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Neurosarcoidosis according to Zajicek and Scolding criteria: 15 probable and definite cases, their treatment and outcomes
Journal of the Neurological Sciences 379 (2017) 84–88
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Clinical Short Communication
Neurosarcoidosis according to Zajicek and Scolding criteria: 15 probable and definite cases, their treatment and outcomes Gonçalo Cação a,⁎, Ana Branco b, Mariana Meireles c, José Eduardo Alves d, Andrea Mateus c, Ana Martins Silva a,e, Ernestina Santos a,e a
Neurology Department, Centro Hospitalar do Porto, Porto, Portugal Internal Medicine Department, Centro Hospitalar da Cova da Beira, Covilha, Portugal Internal Medicine Department, Centro Hospitalar do Porto, Porto, Portugal d Neuroradiology Department, Centro Hospitalar do Porto, Porto, Portugal e Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal b c
a r t i c l e
i n f o
Article history: Received 20 December 2016 Received in revised form 9 May 2017 Accepted 26 May 2017 Available online 27 May 2017 Keywords: Neurosarcoidosis Diagnosis criteria Magnetic resonance imaging Treatment Outcome
a b s t r a c t Introduction: Neurosarcoidosis occurs in about 5% to 15% of patients with sarcoidosis. The purpose of this study was to identify and characterize a cohort of neurosarcoidosis patients and to review the largest previously reported neurosarcoidosis case series. Methods: This retrospective study enrolled all patients with the diagnosis of probable or definitive neurosarcoidosis according to Zajicek and Scolding criteria, followed at the neurology department of a tertiary center in Portugal from January 1989 to December 2015. Results: A total of 15 patients presented a diagnosis of probable or definitive neurosarcoidosis, with a mean age at time of diagnosis of 38.5 years. The presenting neurologic syndrome was isolated cranial neuropathy, aseptic meningitis, myelitis, brain parenchymal lesion, myelorradiculitis and meningomyelorradiculitis. MRI study most often presented different enhancing lesions and the CSF analysis commonly revealed a lymphocytic pleocytosis and raised proteins. Thirteen patients had histopathology confirmation of systemic sarcoidosis and one preformed a spinal cord biopsy. Corticosteroids was the most often used treatment alone or in combination with immunosuppressive drugs. After a mean follow-up of 86.1 months, the majority of patients fully recovered to a mRankin 0. Discussion: Fully comprehension of neurosarcoidosis is still a challenge due to its rarity and limited number of large published series, which renders the epidemiological study of this disease very difficult. In this study, the thoroughly medical records review and the summarize of previous published cohorts allow to add some information in the epidemiological and clinical knowledge of this entity. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Sarcoidosis is characterized by multisystem non-caseous granulomatous disease of an unknown etiology. It has been postulated that it results from an exaggerated T-helper cell immune response to foreign or self-antigens [1]. It most commonly affects lungs, however, virtually any organ or system may be involved including skin, eyes, kidney, heart, and nervous system. Neurologic involvement occurs in about 5% to 15% of patients [2,3]. Notwithstanding, only approximately half of subjects with histological evidence of central nervous system (CNS) disease on autopsy are diagnosed with neurosarcoidosis ante-mortem,
⁎ Corresponding author at: Neurology Department, Centro Hospitalar do Porto, Largo Professor Abel Salazar, 4099-001 Porto, Portugal. E-mail address: [email protected] (G. Cação).
http://dx.doi.org/10.1016/j.jns.2017.05.055 0022-510X/© 2017 Elsevier B.V. All rights reserved.
suggesting a significant number of patients with subclinical disease or misdiagnosed [2]. Neurologic manifestations depend on the location of the lesions namely: CNS involvement (cranial neuropathies, brain parenchymal disease, meningeal disease, spinal cord disease and neuropsychiatric manifestations), peripheral neuropathy, dysfunction of the hypothalamic-pituitary axis and myopathy [4]. Cranial nerve involvement is the most common neurological presentation, occurring in approximately 60% of patients [2,5]. Meningeal disease is common and the meningeal infiltration can be associated with aseptic meningitis, cranial neuropathies, hydrocephalus and cauda equina syndrome [4]. Spinal cord involvement occurs due to leptomeningeal infiltration and/or myelitis, and it typically involves more than three segments, differentiating it from other inflammatory diseases [4]. Peripheral neuropathy occurs in 20% of patients and presents with different clinical manifestations [3,4]. Hypothalamic-pituitary axis involvement most commonly
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presents with diabetes insipidus, but other dysfunction may be observed [3,4]. Involvement of skeletal muscle by sarcoid granulomas can occur in up to 50% with only 1–2% having symptomatic muscle disease [3]. The purpose of this study was to identify and characterize a cohort of neurosarcoidosis patients followed in a Portuguese center and to compare it with the largest previously reported neurosarcoidosis case series. 