Abstract

Objective. To assess the use of mycophenolate mofetil (MMF) in the treatment of refractory primary angiitis of the CNS in childhood (cPACNS).

Methods. A retrospective chart review was performed in patients with cPACNS who were treated with MMF following failure of a combination of corticosteroids and another immunosuppressant.

Results. Three patients from two centres were included in this study. The age of onset of disease was 5, 6 and 9 years. All the patients improved when treated with MMF, such that the dose of corticosteroids could be weaned or stopped.

Conclusions. MMF should be considered for maintenance treatment in the management of patients with cPACNS refractory to the combination of corticosteroids and first-line immunosuppressive agents.

Introduction

CNS vasculitis in children is a relatively newly recognized and potentially severe neurological disease [1]. Primary angiitis of the CNS (PACNS) was initially described in adults by Calabrese et al. [2].

A series of children with PACNS, both with and without characteristic angiography changes, has now been described, applying the adult criteria to the paediatric population [3–6]. The presenting features of PACNS in childhood (cPACNS) reflect, to some extent, the size of the affected vessels. Vasculitis of the large to medium vessels is associated with headache, hemiparesis, hemisensory deficits and fine motor deficits [5]. Intractable seizures, cognitive decline, behavioural changes and systemic features, such as fever and malaise, tend to be associated more frequently with small-vessel inflammation [6].

Treatments for cPACNS included an initial induction period of 6 months, using high-dose steroids and cyclophosphamide, followed by a maintenance period of ≥18 months with low-dose steroids and AZA [1, 6]. The use of anti-platelet or anti-coagulant medications in the treatment for cPACNS has been controversial [7].

In this article, we describe a small series of children with cPACNS who had a partial response to first-line immunosuppression but who achieved disease control with mycophenolate mofetil (MMF).

Materials and methods

Patients with refractory cPACNS, treated at two Paediatric Rheumatology Units in the UK (Bristol and Newcastle-upon-Tyne), were included in the study. The children were diagnosed with cPACNS by experienced paediatric rheumatologists and neurologists. The case notes were reviewed retrospectively to elucidate presenting features, and investigations used to make the diagnosis. The initial management, introduction of MMF and subsequent course were recorded. Patient consent was obtained from the parents of all the three cases discussed.

Results

Three patients, one male and two females, were included. Patient characteristics, investigations and treatments are summarized in Table 1. Each case is discussed in more detail below.

Table 1

Patient characteristics, investigations and treatments

 Patient 1 (male) Patient 2 (female) Patient 3 (female) 
Age at presentation 5 years (July 2006) 9 years (November 2004) 6 years (July 2003) 
Presenting features Generalized tonic–clonic seizures, visual loss, decreased truncal tone, weakness in legs Headaches, nausea, vomiting, pain around eyes, unilateral papilloedema Headache, eye pain, fever, optic neuritis 
Blood tests WCC, ESR, CRP normal Negative autoantibody screen WCC normal ESR 45 mm/h, CRP 22 mg/l Negative autoantibody screen WCC 19.3 × 109/l, Neut 16 × 109/l; ESR 95 mm/h; CRP 56 mg/l Negative autoantibody screen 
CSF WCC and protein normal No growth on culture Increased lymphocytes and protein No growth on culture PCR negative for MBT, Lyme, HSV Mildly increased lymphocytes and protein No growth on culture PCR negative for MTB, HSV 
CT head Normal initially Not performed Not performed 
MRI head Increased T2 signal in cortical and subcortical white matter parieto-occipital and posterior frontal regions DWI confirmed acute ischaemic changes Right optic nerve thickening Thickened and enhancing of left optic nerve Abnormal signal in subcortical white matter of right anterior temporal lobe Meningeal enhancement around brainstem, cerebellum and tentorium Signal changes in subcortical white matter of both hemispheres 
Cerebral angiography/MRA Cerebral angiography—irregularity of distal posterior cerebral arteries bilaterally MRA normal MRA normal 
Brain biopsy Not performed Frontal lesion—small-vessel vasculitis Not performed 
Immunosuppressive medication IV MPDN pulses IV MPDN pulses IV MPDN pulses 
 Prednisolone Prednisolone Prednisolone 
 Cyclophosphamide MTX AZA 
 MTX MMF Cyclophosphamide 
 MMF  MMF 
 Patient 1 (male) Patient 2 (female) Patient 3 (female) 
Age at presentation 5 years (July 2006) 9 years (November 2004) 6 years (July 2003) 
Presenting features Generalized tonic–clonic seizures, visual loss, decreased truncal tone, weakness in legs Headaches, nausea, vomiting, pain around eyes, unilateral papilloedema Headache, eye pain, fever, optic neuritis 
Blood tests WCC, ESR, CRP normal Negative autoantibody screen WCC normal ESR 45 mm/h, CRP 22 mg/l Negative autoantibody screen WCC 19.3 × 109/l, Neut 16 × 109/l; ESR 95 mm/h; CRP 56 mg/l Negative autoantibody screen 
CSF WCC and protein normal No growth on culture Increased lymphocytes and protein No growth on culture PCR negative for MBT, Lyme, HSV Mildly increased lymphocytes and protein No growth on culture PCR negative for MTB, HSV 
CT head Normal initially Not performed Not performed 
MRI head Increased T2 signal in cortical and subcortical white matter parieto-occipital and posterior frontal regions DWI confirmed acute ischaemic changes Right optic nerve thickening Thickened and enhancing of left optic nerve Abnormal signal in subcortical white matter of right anterior temporal lobe Meningeal enhancement around brainstem, cerebellum and tentorium Signal changes in subcortical white matter of both hemispheres 
Cerebral angiography/MRA Cerebral angiography—irregularity of distal posterior cerebral arteries bilaterally MRA normal MRA normal 
Brain biopsy Not performed Frontal lesion—small-vessel vasculitis Not performed 
Immunosuppressive medication IV MPDN pulses IV MPDN pulses IV MPDN pulses 
 Prednisolone Prednisolone Prednisolone 
 Cyclophosphamide MTX AZA 
 MTX MMF Cyclophosphamide 
 MMF  MMF 

