Clinical and Laboratory Characteristics of Patients with Neurosarcoidosis

ABSTRACT

Introduction:

Neurosarcoidosis (NS) represents the most severe complication of sarcoidosis. NS exhibits a diverse array of clinical and radiological features that mimic many inflammatory, infectious, and neoplastic neurological disorders. In our study, we evaluated the demographic, clinical, laboratory, and imaging features of patients with NS.

Methods:

In this retrospective observational study, we included patients with definite and probable NS with at least 6-months of follow-up. Diagnostic tests, including cerebrospinal fluid analysis and imaging findings, lesion localization, therapeutic interventions, and disease course were evaluated. The modified Rankin scale was employed as a metric to assess the severity of the disease.

Results:

Fourteen patients met the inclusion criteria; two were definitively diagnosed with NS through brain biopsy, while twelve received a probable NS diagnosis based on biopsies of non-neuronal tissues. The predominant initial manifestation of NS was cranial neuropathy (64.3%), with facial palsy emerging as the most prevalent subset (35.7%). Five patients exhibited parenchymal involvement, while leptomeningeal involvement was noted in two. All patients were treated with corticosteroids, with nine individuals (64.3%) necessitating additional immunosuppressive interventions. Stable disease or improvement was observed in the majority of patients (85.7%), albeit one case resulted in mortality.

Conclusion:

We observed favorable outcomes in the majority of patients. Nevertheless, it’s imperative to acknowledge that NS can lead to both mortality and severe morbidity. Recognizing clinical patterns is vital for accurate diagnosis and effective treatment. However, there is an existing gap in management, underscoring the necessity for randomized controlled trials aimed at elucidating optimal treatment strategies.

INTRODUCTION

Sarcoidosis is a multi-systemic granulomatous disorder of unknown etiology, usually diagnosed between the third and fifth decade. It exhibits a higher frequency in African Americans and is more prevalent in Northern Europe, with an estimated global prevalence ranging from 1 to 40 per 100,000 individuals (1). Sarcoidosis primarily affects the lungs (90%), but can also involve the skin, eyes, and lymph nodes (2). Histopathological confirmation is mandatory for the definitive diagnosis of sarcoidosis (3). The distinctive pathological characteristic of the disease is the presence of well-formed epithelioid granulomas accompanied by scattered lymphocytes (4).

Highlights

• Verification through tissue pathology remains indispensable for diagnosis.

• Cranial neuropathies and parenchymal disease were the predominant presentations.

• Facial palsy emerged as the most prevalent subset of cranial neuropathies.

• A favorable outcome was achieved in the majority of cases with immunosuppression.

Neurological involvement is relatively infrequent in sarcoidosis, manifesting in 3-10% of patients and referred to as neurosarcoidosis (NS) (4–6). Neurological symptoms constitute the primary presentation of sarcoidosis in 50-70% of NS patients (7–9). Because histopathological evidence is required for the definitive diagnosis of neurosarcoidosis (NS), the diagnostic process may pose significant challenges in patients with isolated NS. The inherent difficulty in obtaining neural tissue biopsies necessitates the initial use of numerous other ancillary tests. This situation can potentially lead to delays in diagnosis.

The initial step of the NS diagnosis entails recognizing the patterns of nervous system involvement and considering sarcoidosis as one of the potential differential diagnoses. Nevertheless, the treatment guidance relies on personal experience and the limited number of case series given the absence of randomized placebo-controlled trials for any treatment in NS (10). Therefore, every piece of information regarding the disease characteristics and course from diverse geographical regions and ethnic backgrounds is valuable for enhancing our comprehension of this condition.

Herein, we conducted a comprehensive assessment of demographic and clinical data, imaging findings, and ancillary tests in addition to the disease course and management of a large cohort of NS patients followed at a tertiary referral center.

