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Abstract
A 52-year-old man experienced a relapse of neurosarcoidosis, characterised by obstructive hydrocephalus and multiple posterior circulation infarcts. He was taking methotrexate, but his prednisolone was being weaned because of adverse effects. Stroke is rare in neurosarcoidosis and typically relates to granulomatous inflammation with a predilection for the perforator arteries. Sarcoidosis generally responds well to corticosteroids; however, patients with leptomeningeal involvement usually require additional immunosuppression as relapses can occur on weaning of corticosteroids. It is worth considering tumour necrosis factor-α antagonists for cases that progress despite first-line therapy.
- stroke
- vasculitis
- neuroimmunology
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Case history
A 52-year-old man presented with a 3-day history of unsteady gait, headache and double vision. He had a history of neurosarcoidosis, having presented 2 years before with a lymphocytic meningitis and communicating hydrocephalus requiring a ventriculoperitoneal shunt. Subsequent biopsy of an avidly enhancing retrosternal lymph node (seen on positron emissiontomography-CT) identified granulomatous inflammation in keeping with sarcoidosis. He improved on treatment with prednisolone and methotrexate, although 3 months later required a shunt revision because of blockage.
One year later he experienced a relapse with headaches and ataxia. The dose of prednisolone was increased to 60 mg. He had gained over 10 kg in weight since starting corticosteroids, and therefore the dose was weaned by 5 mg monthly. At the time of his admission, he was taking oral methotrexate 17.5 mg weekly with folic acid, and prednisolone 10 mg daily.
On examination, there was early optic disc swelling, broken smooth pursuits and a conjugate gaze palsy on leftward gaze. There was mild dysarthria, a subtle left arm drift and left-sided ataxia. He had a mild spastic paraparesis with bilateral extensor plantar responses.
MR scan of the brain (figure 1) showed an enlarged left lateral ventricle compressing the right ventricle at the site of his ventriculoperitoneal shunt. There was prominent leptomeningeal enhancement around the brainstem and cauda equina, with marked progression compared with previous imaging. There was also an area of restricted diffusion in the left tectum in keeping with an acute infarct.
MR scan of the brain (axial FLAIR) (A) showing an enlarged left lateral ventricle with associated compression of the right lateral ventricle, at the site of the previous ventriculoperitoneal shunt. T1 postgadolinium imaging (B) shows enhancement around the brainstem. Diffusion-weighted imaging (C and D) shows an area of restricted diffusion in the left tectum. FLAIR, fluid-attenuated inversion recovery.
The clinical impression was of a relapse of neurosarcoidosis leading to hydrocephalus and a tectal infarct. He started a 5-day course of intravenous methylprednisolone 1 g daily and was transferred to the tertiary neurosciences centre for endoscopic ventricular septotomy. Intraoperatively the foramen of Monro was covered with an inflammatory membrane, and there was a rubbery inflammatory mass attached to the choroid plexus. A biopsy was taken and the foramen of Monro was opened. The ventriculoperitoneal shunt catheter was protruding through a small septostomy; this was enlarged and irrigated, and a second septostomy was created.
The following day he had recovered well with no significant headache and a Glasgow Coma Scale (GCS) score of 15. Later that day, however, he deteriorated to a GCS score of 9 (E2, V1, M6) with a new left hemiparesis, bradycardia, tachypnoea and hypocapnia. He was intubated and ventilated.
MR scan of the brain showed multiple new areas of restricted diffusion in the right thalamus, left internal capsule, both temporal lobes and right cerebellum. There was also faintly restricted diffusion in the left tectum and ventral midbrain (see figure 2). MR angiography was unremarkable, and a review of the anaesthetic record confirmed there was no perioperative hypotension. The impression was of multiple perforator infarcts secondary to basal meningitis due to neurosarcoidosis, with brainstem involvement causing the acute deterioration in respiratory and heart rate. In view of his pre-existing immunosuppression, we investigated him further to exclude other causes of stroke, including infective vasculitis.
MR scan of the brain (diffusion-weighted images) (A–D) 10 days after presentation shows further areas of restricted diffusion within the right cerebellum and both the medial temporal lobes. There is also faintly restricted diffusion in the left tectum and ventral midbrain.
A lumbar puncture showed an opening pressure of 21 cm cerebrospinal fluid (cmCSF), 51 x 106/L white cells (100% lymphocytes), protein 3.9 g/L and glucose 2.1 mmol/L (plasma 6.6 mmol/L), with no organisms or fungal elements. Viral PCR and microscopy for acid-fast bacilli were negative. HIV, syphilis and borrelia serology were negative. Transthoracic echocardiography was normal.
We continued oral prednisolone 60 mg daily and methotrexate 17.5 mg weekly. We started aspirin 300 mg daily and gave intravenous infliximab 5 mg/kg at 0, 2 and 6 weeks initially, followed by 5 mg/kg maintenance at 6 weekly intervals with aciclovir and cotrimoxazole prophylaxis. Histology from the inflammatory mass removed at neurosurgery subsequently showed evidence of chronic granulomatous inflammation with no organisms, consistent with neurosarcoidosis.
On stopping his sedation and neuromuscular blockade, he was tetraparetic, worse on the right. His neurological state subsequently stabilised and he slowly improved. He was transferred back to his local hospital for ongoing treatment and rehabilitation.
