Sarcoidosis and the REVIEW ARTICLE


Nervous System C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
By Siddharama Pawate, MD

ABSTRACT
PURPOSE OF REVIEW: This article provides an overview and update on the
neurologic manifestations of sarcoidosis.

RECENT FINDINGS: The 2018 Neurosarcoidosis Consortium diagnostic criteria

emphasize that biopsy is key for diagnosis and determines the level of
diagnostic certainty. Thus, definite neurosarcoidosis requires nervous
system biopsy and probable neurosarcoidosis requires biopsy from
extraneural tissue. Without biopsy, possible neurosarcoidosis can be
diagnosed if the clinical, imaging, and laboratory picture is compatible and
other causes are ruled out. Recent large retrospective studies from the
United States and France established that infliximab appears to be
efficacious when other treatments are inadequate.

SUMMARY: Sarcoidosis is a multisystem noninfectious granulomatous disorder

that is immune mediated, reflecting the response to an as-yet unidentified
antigen or antigens. Neurosarcoidosis refers to neurologic involvement
due to sarcoidosis that clinically manifests in 5% of cases of sarcoidosis, CITE AS:
with asymptomatic involvement in as many as another one in five patients CONTINUUM (MINNEAP MINN)
with sarcoidosis. Sarcoid granulomas can occur in any anatomic substrate 2020;26(3, NEUROLOGY OF
SYSTEMIC DISEASE):695–715.
in the nervous system, causing protean manifestations that have earned
neurosarcoidosis the sobriquet the great mimic. Nevertheless, central Address correspondence to
nervous system sarcoidosis occurs in well-defined presentations that can Dr Siddharama Pawate,
be classified as cranial neuropathies, meningeal disease, brain parenchymal Vanderbilt Multiple Sclerosis
Center, 3810 Bedford Ave,
(including pituitary-hypothalamic) disease, and spinal cord disease. In Nashville, TN 37215, siddharama.
addition, the peripheral nervous system is affected in the form of peripheral pawate@vumc.org.
neuropathy and myopathy. Glucocorticoids are the cornerstone of RELATIONSHIP DISCLOSURE:
treatment, especially in the acute stage, whereas steroid-sparing agents Dr Pawate has served on an
such as methotrexate, mycophenolate mofetil, and azathioprine are used advisory board for Biogen.

for prolonged therapy to minimize steroid toxicity. Anti–tumor necrosis UNLABELED USE OF
factor agents may help in refractory cases. PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Pawate discusses the
unlabeled/investigational use of
adalimumab, azathioprine,
INTRODUCTION corticosteroids,

T
he history of sarcoidosis begins with Jonathan Hutchinson, who is cyclophosphamide, infliximab,
credited with the first description of sarcoidosis in 1879.1–3 Caesar methotrexate, mycophenolate
mofetil, and rituximab for the
Boeck (1899) independently described 25 cases, including cutaneous treatment of neurosarcoidosis.
as well as systemic disease, and named it sarkoid as it resembled
sarcoma but was benign. Neurologic involvement in sarcoidosis was © 2020 American Academy
recognized by Winkler in 1905, who identified peripheral nerve disease, and by of Neurology.

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SARCOIDOSIS

Heerfordt in 1909, who described facial nerve involvement that came to be

known as Heerfordt syndrome (uveoparotid fever).1–3 Many years later, although
much has been learned, sarcoidosis remains something of a mystery.
Sarcoidosis is a multisystem disease of unknown etiology characterized
histopathologically by the presence of noncaseating epithelioid granulomas
without evidence of infectious organisms.4,5 Intrathoracic involvement (lungs
and mediastinal lymph nodes) is most common, occurring in 90% of patients.
Cutaneous and ocular sarcoidosis are also common, but the heart, liver, nervous
system, and virtually every other organ can also be affected. Biopsy of affected
tissue is generally needed to diagnose sarcoidosis and exclude other disorders,
such as other granulomatous disorders, infections, and neoplasms. This article
discusses the epidemiology and pathology of sarcoidosis and the clinical and MRI
findings and diagnostic approach to the neurologic manifestations of sarcoidosis
(neurosarcoidosis) and suggests treatment approaches. Although this article
focuses on neurosarcoidosis, the multisystem nature of sarcoidosis should be
kept in mind as a multidisciplinary approach to the management of patients with
sarcoidosis is usually required.

EPIDEMIOLOGY
Sarcoidosis may be asymptomatic in a substantial proportion of patients,
making the determination of its true incidence and prevalence difficult. It is a
global disease, with available studies reporting an incidence ranging from
0.2 per 100,000 people in Brazil to 19 per 100,000 people in Sweden.7 In the
United States, the incidence of sarcoidosis is estimated at 3 per 100,000 to
10 per 100,000 among whites6,7 and 35 per 100,000 to 80 per 100,000 among
African Americans.7 The majority of patients (70%) are between the ages of
25 and 45 at diagnosis; in women in Europe and Japan, a second peak in incidence
occurs after age 50.7 Clinical evidence of neurologic involvement of sarcoidosis
is reported in 5% to 10% of all sarcoidosis cases, but clinically occult
neurosarcoidosis is discovered at autopsy in an additional 10% to 15%. Of patients
with neurosarcoidosis, 10% to 17% never develop systemic disease, a condition
termed isolated neurosarcoidosis.8
Both genetic and environmental factors influence sarcoidosis. First- and
second-degree relatives of patients with sarcoidosis, but not spouses, have a
fivefold higher incidence, indicating a genetic predisposition.7 Occupational
exposure to microbe-rich environments such as mold and mildew, health care
and agricultural settings, and animal laboratories is associated with a higher
incidence.9 Although sarcoidosis is not an infectious disease, an exaggerated
immune response to antigens is thought to be the likely mechanism, and thus
microbial exposure may play an indirect role. The highest incidence of
sarcoidosis is in the organs that are most in contact with the external
environment—the lungs, skin, and eyes—and their draining lymph nodes. The
incidence of sarcoidosis in cigarette smokers is one-third of the incidence in
nonsmokers, presumably due to the immunosuppressive effect of tobacco
exposure.10

PATHOLOGY
Granuloma formation (FIGURE 8-1) in sarcoidosis is presumably incited by an
antigen that the immune system does not completely clear.9,11,12 Granulomas
function to confine the antigen and protect the surrounding tissue, but