METHODS

This is a retrospective observational study that includes patients who were diagnosed with NS between 2001 and 2018 and followed up for at least 6 months. Patients’ data were extracted from the electronic medical records system. Diagnostic tests were reviewed by two neurologists (ASE and TG). To classify the diagnostic level of certainty, Neurosarcoidosis Consortium Consensus Group criteria were used (3). The diagnosis of NS is delineated into three tiers: i) definite, ii) probable, and iii) possible. Definite NS is defined as a histopathological diagnosis from neuronal tissue in a patient who has the clinical presentation and laboratory features, including magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF), suggestive of NS. A probable NS diagnosis was made if the histopathological diagnosis was based on non-neuronal tissue. Sarcoidosis was diagnosed histopathologically based on the presence of non-necrotizing granulomas composed of epithelioid histiocytes with multinucleated giant cells, surrounded by lymphocytes and plasma cells (3). Patients without histopathological confirmation of sarcoidosis were excluded from this study to ensure that the selected population consisted entirely of patients with NS. Comprehensive laboratory and imaging investigations were conducted to exclude other potential causes, such as malignancy and infections. Patients presenting solely with peripheral nervous system involvement, devoid of any cranial nerve palsy or central nervous system disease (CNS) in the context of neurosarcoidosis (NS), were not included in our study.

Demographic characteristics, including gender, age at sarcoidosis diagnosis, age at NS diagnosis, and previous medical history, were obtained. Initial involvement sites of sarcoidosis and NS and systemic involvement during the follow-up period were determined. Treatment modalities, including corticosteroids and adjunctive immunosuppressives, were collected. The modified Rankin scale (mRS) was employed to determine the disease severity at diagnosis and during the follow-up period. Response to the treatments and disease severity were evaluated according to the changes in the mRS scale comparing the patients’ baseline and subsequent mRS scores. Treatment response was categorized as follows: “stable disease” indicated patients with an unchanged mRS score during the last visit in comparison to the baseline; “improvement” denoted patients exhibiting a reduced mRS score; and “deterioration” referred to patients with an increased mRS score. Incidences of mortality were reported independently.

Statistical Analysis

We calculated the means, medians, standard deviations, and ranges for continuous variables and the frequencies for categorical variables. We used Kaplan-Meier analysis to present the probability of time to first relapse. Due to the limited size of the population, we did not conduct subgroup comparisons or analyses based on clinical characteristics.

RESULTS

Diagnosis and Clinical Features

A total of 14 patients, all of whom had histopathologic confirmation of sarcoidosis, fulfilled the specified inclusion criteria. Among these, three patients underwent excisional brain biopsy. Within this cohort, a diagnosis of definite neurosarcoidosis was established in two cases (14.3%). One of the brain biopsies yielded necrotic tissue; nonetheless, in this particular patient, a minor salivary gland biopsy revealed pathological features of sarcoidosis (Figure 1). We diagnosed probable neurosarcoidosis in twelve cases (85.7%) by extraneural tissue histopathology of granulomatous inflammation consistent with sarcoidosis. Half of the patients’ biopsies were taken from lymph nodes, three from minor salivary glands, two from skin, one from bone marrow, and one from lung parenchyma. In a single patient, both minor salivary gland and lymph node biopsies failed to yield diagnostic results. However, the diagnosis was successfully ascertained through a positive bone marrow biopsy. Demographic information, clinical characteristics, disease severity, treatments, relapses, and responses to the treatments are provided in Table 1.

Figure 1.

A 32-year-old female presented with epileptic seizures. She was diagnosed with neurosarcoidosis by lung biopsy after extensive work-up. A. T1-weighted MRI imaging with gadolinium shows nodular contrast enhancement in the left frontal area. B. T2-weighted MRI imaging shows a left frontal hyperintense lesion with edema.

Table 1.

Demographic information, clinical characteristics, disease severity, treatments, relapses, and responses to the treatments.

