Abstract
Neurosarcoidosis is a rare disorder in children. We identified 30 pediatric NS cases through a systematic review. Twenty-one (70%) had systemic sarcoidosis with 30% having primary neurosarcoidosis. Eyes (37%), lymph nodes (37%) and lungs (30%) were most commonly involved. Isolated neurosarcoidosis were more likely in children (30%) than in adults (6%, p = 0.0005). Seizures and optic neuritis were also more common in children than adults (33% vs 14%, p = 0.002; and 30% versus 6%, p = 0.008, respectively). Evaluation, imaging, laboratory findings, and treatments are discussed. Additional research, including multi-center studies, is needed.
Keywords: Pediatric neurosarcoidosis, Sarcoidosis in children, Pediatric neuroinflammation
1. Introduction
Sarcoidosis is a granulomatous disease affecting an estimated 3–10/100,000 adults, with an unknown incidence in children (Rao et al., 2016). This disease has a long history, being first described by Jonathan Hutchinson in 1869 (Spagnolo, 2015). Sarcoidosis usually presents as a systemic, multi-organ process and is challenging to diagnose in both adults and children. Neurosarcoidosis (NS), which is when sarcoidosis affects the nervous system, occurs in 5–15% of adults with sarcoidosis (Lord et al., 2020; Hoitsma et al., 2004) but may be as high as 25%, as undiagnosed NS was found in adults with sarcoidosis at autopsy (Tana et al., 2015; Voortman et al., 2019). While NS can occur in systemic sarcoidosis, NS can also present as an isolated process. Neurological involvement in NS includes papilledema, cranial neuropathy, seizures, headaches, hydrocephalus, myopathy, stroke, cerebral parenchymal disease, and neuroendocrine involvement (Lacomis, 2011; Voortman et al., 2019). Cord involvement can also include cauda equina syndrome, intra-, and extra-medullary lesions, and extra- and intra-dural lesions (Lacomis, 2011).
Due to the broad range of manifestations of NS, the differential diagnosis also becomes broad, with a large number of disease mimickers, making clinical diagnosis even more challenging. One of the key aspects of diagnosing NS is the evaluation for other possible diagnoses, done via serology studies, CSF analysis, imaging, biopsy, and other diagnostic modalities such as electroencephalography (EEG), electromyography (EMG), electrocardiogram (EKG), skin examinations, and dilated eye exam with slit lamp. Sarcoidosis is often seen with elevated serum angiotensin-converting enzyme (ACE) levels, but this is an insensitive and nonspecific biomarker (Ungprasert et al., 2016). The most recent proposed diagnostic criteria provide a range of findings that group patients into a possible, probable, and definite diagnosis of NS, see Table 1 (Stern et al., 2018).
Table 1.
Proposed diagnostic criteria for neurosarcoidosis, from the Neurosarcoidosis Consortium Consensus Group, adapted from (Stern et al., 2018).
| Possible | Probable | Definite | |
|---|---|---|---|
| Clinical presentation | Clinical presentation and diagnostic evaluation are consistent with neurosarcoidosis with clinical manifestations and MRI, CSF, and/or EMG/NCS findings typical of granulomatous inflammation of the nervous system, with rigorous exclusion of other causes | Same as possible | Same as possible |
| Pathology | No confirmation of granulomatous disease | Confirmation of systemic granulomatous disease consistent with sarcoidosis | Nervous system pathology is consistent with neurosarcoidosis Type a: Extraneural sarcoidosis Type b: No extraneural sarcoidosis (isolated CNS sarcoidosis) |
Abbreviations: CNS: central nervous system.
Diagnosis of NS in children is even more challenging due to the paucity of studies. Post-pubescent pediatric patients are more likely to present as adults and more likely to present with a cranial neuropathy, which can be seen in 50–75% of adult patients, while prepubertal patients are more likely to present with seizures and hypothalamic deficits (Rao et al., 2016; Anand et al., 2013). Since NS is a rare disease, and even more so in children, we performed a systematic review of manifestations of pediatric NS and also discuss some suggested approaches to evaluation and management of children with NS.
2. Methods
A systematic review of pediatric NS cases was conducted of publications from January 1, 1990, until August 30, 2021, by 2 independent reviewers (M.Y. and M.D.). These dates were chosen due to the evidence needed for diagnosing NS with modern neuroimaging techniques and diagnostic testing according to current diagnostic criteria. Databases searched include: PubMed, Google Scholar, Lincoln Memorial University, and Emory University Library Databases. The terms “neurosarcoidosis,” “pediatric,” and “child” were used and the Boolean “AND” was used to combine “neurosarcoidosis” with “pediatric” or “child.” Cases were included if they met the criteria of patients 18 years old or younger, published after 1990 in English, and had a diagnosis of NS. All duplicate cases, such as those found in previous systematic reviews, were excluded. Clinical data included the following variables: age, sex, presence of systemic sarcoid, presence of eye, lung/chest, lymph node and other systemic involvement, serum and CSF ACE levels, brain and biopsies in extra-neuralaxis locations.
