A Study of the Clinical Profile, Radiologic Features, and Therapeutic Outcomes in Neurosarcoidosis from Two Tertiary Care Centers in Southern India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.288976
Source of Support: None, Conflict of Interest: None
Keywords: Angiotensin Converting Enzyme, granulomatous inflammation, mediastinal adenopathy, Neurosarcoidosis
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology usually diagnosed between 20 and 40 years of age. Sarcoidosis has a propensity for involvement of lungs, lymph nodes, and skin. The prevalence of sarcoidosis is estimated at about 5–50 per 100,000 with the highest prevalence in Northern Europe. Nervous system involvement has been reported in 5–15% of patients and can involve any part of the nervous system, ranging from brain parenchyma, cranial nerves to peripheral nerves. Previous studies have reported neurologic symptoms as the presenting manifestation of sarcoidosis in 50–70% of sarcoidosis patients. The most commonly reported neurological manifestation is cranial neuropathy with the facial and optic nerve being the most frequently affected nerves. Other described neurological complications include parenchymal lesions, hydrocephalus, aseptic meningitis, peripheral neuropathy, and myopathy. Diagnosing neurosarcoidosis (NS) may be difficult because clinical features can be nonspecific. Definite NS requires histological confirmation, which is often not performed in patients with isolated central nervous system (CNS) localization of sarcoidosis. Typically, extensive ancillary investigations are performed to exclude other causes and identify granulomas outside of the CNS for histological confirmation of sarcoidosis. Imaging techniques include cranial and muscle magnetic resonance imaging (MRI), chest X-ray or computed tomography (CT), and positron emission tomography--computed tomography (PET--CT). If the diagnosis of possible, probable, or definite NS is made, treatment can consist of corticosteroids ( first line), methotrexate or azathiopurine (second line), or monoclonal antibodies (third line). The efficacy of these treatments, however, has not been studied systematically. In this study, we evaluated the clinical presentation, ancillary investigations, treatment, and disease course of patients with NS in two tertiary referral centers in Southern India.
This study was conducted at Command Hospital, Air Force Bangalore and INHS Asvini, Mumbai. In this retrospective study, we found 12 cases diagnosed to have NS. We examined all the cases in detail including clinical presentation, diagnostic modalities used, and functional outcomes on follow-up. The cases were selected using retrospective review of electronic medical records between Jan 2014 and Jan 2018. These cases were classified according to the system proposed by Zajicek et al. [Table 1]. For all patients, a case record form was filled with information containing baseline demographic features, presenting symptoms, presence of systemic disease prior and subsequent to neurologic disease, results of ancillary investigations, type of treatment given, length of follow-up, adverse events, and clinical outcome.
The group included 12 patients, comprising of 8 women and 4 men. The mean age at presentation was 44 years ± 9.2 years (range 34–56 years), and mean follow-up period was 1.8 years ± 1.2 years (range 0.6–3). The mean duration of symptoms at the time of diagnosis was 14 months.
Classification of patients according to Zajicek criteria
Based on the Zajicek criteria, there was one case of Definite NS, seven cases of probable NS, and four cases of possible NS in this study. The one case with definite NS had evidence of non caseating granulomas in CNS on meningocortical biopsy. CNS presentation was the initial presentation of sarcoidosis in this case, and there was evidence of multiple mediastinal and hilar lymph nodes on imaging. Among the seven cases with probable NS, two cases had pre-existing systemic sarcoidosis in the form of cutaneous pulmonary and ocular lesions, whereas in the remaining five cases, systemic sarcoidosis was recognized during the work-up of their neurological symptoms. In the remaining four cases, the diagnosis of possible NS was made after exclusion of other possibilities in appropriate clinical settings. In this subgroup, there were two cases previously diagnosed as sarcoidosis, who developed neurological involvement on follow-up, and two cases had isolated NS, without features of systemic involvement.
Neurologic symptoms were the first clinical manifestation of sarcoidosis in 8 of 12 patients (66.7%). The most common neurological symptom at presentation were painful blurring of vision and limb sensorimotor disturbance in four cases (33%), followed by binocular diplopia and ataxia in two cases (20%) each. All patients had multineuraxial involvement, except one case presenting with isolated 6th nerve palsy. Other presenting symptoms included facial palsy, bilateral sensorineural hearing loss, headache, and seizures. In five patients (41.7%), lung involvement was noted at any time during disease course. Eye involvement was noted in five patients (41.7%) and consisted of anterior uveitis (2 cases), and optic neuritis (3 cases). Sensorineural hearing loss was noted in two cases (16.7%).
