Current Treatment Options in Neurology

, Volume 15, Issue 4, pp 492–504

Neurosarcoidosis

Authors

    • Division of Neurology, Department of NeurosciencesMedical University of South Carolina
  • Marc A. Judson
    • Division of Pulmonary and Critical Care MedicineAlbany Medical College
NEUROLOGIC MANIFESTATIONS OF SYSTEMIC DISEASE (A PRUITT, SECTION EDITOR)

DOI: 10.1007/s11940-013-0242-9

Cite this article as:
Nozaki, K. & Judson, M.A. Curr Treat Options Neurol (2013) 15: 492. doi:10.1007/s11940-013-0242-9
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Opinion statement

Neurosarcoidosis can involve either the central nervous system (CNS), the peripheral nervous system (PNS), or both. The clinical manifestations are varied and include cranial neuropathy, aseptic meningitis, hydrocephalus, headache, seizure, neuropsychiatric symptoms, neuroendocrine dysfunction, myelopathy, and peripheral neuropathy. Neurologic problems that develop in sarcoidosis patients should not be assumed to represent neurosarcoidosis, as they are often attributable to another cause. The diagnostic work up of neurosarcoidosis should include an evaluation for potential extra-neural involvement and histologic confirmation of sarcoidosis. If there is no appropriate extra-neurologic organ for biopsy, a biopsy from involved neural tissue needs to be considered. Biopsy of the dura and leptomeninges is less invasive than biopsy of the brain or spinal cord parenchyma. Gadolinium-enhanced magnetic resonance imaging (MRI) of the brain and spinal cord is the most sensitive test for neurosarcoidosis, while the diagnostic specificity of cerebrospinal fluid (CSF) analysis is limited. Corticosteroids are the mainstay of treatment for neurosarcoidosis. In general, oral corticosteroids are used for mild to moderate cases, while high-dose intravenous methylprednisolone is used in severe cases or refractory cases that fail to respond to oral corticosteroids. Immunomodulating and cytotoxic agents are often required for steroid-refractory neurosarcoidosis or for patients who develop significant corticosteroid adverse effects. Methotrexate is used as a first-line corticosteroid sparing agent. Tumor necrosis factor-alpha inhibitors, including infliximab, are effective for refractory neurosarcoidosis. Cyclophosphamide is also used for refractory neurosarcoidosis patients, but, because of the drug’s significant toxicity, it is usually reserved for severe cases that have failed oral therapies when tumor necrosis factor alpha antagonists cannot be obtained. In addition to anti-granulomatous therapy, treatment is frequently required for neurosarcoidosis-associated conditions, such as epilepsy and neuroendocrine dysfunction. Surgical intervention is indicated for life threatening complications such as hydrocephalus, steroid-refractory spinal cord compression, or mass lesions causing increased intracranial pressure.

Keywords

NeurosarcoidosisTreatmentCorticosteroidsMethotrexateCyclophosphamideInfliximabChloroquineHydroxychloroquine

Introduction

Sarcoidosis is a granulomatous disorder that affects multiple organs [1]. Although its etiology is unknown, its pathogenesis is thought to be related to an abnormal immune response. The lung, skin, and eye are the most common organs involved with sarcoidosis. Symptomatic neurologic involvement develops in 5 % to 13 % of sarcoidosis patients [25]. CNS neurosarcoidosis is thought to develop from a granulomatous inflammatory meningitis that may then extend into the brain parenchyma or the spinal cord [6]. It is important to note that only half of sarcoidosis patients with neurologic problems have neurosarcoidosis [3]; the other half have a neurologic condition that is unrelated to sarcoidosis. Therefore, the presence of a neurologic abnormality is inadequate to establish the diagnosis or to initiate treatment of neurosarcoidosis. Treatment decisions need to be based on clinical and laboratory data that support a diagnosis of neurosarcoidosis and exclude alternative causes. In this manuscript, we will review the clinical manifestations, diagnostic work up, and approach to the treatment of neurosarcoidosis.