The diagnosis of sarcoid has been established by the American Thoracic Society and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) (Costabel and Hunninghake, 1999; Judson et al., 2014; Singha et al., 2020). Similarly, the Neurosarcoidosis Consortium Consensus Group established criteria for the diagnosis of NS, classifying patients clinically into possible, probable, and definite NS (Table 1) (Stern et al., 2018). Patients in this review were assigned “possible, probable, or definite” NS criteria based on the clinical data. Only probable or definite NS were included in the review, while those cases that only met the “possible” criteria were excluded. Data on neurological findings including cranial nerve palsies, seizures, headaches, brain MRI findings, and CSF cytology were also collected (Table 2). Statistical analyses were performed using SAS 16.0 (Cary, NC), including summary statistics (Tables 2 and 3) and comparisons using parametric (Chi-square or t-test) and non-parametric (Fisher’s exact or Wilcoxon rank sum) tests as appropriate. The pediatric cohort was compared to a published adult cohort with 85 NS patients (Ramos-Casals et al., 2021).
Table 2.
Systemic signs and symptoms of sarcoidosis in 30 (13 definite and 17 probable) pediatric neurosarcoidosis patients.
| Case # | Age (Y) | Sex (M/F) | Systemic sarcoid (Y/N) | Eye involvement (Y/N) | Lung/chest | Lymph nodes | Other | Serum ACE | CSF ACE | Brain biopsy (Y/N) | Extraneural biopsy site | Probability of diagnosis of Neurosarcoidosis as defined by Stern et al. | Immunetx | Improved (Y/N) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 (Anand et al., 2013) | 7 | M | N | N | N | N | ND | ND | Y | ND | Definite | CS, IG, CYC, AZA | Y | |
| 2 (Rao et al., 2016) | 15 | M | N | N | N | N | NML | ABN | Y | ND | Definite | MTX, CS | Y | |
| 3 (Baumann and Robertson, 2003) | 9 | F | N | N | N | N | ABN | ND | Y | ND | Definite | CS | Y | |
| 4 (Tsao et al., 2007) | 17 | M | N | N | N | N | NML | NML | Y | Cranial bone marrow | Definite | CS, IVMP | Y | |
| 5 (Shijo et al., 2018) | 12 | M | Y | N | Y | N | ABN | ND | Y | ND | Definite | CS | Y | |
| 6 (Kobayashi et al., 2011) | 12 | M | N | N | N | N | ABN | NML | Y | ND | Definite | None | Y | |
| 7 (Galgano et al., 2018) | 9 | F | N | N | N | N | ABN | ND | N | Spine | Definite | CS, MTX | Y | |
| 8 (Kitajima et al., 2010) | 18 | M | Y | N | N | Y | ABN | ND | Y | ND | Definite | IVMP, CS | Y | |
| 9 (Leiba et al., 1996) | 13 | M | Y | Y | N | N | ND | NML | Y | ND | Definite | CS | Y | |
| 10 (Ng et al., 1995) | 14 | F | N | N | N | N | ND | ND | Y | ND | Definite | CS, IVMP | YY | |
| 11 (Konrad et al., 2000) | 10 | F | N | N | N | N | ABN | ND | Y | ND | Definite | None | N/A | |
| 12 (Gmuca and Waldman, 2017) | 15 | M | Y | Y | N | N | Skin | ABN | ND | Y | Bone marrow | Definite | MTX and INX; ADM | Y |
| 13 (Hafner and Vogel, 1993) | 3 | F | Y | Y | N | N | skin, arthritis, fever, hepatosplenomegaly, pericarditis, myocarditis | ND | ND | Y | Liver, Spleen, Lymph nodes, Kidneys, Lungs, GI tract, Bone marrow, Muscle, Synovial tissue, Pericardium | Definite | CS, other+ | Y |
| Definite, N (%) unless otherwise specified | Mean 11.8 y (SD 4.2) |
