Case Study 66 Kenneth Clark, MD

Question 1 This is a 39 year-old African American male with a past medical history of pulmonary sarcoidosis, complex partial seizure disorder, hydrocephalus status post ventriculoperitoneal shunt. He was admitted with confusion, ataxia, and urinary incontinence that has progressed over the last month. Describe the MRI findings.

Axial T1 Axial T1 + Contrast Coronal T1 + Contrast Axial T2 FLAIR

Answer Asymmetric moderate ventricular enlargement, multifocal periventricular T2 FLAIR signal, and subtle diffuse leptomeningeal contrast enhancement with extension into many of the sulcal depths.

Question 2 Is pachymeningeal enhancement a concerning feature?

Answer No. The pachymeninges (dura) contain small vessels that do not provide a blood-brain barrier. Likewise, a number of serum compounds (albumin, fibrinogen, hemosiderin) readily leak into the dura under normal conditions. Contrast material also readily leaks into the dura under normal conditions and invariably results in dural enhancement on MRI. This is not concerning.

Question 3 Is leptomeningeal enhancement a concerning feature?

Answer Yes. The leptomeningeal vessels have intact blood brain barrier function, which should prevent the leakage of contrast material into the leptomeningeal space. If the leptomeninges contrast enhance, this means that some diffuse process is affecting the BBB.

Question 4 What is the differential diagnosis of leptomeningeal contrast enhancement?

Answer Leptomeningeal enhancement is most often associated with diffuse inflammatory processes, most commonly viral meningitis, followed by bacterial and fungal meningitis. However, sometimes neoplasms may spread through the subarachnoid space resulting in “carcinomatous meningitis”, which also results enhancement of the leptomeninges. This type of process, however, usually results in a patchy or “lumpy” quality of enhancement. Tumors known to cause this are primary (medulloblastoma, glioblastoma) and metastatic (lymphoma, breast).

Question 5 The patient sustained intractable seizure activity, developed cardiac arrest and died shortly thereafter. An autopsy was performed. Describe the gross appearance of the brain and spinal cord.

Answer The leptomeninges are diffusely granular, involved by innumerable minute, firm, tan-white nodules measuring up to 3 mm in diameter. In the frontal and parietal parasagittal regions, these small nodules coalesce into thick and irregularly-shaped plaques. Coronal sections of the hemispheres of the fixed brain reveal innumerable uniformly tan-white, firm nodules within the leptomeninges measuring up to 3 mm in diameter, with the majority measuring 1 mm or less. The parasagittal region reveals extensive plaque-like thickening up to 4 mm near the first and second gyral crests. The parasagittal cortex of the frontal and parietal lobes show pale discoloration and near complete effacement of the grey-white junction. Along its length the spinal dura demonstrates multifocal adherence to various regions of the cord. The cauda equina shows innumerable sub-centimeter tan-white to translucent nodules on individual spinal nerves. Many of the nerve fascicles are adherent to one another, and to the underlying conus.

Question 6 Based on this gross appearance of the brain, what is your differential?

Answer Granulomatous meningitis (fungal, tuberculous, idiopathic) Carcinomatous meningitis

Question 7 All sections of the brain examined (cortex, basal ganglia, hippocampus, brainstem, spinal cord) revealed a predominantly angiocentric process with extensive associated fibrosis. Describe these findings. Click to view cortex, hippocampus, pons, cerebellum, pineal gland, spinal cord

Answer The leptomeninges show extensive non-necrotizing granulomatous inflammation with associated severe dense fibrosis and near complete obliteration of the sub-arachnoid space. Most granulomas are perivascular in distribution, and exhibit numerous multinucleate giant cells and variable hyalinization. Rarely granulomas appear to directly extend into the underlying superficial subpial cortex by involving Virchow-Robin spaces. Uninvolved leptomeningeal vessels show mild thickening and trace perivascular lymphocytic infiltrates. The neocortex shows mild, remote neuronal drop-out , predominately in layers III and V, associated with mild gliosis. Scattered neocortical and deep white matter vessels show variable involvement by perivascular granulomatous inflammation, occasionally with complete luminal obliteration.

Question 8 What immunohistochemical stains might help highlight the granulomatous process, and what stains would you order to determine whether it is of infectious etiology?

Answer CD68 – to confirm and highlight the extent of granulomatous involvement Grocott – for fungal organisms Acid Fast – for mycobacterial organisms Frasier-Lendrum – highlight fibrosis Click to view CD68, Frasier-Lendrum

Question 9 CD68 highlights innumerable perivascular granulomas within the leptomeninges and penetrating vessels. Stains for fungal and mycobacterial organisms are negative. What is your final autopsy diagnosis?

Answer Severe extensive non-necrotizing granulomatous inflammation involving all regions of brain and spinal cord, consistent with Neurosarcoidosis

Question 10 What exactly is sarcoidosis and how often does it present in the central nervous system?

Answer Sarcoidosis is a non-necrotizing granulomatous inflammatory disease of unknown etiology that most commonly affects the lungs and lymph nodes. Neurosarcoidosis affects between 5-10% of all patients with presumed sarcoidosis. Less than 1% of patients with neurosarcoidosis have CNS disease exclusive of other organ system involvement. Because sarcoidosis is of unknown pathogenesis, it is a diagnosis of exclusion. All other potential causes (infectious, vasculitis, etc.) must be ruled out in order to establish a diagnosis of sarcoidosis.

Question 11 Are there any ancillary tests that can support the diagnosis of sarcoidosis (neurosarcoidosis or otherwise)?

Answer Patients with sarcoidosis sometimes have elevated serum levels of angiotensin-converting enzyme (ACE), and those with neurosarcoidosis have elevated ACE in the CSF. However, the sensitivity of this marker is low and generally not accepted as a reliable indicator of the disease.

References Lower E, Weiss K. Neurosarcoidosis (2008). Clinics in Chest Medicine. 29(3):475-492. Rosai J. Rosai and Ackerman’s Surgical Pathology, Ninth Edition (2004). Elsevier, Inc. Smirniotopoulos J, et al. Patterns of contrast enhancement in the brain and meninges (2007). Radiographics. 27:525-551.