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 uncontrolled granulomatous KEY POINTS
inflammation, especially in vital
● Sarcoidosis is a
structures such as the heart, eye, multisystem noninfectious
or brain, is deleterious. immune-mediated
Sarcoid granulomas consist of inflammatory
two parts: the core and the crust. granulomatous disease. The
histopathologic hallmark of
The core is a collection of tight
sarcoidosis is the
clusters of macrophages, giant noncaseating granuloma.
cells, epithelioid cells, and CD4+
T lymphocytes. The crust is a ● African Americans in the
collection of lymphocytes, United States are 10 times
more likely to have
FIGURE 8-1 predominantly CD8+ T sarcoidosis than whites, and
Biopsy of a spinal cord lesion that was suspected lymphocytes and B lymphocytes. African American women
to be an astrocytoma on imaging. Hematoxylin In the early stage, the have the highest incidence.
and eosin (H&E)–stained section shows aggregating macrophages are
non-necrotizing granulomatous inflammation ● Neurosarcoidosis has
(circle), 40x magnification with 50-micron converted into epithelioid cells. acquired the reputation of
scale bar. The epithelioid cells then being a challenging disease
Figure courtesy of Bret Mobley, MD. organize into a cluster that makes to diagnose because of its
up an immature granuloma. protean manifestations,
earning it the nickname the
Activated T cells accumulate at
great mimic. However, it is
sites of inflammation. This leads to increased activation and expression of helpful to recognize that
cytokines and chemokines. Tumor necrosis factor (TNF), produced by T cells neurosarcoidosis occurs as
and macrophages, has become recognized as a major mediator of formation and well-defined neurologic
manifestations: cranial
maintenance of mature granulomas. Fibroblast proliferation with collagen
neuropathies, meningitis,
deposition leads to fibrosis. parenchymal disease, spinal
In the central nervous system (CNS), sarcoid granulomas most often involve cord disease, peripheral
the basal meninges, with secondary infiltration of cranial nerves and obstruction neuropathy, and myopathy.
of CSF flow. Granulomas tend to be perivascular (ie, involving Virchow-Robin
● The facial nerve and optic
spaces) and may extend into the parenchyma of the brain and the spinal cord. nerve are the most
Granulomas also occur in peripheral nerves and muscle. commonly affected cranial
nerves in neurosarcoidosis.
CLINICAL AND IMAGING MANIFESTATIONS
● In the brain parenchyma,
The clinical manifestations of CNS sarcoidosis result from the anatomic location
hypothalamic-pituitary
of the granulomas and can be classified as cranial neuropathies, meningeal involvement is common
disease, brain parenchymal disease, and spinal cord disease.13,14 Because of these and causes a variety
varied manifestations, neurosarcoidosis can mimic a number of neoplasms and of neuroendocrine
manifestations.
infections and has been called the great mimic.
● Seizures and focal
Cranial Neuropathies neurologic deficits can
Cranial neuropathies occur in about 60% of all patients with neurosarcoidosis. result from parenchymal
Facial nerve involvement presenting as unilateral or bilateral (in up to one in neurosarcoidosis. The
specific manifestations
three patients) lower motor neuron facial nerve palsy is the most common cranial depend on the size,
nerve presentation.15 As compared to other forms of neurosarcoidosis, facial location, and speed of
nerve paralysis often has a benign prognosis, with resolution within 1 to 3 months. development of the
Over 80% of patients with cranial nerve palsy will have an additional neurologic inflammatory process.
manifestation, which may help distinguish neurosarcoidosis from isolated
cranial nerve syndromes such as Bell’s palsy. Other relatively frequent cranial
neuropathies are optic neuropathy or eighth (vestibulocochlear) nerve
dysfunction, which can also be unilateral or bilateral.16,17 Optic nerve
involvement typically presents as a subacute optic neuropathy (subacute loss of

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SARCOIDOSIS

vision with retrobulbar pain) (FIGURE 8-2) and should be recognized early
and treated aggressively to prevent permanent visual loss. Vision loss in
neurosarcoidosis may also be less commonly due to extrinsic compression of the
optic nerve.18 Isolated hearing loss or vertigo due to selective vestibulocochlear
nerve involvement can also occur.19 Other cranial nerves are involved less
frequently,13 and multiple cranial neuropathies may occur.
Neurologic deficits may reflect the direct granulomatous invasion of the
cranial nerve from adjacent meninges, but other mechanisms include
granulomatous infiltration of the cranial nerve nucleus or fascicles, elevated
intracranial pressure causing sixth nerve palsy, and sarcoidosis affecting the end
organ itself.

Parenchymal Disease
Granulomas within the brain parenchyma can cause varied manifestations
depending on the location, size, and speed of development of the inflammatory
process. Neurosarcoidosis has a predilection for the hypothalamus and pituitary
gland (FIGURE 8-320) (10% to 25% of cases of parenchymal involvement),

FIGURE 8-2
Orbital MRI in a 66-year-old man presenting with bilateral vision loss. Axial (A) and coronal (B,
C) postcontrast images showing enhancement of the optic nerves (arrows) concerning for
bilateral optic nerve sheath meningioma. However, the patient had evidence of systemic
sarcoidosis on chest imaging (not shown) and received aggressive immunotherapy. After
treatment with steroids, methotrexate, and infliximab for 3 months, corresponding axial (D)
and coronal (E, F) images show resolution of the contrast enhancement (arrows). The patient
reported substantial improvement in his vision.