F: 5 (38)
M: 8 (62) |
5 (38) | 3 (23) | 1 (8) | 1 (8) | – | ABN 7/9 (78) | ABN 1/4 (25) |
11 brain
1 spine |
– | – | CS: 9 (69) MTX: 3 (23) ADM: 1 (8) IMX: 1 (8) CYC: 1 (8) AZA: 1(8) RTX: 0 (0) MMF: 0 (0) |
12/12 (100) |
| 14 (Villacis-Nunez and Thakral, 2021) | 17 | F | Y | N | N | N | lacrimal gland | NML | NML | N | Lacrimal gland | Probable | MTX, ADM, IVMP, CS | Y |
| 15 (Kone-Paut et al., 1999) | 12 | F | Y | N | Y | Y | parotid glands, mediastinum, liver, spleen | ABN | NML | N | Cervical mass | Probable | IVMP, CS | Y |
| 16 (John et al., 2009) | 15 | M | Y | Y | N | Y | inner ear structures | ABN | ND | N | Lymph node | Probable | CS, IVMP | Y |
| 17 (Scholten et al., 2009) | 11 | M | Y | Y | N | N | NML | ND | N | Conjunctiva | Probable | CS | Y | |
| 18 (Wurzel et al., 2009) | 13 | M | Y | Y | N | Y | NML | NML | N | Hilar lymphadenopathy | Probable | CS | Y | |
| 19 (Isgro et al., 2012) | 13 | F | Y | N | N | Y | NML | ND | N | Cervical lymph node | Probable | CS, IVMP | Y | |
| 20 (Spinelli et al., 2016) | 16 | M | Y | N | Y | N | ND | ND | N | Lung | Probable | MMF, MTX, CS | Y | |
| 21 (Sukumaran, 2019) | 15 | F | Y | N | N | Y | parotid glands | ABN | ND | N | Lymph node | Probable | CS | Y |
| 22 (Hafner and Vogel, 1993) | 3 | M | Y | Y | N | N | skin, arthritis, myocarditis, hypertension, fever | ND | ND | N | Skin | Probable | CS, other+ | Y |
| 23 (Hafner and Vogel, 1993) | 2 | F | Y | Y | Y | N | skin, arthritis, myocarditis, hypertension | ND | ND | N | Skin and Lungs | Probable | CS, other+ | Y |
| 24 (Hafner and Vogel, 1993) | 0.17 | M | Y | Y | Y | N | skin, arthritis, fever, hepatosplenomegaly, pericarditis, parotitis | ND | ND | N | Skin, Lungs, Liver | Probable | CS, other+ | Y |
| 25 (Lipnick et al., 1993) | 16 | F | Y | N | N | Y | Secondary amenorrhea | ABN | ND | N | Lymph node | Probable | CS | N |
| 26 (Krumholz et al., 1991) | 17 | F | Y | Y | Y | Y | ND | ND | N | Lymph node | Probable | CS | Y | |
| 27 (Ugurlu et al., 2014) | 14 | M | Y | N | Y | Y | ND | ND | N | Bone marrow, Liver, lymph node | Probable | IVMP, MTX, CYC, RTX, ADM | Y | |
| 28 (Wisniewski, 2020) | 16 | F | Y | N | Y | Y | ND | ND | N | Liver | Probable | IVMP, CS, INX + MTX | Y | |
| 29 (Johnson et al., 2014) | 8 | M | N | N | N | N | ND | ND | N | Maxillary and Ethmoid sinuses | Probable | None | N/A | |
| 30 (Earle et al., 2019) | 11 | F | Y | Y | Y | Y | Asthma | NML | ND | N | Lymph node | Probable | IVMP, CS, MTX, CYC, RTX | Y |
| Probable, N (%) unless otherwise specified | Mean 11.3 y (SD 5.5) |
F: 9 (53)
M: 8 (47) |
16 (94) | 8 (47) | 8 (47) | 10 (59) | – | 4/9 (44) | 0/3 (0) | 0 (0) | – | – | CS: 10 (58) MTX: 4 (24) ADM: 1 (6) IMX: 1 (6) CYC: 2 (12) AZA: 0 (0) RTX: 2 (12) MMF: 1 (6) |
|
| Total (Definite and Probable) N (%) unless otherwise specified | Mean 11.8 y (SD 4.8) |
F: 14 (47)
M: 16 (53) |
21 (70) | 11 (37) | 9 (30) | 11 (37) | – | 11/19 (58) | 1/7 (14) |
11 brain
1 spine |
– |
Definite 13 (43)
Probable 17 (57) |
CS: 19 (63) MTX: 7 (23) ADM: 2 (7) IMX: 2 (7) CYC: 3 (10) AZA: 1 (3) RTX: 2 (7) MMF: 1 (3) |
M = male, F = female, Y = yes, N = no; Nml = normal, abn = abnormal, Y = years, ND: not done, SD: standard deviation, Ref: reference.