Cranial neuropathy was the most common initial clinical presentation of NS. Among these, subacute loss of central vision with retrobulbar pain was seen in 4 of 12 (33%) patients [Table 2]. In two patients (16.7%), the involvement of optic nerve was bilateral which occurred in close temporal sequence. Lower cranial nerve involvement was seen in 4/12 (33%) patients, which included facial nerve involvement in 3/12 (25%) patients and bulbar palsy, hearing loss (due to 8th, 9th, and 10th nerve involvement in 2/12, 16.7%). In addition, four patients (33%) presented with myelopathy manifesting as weakness and/or sensory abnormalities of arm and legs.
During the course of the disease, most cases (10/12) developed additional neurological manifestations. The most common additional clinical abnormalities included evidence of cranial nerve palsies in four cases, brain parenchymal involvement and myelopathy in three cases. Three cases presenting with history suggestive of cognitive decline and seizures had extensive brain parenchymal involvement, with involvement of white and grey matter. Two of these cases showed development of hydrocephalus with disease progression requiring shunt procedures.
The utility of investigation results to differentiate sarcoidosis from other granulomatous diseases (most commonly tuberculosis) has been highlighted in [Table 3]. Tissue diagnosis of sarcoid was available only in 6/12 (50%) cases.
T2 hyperintense white matter lesions and pachymeningeal thickening/enhancement were the commonest features seen on MRI brain, found in six patients (50%). Abnormal MRI spine was present in two cases.
Intraparenchymal T2 hyperintense lesions were the most common finding on brain MRI, being seen in four patients, of which two cases showed evidence of contrast enhancement [Figure 1]. Four cases showed evidence of pachymeningeal thickening and enhancement [Figure 2]. There was edema and associated enhancement of optic nerves or chiasm was seen in 2/4 patients who presented with visual loss. Hydrocephalus was present in two cases on follow-up. Abnormalities in cervical or thoracolumbar spine revealed spinal cord edema, meningeal enhancement, and intra-axial contrast enhancing lesions in three cases [Figure 3].
Abnormalities suggestive of sarcoidosis were present in 9/12 cases (65%). Thoracoscopic biopsy of mediastinal lymph nodes [Figure 3]e in five cases revealed evidence of non caseating granulomatous inflammation in 3/5 (60%) cases.
CSF studies and ACE levels
CSF results were available in 11/12 cases. CSF indicators of NS showed features consistent with noninfectious inflammatory changes. Nine cases showed elevated CSF proteins >60 mg/dl. Lymphocytic pleocytosis was present in four cases and one case showed presence of low CSF glucose. Out of these nine cases showing abnormal CSF, MRI brain evidence of pachymeningitis was present in three cases, and two cases showed presence of parenchymal enhancing lesions. CSF positivity for oligoclonal bands (OCBs) was present in two cases. CSF ACE levels, available in four cases, were found to be useful in one case diagnostically. Serum ACE levels were available in all the cases, and raised serum ACE levels (>70 U/L) were present in 6/12 (50%) cases.
Tissue diagnosis of sarcoid was available for 6/12 cases. One case underwent meningeal biopsy, confirming evidence of NS, with presence of pachymeningitis and non caseating granulomas. Five cases underwent biopsy of parahilar lymph nodes with presence of non caseating granulomas on histology, highly suggestive of sarcoidosis. In addition, one case undergoing skin biopsy (non healing ulcer over shin) showed evidence of non caseating granuloma [Figure 4].
All patients received steroids as the initial treatment. An initial pulse of high-dose corticosteroids (IV methylprednisolone 1 g daily for 3--5 days) followed by oral asteroids (Tab prednisolone 1 mg/kg) for 4--8 weeks was the standard protocol followed in all the cases. Immunosuppressive therapies were added and the corticosteroids were gradually reduced over 3--6 months in seven patients [Table 4] to avoid systemic complications of long-term steroids. Two patients with evidence of extensive disease (case with pachymeningitis and parenchymal granulomas, and another case with extensive parenchymal lesions and myelopathy) were initiated on Rituximab pulse therapy. One case was offered Infliximab, due to persistence of disease activity despite being on steroids and immunosuppressive drugs. Two patients with bilateral optic neuritis had poor recovery of vision, with minimal response to treatment. This contrasted with unilateral optic neuritis, where visual recovery was much better. Of the other cranial neuropathies, three cases showed complete resolution of lesions clinically and radiologically (cases with bulbar palsy, binocular diplopia). One case with isolated sixth nerve palsy had stabilized deficit after initiation of treatment. Among the four patients with myelopathy, their clinical symptoms either stabilized or improved.