2. Methods This retrospective study enrolled all patients with the diagnosis of neurosarcoidosis, followed at the neurology department of Centro Hospitalar do Porto, a tertiary center in Portugal from January 1989 to December 2015. The inclusion criteria were based on the diagnostic criteria proposed by Zajicek et al. [6] for definitive and probable neurosarcoidosis. We retrospectively reviewed the medical records and collected demographic features (sex, age at onset, age at diagnosis), extent of the disease (systemic or isolated neurological involvement), classification of disease (probable or definite neurosarcoidosis), initial presenting neurological symptom(s), time interval between symptoms onset and diagnosis, magnetic resonance imaging (MRI) findings, serum and cerebrospinal fluid (CSF) analysis data, biopsy results, treatment and clinical follow-up. 3. Results Twenty-one patients were identified with a previous diagnosis of neurosarcoidosis, but only 15 fulfill the criteria for probable (14) or definitive (1) neurosarcoidosis. Six patients were excluded once during the follow-up an alternative diagnosis for their symptoms was identified or were lost in follow-up. One of the excluded patients was a 69 years old female that presented with cognitive decline associated with periods of hypothermia, hypersomnia, hyperphagia and hyponatremia. The T2-weighted MRI revealed hyperintense lesions on the anteromedial aspect of the thalamus, extending to the hypothalamus and mammillary bodies without restricted diffusion. The additional extensive work-up performed was normal. Due to the lesions characteristics and location, a diagnosis of possible neurosarcoidosis was assumed and the patient presented some improvement with corticosteroids. Notwithstanding, the fluctuating periods of hypothalamic dysfunction continued and a positive anti-aquaporin-4 (AQP4) antibody was disclosed which established a diagnosis of neuromyelitis optica spectrum disorder with AQP4-IgG. The demographic and clinical characteristics of the 15 patients included are described below and summarized on Table 1. Nine were female (60%) and the mean age at time of diagnosis was 38.5 years (SD
85
14.9). Thirteen (86.7%) patients had coexistent systemic sarcoidosis, whereas two (13.3%) were diagnosed with isolated neurosarcoidosis. Most frequent extra-neurological involvement were the lung in ten patients, skin in four, eye in three and articular in three. The mean age of sarcoidosis symptoms onset was 34.9 years (SD 12.7) and the mean age of neurological symptoms onset was 35.9 years (SD 13.1). The mean time interval between the neurological symptoms onset and the diagnosis of neurosarcoidosis was 35.9 months (SD 65) and considering only the 11 patients without a previous diagnosis of sarcoidosis, this interval was 35 months (SD 73.6). Neurosarcoidosis was the initial manifestation of the disease in 11 patients (73.3%). The presenting neurologic syndrome was cranial neuropathy in six patients (40%, of which half presented an isolated cranial neuropathy), aseptic meningitis in six (40%), myelitis in two (13.3%), brain parenchymal lesion in two (13.3%), myeloradiculitis in one (6.7%) and meningomyeloradiculitis in one (6.7%). The cranial nerves involved in the former six patients were the facial nerve in three and the optic, abducens, and vestibulocochlear nerves in the others. No family history of the disease was reported. Fourteen patients performed a MRI, which revealed: spinal cord lesion (3 patients), brain enhanced lesion (2), cranial nerve enhancement (2), meningeal enhancement (2), spinal root enhancement (1) and unspecified white matter lesions (2). The spinal cord lesion involved between two and four contiguous segments, located on the cervical cord in one and on the thoracic and lumbar cord in the remain two. The intrameddulary lesions were centrally located in two and one had associated diffuse leptomeningeal enhancement. Fig. 1 illustrates some of these different CNS involvements present on MRI. It was reported normal in 2 patients. CSF analysis was available in 14 patients, where a lymphocytic pleocytosis was present in 78.6% and proteins were raised in 28.6%. Olygoclonal bands and ACE levels were evaluated in 7 patients, with the former present in 42.9% and the latter elevated in 28.6%. Serum ACE levels were evaluated in all patients being elevated in 33.3%. All patients with probable neurosarcoidosis and spinal cord involvement had negative serum anti-AQP4 antibody. Thirteen patients had histopathology confirmation of sarcoidosis from biopsies at lymph nodes (10 patients), skin (2) and muscle (1). Regarding the patient with definitive neurosarcoidosis, the confirming histopathology was obtained from a spinal cord biopsy. This was 36 years old patient that presented with a paraparesis, posterior cordonal syndrome and vesical dysfunction. An extensive work-up was performed but a diagnosis was not found, with only the MRI showing a lumbar cord lesion, raising the doubt between inflammatory and tumor. It was decided to perform a lesion biopsy, which confirmed the neurosarcoidosis diagnosis.
Table 1 Demographic and clinical characteristics of neurosarcodoisis patients. Sex
First Mf
First NMf
S dx
NS dx
Neurological syndrome
Systemic lesion
Bx
Dx
Txt
mR
M F M F M F M F F F F M F F M
36 53 27 46 28 31 16 26 23 40 65 28 38 40 26
36 56 27 46 33 31 16 26 24 47 65 28 38 40 26
36 53 28 65 28 31 17 27 25 40 66 28 38 48 30
36 56 28 65 33 31 17 27 25 48 66 28 38 48 31
Myelitis Aseptic meningitis Myelitis Isolated cranial neuropathies Aseptic meningitis Aseptic meningitis Isolated cranial neuropathies Aseptic meningitis Meningo-mieloradiculitis Aseptic meningitis Mieloradiculitis Aseptic meningitis Isolated cranial neuropathies Brain parenc. lesion Brain parenc. lesion
No LN, Sk, O, Löfgren O LN LN, L LN S LN, L, Sk LN, E LN, L, Sk LN LN LN No LN, L
SC Sk M LN LN LN Sk LN LN LN LN LN LN No LN
D P P P P P P P P P P P P P P
CT CT + AZA CT + CHL CT CT + AZA + MTX CT CT + AZA CT CT + AZA CT + CTX + MTX No CT + AZA CT No CT + AZA
4 0 5 3 0 1 0 0 0 0 3 0 1 0 6
Legend: M - male; F - female; Mf - manifestation; NMf - neurologic manifestation; S - sarcoidosis; NS - neurosarcoidosis; Dx - diagnosis; Parenc - parenchymal; Bx - biopsy; SC - spinal cord; Sk - skin; M - muscle; LN – lymph node; O - osteoarticular; L - lung; E - eye; D - definitive; P - probable; CT - corticotherapy; AZA - Azathioprine; CHL - chlorambucil; MTX - methotrexate; CTX - cyclophosphamide.