Other immunosuppressants included methotrexate and azathioprine, but was not detailed for each patient.
Table 3.
Neurosarcoidosis manifestations and treatments.
| Case # | Age | Sex (M/F) | Neuro as symptom | Cranial nerve | Seizure | Headache | Other neuro symptom | Abn MRI brain | Brain MRI | Brain MRI enhancement | Spine MRI | CSF WBC | CSF lymph % | CSF pro |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 7 | M | Y | – | Y | N | Weakness | Y | Multiple T2 lesions in bilateral cortex, subcortical GM, deep GM. Cortical restricted diffusion within both cerebral hemispheres | None | ND | 10 | 60 | Abn |
| 2 | 15 | M | Y | – | N | Y | Tandem gait ataxia | Y | Increased T2 signal intensity in bilateral cerebellar hemispheres | LME, linear enhancement in cerebellar folia | ND | 17 | 91 | Abn |
| 3 | 9 | F | Y | VI | Y | Y | Truncal ataxia | Y | None | Anterior frontal lobe | ND | 350 | 52 | Abn |
| 4 | 17 | M | Y | – | N | N | Nystagmus, hyperreflexia, vertigo | Y | None | Cerebellum, vermis, medulla | ND | 21 | ND | Abn |
| 5 | 12 | M | Y | I | N | N | Mass lesion in brain | Y | Extra-axial mass around the cavernous sinus | ND | ND | ND | ND | |
| 6 | 12 | M | Y | – | Y | Y | Aphasia, confusion | Y | None | Nodular enhancement in white matter both cerebral hemispheres | ND | 50 | 93 | Abn |
| 7 | 9 | F | Y | – | N | N | Weakness, pain, urinary dysfunction, hyperreflexia and upgoing toes, sensory deficits below T6 | Y | None | None | T3-T6 epidural mass, causing spinal cord compression | ND | ND | ND |
| 8 | 18 | M | Y | – | Y | N | Y | Isointense T1 and T2 lesions | Nodular enhancement | NML | ND | ND | ND | |
| 9 | 13 | M | N | IV | N | N | Vision changes | Y | None | 3 enhancing lesions: floor of 4th ventricle into cerebellum, internal capsule, basal ganglia | ND | ND | ND | Nml |
| 10 | 14 | F | Y | I | N | Y | Vision changes | Y | Optic nerve edema | None | ND | ND | ND | ND |
| 11 | 10 | F | N | – | N | N | – | Y | T2 hyperintensity of pituitary and lesions in frontal WM | None | ND | ND | ND | ND |
| 12 | 15 | M | Y | I | N | N | – | Y | Optic nerve edema | Optic nerve | ND | ND | ND | ND |
| 13 | 3 | F | N | – | Y | N | Spasticity | ND | ND | ND | ND | ND | ND | ND |
| Definite N (%) unless otherwise specfied | Mean 11.8y (SD 4.2) |
F: 5 (38)
M: 8 (62) |
10 (77) | 5 (38) | 4 (31) | – | 12/12 (100) | Optic nerve: 2/12 (17) Other cranial nerve: 0 (0) T2 hyperintensity: 3/12 (25) Pituitary 1/12 (8) |
LME: 2/12 (17) Nodular:2/12 (17) Extraaxial mass: 2/12 (17) Other enhancement: 3/12 (25) |
1/2 abnormal | 5/5 (100) | Range 52–93 | ABN 5/6 (83) | |
| 14 | 17 | F | N | – | N | Y | – | Y | Pituitary | None | ND | 7 | 91.7 | Nml |
| 15 | 12 | F | N | – | N | N | – | Y | None | Nodular | NML | Nml | ND | Nml |
| 16 | 15 | M | Y | VIII | N | N | Tinnitus, abnormal tandem gait | N | T2 FLAIR in cochlea, semicircular canals | Subtle enhancement of labyrinths | ND | Abn | ND | ND |
| 17 | 11 | M | N | – | Y | N | Y | T2 frontal WM | LME | ND | 20 | 90 | Nml | |
| 18 | 13 | M | Y | – | N | N | Paresthesias | N | None | None | Enhancement of conus and cauda equina | Nml | ND | Abn |
| 19 | 13 | F | Y | – | N | N | Hemiplegia and hemineglect | Y | WM infarcts, vasculitis | None | ND | ND | ND | ND |
| 20 | 16 | M | Y | – | N | N | Pyramidal neurological signs and symptoms | Y | None | Cerebral, cerebellar, brainstem | Perivascular enhancmenet | ND | ND | ND |
| 21 | 15 | F | N | I | N | N | – | Y | Hypothalamic lesion | None | ND | ND | ND | ND |
| 22 | 3 | M | N | – | Y | N | Aphasia | Y | Multiple T2 lesions | None | ND | ND | ND | ND |
