mental changes in 17% and seizures in 8% (1). With cranial nerve involvement, diplopia has been reported in 19% of cases, and tinnitus or hearing loss in 13%; the most common signs are involvement of the third, fourth, and sixth cranial nerves in 18%, and the seventh nerve in 19% (1). With spinal cord involvement, the most common symptoms are back or neck pain in 24% and weakness in 22%; the most common signs are sensory loss in 23% and lower motor neuron weakness in 18% (1). Vision loss may be due to elevated intracranial pressure, infiltration by neoplastic cells, or both. CSF analysis is diagnostic in 28% and MRI in 33% (1). Dr. Sklar: Primary diffuse LMM results from the spread of malignant melanocytes to the leptomeninges and Virchow-Robin 200 spaces with superficial invasion of the brain. Radiologically, the diagnosis of primary malignant LMM may be quite difficult as the imaging findings in the base of skull and spinal meninges may mimic other conditions, including sarcoidosis, TB, meningitis, carcinomatosis, leukemia, lymphomatosis, gliomatosis, and idiopathic hypertrophic pachymeningitis. Melanin signal is classically hyperintense on T1-weighted images and isohypointense on T2-weighted images because of the paramagnetic action of the free radicals in melanin combined with the signal from bleeding (9). Amelanotic melanomas without bleeding could be an exception and may be hypointense on T1-weighted images, which may explain the lack of hyperintensity on the noncontrast T1weighted images of our patient. In cases of primary LMM, the brain MR findings may have a very significant diagnostic value as meningeal T1-weighted hyperintensity before contrast administration is not caused by sarcoidosis, carcinomatosis, and lymphomatosis, but may be caused by melanomatosis (2). Drs. Carey and Lam: The MRI findings in our patient were not typical for leptomeningeal melanoma as described in the literature. The initial article on MRI of intracranial melanomas identified 10 patients with metastases from malignant melanoma and identified 3 patterns; however, only 3 of the patients had histology: "nonhemorrhagic melanotic melanomas" were hyperintense on T1 and mildly hypointense on T2; "nonhemorrhagic and amelanotic" lesions were hypointense to isointense on T1 and isointense to mildly hyperintense on T2; and "hemorrhagic melanomas: had a varied appearance depending on the stage of hemorrhage (10). Subsequently, there was a similar report, which included 30 intracranial metastatic melanomas on MRI; 8 were highly melanotic lesions by histology, and 7 of these were hyperintense on T1 and hypointense on T2; whereas a single lesion was hyperintense on T1 and hyperintense to isointense on T2. This suggests the sensitivity of MRI for identifying high melanin content to be approximately 87.5% based on this small series (11). Additionally, FLAIR hyperintensity is also typical (3). These studies only involved metastatic lesions; there have been no reports of MRI findings in primary meningeal melanomas, which are much rarer and may have different paramagnetic properties because of their intrinsic vascularity. Treatment of LMM has limited efficacy. Most data relate to metastatic disease. One study demonstrated statistically significant benefit with intrathecal chemotherapy compared with radiation and systemic chemotherapy; however, the authors noted that patient selection bias cannot be excluded and likely skewed results in favor of intrathecal chemotherapy (1). In 2013, the Food and Drug Administration approved new treatments for melanoma, targeting molecular pathways. Vemurafenib and dabrafenib target BRAF mutations (the most common mutation in Carey et al: J Neuro-Ophthalmol 2016; 36: 197-201 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study cutaneous melanoma), whereas ipilimumab stimulates cytotoxic T cells to attack melanoma; these treatments have not been studied rigorously and case reports have shown variable results (12-14). Treatments targeting the GNAQ mutation have not be studied in intracranial disease but protein kinase C-targeted therapy has been shown to radiosensitize tumor cells and improve response to radiotherapy in uveal melanoma in laboratory studies (15). Patients with focal primary CNS melanomas have the best prognosis, whereas those with metastatic disease or with diffuse leptomeningeal spread have the worst prognosis, with median survival ranging from 8 to 10 weeks after diagnosis (1,3,16). Primary LMM is a rare disease that often presents with neuroophthalmic signs and symptoms. MRI and CSF cytology may suggest the diagnosis, but biopsy often is needed for confirmation. In our patient, the leptomeninges showed diffuse enhancement but were not hyperintense on precontrast T1 sequences. CSF cytological studies were suggestive of LMM but inconclusive. The diagnosis of LMM ultimately was confirmed by leptomeningeal biopsy. Primary LMM portends a poor prognosis; however, new treatments for melanoma may offer improved outcomes. REFERENCES 1. Harstad L, Hess KR, Groves MD. Prognostic factors and outcomes in patients with leptomeningeal melanomatosis. Neuro Oncol. 2008;10:1010-1018. 2. Arias M, Alberte-Woodward M, Arias S, Dapena D, Prieto A, Suarex-Penaranda JM. Primary malignant meningeal melanomatosis: a clinical, radiological and pathologic case study. Acta Neurol Belg. 2011;111:228-231. 3. Liubinas SV, Maartens N, Drummond KJ. 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J Clin Neurosci. 2014;21:1051- 1052. 201 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.