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Fig. 1. A) Axial post-gadolinium T1-weighted image shows diffuse bilateral leptomeningeal enhancement; B) Coronal T2-weighted image reveals a left temporal expansile lesion, which enhanced after contrast (not shown); C) Coronal T1-weighted image shows bilateral cranial nerve enhancement inside the internal auditory canals; D) Post-gadolinium sagittal T1 image depics extensive cauda equina enhancement.
Thirteen patients received pharmacological treatment, 46.2% of which received isolated corticosteroids and the remain a combination of corticosteroids and immunosuppressive drugs, namely methotrexate, azathioprine, cyclophosphamide and clorambucil (Graph 1). After a mean follow-up of 86.1 months, the majority of patients (8, 53.3%) fully recovered to a mRankin 0. Two patient presented a mild disability (mRankin 1 or 2), three a moderated disability (mRankin 3 or 4) and one a severe disability (mRankin 5). One patient died. Five patients with aseptic meningitis presented a mRankin 0 or 1, while the two patients with myelitis presented a mRankin 4 and 5. The patient who died was from the brain parenchymal lesion group, but the other patient of this group is asymptomatic.
4. Discussion Fully comprehension of neurosarcoidosis is still a challenge due to its rarity with a limited number of large series published. This renders epidemiological studies of this disease very difficult. In order to provide a better understanding of this condition, we reviewed the largest published case series (Table 2).
Graph 1. Pharmacological treatment of neurosarcoidosis patients.
In the reviewed literature (Table 2), we found an overall female predominance of 55.5% and an average age at symptoms onset of 41.7 years, which is in keeping with the current study. Concerning the presence of extra-neurological manifestations, our data is in accordance to the reviewed reports that found coexistent systemic sarcoidosis in 90% of patients. In our study, neurosarcoidosis was the initial manifestation of the disease in 73.3% of patients and 13.3% were diagnosed with isolated neurosarcoidosis. As demonstrated by the diagnosis delay of 35.9 months, this disease is not always suspected at the beginning, and even in patients previously diagnosis with sarcoidosis, the onset of neurological symptoms surprisingly does not immediately prompt the diagnosis. We speculate this is due to these patients are followed on other medical specialties that may not immediately value the neurological symptoms and also due to the extent work-up needed to exclude other neurological disorders. In the present study, cranial neuropathy and meningeal disease were the most frequent presenting neurologic syndrome. In the reviewed literature (Table 2), cranial neuropathy is the most common neurological manifestation, present in 48% of patients, followed by spinal cord disease (31%), brain parenchymal disease (23%), meningeal disease (19%) and peripheral neuropathy (19%). In our study, the most frequently involved cranial nerve was the facial, with one patient presenting a sequential bilateral involvement. The mechanism of cranial nerve paresis is controversial, but most studies endorse that epi- and perineural inflammation and granulomatous vasculitis result in local pressure and ischemia [2]. Cranial neuropathy does not only result from nerve granuloma within the subarachnoid course, but can be caused by increased intracranial pressure, inflammation of the surrounding basilar meninges, or granuloma formation at the cranial nerve nucleus or proximal fiber tract, within the extracranial segment, or at the end organ [2]. MRI is the preferred imaging study for evaluation of neurosarcoidosis, revealing meningeal and cranial nerve enhancement, single or multifocal enhancing lesions, and discrete non-enhancing hyperintense T2-weighted abnormalities [2,5]. Although highly sensitivity (82–97%), it lacks specificity [4,7]. Similar to other series, we found that enhanced lesions in different locations were a frequent MRI finding in patients with neurosarcoidosis. Unfortunately, there are no reliable serologic or CSF assays with high sensitivity or specificity for diagnosis, or dependable laboratory marker for following progress of disease. CSF ACE levels are rather insensitive (24–55%) for the diagnosis of neurosarcoidosis but they may be relatively specific (94–95%) [23] and are useful in monitoring disease activity and response to therapy. Elevated CSF ACE is present in less than half of patients with neurosarcoidosis [7], a finding that is corroborated in the current study. We found a moderate lymphocytic pleocyotosis (10–100 cells/mm3) as the CSF most common finding in our patients. CSF is also important for exclusion of infection and malignancy. Currently, histopathology confirmation remains a key element for definitive diagnosis of neurosarcoidosis, showing the typical non-caseum granulomas [4]. Although highly specific and sensible, its practicability makes it difficult to perform in every patient. This is translated in a reduced number of patients with a definitive diagnosis. From the reviewed series reported on Table 2, were available we found that 176 had definitive diagnosis of neurosarcoidosis, comparing to 502 with probable. Concerning treatment, the aim is to get maximum reversal of symptoms, stabilization and prevention of disease progression. There is no curative treatment but remission is common (70%) after prolonged immunosuppressive therapy [4,24]. The most often recommended treatment is corticosteroids, commonly with oral prednisolone 1 mg/kg/day, but in more severe clinic presentation is used methylprednisolone 1 g/day for 3 to 5 days and then oral tapering for up to 12 months [25]. Second line therapies are methotrexate, chloroquine, azathioprine, mycophenolate mophetil and cyclophosphamide [4]. Immunosuppressive treatment alone is contemplated if prednisone causes adverse effects. In refractory patients can still be considered radiotherapy, infliximab [26], etanercept and thalidomide. Immunoglobulins or