| 23 | 2 | F | N | – | Y | N | Encephalitis | N | ND | ND | ND | ND | ND | Abn |
| 24 | 0.17 | M | Y | – | Y | Y | Somnolence | N | ND | ND | ND | ND | ND | ND |
| 25 | 16 | F | N | – | N | N | – | Y | Hypothalamus, pituitary stalk | None | ND | ND | ND | ND |
| 26 | 17 | F | Y | VII | Y | Y | Meningitis, hydrocephalus, temporal lobe mass | N | ND | ND | ND | ND | ND | ND |
| 27 | 14 | M | Y | – | N | N | right sided hemiplegia, right sided hemianopsia and disarticulated speech | Y | T2 hyperintense optic nerves | None | Spine lesions (not specified) | ND | ND | ND |
| 28 | 16 | F | N | I | N | N | Clonus and focal deficits | Y | Pituitary gland | None | ND | ND | ND | ND |
| 29 | 8 | M | Y | VI, VII, IX, X, XI, XII | N | Y | Vision problem, afferent pupillary defect, right hemiparesis | Y | NML | Diffuse pachymengitis, CN VII and VIII enhancement | ND | Abn | ND | ND |
| 30 | 11 | F | N | II | N | Y | Vision loss, ocular pain, weakness/myelopathy | Y | Optic Nerves | None | ND | Nml | ND | Nml |
| Probable, N (%) unless otherwise specified | Mean 11.3 y (SD 5.5) |
F: 9 (53)
M: 8 (47) |
8 (47) | – | 5 (29) | 5 (29) | – | 10 | Optic Nerves 2/13 (15) Other cranial Nerve 1/13 (8) T2 hyperintensity: 1 (8) Pituitary 4 (31) |
LME: 2/13 (15) Nodular: 1/13 (8) Extraaxial mass: 1/13 (8) Other enhancement: 4/13 (31) |
ABN 4/5 (80) | 4/7 (57) | 90–91.7 | 2/6 (33) |
| Total (Definite and Probable) N (%) unless otherwise specified | Mean 11.8 y (SD 4.8) |
F: 14 (47)
M: 16 (53) |
18 (60) | – | 10 (33) | 9 (30) | – | 22/25 (88) | Optic nerves 5/25 (20) Other cranial Nerve 1/25 (4) T2 hyperintensity: 5/25 (20) Pituitary 5/25 (22) |
LME: 4/25 (16) Nodular: 3/25 (12) Extraaxial mass: 3/25 (12) Other enhancement: 7/25 (35) |
ABN 5/7 (71) | 9/12 (75) | 52–93 | 7/12 (58) |
M = male, F = female, Y = yes, N = no; Nml = normal, abn = abnormal, ND = not done, MRI: magnetic resonance imaging, WM: white matter, GM: gray matter, LME: leptomeningeal enhancement, CS: corticosteroid, IG: immunoglobulin, CYC: cyclophosphamide, MTX: methotrexate, IVMP: methylprednisolone, RTX: rituximab, MMF: mycophenolate mofetil, AZA: azathioprine, ADM: adalimumab, INX: infliximab PHT: phenytoin, CBZ: carbamazepine, BIP: bisphosphonate, FUR: furosemide, DDAVP: desmopressin, OCP: oral contraceptive, LT4: levothyroxine.
This patient was found to have b rain granulomas at autopsy.
3. Results
3.1. Clinical presentation and cases
We identified 790 articles and screened 594 after removing duplicates. After assessing 128 articles for eligibility, 28 articles were included in the analysis (see Fig. 1).
Fig. 1.
Flow diagram of systematic review.
Thirty pediatric patients were included in this study, with 13 definite and 17 probable NS cases, with an average age of 11.8 years (standard deviation 4.8, Table 2). Fourteen (47%) were female and 16 (53%) were male. Twenty-one (70%) had systemic sarcoidosis with 30% having primary NS. Clinical symptoms included eye involvement (11, 37%), lymph node involvement (11, 37%) and lung involvement in 9 (30%). Of the eye findings, uveitis was most common (11, 37%), as well as conjunctivitis in 3 (10%). Neuroendocrine involvement was reported in 2/30 (6%). As for neurological symptoms, 18 (60%) had a neurological symptom at the time of the initial presentation (Table 3). This included 11 (37%) with cranial neuropathies which included 5 (17%) with papilledema. Seizures occurred in 10 (33%), and 9 (30%) had headaches. Glandular involvement can occur including lacrimal and parotid glands. Other neurological symptoms included weakness, areflexia or hyperreflexia, spinal cord involvement, encephalopathy, and speech changes.