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resulting in a range of neuroendocrine disturbances including hypothyroidism, KEY POINTS
hypogonadism, and the syndrome of inappropriate secretion of antidiuretic
● Both the leptomeninges
hormone (SIADH).21 Intraparenchymal lesions occur in 15% of cases of and the dura can be affected
neurosarcoidosis and can present with seizures, encephalopathy, and focal in neurosarcoidosis.
neurologic deficits (CASE 8-1).15,18,26,27 On MRI, these are typically isointense on Headache is a common
T1-weighted images, with variable postcontrast enhancement (6% to 37%), and presentation in these cases.
Hydrocephalus can develop
rarely contain areas of calcification, necrosis, or hemorrhage. For intraparenchymal
as a secondary complication
mass lesions, malignancy (particularly lymphoma), fungal or mycobacterial of meningitis.
meningoencephalitis, and tumefactive demyelination are other diagnostic
considerations. Nonspecific white matter lesions in the periventricular regions, ● A longitudinally extensive
centrum semiovale, and corona radiata are commonly seen in patients with transverse myelitis can be
seen in neurosarcoidosis
neurosarcoidosis and do not typically resolve with treatment or correlate with and can be difficult to
clinical disability, making their significance in neurosarcoidosis unclear. differentiate from
Parenchymal brain involvement may also take the form of cerebrovascular neuromyelitis optica
disease from vasculitis, dural sinus thrombosis, or extrinsic compression of spectrum disorders and
other causes.
vessels by granulomas, causing ischemic stroke, intracranial hemorrhage, and
generalized encephalopathy.28 In ischemic strokes, perforating arteries are most ● The neuropathy of
frequently involved; the infarcts are often small and commonly involve the basal neurosarcoidosis cannot be
ganglia, thalamus, and brainstem.28 Embolic ischemic stroke can occur from distinguished from other
immune-mediated
sarcoidosis-associated cardiomyopathy and arrhythmias.
neuropathies clinically, by
nerve conduction studies
and EMG, or by response to
immunotherapies.

● Small fiber neuropathy in

sarcoidosis is termed a
paraneurosarcoidosis,
reflecting that it is not due to
direct granulomatous
invasion of small fibers but a
distant effect due to
circulating inflammatory
mediators.

● CSF studies are

sensitive to demonstrate
intrathecal inflammation
but lack specificity for
neurosarcoidosis. CSF
findings in neurosarcoidosis
include pleocytosis,
increased protein,
decreased glucose,
elevated IgG index, and
the presence of
oligoclonal bands.
FIGURE 8-3
Spectrum of presentation of pituitary and hypothalamic lesions in neurosarcoidosis.
A, Coronal postcontrast T1-weighted image shows homogeneous enhancement of the
pituitary and infundibulum (arrow). B, Coronal postcontrast T1-weighted image shows an
enhancing, thickened infundibulum (arrow). C, Sagittal postcontrast T1-weighted image
demonstrates homogeneous enhancement of the pituitary, infundibulum, and hypothalamus
(arrows); note the significant leptomeningeal enhancement along the ventral surface of the
pons. D, Sagittal postcontrast T1-weighted image demonstrates heterogeneous
enhancement of the pituitary and infundibulum (arrow).
Reprinted with permission from Carlson ML, et al, Otol Neurotol.20 © 2015 Otology.

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SARCOIDOSIS

Meningeal Disease
Meningeal involvement in neurosarcoidosis typically presents as a subacute
lymphocytic meningitis, with headaches and variable nuchal rigidity with or
without fever.15,18,26,27 Asymptomatic chronic meningitis may also occur.
Leptomeningeal involvement is typical and has a predilection for the base of the
skull (FIGURE 8-5). Hydrocephalus may be a consequence of sarcoid meningitis
and can be either communicating (involvement of arachnoid granulations)
(FIGURE 8-6) or obstructive (compression of the aqueduct or granulomas within

CASE 8-1 A 48-year-old man presented for a second opinion regarding

management of neurosarcoidosis. Six years earlier, he had started to
have seizures and left-sided visual field loss. No abnormality had been
seen on ophthalmologic evaluation at that time; however, a brain MRI
showed extensive T2 hyperintensity and contrast enhancement in the
right occipital region. He was seen by a neuro-oncologist at an academic
center and had a brain biopsy that was inconclusive. He was empirically
treated with high-dose steroids with minimal improvement and therefore
had a second brain biopsy that was thought to be consistent with
sarcoidosis. He was treated with prolonged prednisone and
methotrexate. For about 4 years, methotrexate and prednisone appeared
to stabilize the disease, but he continued to have seizures and
headaches, with incomplete response to divalproex sodium,
levetiracetam, and topiramate. He was then evaluated at another
academic center and was prescribed infliximab 5 mg/kg every 6 weeks.
At presentation, he had been on infliximab for 2 years and prednisone
80 mg/d for “a few” months. His brain MRI continued to show extensive
abnormality in the right parietooccipital region and the right temporal
lobe. Because the neurologic symptoms and MRI findings had not
changed after 2 years on infliximab and prednisone, he was tried on pulse
cyclophosphamide 750 mg/m2. After six infusions of cyclophosphamide,
he had no change clinically and slight worsening on MRI (FIGURES 8-4A
THROUGH 8-4E). As he had not previously been on mycophenolate mofetil,
he was started on it. Because of the long latency of mycophenolate
mofetil and based on a case report22 of rituximab use in neurosarcoidosis,
he also received an infusion of rituximab (1000 mg on day 1 and day 14).
After 3 months, he began to notice a decrease in seizure and headache
frequency and severity. A brain MRI 6 months after the mycophenolate
mofetil–rituximab combination showed slight improvement. Because it
was not clear which of the two medications was responsible for the
improvement, he continued both. After another 6 months, he was able to
stop divalproex, levetiracetam, and topiramate, with no return of
headaches or seizures. He also started to notice a feeling of overall well-
being that had been absent since his symptoms began. Another MRI
18 months into the therapy showed significant improvement of the T2
hyperintensity and contrast enhancement (FIGURES 8-4F THROUGH 8-4J).

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the fourth ventricle). In addition to leptomeningeal disease, dural inflammation
(pachymeningitis) can also occur (CASE 8-2). Occasionally a dural inflammatory
mass mimicking a meningioma can occur.

Spinal Cord Disease

Spinal cord sarcoidosis is very likely to be disabling and particularly difficult
to diagnose.29 In most cases, it is due to a subpial intramedullary lesion, but
meningeal involvement can be seen in up to half the patients (FIGURE 8-8).

FIGURE 8-4
MRIs of the patient in CASE 8-1. Axial fluid-attenuated inversion recovery (FLAIR) images (A–D)
after 6 years of immunotherapy using methotrexate, steroids, infliximab, and cyclophosphamide,
show extensive hyperintensity and edema in the right cerebral hemisphere (arrows), and
the coronal postcontrast T1-weighted image (E) shows foci of contrast enhancement
(arrows). The corresponding axial FLAIR (F–I) images and postcontrast T1-weighted image (J)
after 18 months of therapy with rituximab and mycophenolate mofetil show improvement of
hyperintensity (arrows) and contrast enhancement (arrows).

