Residency · Residency · Pathology

Demyelinating and Inflammatory CNS Disease

Overview

Brain biopsies for demyelinating and inflammatory diseases are uncommon but diagnostically challenging. They are typically performed when clinical and radiologic features are atypical, mimicking neoplasm or infection. The pathologist must recognize demyelination patterns, distinguish them from lymphoma and glioma, and identify specific inflammatory CNS diseases.

Multiple Sclerosis (MS)

Pathogenesis

Multiple sclerosis is an autoimmune-mediated demyelination of CNS white matter. CD4-positive T-cells and macrophages drive destruction of myelin through perivenular inflammation with breakdown of the blood-brain barrier. The clinical course may be relapsing-remitting, secondary progressive, primary progressive, or progressive-relapsing.

Biopsy Indications

Brain biopsy is performed in MS when the radiologic presentation is atypical (particularly tumefactive MS mimicking neoplasm), when there is failure to respond to empiric therapy, or when a single large lesion is present without prior MS history.

Histologic Features

Active Plaque

The active plaque shows sharply demarcated areas of myelin loss with relative axonal preservation, which is the key distinguishing feature from other destructive processes. Perivascular inflammatory cuffs contain lymphocytes (CD3-positive T-cells) and macrophages. Macrophages and microglia laden with myelin debris can be highlighted with Luxol fast blue (LFB) or PAS stains showing positive debris within the phagocytes. Reactive astrocytosis at the plaque border produces Crook cells (large reactive astrocytes with abundant eosinophilic cytoplasm). Neurofilament immunohistochemistry demonstrates intact axons despite myelin loss.

Chronic Active Plaque

The chronic active plaque has a hypocellular, demyelinated center with gliosis and a rim of activated macrophages and microglia at the edge (the smoldering rim), representing a slowly expanding lesion.

Chronic Inactive Plaque

The chronic inactive plaque shows complete demyelination with dense gliosis (astrocytic scar), few inflammatory cells, and possible axonal loss.

Tumefactive MS

Tumefactive MS presents as a large (greater than 2 cm) solitary demyelinating lesion that mimics neoplasm on imaging, often with ring enhancement on MRI and mass effect. Key histologic clues to avoid misdiagnosis as lymphoma or glioma include macrophage-rich inflammation (rather than lymphocyte-dominant), myelin loss with relative axonal preservation (demonstrated by comparing LFB and neurofilament stains), perivascular inflammation (rather than diffuse infiltration), and reactive astrocytes that may appear atypical but lack clonal features. Crook cells should not be misinterpreted as tumor cells.

Ancillary Studies

LFB (Luxol fast blue) demonstrates myelin loss (pale or absent staining in plaques). Neurofilament protein (NFP) IHC shows relative axonal preservation. CD68 IHC highlights macrophages and microglia. GFAP highlights reactive astrogliosis. CD20 and CD3 characterize the inflammatory infiltrate and are important for excluding lymphoma.

Neuromyelitis Optica Spectrum Disorder (NMOSD)

Pathogenesis

NMOSD is mediated by autoantibodies against aquaporin-4 (AQP4) water channels on astrocyte foot processes. The resulting complement-mediated astrocytic injury causes secondary demyelination. It is pathogenetically distinct from MS, requiring different treatment and carrying a different prognosis.

Histologic Features

NMOSD shows perivascular complement deposition (C9neo IHC positive), loss of AQP4 and GFAP immunoreactivity in lesions (reflecting astrocyte destruction), prominent necrosis and cavitation (more destructive than MS), eosinophilic and neutrophilic infiltration (uncommon in MS), a vasculocentric pattern with hyalinized thickened vessel walls, and both myelin loss and axonal loss (unlike MS where axons are relatively preserved).

Distinguishing NMOSD from MS on Biopsy

CNS Vasculitis

Primary Angiitis of the CNS (PACNS)

PACNS is isolated to the CNS and is a diagnosis of exclusion. Biopsy is the gold standard for diagnosis. Three histologic patterns exist: granulomatous (the most common, with granulomatous inflammation of small and medium vessel walls, multinucleated giant cells, and destructive changes resembling GPA or sarcoidosis), lymphocytic (lymphocytic infiltration of vessel walls with mural damage), and necrotizing (fibrinoid necrosis of vessel walls resembling polyarteritis nodosa). The defining feature across all patterns is transmural inflammation with vessel wall destruction. Infection, systemic vasculitis, and lymphoma (intravascular lymphoma can mimic vasculitis) must be excluded.

Biopsy Approach

The biopsy should include leptomeninges and cortex from an affected area guided by imaging. Sensitivity is approximately 75 percent when the biopsy targets radiologically abnormal tissue and lower for non-targeted biopsies. The false-negative rate is significant due to segmental vessel involvement.

Neurosarcoidosis

CNS involvement occurs in approximately 5 to 10 percent of systemic sarcoidosis, with a leptomeningeal predilection and frequent cranial nerve involvement (especially CN VII). Histologically, it shows non-caseating granulomas in the leptomeninges, perivascular spaces, and brain parenchyma. Infections must be excluded (AFB and GMS stains are mandatory). Granulomatous vasculitis may be present. CSF angiotensin-converting enzyme (ACE) is elevated but not specific.