We then compared the pediatric population collected from the literature (N = 30) to adults (N = 85) with NS (Ramos-Casals et al., 2021). Age did not overlap between the two groups (pediatric NS average 11.8 years, range 0.17–18 years, and adults average 43.1 years, range 22–76 years). No differences in sex (pediatric NS: 53% male versus adult NS: 36/85. 42% male p = 0.692) were observed. However, increased rates of isolated NS in children (9/30 = 30%), as compared to adults (5/85 = 6%, p = 0.0005) were observed. As for symptoms, no differences were observed in neurological symptoms at presentation (18/30 = 60% in children, 59/85 = 69% in adults, p = 0.346), cranial neuropathies (11/30 = 37% in children, 37/85 = 36% in adults, p = 0.512), or neuroendocrine involvement (2/30, 6% in children, 6/85 = 9% in adults, p = 0.942). However, adults had higher lung involvement (70/85, 82%) than children (9/30 = 30%, p < 0.0001), and children had higher rates of seizures (10/30, 33%) than adults (6/85 = 7%, p = 0.0004). For cranial neuropathies, cranial nerve (CN) VII palsy was most common in adults (24/85 = 28%) whereas CN II was most involved in children (7/30 = 30%). Moreover, optic nerve involvement was more likely in children (7/30 = 30%) than in adults with NS (5/85 = 6%, p = 0.008).
3.2. Diagnostic evaluation
In addition to the clinical history and exam, diagnostic tools can be used to aid in the diagnosis of NS, including laboratory testing, imaging, and histopathology (Table 4). Diagnostic evaluation varied among the cases of NS. Brain MRI was abnormal in 22 of 25 available brain MRIs (88%) and 5/7 (71%) had abnormal spine MRIs. CSF studies were reported in 11 patients: 8 (73%) had CSF pleocytosis, with 6/6 patients having lymphocytic predominance, and CSF protein was elevated in 7 (64%). Serum ACE was tested in 19 patients and 11 (53%) had an abnormal ACE with 1/7 (14%) with a reported abnormal ACE in CSF.
Table 4.
Recommended diagnostic studies when evaluating a patient for suspected NS.
| Evaluation for a patient with suspected neurosarcoidosis | |
|---|---|
| Laboratory testing | |
| Blood |
Systemic: Complete blood count, comprehensive metabolic panel, ESR, c-reactive protein, 25-OH vitamin D Infections: HIV serology, syphilis serology, tuberculosis testing, fungal and bacterial serology Autoimmune/inflammatory: ANA, ANCA, aquaporin-4 antibody, myelin oligodendrocyte glycoprotein antibody |
| Cerebrospinal fluid | Cell count, protein, glucose, flow cytometry Infections: cryptococcal antigen, tuberculosis Autoimmune/inflammatory: IgG index, oligoclonal bands |
| Imaging | |
| MRI brain and spine with and without contrast (Preferred) | |
| CT chest with and without contrast | |
| Chest X-ray (if chest MRI or CT not possible) | |
| Biopsy | |
| Accessible sites, such as a lymph node; can also perform biopsy of other sites such as skin or lacrimal gland as needed | |
| Other testing | |
| EEG | |
| EKG | |
| Slit lamp/dilated eye examination | |
| Skin examination | |
Abbreviations: EEG: electroencephalography, EKG: electrocardiogram, CBC: complete blood count, ANA: antinuclear antibody, CT: computed tomography, MRI: magnetic resonance imaging.
Neuroimaging findings in children included abnormal brain MRIs in 22/25 (88%) and 5/7 (71%) abnormal spine MRIs. Pituitary lesions occurred in 5/25 (20%) of children. Leptomeningeal enhancement occurred in 4/25 (16%) in children, which was lower than that in adults (18/39, 46%, p = 0.013) (Ramos-Casals et al., 2021). Parenchymal lesions occurred in 6/25 (1 cortical +5 white matter patients, 24%) which was lower than that of adults (23/39, 59%, p = 0.013). Mass lesions occurred in 3/25 (12%) which was similar to that of adults (3/39, 8%, p = 0.067). Cranial nerve enhancement occurred in 6/25 (5 optic nerve, 1 other; 24%) which was similar to that in adults (11/39, 28%, 0.710).