Clinical manifestations

Cranial neuropathies are the most common manifestations of neurosarcoidosis, with a facial nerve palsy being the most frequent [3, 5]. The sarcoidosis-associated facial nerve palsy can occur unilaterally or bilaterally [3, 7]. Another common cranial neuropathy is optic neuritis that typically presents with blurred vision, a change of color vision, or a visual field deficit [8]. Sarcoidosis-related optic neuritis is considered a neuro-ophthalmic emergency because permanent vision loss may occur if therapy is not initiated immediately [8]. Optic nerve damage is caused by granulomatous infiltration or compression with resultant atrophy [3]. Sarcoidosis-related facial nerve palsies tend to have a good prognosis

A lymphocyte-predominant meningitis is another common manifestation of neurosarcoidosis. Its clinical manifestations are similar to other causes of meningitis, including fever, headache, and nuchal rigidity [8]. Hydrocephalus has been described in 5 %–7 % of patients with neurosarcoidosis [9]. Hydrocephalus can be either communicating or non-communicating. Communicating hydrocephalus arises from meningeal arachnoid granulomatous involvement, while non-communicating hydrocephalus is associated with obstructing ventricular lesions, often at the level of the third ventricle and foramen of Munro [10]. Although hydrocephalus is a rare presenting manifestation of sarcoidosis [9, 11], it has a poor long-term prognosis [11]. Spinal cord neurosarcoidosis is a rare entity that occurs in <1 % of sarcoidosis patients [12]; it is an important manifestation because it frequently causes severe neurologic sequelae without prompt diagnosis and management [13].

Headache is a common symptom of neurosarcoidosis, and has a variety of potential causes including meningitis, encephalopathy, a mass lesion, or hydrocephalus [14]. Approximately 15 % of neurosarcoidosis patients will develop seizures [15]. Neurosarcoidosis may cause seizures due to an intracranial granulomatous mass, encephalopathy, vasculopathy, or hydrocephalus.

Neurosarcoidosis is associated with various neuropsychiatric conditions, including depression, encephalopathy, and psychosis. These conditions have numerous causes, including granulomatous infiltration of the neural vasculature, perivascular granulomatous inflammation [3], hydrocephalus [10], psychological stress [16, 17], and an adverse effect of corticosteroid treatment. Neuroendocrine dysfunction may occur from sarcoid granulomas extending into the hypothalamic-hypophysial region [18]. In hypothalamo-pituitary sarcoidosis, anterior pituitary dysfunction is most commonly seen, followed in frequency by diabetes insipidus. Other hormonal abnormalities include gonadotropin deficiency, thyroid stimulating hormone deficiency, and hyperproloctinemia [19].

Sarcoidosis involvement of the peripheral nerves results from granulomas accumulation, mainly in the epineurium and perineurium. A necrotizing vasculitis is seen in approximately 20 % of nerve biopsies [20]. The most common manifestation of large fiber peripheral neuropathy in sarcoidosis is a symmetric axonal polyneuropathy [6, 7]. Other patterns include mononeuritis multiplex [3] and Guillain-Barre-like syndrome [21]. Sarcoidosis associated small fiber neuropathy occurs much more commonly than previously thought and is considered a common cause of chronic pain in sarcoidosis patients [22•]. Sarcoidosis associated small fiber neuropathy usually presents with pain, numbness, burning dysesthesias, and vibrating or electric shock-like sensations [22•]. It may also cause autonomic dysfunction, including hypo- or hyperhidrosis, tachycardia, bradycardia, diarrhea or constipation, urinary incontinence or retention, gastroparesis, orthostatic intolerance, and sexual dysfunction [23]. A skin biopsy may confirm the diagnosis by revealing a significantly decreased intraepidermal nerve fiber density and morphologic changes within the axon [22•]. The diagnosis may also be suggested by psychophysical tests (temperature sensation thresholds [24]), neurophysiological tests (laser evoked potentials [25], contact heat evoked potentials [26]), and quantitative sudomotor axon reflex testing [27]. The exact etiology of axonal loss in sarcoidosis associated small fiber neuropathy is unknown [22•].