Infliximab has emerged as a promising option in severe cases of COMMENT

neurosarcoidosis. However, it has a failure rate of approximately 20%
based on recent large retrospective studies.23,24 Options in such cases are
limited. If the failure is due to anti-infliximab antibodies, the humanized
anti–tumor necrosis factor antibody adalimumab may be an option. Recent
case reports suggest that rituximab may be effective in some cases of
neurosarcoidosis.22,25 Although this patient received both mycophenolate
mofetil and rituximab, the latter is more likely to have caused the
improvement as he started to feel better 3 months after starting these
agents, which is likely not enough time for the full effect of mycophenolate
mofetil to be seen. It is also possible that the combination of rituximab and
mycophenolate mofetil resulted in improvement.

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SARCOIDOSIS

FIGURE 8-5
Leptomeningeal neurosarcoidosis. A–D, Axial postcontrast T1-weighted brain MRI slices
showing extensive nodular leptomeningeal enhancement, predominantly in the posterior
fossa (A, B, arrows) but also in the cerebral hemispheres (C, D, arrows). Also note the
collapsed right lateral ventricle due to prior placement of a ventriculoperitoneal shunt to
treat hydrocephalus. E–H, Corresponding axial postcontrast T1-weighted brain slices after
6 months of treatment with high-dose steroids, mycophenolate mofetil, and infliximab
showing substantial resolution of leptomeningeal enhancement.

The thoracic region is most commonly involved, followed by the cervical

region. Patients present with lower extremity weakness and sensory
disturbances. They may have gradually worsening symptoms for months
before the diagnosis of spinal cord involvement is made. The myelitis may
span more than three vertebral segments (longitudinally extensive transverse
myelitis); thus, neurosarcoidosis is an important mimic of neuromyelitis
optica (NMO) spectrum disorder (FIGURE 8-8).30 A characteristic finding on
axial MRIs is the trident sign of contrast enhancement extending from the
dorsal subpial surface circumferentially bilaterally with a central spoke
extending into the midline of the cord (FIGURE 8-8D). Coexisting meningeal
involvement, especially dural swelling and enhancement, may be a clue
to neurosarcoidosis.

Neuromuscular Sarcoidosis
In addition to CNS sarcoidosis, patients with neurosarcoidosis may manifest
peripheral nervous system (PNS) involvement in the form of neuropathy
and myopathy.

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FIGURE 8-6
Hydrocephalus in neurosarcoidosis. A, Axial fluid-attenuated inversion recovery (FLAIR) MRI
showing enlargement of the lateral ventricles and transudation of CSF in the periependymal
region (white arrows). B, Sagittal noncontrast T1-weighted image showing enlargement of the
third (green arrow) and fourth (red arrow) ventricles indicating communicating hydrocephalus.
C, Corresponding sagittal postcontrast T1-weighted image showing extensive leptomeningeal
disease (white arrows) indicating neurosarcoidosis as the cause of the hydrocephalus.

NEUROPATHY. Symptomatic involvement of the PNS in sarcoidosis is rare,

occurring in only 1% to 2% of patients with systemic disease (CASE 8-3).31,32
Granulomatous inflammation may result in vasculitis or infiltration or direct
compression of peripheral nerve and muscle fibers. Clinical and EMG findings
are nonspecific and often indistinguishable from primary immune-mediated
neuromuscular disorders (eg, polymyositis or chronic inflammatory
demyelinating polyradiculoneuropathy [CIDP]), which respond to
corticosteroids and other immunotherapies used for sarcoidosis. In most cases of
muscle and nerve involvement, the affected tissue is more readily accessible for
biopsy than in patients with CNS disease.
Nerve conduction studies and EMG are the primary tests used in the identification
of sarcoid neuropathy and usually demonstrate changes consistent with axon
loss characterized by reduced nerve amplitudes and fibrillation potentials (with
acute or ongoing lesions) in the affected nerve distribution. Primary demyelinating
abnormalities are occasionally reported and may manifest with prolonged
latencies, conduction velocity slowing, and motor nerve conduction block.

SMALL FIBER NEUROPATHY. In contrast to large fiber nerve involvement,

symptoms of small fiber neuropathy are found in as many as 30% of patients
with systemic sarcoidosis.33 It has been termed a paraneurosarcoidosis as small
fiber involvement is not due to direct granulomatous inflammation but
presumably due to circulating inflammatory mediators. Small fiber neuropathy
is associated with sensory loss and neuropathic pain when somatic sensory
nerves are involved. Hyperhidrosis/hypohidrosis, cardiovascular dysautonomia,
gastrointestinal dysmotility, sicca symptoms, and bladder and sexual dysfunction
result from autonomic small fiber neuropathy. Small fiber neuropathy should be
attributed to sarcoidosis only in patients with well-established systemic sarcoidosis
or neurosarcoidosis after ruling out other causes. Nerve conduction studies are

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SARCOIDOSIS

insensitive to the presence of small fiber neuropathy, but skin biopsy may
demonstrate decreased intraepidermal nerve fiber density and sweat
gland denervation.

MYOPATHY. Although subclinical muscle involvement has been found in 50% to

80% of patients with sarcoidosis on imaging studies or at autopsy, symptomatic
myopathy is reported in only 1.4% to 2.3% of patients with sarcoidosis. Chronic
myopathy is the most common type and is characterized by gradually
progressive muscle weakness primarily affecting proximal muscles, although a
distal predominant pattern has been reported.34 The nodular type is seen more
frequently in men and manifests as stiffness, pain, and palpable nodules. Acute
myositis is rare and has a presentation similar to that of polymyositis.

CSF FINDINGS
No CSF findings are specific for neurosarcoidosis. Even so, in patients suspected
of neurosarcoidosis, a CSF study (unless contraindicated) helps establish the
presence of intrathecal inflammation and rule out infectious and neoplastic

CASE 8-2 A 45-year-old woman presented with a 4-day history of bilateral upper
extremity paresthesia, shortness of breath on exertion, and tachycardia
and 1 day of horizontal diplopia. She also noted that although she had a
long history of migraine, she had a new bifrontal headache. Neurologic
examination was normal, including extraocular movements.
Brain MRI showed dural and leptomeningeal enhancement (FIGURE 8-7).
Lumbar puncture was performed. CSF opening pressure was 28 cm H2O.
CSF protein was 195 mg/dL, glucose was 36 mg/dL (simultaneous serum
glucose was not done), white blood cell count was 269 cells/mm3 with
92% lymphocytes, IgG index was 1.07, and oligoclonal bands were absent.
Chest x-ray was normal. Chest CT showed a solitary subcentimeter
nodule in the lung that was of unclear significance but was otherwise
normal.
The differential diagnosis for the meningeal involvement was thought
to be an infection or immune-mediated process rather than lymphoma.
As chest imaging was unrevealing, she underwent fludeoxyglucose
positron emission tomography (FDG-PET), which showed that the
meningeal lesions were intensely FDG avid, and FDG-avid lesions in the
myocardium and liver were also seen (FIGURE 8-7). A biopsy was performed
on the liver lesion, showing noncaseating granulomas. She was treated
with high-dose steroids and methotrexate with modest clinical
improvement, followed by infliximab. Within a few days of starting
infliximab, she noted a distinct improvement in her neurologic symptoms
(resolution of headaches) and her cardiac symptoms.