Histopathology is the gold standard in the diagnosis of sarcoidosis in adults and in children (Stern et al., 2018). For definite NS, brain pathology was obtained in 12/30 (40%) and one patient had a spinal lesion biopsy for confirmed NS. For at least a diagnosis of probable NS, there must be pathologic evidence of noncaseating granulomas on biopsy (Table 1), with the most common non-neurological site of biopsy for diagnosis were lymph nodes. Other sites were biopsied as seen in Table 2. While EMG/NCS has been suggested as part of the evaluation, this information was not included in any of these cases and should be used only after consideration of the risk/benefit ratio due to the invasiveness of this procedure.
3.3. Treatment and outcomes
Treatments were known in 26 patients. Immune treatments administered in our cohort included steroids (22/26, 85%), methotrexate (7/ 30, 27%), adalimumab (2/30, 8%), cyclophosphamide (3/30, 12%), rituximab (2/30, 8%), azathioprine (1/30, 4%) and mycophenolate mofetil (1/30, 4%). Four patients may have received steroids, methotrexate, or azathioprine, but details were limited (Hafner and Vogel, 1993). Twenty-five of 28 (89%) of patients improved on treatment, with three patients did not improve and two patients their clinical course was unknown. Improvement was designated by improvement or resolution of symptoms, and/or imaging findings.
4. Discussion
We discuss 30 pediatric cases of NS. For children, the most common presenting symptoms were seizures and optic nerve involvement. Our data support that seizures and isolated NS are more common in children with NS as compared to adults but similar rates of cranial neuropathy and neuroendocrine involvement are observed. Differences in neuroimaging included lower rates of parenchymal lesions and leptomeningeal enhancement, but similar rates of mass lesions, and cranial nerve enhancement in children as compared to adults with NS. One unique feature in our cohort that has not been discussed previously is that CN II was the most common in children when CN VII is most common in adults (Fritz et al., 2016). Just as reported in other studies, ACE in both serum and CSF had low yield in these pediatric cases. However, ACE has a low sensitivity and low specificity and thus is not recommended in the routine diagnosis of NS (Ungprasert et al., 2016; Voortman et al., 2019; Bradshaw et al., 2021). Pediatric NS is rare and limitations in our analysis include reporting bias such as cases that are published and also some details may be missing from our cases.
With the differences in presentation of pediatric versus adult NS, further investigation is needed to understand the differences in pathogenesis in pediatric versus adult NS. Some features are similar between children and adults whereas others are different, so understanding whether earlier onset NS involves the same pathways as adult NS, or if earlier onset NS is more severe than adult-onset NS is unclear. Due to limited data on follow-up on the pediatric cases, we were unable to compare clinical outcomes with adults. Seizures are more common in children than in adults, which is likely due to the increased risk for seizures in general in children compared to adults (Aaberg et al., 2017). Factors leading to why children are more likely to have optic nerve involvement and less lung involvement are unclear. While chest imaging is more likely to be normal in children than in adults, chest imaging should still be performed. Chest MRI is preferred due to limiting radiation exposure, but CT chest with and without contrast, or chest x-ray if MRI or CT are not available.
As for treatment in NS, randomized trials have not yet been conducted for NS treatment in either children or adults; therefore, the treatment recommendations are based on observations from case reports and expert opinions. Treatment options for pediatric sarcoidosis have been more readily published, and these recommendations can be modified for pediatric NS. Our approach and treatment recommendations are summarized in Table 4 and Table 5. In the implication of any of these treatment or diagnostic modalities, it is important to consider the risk/benefit ratio for each, including medication side effects, radiation exposure, and the necessity for sedation to obtain imaging or to perform procedures.
Table 5.
Treatments used in pediatric neurosarcoidosis. Note: these are suggested dosages and duration of treatment and side effects are not listed in order of occurrence. Treatment duration is also dependent on the patient and clinical course.