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Table 2 Previous published neurosarcoidosis series. Author (year)
Leonhard et al. [7] Durel et al. [8] Carlson et al. [2] Nozaki et al. [9] Gascón-Bayarri et al. [5] Sakushima et al. [10] Pawate et al. [11] Joseph and Scolding [12] Scott et al. [13] Kellinghaus et al. [14] Spencer et al. [15] Allen et al. [16] Ferriby et al. [17] Ferriby et al. [18] Zajicek et al. [6] Sharma [19] Chapelon et al. [20] Oksanen [21] Pentland et al. [22]
N
52 20 305 70 30 17 54 30 48 13 21 32 27 40 68 37 35 50 19
M/F
25/27 12/8 143/162 23/47 10/20 9/8 14/40 16/14 17/31 NA 12/9 15/17 13/14 20/20 36/32 21/16 17/18 18/32 4/15
Mean age onset
Extra-neuro Neurological syndrome manif CN BPL Mening SC
Treatment
Prognosis
PN
Myo P/Pb/D
CT only
CT + Others No others only txt
Full
NA 37 44,5 41 48,3 46,4 40,8 40 NA 37 41 48 42,3 41,3 38,9 41 46 44 32
79% 95% 62% 86% 97% 100% NA 73% 90% NA 95% 100% 89% 87,5% 91% 95% 83% 100% 100%
17% 0 NA 9% 10% 6% 2% NA NA 23% 5% 47% 48% 33% 0% 29% 40% 18% NA
10% 0 NA NA 10% 0% 0% NA NA 0% 0% 25% 20% 16% 0% 8% 26% 10% NA
25% 50% 51% 37% 83% 82% 11% 33% 42% 92% 43% 47% 82% 40% 50% 54% 71% 60% 100%
58% 50% 41% 57% 7% 18% 69% 53% 54% 8% 33% 12% 18% 40% NA 32% 17% 0% 0%
(67%) 5% 90% NA NA (39%) 31% 45% NA NA NA NA 3% 67% (52%) NA NA NA NA 19% 44% 44% 11% 28% NA NA NA 24% 30% 46% 46% NA NA 52% NA
31% 0% 58% 66% 56% 18% 63% 80% NA 92% 29% 59% 41% 27% 72% 52% 37% 42% 32%
21% 0% NA 63% 7% 29% NA NA NA NA 29% 13% NA NA NA NA NA NA NA
37% 0% NA 36% 7% 12% NA NA NA NA NA NA 30% 27% 12% 24% 17% 8% NA
23% 100% NA 29% 0% 35% 19% 17% NA NA 43% NA NA NA 28% NA 26% 10% NA
Diagnosis
14/37/1 0/18/2 57/157/91 0/55/15 0/23/7 0/16/1 12/33/9 0/17/13 0/36/12 0/10/3 4/11/6 NA NA NA 0/56/12 0/33/4 NA NA NA
0% 0% 6% 0% 0% 0% 0% NA 0% 0% 5% 0% 0% 0% NA NA 0% 0% 0%
12% 0% 2% 6% 10% 0% 20% NA 4% 0% 19% 41% 0% 20% NA 3% 11% 40% 0%
Par
No rec
Death
4% 5% NA 44% 21% NA NA 7% 44% NA NA 34% 44% NA NA 30% 7% NA NA
0% 0% 4% NA 3% NA NA 10% 4% NA 0% 3% 0% 0% 0% 16% 0% 12% 16%
Legend: N - number of patients; M - male; F - female; NA – not available; Neuro - neurologic; Manif - manifestations; CN - cranial neuropathy; BPL - brain parenchimal lesion; Mening meningeal disease; SC - spinal cord; PN - peripheral neuropathy; Myo - myopathy; P - possible; Pb - probable; D - definitive; CT - corticotherapy; Txt - treatment; Full - full recovery; Par - partial recovery; No rec - no recovery.
plasmapheresis is reported as beneficial in anecdotal cases [1,4]. At the conclusion of therapy, clinical examination, MRI, and CSF analysis help determine if a longer course or more aggressive therapy is needed. In the present study, corticosteroids were the main treatment followed by azathioprine and, to a lesser extent, methotrexate. From the reviewed papers, corticosteroids were used isolated on an average of 55% of patients and combined with immunosuppressive drugs in 32%. Only 1% was treated without steroids and an average of 11% did not receive any treatment. The role of surgery is generally limited to diagnostic biopsy rather than therapeutic resection [2]. In rare circumstances, subtotal removal of large non-caseating granulomas has been reported in cases of life-threatening compression or advanced refractory disease [2]. Overall the outcome is variable. In Table 2 we found that an average of 62% of patients improved, comparing with 27% that did not improve or even progressed. In the current study, the majority of patients (53.3%) fully recovered being asymptomatic. Aseptic meningitis was related to a better prognosis and myelitis to a worst. Other studies also reported that PNS involvement and aseptic meningitis present a better prognosis [5]. Where available, on Table 2, the reported mortality was on average 5% of patients, similar to ours (6.7%). In closing, the authors wish to acknowledge the limitations of the current study. By nature of a retrospective review, we were dependent upon the accuracy and completeness of the existing medical records. Also, due to its rarity our cohort is limited. On the strengths side, we would like to enhance the thoroughly medical records review and the summarize of previous published cohorts that allowed to add some information in the epidemiological and clinical knowledge of this entity. In patients presenting with neurological symptoms, without a history of sarcoidosis, establishing a diagnosis can be challenging. More typical neurological syndromes that raise diagnostic suspicion are cranial neuropathies and aseptic meningitis. MRI and CSF are important in the initial evaluation, but histological confirmation remains crucial. Diagnostic difficulties, variability of the clinical course, scarcity and lack of specific markers and the possibility of resistance to therapeutic measures, makes neurosarcoidosis a difficult condition to manage. Conflict of interest The authors declare that they have no conflict of interest.
