Posterior reversible encephalopathy syndrome as a complication of Henoch–Schönlein purpura in a seven-year-old girl

Introduction

Henoch–Schönlein purpura (HSP) is the most common vasculitis of childhood. Small-vessel involvement of skin, joints, gastrointestinal system, and kidneys characterises HSP clinically, and the major clinical findings in patients presenting with HSP include gravity-dependent, nonthrombocytopenic, palpable purpura, arthritis or arthralgia, and abdominal pain. ¹ The incidence of HSP peaks among children aged 4 to 7 years, and most patients are younger than 10 years at onset.^2,3

Central nervous system (CNS) involvement is uncommon in HSP. ⁴ Posterior reversible encephalopathy syndrome (PRES) is a complex condition characterised by a neurotoxic state of transient vasogenic oedema preferentially involving posterior cerebral regions.^2,4–6 On neuroimaging, PRES is characterised by potentially reversible parieto-occipital abnormalities both on computed tomography (CT) and on magnetic resonance imaging (MRI). ⁵ Various underlying conditions may be associated with PRES, ⁷ but only a few cases of HSP complicated by PRES have been previously described.^4,8,9 As delayed treatment of PRES may lead to irreversible neurologic injury, clinicians should be aware of this condition and have a high index of suspicion in HSP patients presenting with new neurologic symptoms. We herein describe a case of a seven-year-old girl with HSP who developed clinical and radiological findings of PRES concomitantly with hypertension and renal impairment and successfully recovered her baseline renal and neurological status after prompt treatment. We also present a brief review of the literature concerning HSP and PRES.

Case presentation

A seven-year-old otherwise healthy female patient was admitted to our hospital with a one-week history of progressive abdominal pain, nausea, poor appetite, and vomiting. She was afebrile and had no arthralgias, diarrhoea, or other complaints. Additionally, she had no history of haemorrhages, recent infections, previous neoplastic diseases, or other comorbidities. Her gestational period had been uneventful. On examination, her vital signs, including arterial blood pressure, were normal. Multiple purpuric eruptions were noted on her oral mucosa and skin, the latter being palpable and predominating in the legs and buttocks. Abdominal examination revealed moderate mesogastric tenderness, but no peritoneal irritation signs. Her laboratory work-up disclosed a prolonged bleeding time, which prompted additional investigation for coagulation and vascular disorders. Further laboratory evaluation, including full blood count, serum electrolytes, liver and kidney function tests, prothrombin time, partial thromboplastin time, and serum IgA, were normal. Skin biopsy was performed and revealed a leukocytoclastic vasculitis. This set of clinical and laboratory findings met the diagnostic criteria for HSP. ¹⁰ Along with supportive therapy, the patient was started on oral prednisone (1 mg/kg/day) and demonstrated gradual improvement of her abdominal pain during the following days. Vital signs were recorded several times each day and remained within normal limits during the first days of admission.

Five days after starting the corticosteroid therapy, the patient suddenly developed severe frontal headache, altered consciousness and bilateral cortical blindness; her vital signs were assessed immediately and revealed a blood pressure of 140/100 mmHg, disclosing an acute blood pressure elevation; 4 h prior, her blood pressure was within normal limits. A few minutes later, she developed generalised tonic–clonic seizures that lasted for 30 min. She was immediately started on antiepileptic drugs (diazepam and phenytoin) and antihypertensives (captopril and furosemide). Blood work-up and urinalysis were performed thereafter, disclosing elevation of serum urea and creatinine, proteinuria in the nephrotic range, and microscopic haematuria that were not present previously during her admission. A MRI scan of brain demonstrated bilateral FLAIR hyperintensities involving the subcortical white matter of parietal and occipital lobes, as well as the right cerebellar hemisphere, which had neither diffusion restriction nor gadolinium enhancement (Figure 1(a) to (d)). On the basis of these clinical and neuroimaging findings, a diagnosis of PRES was made. Blood pressure control was achieved within the first 2 h of antihypertensive therapy. As her blood pressure normalised with medication, she recovered her baseline visual acuity within the first 24 h and had no recurrence of seizures. A kidney biopsy was performed soon afterwards; histopathological and immunofluorescence analyses revealed diffuse mesangial proliferation with <50% crescentic glomeruli (ISKDC grade IIIb) and mesangial IgA deposition, characterising a rapidly progressive glomerulonephritis secondary to HSP. The patient was switched to an angiotensin converting-enzyme inhibitor (ACE-I) and started on immunosuppressive therapy consisting of intravenous pulse methylprednisolone 1000 mg/day for three days followed by oral cyclophosphamide 2 mg/kg/day along with oral prednisone 1 mg/kg/day for three months, which were then slowly tapered. Both the proteinuria and the haematuria quickly improved after pulse therapy. Upon completing the immunosuppressive treatment, patient’s urinalysis demonstrated no residual haematuria nor proteinuria, and the glomerular filtration rate returned to normal. Blood pressure control was successfully achieved by ACE-I therapy, which was maintained throughout the immunosuppressive period and tapered thereafter. Blood pressure measurements after treatment discontinuation revealed consistently normal values. OPEN IN VIEWER

At one-year follow-up, no residual visual symptoms or mental status alteration were detected. The patient was normotensive, did not present any recurrent seizures, had no detectable skin lesions, and did not complain of arthralgias nor abdominal pain over the period. On laboratory work-up, her urinalysis, complete blood cell count, and renal function tests were normal. A repeat MRI scan revealed normal brain parenchyma without residual signal changes.