The clinical outcome in neurosarcoidosis patients with CNS involvement is worse compared with those with PNS involvement [28]. In general, neurosarcoidosis patients with cranial neuropathy (except optic neuropathy), acute meningitis, or peripheral neuropathy have a lower risk for progression than those with intracranial disease including hydrocephalus and chronic meningitis [13]. Spinal cord neurosarcoidosis portends a poor prognosis [29].

Diagnostic workup

The diagnosis of sarcoidosis requires compatible clinical findings, histologic demonstration of non-caseating granulomas and exclusion of other diseases [30]. The recommended initial workup for a patient suspected to have sarcoidosis includes a medical history with attention to possible prior tuberculosis exposure and an occupational history. Chest radiograph, pulmonary function tests, complete blood count (CBC), serum liver function tests (LFTs), serum calcium, urinalysis, electrocardiogram, ophthalmology examination, and tuberculin skin testing are also important [31••]. In patients with suspected neurosarcoidosis and no evidence of extraneural disease despite performance of the aforementioned tests, chest computed tomography, whole-body Gallium (Ga)-67 scanning, and positron emission tomography scan may be helpful in detecting multisystemic sarcoid involvement [32] and locating a biopsy site.

On rare occasions, sarcoidosis may develop exclusively in the nervous system without extraneurologic involvement. In those cases, establishing the diagnosis is problematic [33•] and biopsy of neural tissue may be required. If an MRI suggests dural or leptomeningeal involvement with sarcoidosis, these sites are preferred because such biopsies are less invasive compared with brain or spinal cord biopsies [33•].

MRI is considered the most sensitive test for neurosarcoidosis [31••]. The most common brain MRI finding of neurosarcoidosis is leptomeningeal involvement that is usually seen as thickening and diffuse or nodular enhancement [34] (Fig. 1). Sarcoid granulomas can involve the dura as focal masses or diffuse thickening [34]. In addition, neurosarcoidosis may present as solitary or multiple enhancing intraparencymal masses (Fig. 2) that may be mistaken for a malignancy or demyelinating disease [34, 35]. Distinguishing neurosarcoidosis from multiple sclerosis (MS) may be problematic at times. The Table 1 summarizes the clinical and radiographic differentiating features of neurosarcoidosis from MS. In the case of spinal cord sarcoidosis, intramedullary lesions usually extend three or more spinal segments [36•] as opposed to spinal cord lesions from multiple sclerosis [37].
https://static-content.springer.com/image/art%3A10.1007%2Fs11940-013-0242-9/MediaObjects/11940_2013_242_Fig1_HTML.jpg
Fig. 1

Leptomeningeal lesion. Post-contrast axial T1-weighted image demonstrates diffuse and nodular leptomeningeal enhancement.

https://static-content.springer.com/image/art%3A10.1007%2Fs11940-013-0242-9/MediaObjects/11940_2013_242_Fig2_HTML.jpg
Fig. 2

Enhancing intraparenchial mass. Post-contrast coronal T1-weighted image demonstrates enhancing mass in the hypothalamus and thalamus.

Table 1

Differentiating features of CNS sarcoidosis from MS

 

CNS sarcoidosis

MS

Clinical manifestations

Relapsing/remitting course

Common

Very common

Diverse neurologic findings

Common

Very common

Extra-neural involvement

Highly suggestive

Possible (esp. rheumatologic)

Visual apparatus

Anterior segment > optic nerve

Optic nerve > anterior segment

Cranial neuropathy

Highly suggestive

Possible, but not common

MR findings

Leptomeningeal enhancement

Highly suggestive

Rare

Dural enhancement

Highly suggestive

Rare

Enhancing mass adjacent to meninges

Highly suggestive

Rare

Enhancement of parenchymal lesions

Persistent (more than a few weeks)

Transient (within a few weeks)

Hydrocephalus

Highly suggestive

Rare

Involvement of hypothalamus/pituitary

Highly suggestive

Rare

Nonenhancing periventricular WM lesions

Common

Common

Spinal cord

Intradural extramedullary > Intramedullary

Intramedullary

CSF findings

Lymphocytosis, elevated protein level

Common

Common

Hypoglycorrhachia

Suggestive

Rare

Elevated ACE level

Suggestive

Possible

Oligoclonal bands

Possible

Highly suggestive

ACE angiotensin converting enzyme, CNS central nervous system, CSF cerebrospinal fluid, MR magnetic resonance, MS multiple sclerosis, WM white matter.