	N (%)
Gender
Male, n	3 (21.4%)
Female, n	11 (78.6%)
History of sarcoidosis	3 (21.4%)
History of autoimmune disease	1 (7.1%)
Age at sarcoidosis diagnosis, median (min-max)	39 (28-64)
Age at NS diagnosis, median (min-max)	39 (28-64)
Neurological involvement at onset of sarcoidosis	11 (78.6%)
Initial involvement site of sarcoidosis
CN II	2 (14.3%)
CN VII, unilateral	4 (28.6%)
CN VII, bilateral	1 (7.1%)
CN III, IV or VI	2 (14.3%)
CN VIII	1 (7.1%)
CN IX, X or XII	1 (7.1%)
Cavernous sinus involvement	1 (7.1%)
CNS parenchyma	5 (35.7%)
Leptomeningeal involvement	2 (14.3%)
Spinal cord	1 (7.1%)
Thoracic	3 (21.4%)
Systemic involvement at follow-up	13 (92.9%)
Thoracic	13 (92.9%)
Skin	2 (14.3%)
Eye	3 (21.4%)
Peripheral nervous system	2 (14.3%)
Isolated NS	1 (7.1%)
Diagnostic Classification
Definite	2 (12.5%)
Probable	12 (85.7%)
Follow-up time, months, median (min-max)	63.5 (7-202)
mRS at diagnosis, mean ± SD	2 ± 0.43
mRS at the last follow-up, mean ± SD	2.08 ± 1.66
Treatment
Corticosteroids	14 (100%)
Corticosteroid only	5 (35.7%)
Azathioprine	5 (35.7%)
Methotrexate	3 (21.4%)
Mycophenolate mofetil	1 (7.1%)
Cyclophosphamide	1 (7.1%)
TNF-alpha inhibitors	1 (7.1%)
Relapse
One relapse	2 (14.3%)
>1 relapse	7 (50%)
No relapse	5 (35.7%)
Response to treatment
Improvement	7 (50%)
Stable disease	5 (35.7%)
Deterioration	2 (14.3%)
Mortality	1 (7.1%)

NS: neurosarcoidosis, CN: cranial nerve, CNS: central nervous system, SD: standard deviation, TNF: tumor necrosis factor.

There were three male (21.4%) and eleven (78.6%) female patients in our cohort. The median length of follow-up time was 63.5 months (IQR: 24.7-94.3). The mean mRS score was 2 (IQR: 2-2) at the time of diagnosis. Only one of the patients had a history of other autoimmune disorders besides sarcoidosis. The median age at diagnosis of sarcoidosis and NS was 39 years (IQR: 32.3-46.5). Three patients (21.4%) had previously been diagnosed with sarcoidosis involving non-neural organs. The remaining 11 patients (78.6%) presented with NS. Systemic involvement was evident in 10 of these cases, whereas one patient retained a status of isolated neurosarcoidosis throughout the follow-up period.

Among the patient cohort, pulmonary involvement was detected in 13 patients (92.9%). Additionally, three patients (21.4%) had uveitis, two (14.3%) exhibited skin involvement, and two (14.3%) manifested peripheral nervous system disease. Notably, patients with a preexisting history of sarcoidosis experienced neurological involvement within the initial year of their disease course.

The initial involvement site of sarcoidosis was the cranial nerves in nine patients (64.3%). The most common cranial neuropathy was facial nerve palsy as the initial presentation in five patients (35.7%), which was unilateral in four (28.6%) and bilateral in one. Two patients (14.3%) presented with optic neuritis, and an additional patient had optic nerve involvement in the follow-up period (Figure 2). Oculomotor, trochlear, and/or abducens nerve palsies were observed in two patients (14.3%) as the presenting finding of NS and in another patient in the follow-up. One of these patients had cavernous sinus involvement (Figure 3). One patient presented with unilateral facial palsy and hearing loss attributable to the involvement of the facial and vestibulocochlear nerves. A single patient experienced hoarseness due to recurrent laryngeal nerve palsy, and another patient developed glossopharyngeal and vagal nerve palsy. During the disease course, one of the patients had mononeuritis multiplex, while another presented with multifocal radicular involvement. Five patients (35.7%) had parenchymal CNS disease. Two of the patients had predominant leptomeningeal enhancement, although one patient had adjacent parenchymal involvement. There were three patients with epileptic seizures due to meningeal or parenchymal brain involvement during the follow-up (Figures 4, 5).