WCC: white cell count; Neut: neutrophil count; DWI: diffusion weighted imaging; MRA: magnetic resonance angiography; IV MPDN: intravenous methylprednisolone.

Patient 1

A 5-year-old Caucasian boy presented in July 2006 with two self-limiting, generalized tonic–clonic seizures associated with abdominal pain and vomiting. Several days later, he had a prolonged generalized tonic–clonic seizure. Following recovery from this, he seemed cognitively intact but had lost his vision; he had truncal hypotonia and reduced tone and weakness of the legs, the left more than right. His pupils were equal and reactive to light but his visual acuity was severely impaired.

Initial blood tests, cerebrospinal fluid (CSF) and imaging results are shown in Table 1. Cerebral angiography showed irregularity of the distal posterior cerebral arteries bilaterally.

A diagnosis of CNS vasculitis was made and he was given methylprednisolone (30 mg/kg/dose IV daily, for 3 days) followed by oral prednisolone (2 mg/kg/day). He also commenced aspirin 3 mg/kg/day. Following counselling regarding the possible side effects and long-term complications, cyclophosphamide was commenced at a dose of 500 mg/m2 once a month.

After completing a 6-month course of cyclophosphamide in February 2008, oral MTX was commenced at a dose of 10 mg/m2 once weekly. Three months after completely weaning off steroids, but while still taking MTX, the patient was re-admitted with a wide-based gait, paraesthesiae of his feet, a complex partial seizure and faecal incontinence. MRI showed no new foci of disease and CSF was normal with no growth in cultures. This episode was felt to be a relapse of CNS vasculitis. He received three doses of IV methylprednisolone, prednisolone was restarted (1 mg/kg/day), MTX was continued and MMF was introduced at a dose of 300 mg/m2 twice daily for 3 weeks before increasing to 600 mg/m2 twice daily. Symptoms resolved with no adverse effects attributable to MMF. Steroids were weaned and eventually stopped 12 months after relapse.

Currently, the patient is managing well in primary school and has a mild residual weakness of the left leg but no recurrent symptoms. He remains on MMF 600 mg/m2 twice daily, MTX 10 mg/m2 once weekly and aspirin.

Patient 2

A 9-year-old Caucasian girl presented in November 2004 with a 2-week history of severe morning headaches, nausea, vomiting, pain around her right eye on eye movements and blurring in vision. On examination, she had asymmetry of the discs with swelling on the right, absent venous pulsation but no objective visual dysfunction, suggestive of unilateral papilloedema.