(Reprinted with permission from Nozaki K, Judson MA. Neurosarcoidosis: Clinical manifestations, diagnosis and treatment. Presse Med 2012;41[6 Pt 2]:e331–348. Copyright 2012 Elsevier Masson SAS. All rights reserved.)

The typical cerebrospinal fluid (CSF) findings in neurosarcoidosis are a lymphocytosis and an elevated protein [3]. Characteristically, there is hypoglycorrhachia with CSF glucose less than 50 % of concomitant blood glucose. However, these findings are neither highly specific nor highly sensitive for neurosarcoidosis. The formula is often mistaken for neoplastic or fungal meningitis. The usefulness of CSF angiotensin converting enzyme (ACE) levels for the diagnosis of neurosarcoidosis is controversial [32, 3840].

Treatment

Due to its rarity, there are no class I randomized controlled trials for neurosarcoidosis. Most treatment recommendations derive from expert opinion from centers seeing several dozen cases annually, from case reports or from small uncontrolled case series and are therefore considered class IV evidence. Figure 3 summarizes our suggested treatment approach for neurosarcoidosis (with input from personal communication from Drs. Barney Stern and Robert P. Baughman). Based on our experience, specific treatment for neurosarcoidosis needs to be given for at least 6 months. Tapering of medications should be individualized based on the seriousness of the illness, response to therapy, and toxicity of therapy.
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Fig. 3

Proposed therapeutic algorithm for neurosarcoidosis. Cytotoxic drugs include methotrexate, azathioprine, and mycophenolate. One could also consider cyclosporine and anti-malarial drugs. (Reprinted with permission from Nozaki K, Judson MA. Neurosarcoidosis: Clinical manifestations, diagnosis and treatment. Presse Med 2012;41[6 Pt 2]:e331–48. Copyright 2012 Elsevier Masson SAS. All rights reserved.)

Pharmacologic treatment

  • Corticosteroids are considered the drug of choice for the treatment of sarcoidosis [41]. In general, neurosarcoidosis is not as responsive to corticosteroid therapy as sarcoidosis involvement of other organs [5]. A significant percentage of patients are refractory to corticosteroids or relapse when corticosteroids are tapered to low doses [5, 42, 43]. These patients often require long-term high-dose corticosteroid therapy and/or a trial of additional agents [42]. In a large neurosarcoidosis case series, more than 70 % of patients who were treated with corticosteroids alone developed neurologic deterioration. In addition, there was a tendency for recurrence of symptoms at doses of prednisone less than 20–25 mg/day [44].

  • Immunomodulating and cytotoxic agents such as azathioprine, cyclophosphamide, or methotrexate have been shown to improve the neurologic outcome in approximately one-fifth of cases of neurosarcoidosis refractory to corticosteroids. These therapies allow tapering of the prednisone dose to 10 to 20 mg/day in more than one-third of cases [42]. A combination of corticosteroids and either methotrexate, azathioprine, or cyclophosphamide has resulted in a favorable outcome in neurosarcoidosis patients with severe CNS involvement (intracranial lesions, hydrocephalus, myelopathy, seizures, or encephalopathy) [13].

  • Infliximab, a tumor necrosis factor alpha (TNF-α) inhibitor, has recently been reported as effective in small case series of neurosarcoidosis refractory to cyclophosphamide [45]. Other TNF-α inhibitors, such as adalimumab, pentoxifylline, and thalidomide have been shown to be effective for various types of organ involvement from systemic sarcoidosis [1]. However, their role in the treatment of neurosarcoidosis is unknown.

  • In addition to specific treatment for sarcoidosis, treatment for associated conditions (eg, anti-epileptics and medicines for neuropathic pain) may be required for the management of neurosarcoidosis.