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Clinical Short Communication
Neurosarcoidosis according to Zajicek and Scolding criteria: 15 probable and definite cases, their treatment and outcomes Gonçalo Cação a,⁎, Ana Branco b, Mariana Meireles c, José Eduardo Alves d, Andrea Mateus c, Ana Martins Silva a,e, Ernestina Santos a,e a
Neurology Department, Centro Hospitalar do Porto, Porto, Portugal Internal Medicine Department, Centro Hospitalar da Cova da Beira, Covilha, Portugal Internal Medicine Department, Centro Hospitalar do Porto, Porto, Portugal d Neuroradiology Department, Centro Hospitalar do Porto, Porto, Portugal e Unit for Multidisciplinary Research in Biomedicine, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal b c
a r t i c l e
i n f o
Article history: Received 20 December 2016 Received in revised form 9 May 2017 Accepted 26 May 2017 Available online 27 May 2017 Keywords: Neurosarcoidosis Diagnosis criteria Magnetic resonance imaging Treatment Outcome
a b s t r a c t Introduction: Neurosarcoidosis occurs in about 5% to 15% of patients with sarcoidosis. The purpose of this study was to identify and characterize a cohort of neurosarcoidosis patients and to review the largest previously reported neurosarcoidosis case series. Methods: This retrospective study enrolled all patients with the diagnosis of probable or definitive neurosarcoidosis according to Zajicek and Scolding criteria, followed at the neurology department of a tertiary center in Portugal from January 1989 to December 2015. Results: A total of 15 patients presented a diagnosis of probable or definitive neurosarcoidosis, with a mean age at time of diagnosis of 38.5 years. The presenting neurologic syndrome was isolated cranial neuropathy, aseptic meningitis, myelitis, brain parenchymal lesion, myelorradiculitis and meningomyelorradiculitis. MRI study most often presented different enhancing lesions and the CSF analysis commonly revealed a lymphocytic pleocytosis and raised proteins. Thirteen patients had histopathology confirmation of systemic sarcoidosis and one preformed a spinal cord biopsy. Corticosteroids was the most often used treatment alone or in combination with immunosuppressive drugs. After a mean follow-up of 86.1 months, the majority of patients fully recovered to a mRankin 0. Discussion: Fully comprehension of neurosarcoidosis is still a challenge due to its rarity and limited number of large published series, which renders the epidemiological study of this disease very difficult. In this study, the thoroughly medical records review and the summarize of previous published cohorts allow to add some information in the epidemiological and clinical knowledge of this entity. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Sarcoidosis is characterized by multisystem non-caseous granulomatous disease of an unknown etiology. It has been postulated that it results from an exaggerated T-helper cell immune response to foreign or self-antigens [1]. It most commonly affects lungs, however, virtually any organ or system may be involved including skin, eyes, kidney, heart, and nervous system. Neurologic involvement occurs in about 5% to 15% of patients [2,3]. Notwithstanding, only approximately half of subjects with histological evidence of central nervous system (CNS) disease on autopsy are diagnosed with neurosarcoidosis ante-mortem,
⁎ Corresponding author at: Neurology Department, Centro Hospitalar do Porto, Largo Professor Abel Salazar, 4099-001 Porto, Portugal. E-mail address: [email protected] (G. Cação).
http://dx.doi.org/10.1016/j.jns.2017.05.055 0022-510X/© 2017 Elsevier B.V. All rights reserved.
suggesting a significant number of patients with subclinical disease or misdiagnosed [2]. Neurologic manifestations depend on the location of the lesions namely: CNS involvement (cranial neuropathies, brain parenchymal disease, meningeal disease, spinal cord disease and neuropsychiatric manifestations), peripheral neuropathy, dysfunction of the hypothalamic-pituitary axis and myopathy [4]. Cranial nerve involvement is the most common neurological presentation, occurring in approximately 60% of patients [2,5]. Meningeal disease is common and the meningeal infiltration can be associated with aseptic meningitis, cranial neuropathies, hydrocephalus and cauda equina syndrome [4]. Spinal cord involvement occurs due to leptomeningeal infiltration and/or myelitis, and it typically involves more than three segments, differentiating it from other inflammatory diseases [4]. Peripheral neuropathy occurs in 20% of patients and presents with different clinical manifestations [3,4]. Hypothalamic-pituitary axis involvement most commonly
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presents with diabetes insipidus, but other dysfunction may be observed [3,4]. Involvement of skeletal muscle by sarcoid granulomas can occur in up to 50% with only 1–2% having symptomatic muscle disease [3]. The purpose of this study was to identify and characterize a cohort of neurosarcoidosis patients followed in a Portuguese center and to compare it with the largest previously reported neurosarcoidosis case series. 