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causes. The CSF opening pressure may be elevated. Nonspecific CSF markers of
CNS inflammation (any combination of pleocytosis, elevated protein, oligoclonal
bands, decreased glucose, and IgG index elevation) are seen in 50% to 70% of
patients with neurosarcoidosis.18,27 Although oligoclonal bands are typically
evocative of multiple sclerosis, approximately 20% of patients with
neurosarcoidosis show their presence. Neurosarcoidosis is one of the few
noninfectious diseases that result in low CSF glucose. Simultaneous serum
glucose should be obtained to interpret the CSF glucose level. CSF abnormalities
are most likely to be seen in patients who exhibit leptomeningeal enhancement
on MRI.35 CSF angiotensin-converting enzyme (ACE) levels are of uncertain
value. In one study, mean CSF ACE levels were not significantly different
between patients with or without neurosarcoidosis, and the sensitivity
(66.7%) and specificity (67.3%) of this assay were poor.36 A high CSF ACE level
may still be useful in some patients as a prompt to look more closely for
neurosarcoidosis.18 CSF cytology and flow cytometry should be sent to evaluate
for neoplasms, especially if patients have leptomeningeal enhancement on MRI
or hydrocephalus.

FIGURE 8-7
Imaging of the patient in CASE 8-2 with meningeal sarcoidosis. A, Sagittal postcontrast
T1-weighted MRI showing areas of dural enhancement in the falx cerebri (yellow
arrows) and nodules of contrast enhancement in the upper cervical spinal canal
(green arrow). B, Fludeoxyglucose positron emission tomography (FDG-PET) shows that
the contrast-enhancing regions are intensely FDG avid (white arrows). Note that although
in this case the FDG-PET abnormalities are obvious, because of the high basal metabolic
rate in the brain, PET is less sensitive for detection of neurosarcoidosis than it is for systemic
sarcoidosis. C, Coronal thoracic FDG-PET also shows intensely FDG-avid lesions in the
patient’s heart (red arrow) and liver (gray arrow). Hypometabolism is seen in the
myocardium outside of the FDG-avid nodule. A biopsy was done on the liver lesion and
disclosed noncaseating granulomas.

This case highlights the fact that sarcoidosis can be active in multiple organ COMMENT
systems concurrently. It also shows the importance of FDG-PET to identify
extrathoracic lesions amenable to biopsy. In addition, in this patient, by
detecting potentially fatal myocardial sarcoidosis, FDG-PET allowed early
aggressive therapy that resulted in a good outcome.

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SARCOIDOSIS

DIAGNOSIS
No specific diagnostic test or
biomarker has been established
for sarcoidosis. Demonstration of
noncaseating granulomas in
affected tissues in which no
microorganisms are detectable
is the most helpful tool available.
However, granulomas may
also be due to other infectious
and noninfectious causes.
Therefore, although biopsy is
vital, the diagnosis of sarcoidosis
requires the integration of
clinical manifestations and
laboratory and imaging findings
with the histopathology.
Biopsy is not always feasible
in neurosarcoidosis because
of the risk of permanent
neurologic deficits induced
by the procedure. Diagnostic
criteria over the years have
tried to address these issues.37
FIGURE 8-8 In 2018, the Neurosarcoidosis
Spinal cord sarcoidosis. A, Sagittal T2-weighted Consortium Consensus Group
MRI of the cervical spinal cord shows swelling and
T2 hyperintensity (arrow) spanning five vertebral
issued diagnostic criteria for
segments (longitudinally extensive transverse neurosarcoidosis encompassing
myelitis). B, Sagittal postcontrast T1-weighted both CNS and PNS involvement
MRI shows contrast enhancement (arrow) within (TABLE 8-1).37 The criteria affirm
the spinal cord and posterior meninges. C,
D, Axial postcontrast T1-weighted images show
the centrality of histopathology
contrast enhancement (C, arrow), and panel D for the diagnosis. Thus,
shows the trident sign (contrast enhancement definite or highly probable
extending from the dorsal subpial surface neurosarcoidosis requires biopsy
circumferentially bilaterally with a central spoke
extending into the midline of the cord) (arrow).
of affected central or peripheral
Figure courtesy of Eoin Flanagan, MD. neural tissue. Demonstration of
sarcoid pathology in non-neural
tissue allows the diagnosis of
probable neurosarcoidosis. In the absence of biopsy, possible neurosarcoidosis
can be diagnosed based on clinical, imaging, and laboratory findings.
In the case of PNS sarcoidosis, nerve conduction studies and EMG do not show
any specific findings suggestive of sarcoidosis. Thus, histologic confirmation of
the affected tissue is required for a diagnosis of definite peripheral
neurosarcoidosis, and evidence of systemic disease is required for a diagnosis of
probable peripheral neurosarcoidosis.