Corticosteroids

This class includes prednisone, prednisolone, and intravenous (IV) methylprednisolone (MP), agents used extensively in systemic immune-mediated diseases.
  • Oral prednisone is the first-line drug for neurosarcoidosis.

  • High-dose intravenous IVMP is recommended for severe cases (eg, altered sensorium, visual loss, or weakness) and cases not responding to oral agents [7].

Standard dosage

For mild to moderate disease, usually initiate with 20–60 mg/day (prednisone equivalent).

For severe disease, MP 1000 mg/day intravenously for 3–5 consecutive days, followed by weekly IVMP or daily oral prednisone.

Contraindications

Hypersensitivity, systemic fungal infection, active tuberculosis. Patients with diabetes mellitus require careful glucose monitoring.

Main drug interactions

Combination therapy should be avoided with following agents: aldesleukin, axitinib, BCG, mifepristone, natalizumab, pimecrolimus, tacrolimus [46]. Hepatic enzyme inducers such as phenytoin, carbamazepine, and phenobarbital may increase glucocotricoid clearance. There are variable interactions with warfarin necessitating close coagulation parameter monitoring.

Main side effects

Glucose intolerance, obesity, edema, insomnia, mood changes/psychosis, osteoporosis, hypertension, increased risk of infection, wound healing delay, bruising, gastritis/peptic ulcer, steroid myopathy, cataracts, glaucoma.

Special points

Prophylactic treatment for peptic ulcer should be considered.

Monitoring: CBC, serum glucose, electrolytes, weight, blood pressure, ophthalmology evaluations, cortical bone density.

Clinicians should be aware of the possible occurrence of adrenal insufficiency when corticosteroids are discontinued.

Cost/cost-effectiveness

Inexpensive.

Methotrexate

Methotrexate is a favored corticosteroid sparing agent in neurosarcoidosis [44]. Lower and colleagues [5] reported a beneficial response in neurosarcoidosis patients who failed prednisone monotherapy. However, relapse occurred in most patients who had methotrexate discontinued.
Standard dosage

Usually, initiate at 7.5 mg oral once a week and titrate up to 15–25 mg weekly. Dose adjustment is required for renal insufficiency, hepatic impairment, hematologic, and other toxicities.

Contraindications

Hypersensitivity, breast-feeding, pregnancy, chronic liver disease including alcoholism, pre-existing blood cytopenias/dyscrasias [46].

Main drug interactions

Combination therapy should be avoided with following agents: acitretin, BCG, clozapine, natalizumab, pimecrolimus, tacrolimus [46].

Main side effects

Gastrointestinal upset, hepatotoxicity, renal insufficiency, pneumonitis, bone marrow suppression, teratogenicity, headache, lethargy. Central nervous system demyelination can occur with concomitant radiation therapy.

Special points

Baseline testing: CBC with differential, serum renal function tests, serum liver function tests, chest radiograph, serology for hepatitis B and C.

Monitoring: CBC with differential, serum renal function tests and serum liver function tests.

Women should have a pregnancy test before starting treatment and avoid pregnancy during treatment and ≥1 ovulatory cycle after completing treatment. The female partner of a male patient should avoid pregnancy during treatment and ≥3 months after completing treatment [46]. Supplemental use of folic acid (1 mg/day) is recommended in order to minimize toxicity.

Cost/cost-effectiveness

Inexpensive.

Cyclophosphamide

Cyclophosphamide has demonstrated symptomatic improvement in neurosarcoidosis patients who failed monotherapy with prednisone or combination therapy with prednisone and methotrexate [5, 41]. It also is corticosteroid sparing for neurosarcoidosis and the maintenance corticosteroid dose can usually be tapered to 10 mg/day or less of prednisone equivalent [5, 41].