Figure 2.

A 32-year-old female had left optic neuritis and was diagnosed with neurosarcoidosis by lymph node biopsy. A. Coronal FLAIR image shows left optic nerve hyperintensity (red arrow). B. Axial FLAIR MRI images show long-segment hyperintensity along the left optic nerve.

Figure 3.

A 64-year-old female patient presented with diplopia and vision loss in the left eye. A. T2-weighted MRI imaging shows a left cavernous sinus lesion (red arrow). B. T1-weighted axial and coronal MRI images show gadolinium enhancement in the left cavernous sinus potentially involving optic chiasm (red arrows).

Figure 4.

A 45-year-old female patient presented with facial palsy, hemiparesis, and seizures. A. T1-weighted MRI imaging with gadolinium shows nodular enhancements (red arrows). B. FLAIR images show hyperintense confluencing lesions in the left insular cortex, bilateral temporal, and occipital regions, and left frontoparietal regions.

Figure 5.

A 50-year-old male patient had probable neurosarcoidosis and died due to parenchymal brain involvement with mass effect. A. T2-weighted MRI images of heterogenous hyperintensity with mass effect from centrum semiovale to brainstem and cerebellum. B. Peripherally enhancing lesions were extending from the centrum semiovale to the left pontine area and the right cerebellar peduncle to the right cerebellum.

Laboratory and Imaging Characteristics

Ancillary investigations at the time of diagnosis are reported in Table 2. Five patients (41.7%) had increased C-reactive protein (CRP), and three (37.5%) had an elevated erythrocyte sedimentation rate (ESR). None of the patients had increased calcium levels in their serum, and only one patient had an elevated serum angiotensin-converting enzyme (ACE) level.

Table 2.

Ancillary investigations at the time of diagnosis.

	n/N (%)
Blood tests at diagnosis (serum)
ACE > 50 units/L	1/7 (14.3%)
Calcium > 10.5 mg/dl	0/11 (0%)
ESR > 20	3/8 (37.5%)
CRP > 5 mg/dl	5/12 (41.7%)
CSF
Leukocyte count, median (min-max)	3 (0-48)
Lymphocyte > 5/mm3	5/13 (38.5%)
Total protein (mg/dl)	57.3 (23-332)
Total protein > 45 mg/dl	9/13 (69.2%)
Glucose, median (mg/dl)	66 (26-81)
Glucose < 40 mg/dl	1/11 (9.1%)
IgG index, median (min-max)	0.60 (0.40-0.88)
IgG index > 0.64	4/9 (44.4%)
ACE	0/4 (0%)
Oligoclonal Band
Not present	4/8 (50%)
Pattern 2	3/8 (37.5%)
Pattern 4	1/8 (12.5%)
Imaging suggestive of sarcoidosis
Chest CT	11/12 (91.7%)
Cranial MRI	10/14 (71.4%)
Spinal MRI	1/7 (14.3%)
Histopathologic analysis sites
Brain	3/14 (21.4%)
Lymph node	7/14 (50%)
Lung	1/14 (7.1%)
Skin	2/14 (14.3%)
Minor salivary gland	3/14 (21.4%)
Bone marrow	1/14 (7.1%)

ACE: angiotensin-converting enzyme, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, CSF: cerebrospinal fluid, IgG: immunoglobulin, CT: computerized tomography, MRI: magnetic resonance imaging,

Increased cerebrospinal fluid (CSF) total protein level (69.2%) emerged as the predominant finding in CSF analysis. Despite displaying a broad spectrum spanning from 23 mg/dl to 332 mg/dl, the median total protein level was 57.3 mg/dl. The median leukocyte count was 3/mm³ (0–48/mm³). An increased number of lymphocytes was found in the CSF of five patients (38.5%), while eight had lymphocyte counts within the normal range. We observed a markedly decreased glucose level in only one patient and the median glucose level was 66 mg/dl (26-81 mg/dl). While the number of patients with available CSF angiotensin-converting enzyme (ACE) results were limited to four, none of them exhibited elevated ACE levels. Oligoclonal bands (OCB) in CSF (pattern 2) were present in three patients (37.5%), while one patient had the same OCB in CSF and serum (pattern 4). A higher Immunoglobulin G index was observed in four patients (44.4%), with values ranging between 0.40 to 0.88.