Approach to the Patient

The differential diagnosis of neurosarcoidosis is wide (TABLE 8-2). Therefore,
extensive workup may be needed and is guided by the clinical context. In
patients with known systemic sarcoidosis, neurosarcoidosis is usually high on the

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differential when neurologic manifestations occur. Patients with no known KEY POINTS
systemic sarcoidosis pose more of a challenge and require a high index of
● The Neurosarcoidosis
suspicion to make the correct diagnosis. When a patient in the latter group Consortium Consensus
presents with symptoms consistent with CNS sarcoidosis (cranial neuropathies, Group criteria for
meningitis, parenchymal lesions, or spinal cord lesions), the first steps are the neurosarcoidosis seek to
demonstration of CNS inflammation by MRI and CSF studies and ruling out standardize the definition of
neurosarcoidosis
infections and neoplasms. If the MRI shows brain or spinal cord lesions amenable
encompassing both central
to biopsy, it should be considered. Otherwise, systemic imaging (chest CT, nervous system and
positron emission tomography [PET]) may show lesions that can be biopsied. peripheral nervous system
involvement. They affirm the
vital role of biopsy in the
BRAIN AND SPINAL CORD IMAGING. MRI of the brain and spinal cord is sensitive
diagnosis.
to the presence of granulomatous inflammation but is not specific and can mimic
a range of immune-mediated illnesses, infections, and neoplasms. The figures ● A biopsy of the nervous
throughout this article detail MRI findings observed in neurosarcoidosis; system lesion is required for
however, note that most of these MRI findings can also be seen in other diseases. the diagnosis of definite
neurosarcoidosis.
Extraneural biopsy
SYSTEMIC IMAGING. Systemic imaging is helpful to demonstrate sarcoidosis in consistent with sarcoidosis,
extraneural tissues and provide possible targets for biopsy. As 90% of patients in conjunction with central
with sarcoidosis have pulmonary and mediastinal involvement, a chest x-ray and nervous system
inflammation suggestive of
thorax CT are valuable initial studies. When CT is unrevealing, whole-body sarcoidosis, allows the
fludeoxyglucose (FDG)-PET may identify otherwise occult targets for biopsy diagnosis of probable
(CASE 8-2 and FIGURE 8-7).38 Gallium scintigraphy is an option where PET is neurosarcoidosis. In the
not available. absence of histopathologic
confirmation, possible
neurosarcoidosis can be
LABORATORY STUDIES. Serum studies are not diagnostic for neurosarcoidosis diagnosed in the presence
but can establish systemic inflammation and may identify alternative of appropriate clinical,
etiologies. Mean serum ACE levels are higher for patients with sarcoidosis than imaging, and laboratory
findings.
controls, but poor sensitivity and specificity limit the diagnostic utility of ACE
levels for neurosarcoidosis. Screening for tuberculosis using an interferon ● As with CSF, MRI is
gamma release assay is useful to exclude infection by tuberculosis as an sensitive to the presence of
alternative diagnosis. inflammation but is not
As noted above, more than 50% of patients with neurosarcoidosis will have specific for
neurosarcoidosis.
abnormal CSF findings suggestive of intrathecal inflammation, although none
are specific for the diagnosis. In addition to routine studies, fungal/mycobacterial ● Chest imaging is a vital
cultures, cytology, and flow cytometry should be obtained in the appropriate initial study in the
clinical context. investigation of
neurosarcoidosis because
90% of patients with
TREATMENT sarcoidosis will have
The treatment of neurosarcoidosis can be challenging. The clinical course is intrathoracic involvement. A
uncertain. Neurosarcoidosis is occasionally detected incidentally (eg, by chest CT can pick up
additional cases missed by
meningeal enhancement) but, given the potentially devastating consequences
chest x-ray.
of neurologic damage, treatment must be considered. Potential side effects of
treatments, especially opportunistic infections, must be balanced against the ● If clinical suspicion is high
potential benefits. In the absence of data from clinical trials, the treatment of and chest imaging is
neurosarcoidosis is based on observations from case series and case reports. negative, positron emission
tomography can show
Given this, the decision to initiate, increase, taper, or discontinue medications extrathoracic systemic
must be individualized. sarcoidosis and provide
Classifying patients with neurosarcoidosis into mild, moderate, and severe cases targets for biopsy.
may provide a useful framework for treatment decisions.39 Thus in mild cases, such
as isolated facial nerve palsy with no other MRI findings and aseptic meningitis,

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SARCOIDOSIS

prednisone 40 mg/d for 1 month followed by a slow taper may be adequate. These
cases tend to be monophasic and do not require prolonged therapy. In moderate
cases, such as chronic meningitis, multiple cranial neuropathies, and parenchymal
disease, IV methylprednisolone 1000 mg/d for 3 to 5 days followed by oral
prednisone 60 mg/d to 80 mg/d for 1 month followed by a slow taper may be
required. In these cases, early initiation of steroid-sparing agents such as

CASE 8-3 A 38-year-old man with a 5-year history of sarcoidosis with cutaneous
and pulmonary involvement presented with a 6-day history of
progressive, bilateral, ascending lower extremity weakness. Neurologic
examination showed normal mental status, cranial nerves, and upper
extremity strength and sensation. He had mild paraparesis (4/5 strength)
and lower extremity areflexia. No sensory deficits were noted in his lower
extremities.
Nerve conduction studies and EMG revealed evidence of a primarily
demyelinating sensorimotor polyneuropathy consistent with Guillain-
Barré syndrome. CSF showed elevated protein of 318 mg/dL with a white
blood cell count of 3 cells/mm3.
He was treated with IV immunoglobulin (IVIg) 2 g/kg over 5 days for
acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and
discharged to rehabilitation. Four days later, he returned with worsened
lower extremity weakness, now 2/5 to 3/5 strength. The IVIg was deemed
a failure, and he underwent plasma exchange. He was discharged after
1 week with a strength of 4–/5 to 4+/5 in the lower extremities.
One week later, he was readmitted with complete paraplegia. Spinal
cord MRI (FIGURE 8-9A) showed thickening and contrast enhancement of
the cauda equina and the meninges surrounding the lower lumbar cord.
The thoracic cord showed normal signal. Extensive retroperitoneal
lymphadenopathy was also seen. This raised a question of whether the
cause was paraneoplastic AIDP versus lymphoma. Lymph node biopsy
showed noncaseating granulomas.
He was then treated with high-dose steroids with some improvement
and referred to a neuroimmunology clinic. Because this presentation was
consistent with probable neurosarcoidosis, he was treated with a steroid
taper, methotrexate, and infliximab. Within 4 months, he had improved to
normal ambulation and follow-up lumbar MRI showed substantial
improvement (FIGURE 8-9B).

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mycophenolate mofetil or methotrexate should be considered and continued for 2 to
3 years. In severe cases such as optic neuropathy and spinal cord disease, early
initiation of infliximab should be considered in addition to steroids and
steroid-sparing agents. The role of surgery is typically limited to biopsy, but
hydrocephalus may require a ventriculoperitoneal shunt. TABLE 8-3 summarizes the
agents commonly used in the treatment of neurosarcoidosis.