Because of its high toxicity and significant side effects, including bone marrow suppression, teratogenicity and carcinogenicity, the use of cyclophosphamide is usually limited to the patients with severe disease refractory to other agents [30].
Standard dosage

The preferred dose is 500–1000 mg intravenously over 30–60 min every 2–4 weeks. An alternative regimen is 0.5 g/m2 of body surface area intravenously every 4 weeks. Dosage may be adjusted based on age, leukocyte count or renal function. Intravenous administration of cyclophosphamide is preferred over oral administration because the side effect profile is better with the former route of administration [47]. The initial oral dose of cyclophosphamide is 25–50 mg/day. The dose is increased by 25 mg increments to ensure adequate immunosuppression; the goal being a WBC count between 4000 and 7000/mm3. The maximum oral dose is 150 mg/day, above which the rate of side effects exceeds clinical efficacy.

Contraindications

Hypersensitivity, severely depressed blood cell lines [46], pregnancy, lactation.

Main drug interactions

Combination therapy should be avoided with following agents: BCG, belimumab, clozapine, etanercept, natalizumab, pimecrolimus, pimozide, tacrolimus, live vaccines [46]. Barbiturates and phenytoin increase metabolite levels, potentiating bone marrow suppression and leukemic effect.

Main side effects

Hemorrhagic cystitis, neutropenia, cardiac toxicity, carcinogenicity (leukemia and bladder cancer), infertility, teratogenicity, azotemia.

Special points

Intravenous fluid administration is required before, during and after intravenous treatment.

Monitoring: CBC, serum liver function tests, and serum renal function tests

urinalysis during and 1 day after treatment.

Women of childbearing potential should avoid pregnancy while receiving cyclophosphamide treatment. Cyclophosphamide may also cause sterility in men and women [46].

Cost/cost-effectiveness

Relatively inexpensive.

Azathioprine

Azathioprine has been used for chronic pulmonary and dermatologic manifestations of sarcoidosis and in these situations acts as a corticosteroid sparing agent [48, 49]. However, we are unaware of clinical data concerning the effectiveness of azathioprine for neurosarcoidosis. Azathioprine is less teratogenic compared with cyclophosphamide and methotrexate [30].

Mycophenolate mofetil

A few case reports and small series have suggested a potential role for mycophenolate mofetil in the treatment of neurosarcoidosis [5052]. Interestingly, a retrospective study of 10 neurosarcoidosis cases suggested that mycophenolate is effective for CNS sarcoidosis but not for sarcoidosis myopathy [53].

Infliximab

Infliximab is a chimeric monoclonal antibody that attenuates TNF-α bioactivity [45]. Case reports and case series have demonstrated that infliximab may be useful for neurosarcoidosis that is refractory to other agents [45, 51, 5457]. In a recent case series of 29 patients with spinal cord neurosarcoidosis, infliximab was the second most frequently used immunosuppressive agent after corticosteroids; infliximab was most commonly used for refractory neurosarcoidosis and/or corticosteroid-induced complications [36•].
  • Antibody formation is associated with loss of response. Concomitant immunosuppressive treatment with low dose methotrexate may optimize response to infliximab by preventing the formation of antibodies [23].

  • Various neurologic deficits may occur during treatment with TNF- α blockers, including CNS or PNS demyelination [58].

Standard dosage

3–5 mg/kg intravenously every 4–8 weeks. Often, patients receive an initial loading dose of 3–5 mg/kg intravenously at weeks 0, 2, and 6.

Contraindications

Hypersensitivity, New York Heart Association class III and IV heart failure [46].

Main drug interactions

Combination therapy should be avoided with following agents: abatacept, anakinra, BCG, belimumab, canakinumab, certolizumab, natalizumab, pimecrolimus, rilonacept, tacrolimus, live vaccines [46].

Main side effects

Allergic reactions, infection, congestive heart disease, malignancy, autoimmunity, demyelinating central or peripheral nervous system disease, bone marrow suppression, hepatic reactions.

Special points

Monitoring: CBC, LFTs, hepatitis B virus, tuberculosis.

Cost/ cost-effectiveness

Expensive.

Chloroquine

Chloroquine is an anti-malarial agent. It has anti-inflammatory effects for which it is used to treat rheumatoid arthritis and lupus erythematosus [59]. It is also effective in sarcoidosis, especially in patients with sarcoidosis-induced hypercalcemia and sarcoidosis skin lesions.
Standard dosage

250–750 mg daily. Dosing adjustment is required for renal impairment.