2. Methods This retrospective study enrolled all patients with the diagnosis of neurosarcoidosis, followed at the neurology department of Centro Hospitalar do Porto, a tertiary center in Portugal from January 1989 to December 2015. The inclusion criteria were based on the diagnostic criteria proposed by Zajicek et al. [6] for definitive and probable neurosarcoidosis. We retrospectively reviewed the medical records and collected demographic features (sex, age at onset, age at diagnosis), extent of the disease (systemic or isolated neurological involvement), classification of disease (probable or definite neurosarcoidosis), initial presenting neurological symptom(s), time interval between symptoms onset and diagnosis, magnetic resonance imaging (MRI) findings, serum and cerebrospinal fluid (CSF) analysis data, biopsy results, treatment and clinical follow-up. 3. Results Twenty-one patients were identified with a previous diagnosis of neurosarcoidosis, but only 15 fulfill the criteria for probable (14) or definitive (1) neurosarcoidosis. Six patients were excluded once during the follow-up an alternative diagnosis for their symptoms was identified or were lost in follow-up. One of the excluded patients was a 69 years old female that presented with cognitive decline associated with periods of hypothermia, hypersomnia, hyperphagia and hyponatremia. The T2-weighted MRI revealed hyperintense lesions on the anteromedial aspect of the thalamus, extending to the hypothalamus and mammillary bodies without restricted diffusion. The additional extensive work-up performed was normal. Due to the lesions characteristics and location, a diagnosis of possible neurosarcoidosis was assumed and the patient presented some improvement with corticosteroids. Notwithstanding, the fluctuating periods of hypothalamic dysfunction continued and a positive anti-aquaporin-4 (AQP4) antibody was disclosed which established a diagnosis of neuromyelitis optica spectrum disorder with AQP4-IgG. The demographic and clinical characteristics of the 15 patients included are described below and summarized on Table 1. Nine were female (60%) and the mean age at time of diagnosis was 38.5 years (SD
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14.9). Thirteen (86.7%) patients had coexistent systemic sarcoidosis, whereas two (13.3%) were diagnosed with isolated neurosarcoidosis. Most frequent extra-neurological involvement were the lung in ten patients, skin in four, eye in three and articular in three. The mean age of sarcoidosis symptoms onset was 34.9 years (SD 12.7) and the mean age of neurological symptoms onset was 35.9 years (SD 13.1). The mean time interval between the neurological symptoms onset and the diagnosis of neurosarcoidosis was 35.9 months (SD 65) and considering only the 11 patients without a previous diagnosis of sarcoidosis, this interval was 35 months (SD 73.6). Neurosarcoidosis was the initial manifestation of the disease in 11 patients (73.3%). The presenting neurologic syndrome was cranial neuropathy in six patients (40%, of which half presented an isolated cranial neuropathy), aseptic meningitis in six (40%), myelitis in two (13.3%), brain parenchymal lesion in two (13.3%), myeloradiculitis in one (6.7%) and meningomyeloradiculitis in one (6.7%). The cranial nerves involved in the former six patients were the facial nerve in three and the optic, abducens, and vestibulocochlear nerves in the others. No family history of the disease was reported. Fourteen patients performed a MRI, which revealed: spinal cord lesion (3 patients), brain enhanced lesion (2), cranial nerve enhancement (2), meningeal enhancement (2), spinal root enhancement (1) and unspecified white matter lesions (2). The spinal cord lesion involved between two and four contiguous segments, located on the cervical cord in one and on the thoracic and lumbar cord in the remain two. The intrameddulary lesions were centrally located in two and one had associated diffuse leptomeningeal enhancement. Fig. 1 illustrates some of these different CNS involvements present on MRI. It was reported normal in 2 patients. CSF analysis was available in 14 patients, where a lymphocytic pleocytosis was present in 78.6% and proteins were raised in 28.6%. Olygoclonal bands and ACE levels were evaluated in 7 patients, with the former present in 42.9% and the latter elevated in 28.6%. Serum ACE levels were evaluated in all patients being elevated in 33.3%. All patients with probable neurosarcoidosis and spinal cord involvement had negative serum anti-AQP4 antibody. Thirteen patients had histopathology confirmation of sarcoidosis from biopsies at lymph nodes (10 patients), skin (2) and muscle (1). Regarding the patient with definitive neurosarcoidosis, the confirming histopathology was obtained from a spinal cord biopsy. This was 36 years old patient that presented with a paraparesis, posterior cordonal syndrome and vesical dysfunction. An extensive work-up was performed but a diagnosis was not found, with only the MRI showing a lumbar cord lesion, raising the doubt between inflammatory and tumor. It was decided to perform a lesion biopsy, which confirmed the neurosarcoidosis diagnosis.
Table 1 Demographic and clinical characteristics of neurosarcodoisis patients. Sex
First Mf
First NMf
S dx
NS dx
Neurological syndrome
Systemic lesion
Bx
Dx
Txt
mR
M F M F M F M F F F F M F F M
36 53 27 46 28 31 16 26 23 40 65 28 38 40 26
36 56 27 46 33 31 16 26 24 47 65 28 38 40 26
36 53 28 65 28 31 17 27 25 40 66 28 38 48 30
36 56 28 65 33 31 17 27 25 48 66 28 38 48 31
Myelitis Aseptic meningitis Myelitis Isolated cranial neuropathies Aseptic meningitis Aseptic meningitis Isolated cranial neuropathies Aseptic meningitis Meningo-mieloradiculitis Aseptic meningitis Mieloradiculitis Aseptic meningitis Isolated cranial neuropathies Brain parenc. lesion Brain parenc. lesion
No LN, Sk, O, Löfgren O LN LN, L LN S LN, L, Sk LN, E LN, L, Sk LN LN LN No LN, L
SC Sk M LN LN LN Sk LN LN LN LN LN LN No LN
D P P P P P P P P P P P P P P
CT CT + AZA CT + CHL CT CT + AZA + MTX CT CT + AZA CT CT + AZA CT + CTX + MTX No CT + AZA CT No CT + AZA
4 0 5 3 0 1 0 0 0 0 3 0 1 0 6
Legend: M - male; F - female; Mf - manifestation; NMf - neurologic manifestation; S - sarcoidosis; NS - neurosarcoidosis; Dx - diagnosis; Parenc - parenchymal; Bx - biopsy; SC - spinal cord; Sk - skin; M - muscle; LN – lymph node; O - osteoarticular; L - lung; E - eye; D - definitive; P - probable; CT - corticotherapy; AZA - Azathioprine; CHL - chlorambucil; MTX - methotrexate; CTX - cyclophosphamide.