Unfortunately he did not tolerate infliximab due to significant abdominal pain, vomiting and weight loss (7 kg over 1 month). The infliximab was replaced by monthly intravenous cyclophosphamide, but he deteriorated further and died a few months later. An autopsy was not performed.
Discussion
Sarcoidosis is a multisystem disorder characterised by non-caseating granulomas. Neurological involvement occurs in approximately 5% of cases,1 although with much higher rates evident at postmortem.2 The most common presentation of neurosarcoidosis is with cranial nerve palsy; however, it can present in a wide variety of ways including aseptic meningitis, hydrocephalus, intracranial mass lesion, neuroendocrine dysfunction, neuropsychiatric symptoms, myelopathy, peripheral neuropathy and myopathy.3 4 Central nervous system (CNS) involvement at onset indicates a worse prognosis than in those with peripheral nervous system presentations.5
Cerebrovascular involvement in neurosarcoidosis
Stroke is a rare manifestation of neurosarcoidosis, with few cases reported in the literature. The predominant mechanism is probably granulomatous inflammation of the intracranial blood vessels, which is supported by postmortem findings with preferential involvement of perforator arteries.6 7 Such distribution correlates with the pattern of strokes seen in this patient.
Other potential mechanisms for stroke include large-vessel vasculitis, distal embolisation in patients with cardiac sarcoidosis, infective vasculopathy secondary to immunosuppression or hypertensive-related stroke in patients with renal involvement.
Treatment of neurosarcoidosis
Treatment aims to suppress inflammatory activity to allow neurological recovery but also to prevent further relapse. There are no randomised controlled trials to guide optimal treatment of neurosarcoidosis, and so decisions are based on previous case series and the extrapolation of results from trials in systemic sarcoidosis.
Corticosteroids are the mainstay of treatment, often leading to a rapid and clinically significant response. In potentially disabling neurological disease, the recommended treatment is 1 g intravenous methylprednisolone given for 3 days, followed by 0.5–1.0 mg/kg daily oral prednisolone. In milder cases (such as those with isolated facial nerve palsy), lower doses such as 0.5 mg/kg oral prednisolone daily can be given followed by a taper.8 9
Although corticosteroids are usually highly effective, their long-term use is limited by many potential adverse effects. Frequently, however, patients relapse on reducing the corticosteroids, and Joseph and Scolding8 suggested that relapse can occur when the dose of prednisolone is less than 20 mg per day—as in our patient who relapsed while taking 10 mg daily, despite also taking methotrexate. Figure 3 illustrates the relationship between our patient’s relapses and medication doses. Combination therapy with corticosteroid-sparing agents is therefore recommended early in patients with significant CNS involvement to reduce the risk of relapse on steroid weaning. Dutra et al 9 highlighted three studies showing that fewer than 40% of patients with neurosarcoidosis treated with corticosteroids alone either stabilised or improved, further supporting the need for additional immunosuppressive treatment.
Graph showing the clinical course and timing of relapses in relation to the dose of prednisolone (*or equivalent dose for dexamethasone) and methotrexate.
Commonly used corticosteroid-sparing immunosuppressive agents include methotrexate, azathioprine and mycophenolate mofetil. All three appear equally effective, although methotrexate is usually advocated as the initial choice. When neurosarcoidosis is refractory to corticosteroid treatment, cyclophosphamide can reduce disease activity and even give clinical improvement.10
There is increasing evidence to suggest that tumour necrosis factor-α (TNF-α) antagonists are effective in treating refractory neurosarcoidosis. Sarcoidosis is probably a CD4+ T lymphocyte-mediated disease, with the release of TNF-α being important in the pathogenesis of granuloma formation.11 In 2011, Pereira et al 12 summarised 23 cases of refractory sarcoidosis that subsequently responded to treatment with infliximab. Most had previously received corticosteroids and an additional immunosuppressive agent. More recently, a multi-institutional series13 of 66 patients with neurosarcoidosis reported clinical improvement in 77% of cases treated with infliximab and clinical stability in 18%. Ten per cent of patients developed infections, and one developed myositis that was felt likely to be medication-related.
Adverse effects can limit the use of TNF-α antagonists. A large multicentre study14 of 132 patients with refractory sarcoidosis reported a high rate of adverse events (52%) while taking TNF-α antagonists, with infection (36%) and allergic reactions (8%) being the most common. Treatment was interrupted in 31 patients (23%) because of adverse events, and of these 13 experienced relapses.
Unfortunately our patient did not tolerate infliximab due to adverse effects; however, the improvement in his MRI and CSF markers would further support the use of this medication in patients with refractory disease.
Key Points
Stroke is a rare complication of neurosarcoidosis with a predilection for the perforator arteries, often occurring in active disease with cerebrospinal fluid pleocytosis.
Patients typically respond well to corticosteroids; however, combination therapy is recommended early in patients with significant central nervous system involvement.
Relapses can occur when the prednisolone dose is reduced, particularly below 20 mg; below this dose we recommend more gradual reduction and close monitoring.
Tumour necrosis factor-α antagonists appear to be a promising treatment alternative for refractory cases.
References
Footnotes
Contributors MJH performed a literature search and review and drafted the article. GP and MDC provided clinical expertise and critical appraisal of the article.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests MJH and GP have no acknowledgements to make in terms of financial support. MDC has received consulting fees, lecture fees and travel grants from Sanofi Genzyme, Biogen and Merck Serono.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed by Neil Scolding, Bristol, UK.
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