FIGURE 8-9
MRI of the patient in CASE 8-3 with sarcoidosis of the cauda equina. A, Sagittal postcontrast
T1-weighted image shows thickening and contrast enhancement in the cauda equina (arrows)
and the meninges surrounding the conus medullaris. B, Sagittal postcontrast T1-weighted
image 4 months after treatment with steroids, methotrexate, and infliximab shows
improvement of enhancement (arrows), and clinically the patient was back to his premorbid
condition.

This patient has a neuromuscular presentation of neurosarcoidosis. COMMENT

Although the patient had a prior history of pulmonary and cutaneous
sarcoidosis, the neurologic presentation, nerve conduction studies and
EMG, and CSF analysis were sufficiently consistent with AIDP that
neurosarcoidosis was overlooked as a possibility until the third admission.
While his EMG showed demyelinating changes in the right ulnar nerve, his
upper extremities remained clinically normal throughout the course, which
would be unusual for AIDP. An AIDP-like presentation has been described
in neurosarcoidosis. In this patient, the lower extremity weakness resulted
from a combination of peripheral nerve and cauda equina involvement.
Whereas infliximab has been reported to be effective in central nervous
system sarcoidosis, this case indicates that it may be equally effective in
peripheral nervous system sarcoidosis.

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SARCOIDOSIS

Corticosteroids
If no contraindications are present, glucocorticoids are typically used as first-line
therapy. Although no clinical trial data are available, in a meta-analysis by Fritz
and colleagues,13 83% of 655 patients were treated with corticosteroids. Severe
presentations may require pulse dose glucocorticoids (methylprednisolone 1 g IV
daily for 3 to 5 days) followed by a prolonged oral prednisone taper. For less
severe presentations, high-dose prednisone (1 mg/kg/d) or lower-dose
glucocorticoids may be sufficient. However, approximately one in five patients
will be refractory to glucocorticoids, relapse when attempting to taper doses, or
have unacceptable side effects.40 Therefore, steroid-sparing agents are important
in the treatment of neurosarcoidosis.

Steroid-sparing Agents
Steroid-sparing agents include azathioprine, methotrexate, and mycophenolate
mofetil.18 Little literature is available to support the choice of one over the others.
A 2016 retrospective study including 40 patients with neurosarcoidosis suggested
greater efficacy of methotrexate over mycophenolate mofetil but also more
adverse effects with methotrexate.41 Cyclophosphamide was found to benefit
patients with severe neurosarcoidosis in one report.42 Rituximab, a monoclonal
antibody directed against CD20, depletes B lymphocytes and has been used
successfully for neurosarcoidosis in isolated cases.22,25

TABLE 8-1 Criteria for the Diagnosis of Neurosarcoidosis as Proposed by the

Neurosarcoidosis Consortium Consensus Groupa

Definite
◆ Clinical presentation and diagnostic evaluation suggest neurosarcoidosis as defined by the
clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous
inflammation of the nervous system and rigorous exclusion of other causes
◆ Nervous system pathology is consistent with neurosarcoidosis
◇ Extraneural sarcoidosis is evident
◇ No extraneural sarcoidosis is evident (ie, isolated central nervous system sarcoidosis)
Probable
◆ Clinical presentation and diagnostic evaluation suggest neurosarcoidosis as defined by the
clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous
inflammation of the nervous system and rigorous exclusion of other causes
◆ There is pathologic confirmation of systemic granulomatous disease consistent with
sarcoidosis
Possible
◆ Clinical presentation and diagnostic evaluation suggest neurosarcoidosis as defined by the
clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous
inflammation of the nervous system and rigorous exclusion of other causes
◆ There is no pathologic confirmation of granulomatous disease

CSF = cerebrospinal fluid; EMG = electromyography; MRI = magnetic resonance imaging; NCS = nerve
conduction studies.
a
Reprinted with permission from Stern BJ, et al, JAMA Neurol.37 © 2018 American Medical Association.

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Selected Differential Diagnostic Considerations for Neurosarcoidosis
Category
Systemic and central
nervous system (CNS)
infections
Malignancies
Other neuro-
inflammatory disorders
Neurologic involvement
from systemic disorders
Vascular
CSF = cerebrospinal fluid; CT = computed tomography; IgG4 = immunoglobulin G4.
a
MRI and CSF studies are sensitive in detecting central nervous system pathology but do not differentiate between sarcoidosis, other immune-
mediated conditions, infectious, and neoplastic etiologies. Thus, additional studies are required to discern other possibilities as indicated by the
clinical context.
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TABLE 8-2
Examples Commentsa
Tuberculosis Cultures, serologies, polymerase chain
reaction as appropriate to detect infectious
Atypical Mycobacterium (very rare in the
organisms may help establish an infectious
absence of prior neurosurgery or hardware)
etiology
CNS fungal infections: coccidioidomycosis,
histoplasmosis, cryptococcosis, sporotrichosis,
blastomycosis
Spirochetal infections: neurosyphilis,
neuroborreliosis (Lyme disease)
Tropheryma whipplei (neuro-Whipple disease)
Progressive multifocal leukoencephalopathy
Parasitic infection (in the appropriate
neuroimaging, CSF examination, or
epidemiologic context)
Lymphoma (primary CNS lymphoma or systemic Histopathology will detect neoplasms
lymphoma with neurologic involvement)
CNS tumors (glioma, germ cell tumor,
craniopharyngioma)
Meningeal carcinomatosis
Histiocytosis (Erdheim-Chester disease) Histopathology may help detect other
etiologies; CT angiogram or conventional
Multiple sclerosis, especially tumefactive
cerebral angiogram may be required when
lesions
vasculitis is suspected; aquaporin-4 or MOG
Acute disseminated encephalomyelitis (ADEM) antibodies may be detected in patients with
NMO spectrum disorders
Neuromyelitis optica (NMO) spectrum disorders
CNS vasculitis
Autoimmune astrocytopathy with anti-glial
fibrillary acidic protein (GFAP) antibodies
Anti–myelin oligodendrocyte glycoprotein
(MOG) antibody syndrome
Systemic lupus erythematosus (SLE) Clinical and rheumatologic criteria may help
point to systemic inflammatory diseases;
IgG4-related hypertrophic pachymeningitis
histopathology is definitive for IgG4-related
Sjögren syndrome disease
Behçet disease
Vogt-Koyanagi-Harada disease
Common variable immunodeficiency
Dural arteriovenous fistula (brain or spinal cord) Clinical context and vascular imaging
or other vascular malformations such as
arteriovenous malformations
Stroke
711
SARCOIDOSIS

