2019 NPA-05

This case was originally published in 2019. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

The patient is a 53-year-old man with a history of partial complex seizures and left leg weakness. This had progressed over time to episodes of status epilepticus and generalized encephalopathy. Neuroimaging revealed patchy fluid-attenuated inversion recovery (FLAIR) signal abnormalities, including a right temporal lobe mass with contrast enhancement and meningeal thickening. He underwent a right temporal amygdalohippocampectomy.

Tissue Site
Right temporal lobe

The whole slide image provided is an H&E-stained slide of the left temporal lobe of the brain from an amygdalo-hippocampectomy.

The final clinicopathologic diagnosis in this case is neurosarcoidosis, which is a diagnosis of exclusion, similar to that of sarcoidosis in general. Not shown above, but performed in this case, was a series of negative histochemical stains (acid-fast bacilli (AFB), Gomori's methenamine silver (GMS), and Steiner) and negative clinical workup to rule out infections and collagen vascular disorders. The clinical workup included negative results with QuantiFERON-TB Gold, as well as blood and CSF cultures, serologies, and polymerase chain reaction (PCR) studies for numerous other organisms. Antinuclear antibody (ANA), neuromyelitis optica, and treponeme antibody assays were similarly negative. Nonspecific, but supportive data for the diagnosis of neurosarcoidosis included:

1. Chest CT showing symmetric, mildly enlarged hilar lymph nodes
2. CSF findings of increased leukocytes, elevated protein (including IgG), and oligoclonal bands
3. Evidence of optic neuritis on review of a prior head MRI
4. Extensive right supratentorial pachymeningeal enhancement on a follow-up head MRI

Subsequent neuroimaging following a course of high-dose oral steroids showed resolution of all leptomeningeal enhancement. His mental status also improved dramatically, although he continued to experience occasional seizures. At his last exam, he had no light perception in either eye, and there was evidence of optic nerve atrophy bilaterally. The plans were to obtain whole body FDG-PET to further screen for potential sites of involvement by sarcoidosis and to switch the patient to a steroid-sparing immunosuppressive therapy (infliximab) in combination with methotrexate.

Along with other diseases, such as lupus and syphilis, sarcoidosis has been described as “the great mimicker” due to the long and varied constellation of possible clinical presentations often leading to misdiagnoses such as multiple sclerosis and many others. Despite over a century of studies, it remains an idiopathic, multiorgan inflammatory disorder that often presents in young to middle aged patients and is overrepresented in African Americans and women. Lungs and intrathoracic lymph nodes are most commonly involved, but essentially any site can be affected.

Neurosarcoidosis (central and/or peripheral nervous system involvement, the former including brain and/or spinal cord and the latter including peripheral nerve and skeletal muscle) is seen in 5% to 15% of sarcoidosis patients but can reach as high as 25% in autopsy series. In rare cases, neurosarcoidosis is an isolated entity. As with tuberculosis, the leptomeninges at the base of the brain are most often involved (Image A and Image B), where it frequently spreads to adjacent dura, brain, cranial nerves, and/or the hypothalamic/pituitary region. Of the associated cranial neuropathies, the optic (CN II; as in this case) and the facial (CN VII) are most common. However, parenchymal disease is also possible, as in this case, and in most cases results from the granulomas tracking along perivascular Virchow-Robin spaces into the deeper brain (Image C and Image D [arrow pointing to blood vessel]). The histologic features are essentially identical to sarcoidosis elsewhere and feature tight, predominantly nonnecrotizing granulomas with epithelioid macrophages, Langhans (and occasionally foreign body) type giant cells, and only a thin surrounding lymphocytic rim imparting the impression of “naked granulomas.” The granulomas are often angiocentric but not angiodestructive (in contrast to primary CNS vasculitis), may coalesce to form larger tumor-like masses, and variably hyalinize concentrically from the outer portions centrally. The epithelioid cells stain with histiocytic markers such as CD68 or CD163, while the lymphoid infiltrate is typically T-cell predominant (Image E). Adjacent brain often appears gliotic and may feature activated CD68-positive microglia (Image F). The mechanisms leading to this pathology are poorly understood but are thought to involve incomplete antigen degradation in genetically predisposed individuals, whose immune systems mount an excessive macrophage, T-cell, and B-cell immune reaction to this chronic antigenic stimulation of unknown source.

The clinical and imaging features are often nonspecific and typically generate a long list of differential diagnostic considerations. Nonetheless, chest CT, postcontrast head MRI, and whole body FDG-PET studies can be helpful in establishing sites of active disease in patients with suspected sarcoidosis. Neurologic symptoms account for the initial presentation in up to 70% of patients with neurosarcoidosis with a small population showing no evidence of disease beyond the nervous system. A definitive diagnosis requires tissue confirmation with both pathologic and clinical exclusion of other granulomatous disorders. The CSF findings are often those of an inflammatory process and include elevated leukocyte counts and oligoclonal bands; therefore, this represents a sensitive, albeit nonspecific, form of diagnostic support. Unfortunately, serum and CSF angiotensin converting enzyme (ACE) levels, as well as erythrocyte sedimentation rates (ESR) are only elevated in a minority of patients, so these assays have limited utility. Nevertheless, once a diagnosis of neurosarcoidosis is established, one can opt to observe the patient if the manifestations are mild or treat with corticosteroids if more severe, the latter often being highly effective. For those with more serious and longstanding manifestations, steroid-sparing immunomodulatory agents are recommended as a second line approach. Potentially effective agents include methotrexate and anti-TNF-alpha agents such as infliximab and adalimumab. In cases such as this one, some studies suggest that seizures are associated with a more severe form of disease and a worse long-term prognosis.

Diagnosis
Neurosarcoidosis

• Neurosarcoidosis has highly characteristic histopathologic features but remains a diagnosis of exclusion for both the pathologist and the neurologist.
• Special stains should be performed to rule out mycobacterial, fungal, and treponemal infections.
• As a clinicopathologic diagnosis, neurosarcoidosis requires an active collaboration between the pathologist and the rest of the clinical team to exclude infectious etiologies and collagen vascular disorders.
• Neurosarcoidosis remains an idiopathic disorder but is an important diagnostic consideration given the often dramatic response to steroids and other immunomodulatory therapies.
• Imaging and cerebral spinal fluid studies are often diagnostically helpful and sensitive for detecting neurosarcoidosis but are not sufficiently specific to exclude other differential diagnostic considerations.

1. Tana C, Wegener S, Borys E, et al. Challenges in the diagnosis and treatment of neurosarcoidosis. Ann Med. 2015;47(7):576-91.
2. Bagnato F, Stern BJ. Neurosarcoidosis: diagnosis, therapy and biomarkers. Expert Rev Neurother. 2015;15(5):533-48.
3. Agnihotri SP, Singhal T, Stern BJ, Cho TA. Neurosarcoidosis. Semin Neurol. 2014;34(4):386-94.
4. Nozaki K, Judson MA. Neurosarcoidosis: Clinical manifestations, diagnosis and treatment. Presse Med. 2012;41(6 pt 2):e331-48.
5. Perry A, Brat D. Practical Surgical Neuropathology, 2nd Edition. Philadelphia, PA: Elsevier/Churchill Livingstone; 2018.