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Fig. 1. A) Axial post-gadolinium T1-weighted image shows diffuse bilateral leptomeningeal enhancement; B) Coronal T2-weighted image reveals a left temporal expansile lesion, which enhanced after contrast (not shown); C) Coronal T1-weighted image shows bilateral cranial nerve enhancement inside the internal auditory canals; D) Post-gadolinium sagittal T1 image depics extensive cauda equina enhancement.
Thirteen patients received pharmacological treatment, 46.2% of which received isolated corticosteroids and the remain a combination of corticosteroids and immunosuppressive drugs, namely methotrexate, azathioprine, cyclophosphamide and clorambucil (Graph 1). After a mean follow-up of 86.1 months, the majority of patients (8, 53.3%) fully recovered to a mRankin 0. Two patient presented a mild disability (mRankin 1 or 2), three a moderated disability (mRankin 3 or 4) and one a severe disability (mRankin 5). One patient died. Five patients with aseptic meningitis presented a mRankin 0 or 1, while the two patients with myelitis presented a mRankin 4 and 5. The patient who died was from the brain parenchymal lesion group, but the other patient of this group is asymptomatic.
4. Discussion Fully comprehension of neurosarcoidosis is still a challenge due to its rarity with a limited number of large series published. This renders epidemiological studies of this disease very difficult. In order to provide a better understanding of this condition, we reviewed the largest published case series (Table 2).
Graph 1. Pharmacological treatment of neurosarcoidosis patients.
In the reviewed literature (Table 2), we found an overall female predominance of 55.5% and an average age at symptoms onset of 41.7 years, which is in keeping with the current study. Concerning the presence of extra-neurological manifestations, our data is in accordance to the reviewed reports that found coexistent systemic sarcoidosis in 90% of patients. In our study, neurosarcoidosis was the initial manifestation of the disease in 73.3% of patients and 13.3% were diagnosed with isolated neurosarcoidosis. As demonstrated by the diagnosis delay of 35.9 months, this disease is not always suspected at the beginning, and even in patients previously diagnosis with sarcoidosis, the onset of neurological symptoms surprisingly does not immediately prompt the diagnosis. We speculate this is due to these patients are followed on other medical specialties that may not immediately value the neurological symptoms and also due to the extent work-up needed to exclude other neurological disorders. In the present study, cranial neuropathy and meningeal disease were the most frequent presenting neurologic syndrome. In the reviewed literature (Table 2), cranial neuropathy is the most common neurological manifestation, present in 48% of patients, followed by spinal cord disease (31%), brain parenchymal disease (23%), meningeal disease (19%) and peripheral neuropathy (19%). In our study, the most frequently involved cranial nerve was the facial, with one patient presenting a sequential bilateral involvement. The mechanism of cranial nerve paresis is controversial, but most studies endorse that epi- and perineural inflammation and granulomatous vasculitis result in local pressure and ischemia [2]. Cranial neuropathy does not only result from nerve granuloma within the subarachnoid course, but can be caused by increased intracranial pressure, inflammation of the surrounding basilar meninges, or granuloma formation at the cranial nerve nucleus or proximal fiber tract, within the extracranial segment, or at the end organ [2]. MRI is the preferred imaging study for evaluation of neurosarcoidosis, revealing meningeal and cranial nerve enhancement, single or multifocal enhancing lesions, and discrete non-enhancing hyperintense T2-weighted abnormalities [2,5]. Although highly sensitivity (82–97%), it lacks specificity [4,7]. Similar to other series, we found that enhanced lesions in different locations were a frequent MRI finding in patients with neurosarcoidosis. Unfortunately, there are no reliable serologic or CSF assays with high sensitivity or specificity for diagnosis, or dependable laboratory marker for following progress of disease. CSF ACE levels are rather insensitive (24–55%) for the diagnosis of neurosarcoidosis but they may be relatively specific (94–95%) [23] and are useful in monitoring disease activity and response to therapy. Elevated CSF ACE is present in less than half of patients with neurosarcoidosis [7], a finding that is corroborated in the current study. We found a moderate lymphocytic pleocyotosis (10–100 cells/mm3) as the CSF most common finding in our patients. CSF is also important for exclusion of infection and malignancy. Currently, histopathology confirmation remains a key element for definitive diagnosis of neurosarcoidosis, showing the typical non-caseum granulomas [4]. Although highly specific and sensible, its practicability makes it difficult to perform in every patient. This is translated in a reduced number of patients with a definitive diagnosis. From the reviewed series reported on Table 2, were available we found that 176 had definitive diagnosis of neurosarcoidosis, comparing to 502 with probable. Concerning treatment, the aim is to get maximum reversal of symptoms, stabilization and prevention of disease progression. There is no curative treatment but remission is common (70%) after prolonged immunosuppressive therapy [4,24]. The most often recommended treatment is corticosteroids, commonly with oral prednisolone 1 mg/kg/day, but in more severe clinic presentation is used methylprednisolone 1 g/day for 3 to 5 days and then oral tapering for up to 12 months [25]. Second line therapies are methotrexate, chloroquine, azathioprine, mycophenolate mophetil and cyclophosphamide [4]. Immunosuppressive treatment alone is contemplated if prednisone causes adverse effects. In refractory patients can still be considered radiotherapy, infliximab [26], etanercept and thalidomide. Immunoglobulins or