| Name | Suggested dosage | Suggested duration | Side effects | Monitoring |
|---|---|---|---|---|
| First Line | ||||
| Prednisone | 0.5–1.0 mg/kg/day PO | 2–3 months | Hyperglycemia, weight gain, mood change, psychosis, GI upset, hypertension, adrenal insufficiency, psychosis | Blood glucose, blood pressure |
| Methylprednisolone | 30/mg/kg/dose (max 1000 mg) IV daily | 3 days | Same as prednisone | Same as prednisone |
| Second Line | ||||
| Methotrexate | 15 mg/m2 (max 25 mg) PO or SC weekly (Note: take with folic acid 1 mg QD) |
1 year | GI upset, hepatotoxicity, cytopenia, hair loss, mucositis, pneumonitis, infections | CBC, CMP |
| Mycophenolate mofetil | 600 mg/m2 per dose twice a day (max 1500 mg per day) | 1 year | Anemia, cytopenia, teratogenicity, hepatitis, GI upset | CBC, CMP |
| Azathioprine | 2–2.5 mg/kg PO daily | 1 year | Anemia, neutropenia, hepatitis | CBC, CMP. Obtain TPMT activity prior to initiation |
| Leflunomide | <40 kg: 10 mg PO daily >40 kg: 20 mg PO daily |
1 year | GI complaints, anemia, cytopenia, rash, hepatotoxicity | CBC, CMP |
| Third Line | ||||
| Infliximab | Induction: 5 mg/kg IV given at 0,2 and 6 weeks Maintenance: 5 mg/kg IV every 4 to 8 weeks |
1 year | Infusion reactions, hepatitis, drug induced lupus, antidrug antibodies, demyelinating disease, malignancy | CBC, CMP. Obtain QuantiFERON Gold Tb test prior to initiation. |
| Adalimumab | <40 kg: 20 mg SC every 2 weeks >40 kg: 40 mg SC every 2 weeks |
1 year | Same as infliximab | Same as infliximab |
Abbreviations: IV-intravenous, PO – oral, SC- subcutaneous, kg: kilogram, mg: milligram, m = meter, GI: gastrointestinal, CBC: complete blood count, CMP: comprehensive metabolic panel, Tb: tuberculosis, TPMT: thiopurine S-methyltransferase.
Monitoring treatment response includes a thorough and frequent history and physical examination, laboratory, and radiographic evaluation, including MRIs of the brain and spinal cord with contrast if possible. Prognostic factors have not yet been established in children with pediatric sarcoidosis (Nathan et al., 2019). There is also no guideline for children regarding follow-up. In a patient with abnormal abnormal brain or spinal cord MRI findings due to NS, repeating the previously abnormal imaging 2–4 months after the initiation of treatment is a reasonable approach (Bradshaw et al., 2021). Radiographic monitoring can be spaced out over time based on treatment response. It is important to note that clinical response may lag MRI results.
Certain genes have been associated with NS in adults, such as HLA DRB1*1101, HLA DRB1*1301 (Rossman et al., 2003; Berlin et al., 1997). Other genes including butyrophilin-like 2 gene (BTNL2), AnnexinA11 (ANXA11), and angiotensin-converting enzyme (ACE) variants are also reported in NS (Fischer and Rybicki, 2015). Early onset sarcoidosis (EOS) in children such as Blau syndrome/EOS, is associated with mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene also known as CARD15 (caspase recruitment domain-containing protein) (Achille et al., 2016; Miceli-Richard et al., 2001). However, none of the pediatric cases reported genetic testing results, so whether genetic causes contributed to this cohort is unknown. The investigation of the genetic role of NS may be a very beneficial focus for future research in the identification and causation of childhood NS. Moreover, there are no specific or reliable biomarkers to monitor disease activity for NS in children, which should also be a focus of future studies.
4.1. Outlook and future studies in pediatric NS
NS is a rare neuroinflammatory condition that is challenging to diagnose, especially in children. Since NS is a rare disease, a multi-center, international collaboration would be vital to prospectively study children with NS to understand how to diagnose patients earlier and the natural history of NS. The goal of this review is to highlight clinical manifestations of children with NS so that NS can be considered in patients with suspected neuroinfectious or neuroinflammatory diseases. Additionally, we highlight evaluation for NS and suggested treatment options. Future randomized trials and studies would help determine medical and clinical management in pediatric NS patients.
There is much room for future research on pediatric NS. Future studies may focus on the pediatric pathophysiology of neurosarcoidosis, and how it differs from the adult, which makes up the majority of the literature we currently have on the pathophysiology of NS. Another research opportunity would be the specific risks, benefits, and outcome differences between the treatments used to come up with a formal treatment recommendation, the role of genetic testing, and more accurate diagnostic or treatment biomarkers in NS.
Funding
This work was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002378 and KL2TR002381.
Declaration of Competing Interest
M.Y., A.G-Y., M.A., M.D., A.T., D.W. have nothing to declare.
G.G. receives part time salary support from the Centers for Disease Control and Prevention for acute flaccid myelitis surveillance.
Abbreviations:
- NS
neurosarcoidosis
- CSF
cerebrospinal fluid
- CN
cranial nerve
- EEG
electroencephalography
- EMG/NCS
electromyography/nerve conduction study
- EKG
electrocardiogram
- CBC
complete blood count
- ANA
antinuclear antibody
- CT
computed tomography
- MRI
magnetic resonance imaging
- APC
antigen presenting cell
- PNS
peripheral nervous system
- CNS
central nervous system
- ACE
angiotensin converting enzyme
Data availability
Data will be made available on request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data will be made available on request.