Agents Targeting Tumor Necrosis Factor

As noted earlier, TNF plays a key role in the inflammatory response and is
thought to contribute to formation and maintenance of granulomas in
sarcoidosis. Therefore, TNF has been targeted in the treatment of both systemic
sarcoidosis and neurosarcoidosis. Two 2017 retrospective studies investigated the
use of infliximab in neurosarcoidosis.23,24 A multicenter study from the
United States looked at infliximab use in 66 patients. In the majority of patients,
infliximab was combined with an oral agent (mycophenolate mofetil or
methotrexate) with the aim of obtaining synergistic effects as well as a reduction
of formation of anti-infliximab antibodies that reduce the effectiveness of
infliximab.43 Over 80% of patients had favorable responses clinically and
radiographically. The other study, from France, had similar results. In both
studies, approximately half of patients relapsed in the same location after
discontinuation of infliximab, indicating that infliximab suppresses disease
activity but may not result in its eradication in the period for which the patients

TABLE 8-3 Agents Used in the Treatment of Neurosarcoidosis

Agent Dosage Adverse Effects Monitoring

Corticosteroids

Prednisone Start 40 mg/d or up to 1 mg/kg/d
depending on severity, with
aim to taper as fast as feasible
to minimum required
Numerous side effects include Clinical monitoring
effects on blood glucose, Cushing
syndrome, fluid retention,
gastrointestinal upset,
osteoporosis, cataracts; with
pulse steroids, a 1 in 10,000 chance
of avascular hip necrosis (1 in 1000
after repeated courses)

IV Initial treatment of moderate Numerous side effects include Clinical monitoring

methylprednisolone to severe cases, 1000 mg/d
pulse for 3–5 days, followed by
transition to oral prednisone
regimen above
effects on blood glucose, Cushing
syndrome, fluid retention,
gastrointestinal upset,
osteoporosis, cataracts; with
pulse steroids, a 1 in 10,000 chance
of avascular hip necrosis (1 in 1000
after repeated courses)

Steroid sparing agents

Azathioprine 50–150 mg/d Bone marrow suppression, Complete blood cell count
gastrointestinal upset with differential counts, liver
functions monthly initially,
1 in 300 whites are deficient in
then every 3–6 months; check
thiopurine methyltransferase, an
thiopurine methyltransferase
enzyme that metabolizes
before initiation
azathioprine, and azathioprine
should be avoided in these
individuals

CONTINUED ON PAGE 713

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were treated. Another anti-TNF agent, adalimumab, has much more limited data
in the form of isolated case reports.44

OUTCOMES
In general, the outcome of patients with neurosarcoidosis is favorable. Mild
disease, such as facial nerve palsy and aseptic meningitis, typically recovers
completely. In more severe cases, the extent of permanent CNS or PNS damage
contributes to less than optimal clinical recovery. In some patients, clinical
deficits may take significantly longer to recover than imaging findings.

CONCLUSION
Given its varied manifestations, most neurologists regardless of subspecialty
will encounter patients with neurosarcoidosis. Although the diagnosis of
neurosarcoidosis can be challenging, familiarity with its manifestations will

CONTINUED FROM PAGE 712

Agent Dosage Adverse Effects Monitoring

Methotrexate 10–25 mg/wk along with folic Bone marrow suppression, Complete blood cell count
acid 1 mg/d gastrointestinal upset with differential counts, liver
functions every 4–6 weeks
initially and once every
3–6 months after stabilized

Mycophenolate 1000–1500 mg 2 times a day Gastrointestinal upset, Complete blood cell count
mofetil headaches, leukopenia with differential counts every
6 weeks for 6 months, then
every 3–6 months

Cyclophosphamide Pulse dosing 500–750 mg/m2
IV every 4 weeks, typically for
6–9 months as induction
therapy
Hemorrhagic cystitis (can be
avoided by careful hydration),
leukopenia, infections
Complete blood cell count with
differential counts before
infusion and midway between
infusions to monitor white
blood cell counts, urinalysis
before infusion to confirm the
absence of hematuria

Rituximab 1000 mg IV infusion on day 1 Well tolerated, opportunistic Lymphocyte subsets to guide
and day 15, then 1000 mg every infections are a concern; after dosing or may dose once
6–8 months depending on prolonged use, may require IgG every 6 months
CD19 counts repletion

Anti–tumor necrosis factor therapy

Infliximab 3–7 mg/kg IV infusions, Infusion reactions, central nervous Confirm the absence of
weeks 0, 2, and 6, then every system demyelination, tuberculosis before initiation
4–6 weeks opportunistic infections

Adalimumab 40 mg subcutaneously every Infusion reactions, central nervous Confirm the absence of
2 weeks system demyelination, opportunistic tuberculosis before initiation
infections, injection site reactions

IgG = immunoglobulin G; IV = intravenous.

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SARCOIDOSIS
KEY POINTS
● Corticosteroids are the
first-line agents in therapy
of neurosarcoidosis, but
their long-term use is
fraught with adverse
effects. The goal should be
to minimize their use to the
shortest possible duration.
● Steroid-sparing agents
have been used in patients
requiring long-term
immunotherapy to minimize
steroid adverse effects;
they include methotrexate,
mycophenolate mofetil, and
azathioprine.
● Infliximab has emerged as
a cornerstone in the
treatment of refractory or
severe cases of
neurosarcoidosis.
714
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allow the clinician to maintain a high index of suspicion and initiate a rational
diagnostic approach. Tissue diagnosis may not always be possible, despite
appropriate efforts; thus, clinical judgment and a multidisciplinary approach are
especially important. Although no randomized placebo-controlled clinical trials
have been performed in neurosarcoidosis, retrospective evidence supports the
use of glucocorticoids and steroid-sparing agents. TNF inhibitors appear to be
effective in cases refractory to usual therapy and for those with severe presentations.
ACKNOWLEDGMENTS
The author would like to thank Barney Stern, MD, FAAN; Michael Bradshaw,
MD; Subramaniam Sriram, MD; Megan Rahmlow, MD; Matthew Schrag, MD;
Derek Wood, MD; and Caroline Germany, MD, for reading the manuscript and
offering helpful suggestions.
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