Initial blood tests and CSF results are shown in Table 1. Since lumbar puncture revealed lymphocytic meningitis, she was initially treated for presumed tuberculous meningitis; however, three CSF cultures and Mycobacterium tuberculosis (MBT) PCR were subsequently negative. MRI showed only right optic nerve thickening. Two weeks after the initial presentation, she developed pain behind her left eye and the vision in this eye became subjectively hazy. Repeated MRI scan showed a thickened and enhancing left optic nerve.

An inflammatory process was suspected and a single dose of 30 mg/kg IV methylprednisolone given empirically resulted in dramatic improvement in symptoms, so she was commenced on oral prednisolone (1 mg/kg/day). However, symptoms recurred on two occasions when steroids were reduced to <10 mg/day and on both occasions, she responded to methylprednisolone ‘pulses’ (30 mg/kg daily for 3 days).

A repeat MRI in February 2005 showed extensive inflammatory changes involving the left optic nerve, chiasm, optic tracts and extension into the subthalamic region (Fig. 1). As magnetic resonance angiography (MRA) was normal, she underwent stereotactic brain biopsy of the frontal lesion. Histopathology showed no evidence of granuloma or a glial tumour but non-specific reactive changes, with peri-vascular lymphocytes and macrophages and reactive astrocytosis, were suggestive of small-vessel vasculitis.

Fig. 1

MRI of Patient 2, ∼10 weeks after initial presentation, to show the extent of signal change, which appears contiguous. (A) Coronal FLAIR imaging through anterior temporal lobes just anterior to chiasm. (B–D) T2 fat-saturation sequences. B is at same level as A. C is just posterior to the chiasm. (E) T1 weighted image showing area of signal change and approximate biopsy site (indicated by an arrow).

Fig. 1

MRI of Patient 2, ∼10 weeks after initial presentation, to show the extent of signal change, which appears contiguous. (A) Coronal FLAIR imaging through anterior temporal lobes just anterior to chiasm. (B–D) T2 fat-saturation sequences. B is at same level as A. C is just posterior to the chiasm. (E) T1 weighted image showing area of signal change and approximate biopsy site (indicated by an arrow).

After a 3-day course of IV methylprednisolone, MRI showed marked resolution of the previous changes and her symptoms remained subsequently well controlled on a low dose of oral prednisolone (5 mg/day) for 16 months. This was the reason for not introducing the ‘standard’ cyclophosphamide treatment. After ophthalmology review showed early signs of posterior lens opacification, oral weekly MTX (10 mg/m2) was introduced as a steroid-sparing maintenance immunosuppressive agent in July 2006.

During the next 2 years, MTX was changed to the subcutaneous route because of gastrointestinal intolerance and the dose was increased to 12.5 mg/m2 and then to 15 mg/m2 once weekly. Despite this, she experienced further relapses in an attempt to reduce the steroid dose. After the addition of MMF (300 mg/m2 initially, and thereafter 600 mg/m2; twice daily) in June 2008, her symptoms settled and steroids were slowly weaned and stopped in January 2009.

Patient 3

A 6-year-old Caucasian girl presented in July 2003 with a 2-week history of left-sided eye pain and headache with subsequent fever and encephalopathy. Initial blood tests, CSF and MRI results are shown in Table 1.

The raised inflammatory markers and meningeal enhancement on MRI were suggestive of infection or inflammation. She failed to respond to acyclovir, cefotaxime and anti-MBT treatment. Three pulses of IV methylprednisolone (30 mg/kg/day), given empirically, led to resolution of the clinical symptoms and normalization of inflammatory markers. She remained well on oral steroids (2 mg/kg/day), which were slowly tapered and stopped in March 2004.

Over the next year, she re-presented with two further episodes of neurological and ocular symptoms associated with high signal lesions in the peripheral subcortical white matter in both hemispheres on brain MRI, which always resolved completely after steroid treatment. MRA was normal and a brain biopsy was not felt to be safe in view of the location of the lesions. There were no clinical or laboratory features suggestive of systemic vasculitis, including negative autoantibody tests. No infective organisms, including mycobacteria, were identified on microscopy and culture of CSF samples obtained during these episodes. A diagnosis of cPACNS was thought to be most likely.

Both relapses were treated with, and responded to, increased doses of steroids. Despite commencing AZA (1 mg/kg/day) in May 2005, she suffered a further relapse 6 months later with left-sided optic neuritis and MRI changes in the left parietal lobe. She was started on IV cyclophosphamide at a dose of 750 mg/m2 monthly for 6 months.

