1 Department of Paediatric Nephrology, 2 Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK and 3 Department of Neuroradiology, Newcastle General Hospital, NE4 6BE, UK
Correspondence and offprint requests to: Dr Anna Basu, BMBCh, Sir James Spence Institute, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK. Email: a.p.basu{at}ncl.ac.uk
Keywords: anti-glomerular basement membrane glomerulonephritis; central nervous system; child; vasculitis
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Introduction |
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Case |
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Respiratory review revealed fluid in the right horizontal fissure on chest X-ray and haemosiderin-laden macrophages on bronchial alveolar lavage. Lung function tests including carbon monoxide transfer were reassuringly normal. She was dialysed within 24 h of presentation and, in view of the respiratory findings, was started on prednisolone (1 mg/kg), intravenous (i.v.) cyclophosphamide with planned monthly infusions (500 mg; reduced in view of glomerular filtration rate <10 on presentation), and 14 sessions of daily plasmapheresis. Anti-GBM titres fell rapidly in response to treatment and were negative at 2 weeks. The non-specifically raised ANA and sm Ab titre were unaltered by treatment.
On day 29 of admission, she had three generalized convulsions over a 5 h period. She was loaded with phenytoin and subsequently started on maintenance treatment. At the time of the seizures, she was normotensive and serum biochemistry was within normal limits (Na 141 mmol/l, K 4 mmol/l, Ca 1.12 mmol/l, Mg 0.83 mmol/l, glucose 6 mmol/l). ANCA levels were still negative, as were the anti-GBM titres. A magnetic resonance imaging (MRI) scan of the brain (Figure 1) was consistent with bilateral cortical ischaemia of the occipital lobes, seen best on FLAIR (fluid-attenuated inversion recovery) sequence, but with no evidence of abnormality on diffusion-weighted imaging. Time of flight MR angiography did not show any abnormality of the major intracranial vessels. A provisional diagnosis of CNS vasculitis was made. For this reason, her treatment was intensified to 3 weekly cyclophosphamide, and plasmapheresis was re-started.
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The patient underwent a follow-up cranial MRI scan on day 42, which showed complete resolution of the previous abnormalities. She was discharged on a weaning course of prednisolone and 3 weekly i.v. cyclophosphamide (planned for a duration of 6 months). However, 4 weeks after discharge, by which time her prednisolone had been weaned to 40 mg on alternate days, she had a second seizure. Clinical parameters remained unchanged, i.e. she was normotensive, had normal biochemistry (Na 140, K 4, glucose 6.3, Ca 1.22) and was both anti-GBM antibody and ANCA negative, with raised ANA and marginally raised sm Abs. Phenytoin levels were within the therapeutic range. A further MRI showed extensive multifocal signal abnormalities, this time with evidence of abnormality on diffusion-weighted sequence (Figure 2). Conventional arteriography was normal. She again responded well to an increase in her immunosuppressive treatment (reverting to high dose daily prednisolone). Three weeks after this event, a fourth MRI was normal.
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Discussion |
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Although Goodpasture's syndrome is only rarely associated with other autoimmune diseases [4], its association with ANCA-positive vasculitis has become increasingly recognized [5]. Goodpasture's syndrome is a rare diagnosis in childhood, with <10 confirmed anti-GBM-positive cases reported in the recent literature. It is, however, our patient's ANCA-negative status in the presence of CNS vasculitis that has proven to be the most unusual feature. This has only been reported in two previous cases, both in adults.
The first case [6] was an 18-year-old man with Goodpasture's syndrome who developed seizures progressing to status epilepticus. MRI showed multiple lacunar infarcts suggestive of a vasculitis which was subsequently proven on meningeal biopsy. In this instance, the anti-GBM antibodies were still elevated (83 U, having fallen from a peak of 1780 U). The patient made a good neurological recovery following an increase in his immunosuppression. He received a living-related renal transplant 1 year after initial presentation.
A second such case was reported in 2003 [7] in a 55-year-old woman who developed episodes of confusion in the year following her diagnosis with Goodpasture's syndrome. Neurological signs varied but included aphasia and evidence of frontal lobe dysfunction. An MRI showed a left parietal area infarct, and cerebral angiography showed multifocal stenoses affecting the distal branches of the middle cerebral artery bilaterally. Her anti-GBM antibody status during each episode is not quantified other than normalization after the resolution of the first confusional episode. Repeat angiography 9 months later was normal following immunosuppressive treatment. Interpretation of the findings in this case is complicated by the presence of hypertension (BP 190/140).
In our subject, the diagnosis of Goodpasture's syndrome was made on the basis of a significantly elevated anti-GBM antibody, intense linear deposition of IgG along the GBM on immunofluoresence and normal thickness basement membrane on electron microscopy. The diagnosis of cerebral vasculitis was made on the basis of clinical presentation and MRI findings and supported by the rapid response to immunosuppressive treatment. The finding of normal vessels on either conventional or MR angiography does not exclude a diagnosis of small vessel vasculitis. In fact, in one series of 14 patients with biopsy-proven primary cerebral angiitis, 64% had normal angiograms [8]. Although brain biopsy is still considered the gold standard in diagnosing CNS vasculitis [9], it was not performed in this case in view of the clinical response to treatment and the potential risks involved.
The aetiology of the vasculitis is unclear. Rydel et al. speculate on the role of anti-GBM antibodies in CNS vasculitis in Goodpasture's syndrome [6]. However, in our patient, anti-GBM antibodies were in the normal range at the time of the CNS symptoms on both occasions and the anti-GBM titre was normalizing in Rydel's patient at the time of presentation with seizures. The findings of a raised ANA and marginally raised sm Abs in our patient are non-specific, and diagnostic criteria for other autoimmune disorders have not been met.
In conclusion, we report the case of a 14-year-old girl with Goodpasture's syndrome in end-stage renal failure who developed CNS vasculitis in the absence of ANCAs or of persisting anti-GBM antibodies. This has raised several important issues. First, how should the cerebral vasculitis be monitored in order to tailor immunosuppressive treatment? This was particularly relevant in our case, with her second seizure occurring whilst still on a substantial dose of prednisolone. As cranial MRI scans reflected her neurological state, and in the absence of other reliable markers, we elected to use serial MRI scans to monitor the course of her CNS disease. However, the sensitivity of MRI scans in angiogram-positive CNS vasculitis is 75% [10] and as such may not be appropriate for less significant disease. Secondly, the benefit of an identically matched donor must be weighed against the potential risk of recurrent disease and perhaps even recurrent CNS vasculitis. The most challenging issue, however, remains the aetiology of the vasculitis. Without this knowledge, markers for monitoring effective treatment remain elusive.
Conflict of interest statement. None declared.
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References |
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