Neurosarcoidosis

Nervous system involvement by sarcoidosis, also termed neurosarcoidosis, is relatively common among patients with systemic sarcoidosis and has a bewildering variety of manifestations, often making diagnosis difficult.

Although neurosarcoidosis encompasses involvement of either or both of the central and peripheral nervous systems, this article will focus on central nervous system involvement, which is most common ¹².

For a general discussion of the underlying condition, please refer to the article sarcoidosis. 

Epidemiology

The demographics of affected patients is similar to that of systemic sarcoidosis, typically affecting patients 30-40 years of age with a female predilection ².

Clinical presentation

Central nervous system involvement by sarcoidosis is very variable, with lesions potentially involving the leptomeninges, pituitary and parenchyma of all parts of the intracranial compartment. Thus, clinical presentation is also very variable and nonspecific ¹²:

• cranial nerve palsies (most common overall presentation)

  • optic nerve involvement ⁵ (particularly common): visual loss, eye pain

  • facial nerve palsy: often recurrent and/or bilateral

  • vestibulocochlear nerve involvement: vestibular dysfunction, hearing loss

• manifestations of parenchymal disease

  • seizures/epilepsy

  • focal neurological deficits, e.g. weakness, altered sensation, dysarthria, or dysphagia

  • encephalopathy

  • stroke

• manifestations of spinal cord disease: myelopathy ⁵

• manifestations of meningeal disease

  • similar to those of parenchymal or spinal cord disease

  • features of raised intracranial pressure due to hydrocephalus

• endocrine features of hypothalamic/pituitary sarcoidosis ⁷

  • diabetes insipidus

  • SIADH

  • hyperprolactinemia

  • hypothyroidism

  • hypoadrenalism

  • panhypopituitarism

Although it is very rare (range 1-17% ^1,6) to have isolated neurosarcoidosis (i.e. without systemic disease), central nervous system symptoms are not uncommonly the first manifestation, and as such patients are often imaged without the diagnosis of systemic sarcoidosis having yet been made. 

Interestingly up to 10% of patients with the systemic disease will demonstrate positive imaging findings; thus not all patients with demonstrable imaging findings of neurosarcoidosis are symptomatic. 

Pathology

Histologically, central nervous system involvement is seen in ~20% (range 14-27%) of patients with systemic sarcoidosis, although only ~10% (range 3-15%) are symptomatic ^1-3. 

Radiographic features

The radiographic features of neurosarcoidosis can be thought of as occurring in one or more of five compartments. From superficial to deep they are:

• skull vault involvement (refer to musculoskeletal manifestations of sarcoidosis)

• pachymeningeal involvement (rare ¹²)

• leptomeningeal involvement (seen in up to 40% of cases ¹) 

  • pituitary and hypothalamic involvement

  • cranial nerve involvement

• parenchymal involvement (most common, seen in up to 50% of cases ¹²)

CT

Although CT is usually the first modality used in the workup of patients with neurosarcoidosis, it is not as sensitive or specific as MRI, with up to 60% of patients with subsequently proven neurosarcoidosis having negative CT scans ². The features will be similar and regions that demonstrate enhancement on MRI may also be seen to enhance on CT, although often less dramatically. 

On non-contrast scanning lesions, be they pachymeningeal, leptomeningeal or parenchymal, can appear hyperdense ². 

Often the only finding is hydrocephalus due to occult leptomeningeal disease ². 

MRI

MRI with contrast is the modality of choice for investigating suspected neurosarcoidosis. In general, lesions follow a standard signal intensity ^1,2:

• T1: iso- or hypointense to adjacent grey matter

• T2/FLAIR

  • variable

  • most are hyperintense

  • some lesions can be iso- or hypointense

• T1 C+ (Gd): homogeneous enhancement

Pachymeningeal involvement

Pachymeningeal disease often takes the form of pachymeningeal thickening with homogeneous enhancement. In some cases, the masses can be low on T2 weighted images, which although a helpful clue, is not pathognomonic. 

Leptomeningeal involvement

The primary sequence is T1 weighted with contrast, as quite prominent changes may be inapparent on other sequences. There may be focal or generalized leptomeningeal enhancement ³:

• particularly around the basal aspects of the brain and circle of Willis

• nodular or smooth 

• may follow perforating vessels up into the brain (via the perivascular spaces) 

  • sometimes referred to as tongues of fire sign ²

  • can mimic parenchymal lesions

  • can result in a CNS vasculitis picture, especially if a leptomeningeal disease is subtle elsewhere ^1,2

• may lead to hydrocephalus

Pituitary and hypothalamic involvement

Although pituitary and hypothalamic involvement are frequently seen as part of a more extensive leptomeningeal disease, it may also be encountered in isolation, sometimes with limited disease confined to the infundibulum. 