During the following year, her vision greatly improved with complete recovery of optic neuritis and visual function, and a complete resolution of the previous changes on a repeat MRI, but she was left with residual optic atrophy. Steroids were weaned to 5 mg on alternate days. However, in October 2007, she developed another relapse. She was treated with three pulses of IV methylprednisolone followed by oral prednisolone (2 mg/kg/day). In view of the relapse while on AZA, this was stopped and MMF was introduced at an initial dose of 300 mg/m2 twice daily. Repeat MRI scans in 2008 showed further resolution of previous lesions. She has had no relapse for >1 year and has not developed side effects related to MMF. She is currently on MMF (500 mg/m2 twice daily) and slowly weaning prednisolone on an alternate day regimen.

Discussion

We have discussed here three children who presented with a newly-acquired neurological deficit. All had some visual disturbance in addition to other abnormalities. Two patients had raised inflammatory markers but all had sterile CSF. There were no clinical features of multi-system inflammatory disease and tests for routine autoantibodies were negative. All patients had evidence of significant inflammatory changes in the CNS on MRI scans.

Patient 1 had abnormalities on cerebral angiography in the distal posterior cerebral arteries bilaterally, which would be consistent with a large- to medium-vessel vasculitis. This is in contrast with the location of angiographic changes seen in a series of patients by Aviv et al. [8]. where the lesions occurred proximally and unilaterally in the anterior circulation [8]. MRA performed on both Patients 2 and 3 was reported as normal. However, conventional angiography is considered the gold standard and MRA may miss distal vessel stenosis [7]. Patient 2 had a stereotactic biopsy of a lesion performed, which on histopathology showed some evidence of small-vessel vasculitis. In Patient 3, due to the location of the abnormalities on MRI, it was not felt that lesional brain biopsy could be performed safely.

All these patients were managed at tertiary referral centres for paediatric rheumatology in the UK. At present, there is no standardized protocol for treatment of cPACNS that is based on evidence from controlled trials [1]. The usual practice employed in the management of systemic inflammatory conditions, such as SLE, is an initial period of treatment to induce remission followed by a longer maintenance phase [9].

All the patients presented here initially received and responded to IV methylprednisolone followed by oral prednisolone that was gradually tapered. Repeated pulses of IV methylprednisolone were given for flares of disease. Patient 1 received 6 months of cyclophosphamide initially, followed by a maintenance dose of MTX. Patient 2 received increasing doses of maintenance MTX after initial failure of control with steroids alone. Patient 3 was given maintenance treatment of AZA and also received a 6-month course of cyclophosphamide.

All patients relapsed while on either MTX or AZA and steroids, hence MMF was introduced. Subsequently, steroids were stopped completely in the two patients on maintenance MTX and MMF with no recurrent symptoms or side effects to date. The third patient on MMF alone is weaning steroids and there have been no new lesions on MRI.

MMF initially entered clinical use as an immunosuppressive agent to prevent rejection following solid organ allografts. Its major mechanism of action is by inhibition of the rate-limiting enzymatic step in the de novo pathway of purine synthesis. This has the effect of reducing B- and T-lymphocyte proliferation [10]. MMF has been used successfully to treat several autoimmune or inflammatory conditions in patients. It has been employed in children with lupus nephritis and some clinical trials have suggested it to be superior to cyclophosphamide for maintenance treatment [11]. MMF has reportedly been used effectively to treat lupus nephritis in patients who are intolerant to side effects of other immunosuppressants or whose disease is resistant to or relapsed on other therapies.

There have been several case reports of MMF being used successfully to treat vasculitides including WG [12], microscopic polyangiitis [12] and Takayasu’s arteritis [13]. Case reports also detail use of MMF as maintenance therapy to treat CNS vasculitis associated with SLE [14, 15].

There have been no published reports of MMF use in children with primary CNS vasculitis, except for a preliminary report in children with angiography-negative, biopsy-positive cPACNS [16]. Here we have presented three patients with cPACNS who were successfully maintained in remission when MMF was used as a second-line agent following relapse while on other medication. We believe that MMF might add to the therapeutic armamentarium in the management of cPACNS. While well-controlled studies are required to elucidate the role of MMF in cPACNS, the relative rarity of the condition makes this difficult. We would suggest that MMF be considered as the maintenance immunosuppressive agent in the management of patients with refractory cPACNS.

graphic

Acknowledgement

We would like to acknowledge the clinical advice provided by Dr S. Benseler (Hospital for Sick Children, Toronto) in the management of these patients.

Disclosure statement: The authors have declared no conflicts of interest.

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