Out of the 12 patients with available thorax computed tomography, 11 patients (91.7%) exhibited lung involvement. All the patients had brain MRIs and 10 (71.4%) of them had imaging findings suggestive of NS. Spinal MRIs were performed on seven patients, revealing a short-segment cervical spinal lesion in one of them.

Treatment and Prognosis

In all cases, patients were treated with corticosteroids. Nine of the patients (64.3%) received adjunctive immunosuppressive treatments during the disease course, while five of the patients (35.7%) were treated by corticosteroids alone. Among these patients, one individual who initially received a diagnosis of neurosarcoidosis (NS) presented with facial palsy and parenchymal brain involvement. He was treated with intravenous and oral steroids. Nevertheless, within the first year of the disease course, this patient developed multi-cranial neuropathy, hemiparesis, and ataxia, due to the parenchymal brain disease (Figure 1). Despite intensive therapeutic intervention, the patient died of aspiration pneumonia.

Another cognitively impaired patient with a disability level of mRS 5, exclusively received corticosteroid treatment. The remaining three patients who presented with cranial neuropathy were administered corticosteroid treatment exclusively, resulting in a favorable response.

Azathioprine (AZA) (35.7%) was the most common adjunctive immunosuppressive agent used for the treatment, followed by methotrexate (MTX) (21.4%), mycophenolate mofetil (MMF) (7.1%), cyclophosphamide (7.1%), and infliximab (7.1%). In a relapsing patient, the treatment regimen was switched from AZA to cyclophosphamide. This change was necessitated by the patient’s contraindication for corticosteroid usage due to the bilateral avascular necrosis of the femur head.

In another patient, we switched AZA to MMF due to headaches. Infliximab treatment was stopped considering sufficient treatment for three years and switched to MTX in another patient.

Throughout the follow-up period, we observed at least one relapse in nine patients (64.3%) while half of these individuals had multiple relapses. Notably, five patients had remission during a median of 42.7 months (IQR: 18.7-67.9) follow-up. The Kaplan-Meier curve presenting the probability of time to first relapse is provided in Figure 6. The mean mRS was 2.1 (IQR: 1-2) at the last visit. Improved mRS scores were observed in half of the patients, while five patients maintained stable mRS scores. Consequently, stable disease or improvement was attained in 85.7% of the patients. Conversely, two patients (14.3%) exhibited elevated mRS scores during their last visit, which included the aforementioned patient with the documented mortality.

Figure 6.

The Kaplan-Meier curve presents the probability of time to first relapse.

DISCUSSION

The neurological involvement of sarcoidosis consists of a wide variety of clinical and imaging features. NS is reported between 3% to 10% of sarcoidosis cases (4–6). Given its potential to imitate infectious processes, lymphoproliferative disorders, malignancies, and various inflammatory conditions, histopathological confirmation is crucial (11). Similarly, obtaining a histopathological examination of neural tissue is a requisite for the definitive diagnosis of NS according to the established guidelines (3).