Discussion

Neurologic manifestations are very uncommon in HSP but may cause significant morbidity and mortality. Subjects presenting with neurologic symptoms often exhibit multiorgan involvement, renal impairment, and arterial hypertension.^11,12 PRES has become increasingly recognised in childhood, especially in the setting of autoimmune diseases, cancer, and renal diseases. ¹³ However, the precise mechanism of PRES remains to be elucidated and appears to be multifactorial. Acute elevation in blood pressure has long been considered the most frequent precipitating factor of PRES both in patients with and without HSP, but it may be absent in up to 20%–40% of cases.^12,13 Additionally, systemic inflammatory states and impaired renal function have been shown to predispose to PRES, and therefore HSP patients presenting with severe nephritis are especially prone to developing PRES owing to multiple concomitant risk factors – mainly hypoalbuminaemia, proteinuria, and nephrotic syndrome.^14,15 We also cannot rule out a possible contributing role of corticosteroid therapy in exacerbating arterial hypertension and thereby potentially triggering PRES due to their effect on mineralocorticoid receptors. ¹⁵ Specifically in HSP, PRES may stem from a dysfunction of cerebral blood flow autoregulation (most often triggered by hypertension) and/or from HSP-related CNS vasculitis, ⁹ thereby disrupting the blood–brain barrier and causing the characteristic vasogenic cerebral oedema. Therefore, PRES in our patient was probably precipitated by multiple risk factors rather than by a single predisposing condition.

The major symptoms of PRES both in adults and children include headache, cortical blindness, altered consciousness, and seizures. ¹⁴ Neuroimaging typically reveals areas of bilateral vasogenic oedema affecting the parietal and occipital lobes, seen as hypodense areas on CT and high signal intensity regions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MRI. ⁵ These regions usually do not display contrast enhancement or restriction to diffusion on diffusion-weighted imaging. Despite the severity of acute PRES, once prompt and appropriate therapy is undertaken, both the clinical signs and imaging abnormalities tend to resolve completely. Long-term prognosis after PRES recovery is favourable and recurrences after the first episode are rare. ¹⁶

Even though a high proportion of HSP patients may have haematuria and/or proteinuria over the disease course, only a minority develop severe glomerulonephritis. ¹⁷ Manifestations of HSP nephritis in children include microscopic haematuria with or without proteinuria, hypertension, nephritic and/or nephrotic syndrome, and renal insufficiency. ¹⁷ The long-term prognosis of HSP is directly related to the severity of renal disease, as severe and/or untreated nephritis may result in chronic kidney disease and poorer outcomes. ¹⁷ Additionally, both nephrotic syndrome and severe hypertension are predisposing conditions for developing PRES in children. ¹³ Therefore, monitoring renal function and arterial blood pressure both at onset of HSP and at subsequent follow-ups has clinical and prognostic importance.

Potentially life-threatening complications – such as brain infarction, hemorrhage, and cytotoxic oedema – and persistent brain lesions may result if treatment of PRES is delayed, so clinicians should ensure that prompt and timely therapy is administered as soon as PRES is suspected. ¹⁴ Acute therapy consists of removal of potentially causative agents, seizure control with antiepileptic drugs, and correction of hypertension. Long-term treatment should be directed towards the underlying disease associated with PRES. In the setting of HSP nephritis, early kidney biopsy is recommended in children presenting with haematuria and/or proteinuria to evaluate the degree of renal damage and to establish a treatment plan. ACE-Is have been shown to be useful in controlling blood pressure and reducing proteinuria in HSP nephritis. ¹⁸ In addition, various immunosuppressive agents have been used in the treatment of rapidly progressive glomerulonephritis, but there is no definitive evidence to support a single drug or multi-drug regimen. ⁷ Our case report suggests that pulse methylprednisolone therapy followed by oral prednisone combined with cyclophosphamide may be efficacious for inducing remission of HSP nephritis, as reported elsewhere. ¹⁸

Conclusion

In summary, PRES is a challenging complication of HSP that occurs mostly in the setting of abrupt hypertension and renal injury. As such, clinicians should monitor blood pressure and renal function in patients with HSP and be aware that HSP nephritis and hypertension may predispose to severe neurologic involvement. Ensuring prompt diagnosis and therapy with antihypertensives and anticonvulsants is the main determinant for preventing progression to irreversible neurologic injury or even death in HSP complicating with PRES.