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Table 2 Previous published neurosarcoidosis series. Author (year)
Leonhard et al. [7] Durel et al. [8] Carlson et al. [2] Nozaki et al. [9] Gascón-Bayarri et al. [5] Sakushima et al. [10] Pawate et al. [11] Joseph and Scolding [12] Scott et al. [13] Kellinghaus et al. [14] Spencer et al. [15] Allen et al. [16] Ferriby et al. [17] Ferriby et al. [18] Zajicek et al. [6] Sharma [19] Chapelon et al. [20] Oksanen [21] Pentland et al. [22]
N
52 20 305 70 30 17 54 30 48 13 21 32 27 40 68 37 35 50 19
M/F
25/27 12/8 143/162 23/47 10/20 9/8 14/40 16/14 17/31 NA 12/9 15/17 13/14 20/20 36/32 21/16 17/18 18/32 4/15
Mean age onset
Extra-neuro Neurological syndrome manif CN BPL Mening SC
Treatment
Prognosis
PN
Myo P/Pb/D
CT only
CT + Others No others only txt
Full
NA 37 44,5 41 48,3 46,4 40,8 40 NA 37 41 48 42,3 41,3 38,9 41 46 44 32
79% 95% 62% 86% 97% 100% NA 73% 90% NA 95% 100% 89% 87,5% 91% 95% 83% 100% 100%
17% 0 NA 9% 10% 6% 2% NA NA 23% 5% 47% 48% 33% 0% 29% 40% 18% NA
10% 0 NA NA 10% 0% 0% NA NA 0% 0% 25% 20% 16% 0% 8% 26% 10% NA
25% 50% 51% 37% 83% 82% 11% 33% 42% 92% 43% 47% 82% 40% 50% 54% 71% 60% 100%
58% 50% 41% 57% 7% 18% 69% 53% 54% 8% 33% 12% 18% 40% NA 32% 17% 0% 0%
(67%) 5% 90% NA NA (39%) 31% 45% NA NA NA NA 3% 67% (52%) NA NA NA NA 19% 44% 44% 11% 28% NA NA NA 24% 30% 46% 46% NA NA 52% NA
31% 0% 58% 66% 56% 18% 63% 80% NA 92% 29% 59% 41% 27% 72% 52% 37% 42% 32%
21% 0% NA 63% 7% 29% NA NA NA NA 29% 13% NA NA NA NA NA NA NA
37% 0% NA 36% 7% 12% NA NA NA NA NA NA 30% 27% 12% 24% 17% 8% NA
23% 100% NA 29% 0% 35% 19% 17% NA NA 43% NA NA NA 28% NA 26% 10% NA
Diagnosis
14/37/1 0/18/2 57/157/91 0/55/15 0/23/7 0/16/1 12/33/9 0/17/13 0/36/12 0/10/3 4/11/6 NA NA NA 0/56/12 0/33/4 NA NA NA
0% 0% 6% 0% 0% 0% 0% NA 0% 0% 5% 0% 0% 0% NA NA 0% 0% 0%
12% 0% 2% 6% 10% 0% 20% NA 4% 0% 19% 41% 0% 20% NA 3% 11% 40% 0%
Par
No rec
Death
4% 5% NA 44% 21% NA NA 7% 44% NA NA 34% 44% NA NA 30% 7% NA NA
0% 0% 4% NA 3% NA NA 10% 4% NA 0% 3% 0% 0% 0% 16% 0% 12% 16%
Legend: N - number of patients; M - male; F - female; NA – not available; Neuro - neurologic; Manif - manifestations; CN - cranial neuropathy; BPL - brain parenchimal lesion; Mening meningeal disease; SC - spinal cord; PN - peripheral neuropathy; Myo - myopathy; P - possible; Pb - probable; D - definitive; CT - corticotherapy; Txt - treatment; Full - full recovery; Par - partial recovery; No rec - no recovery.
plasmapheresis is reported as beneficial in anecdotal cases [1,4]. At the conclusion of therapy, clinical examination, MRI, and CSF analysis help determine if a longer course or more aggressive therapy is needed. In the present study, corticosteroids were the main treatment followed by azathioprine and, to a lesser extent, methotrexate. From the reviewed papers, corticosteroids were used isolated on an average of 55% of patients and combined with immunosuppressive drugs in 32%. Only 1% was treated without steroids and an average of 11% did not receive any treatment. The role of surgery is generally limited to diagnostic biopsy rather than therapeutic resection [2]. In rare circumstances, subtotal removal of large non-caseating granulomas has been reported in cases of life-threatening compression or advanced refractory disease [2]. Overall the outcome is variable. In Table 2 we found that an average of 62% of patients improved, comparing with 27% that did not improve or even progressed. In the current study, the majority of patients (53.3%) fully recovered being asymptomatic. Aseptic meningitis was related to a better prognosis and myelitis to a worst. Other studies also reported that PNS involvement and aseptic meningitis present a better prognosis [5]. Where available, on Table 2, the reported mortality was on average 5% of patients, similar to ours (6.7%). In closing, the authors wish to acknowledge the limitations of the current study. By nature of a retrospective review, we were dependent upon the accuracy and completeness of the existing medical records. Also, due to its rarity our cohort is limited. On the strengths side, we would like to enhance the thoroughly medical records review and the summarize of previous published cohorts that allowed to add some information in the epidemiological and clinical knowledge of this entity. In patients presenting with neurological symptoms, without a history of sarcoidosis, establishing a diagnosis can be challenging. More typical neurological syndromes that raise diagnostic suspicion are cranial neuropathies and aseptic meningitis. MRI and CSF are important in the initial evaluation, but histological confirmation remains crucial. Diagnostic difficulties, variability of the clinical course, scarcity and lack of specific markers and the possibility of resistance to therapeutic measures, makes neurosarcoidosis a difficult condition to manage. Conflict of interest The authors declare that they have no conflict of interest.
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