Approximately two-thirds of neurosarcoidosis (NS) patients exhibit CNS involvement, a prevalence higher than that of peripheral nervous system involvement (12). However, it is crucial to recognize that in many clinical scenarios, conducting brain or spinal cord biopsies for every case is not feasible. Nonetheless, there are situations where such biopsies become necessary, particularly in cases presenting with isolated forms of the disease or in instances of progressive parenchymal involvement. Within our case series, there was only a single patient with isolated cerebral parenchymal NS, leading to quadriparesis and progressive cognitive decline. Therefore, we needed to obtain a brain biopsy to establish a definitive diagnosis. Unfortunately, the patient’s disease course was refractory to corticosteroids, culminating in a mRS score of 5 during his last visit. An additional two patients within the cohort underwent excisional brain biopsies. It was diagnostic in one of the patients, who also had concurrent leptomeningeal involvement. Conversely, the pathological assessment of the other patient yielded necrotic tissue. This patient experienced parenchymal involvement accompanied by a significant mass effect, ultimately leading to mortality (Figure 1). This patient had a probable diagnosis of neurosarcoidosis via a minor salivary gland biopsy. The remaining patients received their NS diagnosis relying on histopathological evidence obtained from extraneural tissues.

A systematic review and subsequent meta-analysis reported that approximately 19% of the patients documented within the NS case series reports lacked any histopathological confirmation, acquired from neural or non-neural tissues (9). We postulate that this issue could potentially impede our comprehension of the distinctive characteristics and behavior of NS. Consequently, we opted to exclusively include cases that were confirmed through histopathology in our study. However, we think that physicians should be encouraged to consider the possibility of NS not only in cases with well-defined clinical features but also in instances presenting with atypical manifestations.

In our study cohort, we noted a predominance of females (78.6%), with a median age of disease onset at 39 years. Previous studies have reported median ages of NS onset between 40 and 48 years (5,8,12–14). Furthermore, the distribution of females within NS case series reports exhibits a range from 44% to 74% (5,8,12–15). A systematic review also highlighted that 55% of patients within the literature were reported as females (9). In our case series, the age of onset for NS and the distribution by gender align closely with the literature. However, it is important to emphasize that while the median age of onset typically centers around 40 years, NS can manifest in individuals ranging from the early years of their third decade to the later years of their seventh decade.

The initial manifestation of sarcoidosis was neurological involvement in 78.6% of our patients. This is in line with the previous findings that have reported rates as high as 74% (16). We also identified one patient with isolated NS, accounting for 7.1% of the cases, a figure consistent with a 4% observation from a prospective case series (12). Given the high proportion of cases with neurological symptoms as the initial manifestation of the disease, clinicians must recognize the diverse disease patterns and include sarcoidosis among their differential diagnoses.

Thorough ancillary investigations should be conducted for each patient to systematically eliminate other potential diagnoses. In a systematic review, 35% of patients had higher levels of angiotensin-converting enzyme (ACE) in their blood, while 46% of patients had higher levels of ACE in their CSF. However, these rates exhibit variability across different cohorts, displaying both lower and higher rates (15,17). Within our study, an elevated serum ACE level was observed only in a single patient (14.3%), and we did not observe any increase in CSF ACE levels in any of the four patients who tested. The limited size of the patient subset with available ACE levels complicates the interpretation of these findings. It has been established that the sensitivity and specificity of CSF ACE are relatively modest and of limited clinical value (18). Nevertheless, we recommend that while an increased ACE level favors the diagnosis of NS, normal levels do not necessarily exclude the diagnosis.

Our observation of elevated CSF total protein and increased lymphocyte count concur with the literature (8,9,12,15–17). We found the intrathecal synthesis of oligoclonal bands in 37.5% of the patients and another patient exhibited the same OCB in serum and CSF (pattern 4). In addition, 44.5% of our patients displayed an increased IgG index. However, in the literature, OCB presence was reported in 15 to 38% of patients (8,14–17). Notably, we did not observe any significant clinical difference between the OCB-positive and negative patients. We propose that a slightly higher rate of OCB presence and increased IgG index could be attributed to the relatively small size of our study cohort.