Infections Mimicking Demyelination

Progressive multifocal leukoencephalopathy (PML) is caused by JC virus and shows bizarre enlarged oligodendrocytes with ground-glass nuclei, confirmed by SV40 IHC. Acute disseminated encephalomyelitis (ADEM) is a post-infectious perivenular demyelination with sleeves of demyelination around veins and a monophasic course. HIV-associated leukoencephalopathy shows multinucleated giant cells and microglial nodules.

Frozen Section Pitfalls

Demyelinating disease on frozen section is easily misdiagnosed as lymphoma (due to macrophage-rich inflammation) or high-grade glioma (due to reactive astrocytes mimicking tumor cells). If a brain biopsy shows macrophage-rich perivascular inflammation, permanent sections should be requested before rendering a definitive diagnosis. Erring on the side of "defer to permanent sections" is far preferable to incorrectly calling lymphoma on frozen section in atypical cases.

<image>A medical illustration of multiple sclerosis biopsy findings. Panel A: Low-power view showing a sharply demarcated active demyelinating plaque with loss of myelin (pale area on LFB stain) adjacent to normal myelinated white matter (blue on LFB stain). Panel B: High-power of the plaque edge showing macrophages laden with LFB-positive myelin debris (foamy macrophages), perivascular lymphocytic cuffs, and reactive Crook astrocytes with abundant eosinophilic cytoplasm. Panel C: Neurofilament IHC showing preserved axons traversing the demyelinated plaque, demonstrating the characteristic relative axonal preservation. Panel D: CD68 IHC highlighting dense macrophage/microglial infiltration within the active plaque.</image>

<image>A medical illustration comparing MS and NMOSD biopsy findings. Left panels (MS): LFB stain showing demyelination with preserved axons on neurofilament stain, retained AQP4 expression, and macrophage-dominated inflammation. Right panels (NMOSD): LFB stain showing demyelination with neurofilament stain showing axonal loss/destruction, lost AQP4 immunoreactivity in the lesion (negative staining in lesion contrasted with normal staining around the lesion), and C9neo complement deposition along vessel walls with eosinophils and neutrophils in the inflammatory infiltrate.</image>

<image>A medical illustration of CNS vasculitis and neurosarcoidosis. Panel A (Granulomatous PACNS): Small leptomeningeal artery showing transmural granulomatous inflammation with multinucleated giant cells, intimal thickening, and narrowing of the vessel lumen. Panel B (Lymphocytic PACNS): Small parenchymal vessel with dense lymphocytic infiltration of the vessel wall and early fibrinoid necrosis. Panel C (Neurosarcoidosis): Leptomeningeal biopsy showing well-formed non-caseating granulomas with epithelioid histiocytes in the leptomeninges, perivascular distribution. Panel D (PML): Oligodendrocytes with enlarged ground-glass intranuclear inclusions at the edge of a demyelinated area, SV40 IHC inset showing positive nuclear staining.</image>

Clinical Pearls

The most critical mistake in CNS biopsy interpretation is misdiagnosing tumefactive MS as lymphoma. The key is to look for macrophage-dominant (not lymphocyte-dominant) inflammation, perivascular pattern, and relative axonal preservation (demonstrated by neurofilament IHC) before calling lymphoma. On frozen section of a brain biopsy, if the differential includes demyelinating disease, the diagnosis should be deferred to permanent sections; reactive astrocytes in demyelinating lesions can appear highly atypical and mimic high-grade glioma.

Loss of AQP4 immunoreactivity and prominent complement deposition (C9neo) distinguish NMOSD from MS on biopsy. This distinction is clinically critical because NMOSD is treated with different immunosuppressive agents and does not respond to standard MS therapies. In suspected CNS vasculitis, the biopsy must include leptomeninges to maximize diagnostic yield; parenchyma-only biopsies miss up to 25 percent of cases.

AFB and GMS stains should always be ordered on any CNS biopsy showing granulomatous inflammation, even when clinical suspicion for infection is low. Infectious granulomatous disease must be excluded before diagnosing sarcoidosis or granulomatous PACNS. ADEM is distinguished from MS by its monophasic course, perivenular sleeves of demyelination (rather than confluent plaques), and occurrence after viral illness or vaccination.

References

• Love S, et al. Greenfield's Neuropathology. 9th ed. CRC Press; 2015.
• Lucchinetti CF, et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol. 2000;47(6):707-717.
• Lucchinetti CF, et al. A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain. 2002;125(Pt 7):1450-1461.
• Salvarani C, et al. Primary central nervous system vasculitis: analysis of 101 patients. Ann Neurol. 2007;62(5):442-451.
• Hardy TA, et al. Tumefactive demyelination: an approach to diagnosis and management. J Neurol Neurosurg Psychiatry. 2017;88(12):1033-1048.

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