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Positivity to p-ANCA in patients with status epilepticus
© Ferlazzo et al.; licensee BioMed Central Ltd. 2014
Received: 22 February 2014
Accepted: 11 July 2014
Published: 17 July 2014
Status epilepticus (SE) may occur in the setting of several internal or neurologic diseases. Anti-neutrophilic cytoplasmic antibodies (ANCA) are a group of Ig that may be observed in patients with different autoimmune disorders but are particularly associated with systemic vasculitis named ANCA-associated-vasculities (AAV). We herein report 3 patients with SE and positivity to p-ANCA.
One patient had a catastrophic evolution and died 5 months after disease onset. The other two patients had a good outcome and remained seizure-free at 30 months and 5 years of follow-up respectively.
This report highlights the importance of considering ANCA dosage in patients with SE of unclear origin.
Status epilepticus (SE) may occur in the setting of several neurologic or internal diseases. Anti-neutrophilic cytoplasmic antibodies (ANCA) are a group of Ig that may be observed in patients with different autoimmune disorders but are particularly associated with systemic vasculitis. ANCA-associated vasculitis (AAV) are rare systemic autoimmune diseases affecting small to medium sized blood vessels . AAV include granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). These conditions may rapidly lead to multiple organ failure and death if not early diagnosed . AAV may involve different organs especially upper and lower respiratory tracts, kidneys, skin. Neurological manifestations are observed in about 20% of patients, in particular peripheral neuropathy . Seizures, headache and stroke have rarely been reported in AAV [2–7]. We herein report 3 patients presenting SE of unclear origin, whose sera were positive for p-ANCA.
A 44-year-old coeliac man presented with fever, lymphadenopathy and haemolytic anaemia of unknown origin, treated with prednisone 1 mg/kg/day. In the same epoch he presented weekly short-lasting episodes of epigastric aura with sweating and was prescribed levetiracetam 1 gr/day. Two months later he was admitted for refractory SE with left hemibody clonic jerks not responding to i.v. boli of lorazepam 4 mg and phenytoin 20 mg/kg. Neurological examination was otherwise normal. He was given oral levetiracetam 2 gr/day and topiramate 200 mg/day, but clonic jerks persisted. EEG showed periodic lateralized epileptic activity over right fronto-centro-temporal regions. Neither skin lesions nor joints involvement joints were evident. Brain MRI showed multiple lesions involving cortico-subcortical fronto-temporal regions (Figure 1D, E) without contrast enhancement. The same laboratory panel as patient 1 was unremarkable except for ANA 1:320 (speckled pattern as detected by indirect fluorescence antibody test), ESR 24 mm/h, C reactive protein 257 mg/l, positivity to p-ANCA (as detected by both indirect immunofluorescence and ELISA for ANCA-MPO). Urinalyses, including microalbuminuria, and serum creatinine were normal. CSF analysis showed oligoclonal bands; cultures were negative. Abdominal and pelvic CT scans, electrocardiography and echocardiography were normal. Methylprednisolone 1 gr/day was administered for 5 days. He was then given i.v. rituximab (600 mg/week for 4 weeks). During the following 5-year follow-up he had no relapses and remained seizure-free with levetiracetam 2 gr/day. A control MRI performed 3 years later was normal (Figure 1F).
In our series, SE represented the main or first neurological manifestation. Although the presence of a CNS vasculitis was not confirmed by brain biopsy or angiography, positivity to p-ANCA prompted us to suspect an autoimmune aetiology and to begin immunotherapy. Moreover, the proposed diagnostic criteria of AAV are based on systemic symptoms and signs, serological, radiological or histological findings, exclusion of other conditions as malignancy, infections, drugs, sarcoidosis, secondary vasculitis . Patient #1 fulfilled the diagnostic criteria for AAV  with central nervous system (CNS) involvement. Indeed, he had positivity for p-ANCA along with systemic signs of disease (glomerulonephritis and pulmonary interstitiopathy), histological proof of vasculitis and no other diagnosis accounting for the clinical picture. MRI picture could suggest a “posterior reversible encephalopathy syndrome or PRES . However, contrast enhancement at MRI, normality of blood pressure, and absence of worsening of kidney function during SE, does not support this hypothesis. Patient 2 also had positivity of p-ANCA, in the presence of non-specific signs of vasculitis (fever, lymphadenopathy and haemolytic anaemia) along with absence of other diagnosis accounting for the clinical picture, thus fulfilling only 2 out of 3 necessary criteria. However, the positivity of p-ANCA prompted us to start treatment with rituximab with good outcome. Patient 3 also fulfilled 2 out of 3 proposed criteria for AAV (positivity for p-ANCA and exclusion for other conditions accounting for her symptoms, including the above-mentioned diseases). An atypical form of Rasmussen encephalitis could be suggested in this patient . However, the clinical findings as well as the extensive laboratory investigation, including the MRI features (with no characteristic evolutional changes of MRI occurring at long-term follow-up, including the atrophy of the head of the caudate nucleus) made this diagnosis very unlikely. Therefore, all these data, along with the prompt response to azathioprine treatment, strongly suggested the diagnosis of an autoimmune disorder with p-ANCA positivity limited to CNS in this young patient. Of interest, in the same patient, we also excluded genetic conditions potentially leading to focal brain lesions and seizure disorder, including POLG mutations. Indeed, it is known that POLG mutations may cause a progressive neurological disorder usually starting in teens with occipital lobe epilepsy and frequent SE . This observation suggests that AAV should be considered in the differential diagnosis with POLG mutations in patients presenting with occipital seizures or SE.
A study  on natural history of AAV found that average patient survival is about five months and more than 90% of patients die within two years. Standard treatment of AAV usually consists of inducing remissions with high dose steroids or cyclophosphamide, and maintaining remission with immunosuppressants. New therapeutic agents include rituximab, a monoclonal antibody depleting B cell, approved by FDA in US for use in AAV. The striking and long-lasting response in patient 2 confirms that rituximab may represent a therapeutic alternative to classic immunosuppressant for AAV in some patients. Patient 3 too had a good outcome and remained seizure-free at follow-up with immunosuppressant and antiepileptic treatment. On the contrary, patient 1 had extremely rapid and fatal evolution due to small vessel necrotizing vasculitis and multiple organs bleeding despite treatment with steroids.
The exact nature of cortico-subcortical hyperintensities associated with SE remains elusive, even if such changes may be at least in part related to cytotoxic edema . Regardless the pathophysiological mechanism, we believe that the present series strengthens the view that both SE and brain hyperintensities should be targets of rational treatment, as there is now agreement that SE and its combination with sterile brain inflammation are the major determinants of sequelae . In this way, it may be questioned if an earlier immunosuppressive treatment in our patient #3 could have prevented the irreversible loss of brain parenchyma.
In conclusion, physicians should consider ANCA dosage in patients presenting with otherwise unexplained SE or seizures, inflammatory changes at brain MRI, with or without other systemic signs or symptoms of AAV. Indeed, in this peculiar clinical setting, ANCA positivity may lead physicians to suspect an autoimmune aetiology and to promptly start adequate immunotherapy.
Written informed consents were obtained from the patients #2,3 for publication of this case series and any accompanying images. Written informed consent was obtained from the wife of patient 1 for publication of this case series and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
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