Cranial neuropathies stood out as the prevailing clinical manifestations in our series. Among these, nine patients (64.3%) presented with cranial neuropathy, with facial palsy (35.7%) being the most frequently encountered subtype. The parenchymal involvement of the CNS (35.7%) emerged as the second most common form of the disease, including four cases of brain parenchymal disease and one case of spinal cord disease. Leptomeningeal disease was identified in two patients (14.3%). We had only a single patient with spinal involvement demonstrating short-segment transverse myelitis. Notably, literature has reported meningeal involvement rates spanning from 4 to 64% across different case series (5,7,8,12,14–17,19). Furthermore, there are diverse observations of parenchymal involvement rates extending from 16% to 70% (12). This variability also applies to spinal cord involvement and cranial neuropathies. Notably, among retrospective case series, optic neuritis emerged as the most prevalent disease manifestation in one study, while myelopathy took precedence in another (14,16). Such disparities could potentially be attributed to ethnic disparities, the retrospective nature of the studies, referral biases, and selection biases inherent to case series. Even though the rates diverge in the literature, it is essential to know that NS tends to involve cranial nerves, particularly facial and optic nerves (9). Moreover, NS is a distinct disease capable of causing a broad spectrum of clinical and imaging manifestations, from meningeal disease to parenchymal disease with mass effects (11).

In our cohort, the mean mRS at the time of diagnosis was 2.0. Following a median follow-up period of 63.5 months, the mean mRS had altered slightly to 2.1. AZA, MTX, MMF, and infliximab were used as adjunctive treatments and steroid-sparing agents. Infliximab was started as an adjunctive immunomodulator in only one patient due to high initial disease activity. After three years of treatment, infliximab treatment was switched to MTX because adequate response had been achieved with the anti-TNF regimen. Additionally, one patient, under treatment with AZA and corticosteroids, developed bilateral avascular necrosis of the femur head. Therefore, the corticosteroid regimen was tapered off. However, after six months, the patients experienced another relapse, necessitating treatment with cyclophosphamide.

Disease activity was effectively managed, resulting in stable disease or improvement for eight patients (88.9%) treated with adjunctive immunosuppressives. In our cohort, 14.3% of the patients had a single relapse, while 50% had multiple relapses during their follow-up period. However, the mild clinical nature of these relapses permitted successful control with corticosteroids. Furthermore, we observed improvement from baseline in 50% of the patients, while 35.7% experienced stable disease. Deterioration occurred in only two patients (14.3%), and regrettably, one of them resulted in mortality (7.1%).

In the literature, AZA, MTX, and MMF were the most commonly selected immunosuppressive agents for treating NS (9). In a retrospective cohort, early immunosuppressive treatment with AZA, MTX, or infliximab substantially improved outcomes, with an overall favorable outcome reported in 87% of cases (20). Additionally, a prospective study revealed clinically significant improvement in 75% of NS patients through immunosuppressive treatment within a one-year follow-up, consistent with our observations over a longer duration (21). Anti-TNF agents were shown to be more effective in achieving stable disease in a retrospective study (15). However, discontinuation of anti-TNF treatment can lead to relapse rates as high as 50%, as highlighted in another literature review (17).

Since no randomized placebo-controlled study of any form of treatment has been conducted in NS, our current therapeutic strategies are still based on clinical experiences (10). Emerging biological treatment options, including anti-TNF agents, are becoming more prevalent, though the optimal duration of treatment remains uncertain.

There are certain limitations to our study, foremost among them being the relatively small sample size. The retrospective design of the study could introduce variability in the diagnostic assessment and treatment approaches. However, it’s crucial to note that we exclusively incorporated pathologically confirmed cases and took measures to standardize clinical evaluation by utilizing the mRS during follow-ups.

As a result, neurological involvement in sarcoidosis exhibits a wide array of clinical manifestations and imaging features. Verification through tissue histology remains indispensable for diagnosis, as the condition’s presentation may resemble infections, lymphoproliferative diseases, malignancies, and other inflammatory disorders. Within our study group, cranial neuropathies and parenchymal involvement stood out as the predominant clinical presentations of NS. Notably, a favorable outcome was achieved for 85.7% of cases through the administration of corticosteroids and adjunctive immunosuppressives. Given the rare nature of NS, there persists a notable gap regarding randomized controlled trials aimed at delineating optimal treatment strategies. We firmly believe that every contribution of insights from diverse populations and geographic regions serves to enrich the collective comprehension of NS.