Contraindications

Hypersensitivity to and, retinal or visual field changes attributable to 4-aminoquinoline compounds [46].

Main drug interactions

Combination therapy should be avoided with following agents: agalsidase alfa and beta, artemether, conivaptan, QTc-prolonging agents, lumefantrine, mefloquine, mifepristone, thioridazine [46].

Main side effects

Retinal toxicity, seizures, hearing loss, G6PD deficiency, hematologic reactions, myopathy.

Special points

Monitoring: ophthalmologic examination at baseline and regularly during prolonged treatment; periodic CBC during prolonged therapy.

Cost/cost-effectiveness

Inexpensive.

Hydroxychloroquine

Hydroxychloroquine is a derivative of chloroquine. Compared with chloroquine, hydroxychloroquine has lower risk of ocular toxicity [30]; however, hydroxychloroquine is thought to be less effective than chloroquine. Since hydroxychloroquine reduces serum glucose levels, it may be useful for patients with steroid induced hyperglycemia [32].
Standard dosage

200–400 mg daily.

Contraindications

Hypersensitivity to and, retinal or visual field changes attributable to 4-aminoquinoline compounds [46].

Main drug interactions

Combination therapy should be avoided with following agents: artemether, BCG, lumefantrine, mefloquine, natalizumab, pimecrolimus, tacrolimus [46].

Main side effects

Retinal toxicity, seizures, hearing loss, G6PD deficiency, hematologic reactions, myopathy.

Special points

Monitoring: ophthalmologic examination at baseline and regularly during prolonged treatment; periodic CBC during prolonged therapy.

Cost/cost-effectiveness

Moderate.

Treatment of associated conditions

  • Anti-epileptic agents (AEDs) alone without anti-sarcoidosis medications are not effective for epilepsy management, since granulomatous inflammation of the CNS is almost always a contributing cause [8, 32]. Acceptable seizure control can almost always be achieved by a combination of an antiepileptic with corticosteroids [15]. It is advisable to choose a non enzyme-inducing AED such as levetiracetam to avoid interactions with concomitant corticosteroid therapy.

  • Neuroendocrine dysfunction seems to be related to irreversible neuronal damage [60]; therefore, most endocrine deficits are irreversible and life-long hormonal replacement therapy is required [19]. Despite the permanence of the neuroendocrine dysfunction, corticosteroid therapy improves the radiographic findings.

Other treatments

Radiotherapy

Radiotherapy to the CNS might be considered when medical therapy fails or causes intolerable side effects [8, 61]. It should be considered as a procedure of last resort. There are minimal long-term data concerning the outcome of neurosarcoidosis treated with radiotherapy. Sarcoid meningitis appears to be sensitive to radiotherapy. Although CNS sarcoidosis in other locations might be less sensitive, radiotherapy is still effective at times [62]. The suggested dose of radiation for neurosarcoidosis is approximately 20 Gy at 2 Gy per treatment [62, 63], though there is lack of enough evidence to support it. The mechanism of action for radiotherapy in sarcoidosis is not well understood.

Surgery

Surgery for neurosarcoidosis is indicated for life threatening complications such as hydrocephalus, expanding mass lesions, or mass lesions causing increased intracranial pressure or spinal cord compression [32]. Surgical resection of CNS neurosarcoidosis lesions should be considered as a procedure of last resort, and should only be considered when corticosteroids and/or other sarcoidosis pharmacotherapy have failed or is contraindicated [7]. Although ventricular drainage is usually lifesaving in symptomatic hydrocephalus [11], asymptomatic ventricular enlargement does not require treatment.

Conflict of Interest

Kenkichi Nozaki declares that he has no conflict of interest.

Marc A. Judson has served as a consultant for Centocor, Pulmonary Reviews, Janssen, and Celgene; has received institutional grants from T2 Biosystems and GlaxoSmithKline; and has received royalties from UpToDate.

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