Maintenance immunosuppression was started in all cases, and consisted of low dose prednisone alone, and/or steroid sparing agents, usually methotrexate, azathioprine, or mycophenolate mofetil. Three cases, with aggressive disease course, were started on Rituximab pulse therapy.
Patients with bilateral optic neuritis showed no significant improvement in visual acuity (last recorded visual acuity being 20/400), compared with an those with unilateral optic neuritis. In addition, patients with myelopathy and isolated 6th cranial nerve palsy showed marginal clinical response.
In this retrospective review of 12 cases with NS, the mean age at diagnosis was 44 years, consistent with previous studies. The male: female ratio in this study was 2:1, which is attributable to the fact that these two centers are service hospitals, and majority of patients are male members of the Armed forces. Recently published meta-analysis of 29 studies has shown significant preponderance in females. Neurological involvement preceded the diagnosis of sarcoidosis in 10 patients (83.3%), consistent with prior studies showing results of 31--74%., Two patients (16.7%) with previous diagnosis of sarcoidosis presented with neurological symptoms suggestive of NS on follow-up, consistent with previous studies reporting NSon follow-up in 5--10% of patients with systemic sarcoidosis, typically within 2 years of initial diagnosis., In this series, there was no evidence of extra neurological involvement in two cases (16.7%), consistent with previous studies, reporting isolated neurological involvement in 10--17% cases. Out of 12 cases, one case was confirmed as definite NS, on the basis of meningeal biopsy, seven cases with probable NS (biopsy of mediastinal, pretracheal lymph nodes) suggestive of non caseating granulomatous inflammation and negative evaluation for tuberculosis, and four cases have been labeled as possible NS (raised serum ACE levels, and negative work-up for other etiologies) in the absence of definite histopathological diagnosis.
The most common clinical presentation in this series was optic neuritis (4/12, 33%) and myelopathy (4/12, 33%). In addition, four cases developed ataxia during follow-up, which has been explained due to extensive frontal subcortical white matter changes seen in these cases. Also, one case showed radiological involvement of cerebellum. Facial palsy was present in four cases, with two of them having bilateral facial nerve palsy. Two cases presented with external ophthalmoplegia, including isolated 6th nerve palsy (one case) and one case with orbital apex syndrome (pachymeningitis along anterior cavernous sinus). Meta-analysis of 24 articles describing 1,088 patients diagnosed cases of sarcoidosis (NS confirmed in 5% cases) has also described most common cranial neuropathies (2nd, followed by 7th, and 3rd, 4th, and 6th cranial nerves).
Myelopathy was present in 3/12 (25%) cases, with predominant involvement of thoracic and cervical cord. There was patchy involvement of spinal cord, with partial improvement following treatment. Spinal cord involvement is seen in fewer than 10% of patients with NS. The thoracic segment is most commonly affected, followed by the cervical segment, and lower extremity weakness and paresthesias are the most common presentations.
There is controversy regarding the utility of ACE levels in making the diagnosis of NS. In this study, serum ACE level was elevated in 6/12 (50%) cases, with no corelation between levels and disease activity. Similar results have been described in various studies, indicating limitation of serum ACE levels in diagnosis and predicting clinical course in patients with NS.
In the current study, CSF abnormality was present in six cases. CSF pleocytosis (>5 cells/cm) was seen in two cases, CSF protein >60 mg/dl was seen in six cases, and low CSF glucose <40 mg/dl was present in two cases. CSF--ACE level done only in one case was normal. Two cases showed positive CSF oligoclonal bands. Four cases out of 6 showing abnormal CSF study had evidence of leptomeningitis and pachymeningitis on MRI brain. Other two cases showed evidence of myelopathy (intramedullary T2-hyperintense lesions in MRI spine). Abnormal CSF study can be seen in other forms of neuro inflammatory conditions like Neuro Bechet's disease, neuropsychiatric lupus erythematosus, Sjogrens syndrome, neuroborreliosis, and multiple sclerosis. In a study by Zajicek et al., 50 out of 62 (81%) patients with NS had elevated CSF protein and/or mild to moderate pleocytosis. Other studies have reported normal CSF in nearly one-third of patients., Reduced glucose levels are less common (10%)., Oligoclonal bands and/or increased IgG index have been found in 25–50% of cases., In a study by Bridel et al., there was no significant difference between serum and CSF--ACE levels in biopsy confirmed cases of NS. The clinical utility of CSF--ACE levels for NS diagnosis is limited by its poor sensitivity and specificity, thus is considered of little utility.