Cranial nerve involvement

Cranial nerves may be involved either as part of a more widespread leptomeningeal disease or in isolation. Although any nerve can be involved, the facial nerve and optic nerve are most commonly affected ¹²:

• facial nerve involvement is usually symptomatic but imaging of the facial nerve is often normal

• optic nerve involvement can be anywhere along its course from the globe to the optic chiasm (e.g. optic neuritis, optic perineuritis)

See orbital manifestations of sarcoidosis for a discussion of the non-optic nerve orbital disease spectrum.

Parenchymal involvement

Parenchymal involvement is the most common finding and can be in many forms ^1,5:

• extension of leptomeningeal disease up perivascular spaces

• periventricular high T2 signal white matter lesions

  • often indistinguishable from multiple sclerosis or leukoaraiosis

  • may have low T2 signal components (without hemorrhage) due to high cellularity

• enhancing masses or nodules

Spinal cord involvement

Spinal cord involvement is very rare. Myelitis is usually seen to affect multiple spinal cord segments, often in a longitudinally extensive transverse myelitis pattern ^9,12. The cervical and thoracic cord is most commonly affected ⁹. With gadolinium contrast, intramedullary enhancement is seen in most patients, and leptomeningeal enhancement may less commonly also be seen ⁹. On axial images post-gadolinium administration, the characteristic trident sign may be appreciated ¹⁰.

Nuclear medicine

Gallium-67 citrate scan is insensitive to central nervous system involvement, positive in only 5% of cases. However, it is helpful in confirming the presence of a systemic disease when neurological manifestations are the presenting complaint. In this setting, the gallium scan is positive in approximately 45% ¹. Care should be taken however in interpreting results as other inflammatory/white cell abundant diseases may also be positive, some of which are on the differential for neurosarcoidosis (e.g. tuberculosis and lymphoma). 

Treatment and prognosis

Treatment of neurosarcoidosis remains poorly established. Corticosteroids are the first-line therapy with other immunosuppressive agents, such as infliximab (TNF-α inhibitor), being used subsequently ¹¹. 

It is important to note that imaging correlates poorly with treatment response. Recurrence of symptoms and imaging evidence of disease progression is common. 

Differential diagnosis

The differential is broad and depends on the pattern of involvement. 

For pachymeningeal involvement consider

• meningioma

• dural metastases including lymphoma

• Erdheim-Chester disease

• idiopathic hypertrophic cranial pachymeningitis

For leptomeningeal involvement consider

• tuberculous leptomeningitis

• lymphoma/leukemia infiltration

• leptomeningeal metastases

• CNS cryptococcosis

  • cryptococcal meningitis is a rare but life-threatening complication of sarcoidosis and patients may be misdiagnosed as neurosarcoidosis, which can result in considerable treatment delay and worse outcome; CSF cryptococcal antigen tests are advised in patients with sarcoidosis and meningitis ⁸

For pituitary and hypothalamic involvement consider

• Langerhans cell histiocytosis

• pituicytoma

• ectopic posterior pituitary: intrinsic high T1 signal

• lymphocytic hypophysitis

• IgG4-related hypophysitis

• metastasis

• local masses

  • meningioma

  • optic nerve glioma

  • hypothalamic astrocytoma

For cranial nerve involvement consider

in addition to all causes of leptomeningeal disease (see above), specific entities to be considered include ¹:

• optic nerve

  • optic neuritis

  • optic perineuritis

  • optic nerve glioma

  • optic nerve meningioma

• facial nerve

  • infections (e.g. Lyme disease)

For parenchymal involvement consider

• multiple sclerosis

• ADEM

• leukoaraiosis: in asymptomatic cases, it is often not possible to distinguish between these and neurosarcoidosis lesions

• when enhancing other entities to consider include:

  • cerebral metastases

  • tumefactive demyelination or acute demyelination

  • primary brain tumors

  • CLIPPERS

  • supratentorial lymphocytic inflammation with parenchymal perivascular enhancement responsive to steroids (SLIPPERS)

  • autoimmune glial fibrillary acid protein (GFAP) astrocytopathy