In this series, four patients showed evidence of T2-hyperintense lesions in periventricular white matter region, predominantly frontal subcortical region. In two cases, there was corresponding post-contrast enhancement on T1-weighted imaging. In two of these cases, there was resolution of lesions following administration of immunosuppressive treatment. The incidence of abnormal changes in T2-weighted MRI ranges between 30% and 46%., Enhancing lesions are reported in a variable percentage of patients that is, 6% to 37%.
There was evidence of pachymeningitis (homogenous enhancement of dura andarachnoid) in two cases, and leptomeningitis in two cases. Meningeal enhancement, seen as enhancement on post-contrast T1-weighted MRI, is an important distinguishing feature of NS, rarely present in other disease such as multiple sclerosis. Studies report an incidence of meningeal enhancement in a variable percentage of patients ranging from 19% to 37%. Dural and leptomeningeal involvement are rarely seen at the same time in the same region of the brain. Dural enhancement may appear hypo intense on T2-weighted MRI, a typical feature of NS compared with other types of disease processes. Despite this radiological sign, NS may still remain indistinguishable from a calcified meningioma or very cellular metastatic disease. Leptomeningeal enhancement along perivascular spaces was seen in one case. Leptomeningeal enhancement, most frequently basilar meninges, may be nodular or diffuse and spread through the perivascular spaces.
Three cases presenting with spastic paraparesis had evidence of myelopathy, with T2-hyperintense intramedullary lesions. All these cases showed evidence of leptomeningeal enhancement. In a study by Sohn et al. in a cohort of 29 histologically proven sarcoidosis patients with spinal cord involvement, MRI evidence of spinal cord involvement was reported in about 11–15% of the patients. The average size of a lesion spanned four spine segments (range 1–9), and 77% of the patients with intramedullary NS had >3 spine segments involved. All the cases were initially managed with glucocorticoids, followed by immuno modulators. In the present cohort, two cases with continued disease progression despite adequate treatment were managed with Rituximab. Neurosurgical intervention was sought in one case, who developed obstructive hydrocephalus while on treatment. There have been no controlled trials of treatment in NS. Corticosteroids are accepted as the first line of treatment and have been useful to induce remission in nearly 70% of cases. There is comparable efficacy between long-term methotrexate, azathioprine, and mycophenolate mofetil, and treatment decisions may be made on the basis of tolerability and adverse effects. Of the cytotoxic agents used for NS, TNF-alpha antagonist Infliximab is more studied, and more widely used in systemic sarcoidosis.
Following institution of treatment, two cases showed complete resolution clinically and radiologically: a case with multiple lower cranial nerve/bulbar palsy and case with orbital apex syndrome [Table 5]. There was partial resolution of lesions in four cases with intracranial sarcoidosis, and no significant clinical and radiological response in cases with myelopathy. In the meta-analysis by Fritz et al., complete remission was achieved in 126 of 465 patients (27%, 95% CI 23–31%), incomplete remission in 147 of 465 (32%, 95% CI 27–36%), stable disease in 111 of 465 (24%; 95% CI 20–28%), and deterioration in 28 of 465 patients (6%; 95% CI 4–8%). Identification of spinal cord involvement is important, since it might indicate patients with a poor response and protracted disease course requiring earlier initiation of aggressive biologic therapies. The clinical details and radiologic features along with CSF picture and response to therapy of all 12 cases in this study and their comparision with other similar studies is given in [Table 6].
NS remains difficult to diagnose condition with varied and multi-axial presentation in the neuraxis. It can be the initial manifestation of sarcoidosis or develop later in the disease course in previously diagnosed patients. When it presents in isolation, the presence of mediastinal and hilar adenopathy, along with inflammatory CSF with lymphocytic pleocytosis and meningeal enhancement on MRI, are important clues to the possibility of NS. Tissue diagnosis is best achieved by mediastinal/hilar lymph node biopsy under CT guidance or video scopic assistance (VATS). In some cases where no other tissue is available, a meningocortical biopsy of an effected area (on MRI) can be rewarding. Serum and CSF--ACE levels have poor sensitivity of about 50% and are not very useful screening tools. Steroids followed by systemic immunosuppression remain the mainstay of therapy in most cases. However, presence of myelopathy, ataxia with extensive white matter disease and hydrocephalus, usually suggest an aggressive disease with poor response to conventional therapy. Such cases should be considered for early initiation of biologic therapy with Rituximab/Infliximab. This Indian study brings out the clinical profile of our patients with NS and gives insights into diagnostic clues and management strategies based on real world experience at two tertiary care centers of the Armed Forces.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]