Polyarteritis nodosa presenting with posterior reversible leukoencephalopathy syndrome
- Rosie Heartshorne ,
- May Nwe ,
- Athar Barakat and
- Sundus Alusi
- Neurology, The Walton Centre NHS Foundation Trust, Liverpool, UK
- Correspondence to Dr Rosie Heartshorne; r.heartshorne@nhs.net
Abstract
A man in his 20s presented following a generalised tonic–clonic seizure on a background of a recent diagnosis of hepatitis B (HBV). During admission, he was severely hypertensive and imaging findings confirmed a diagnosis of posterior reversible leukoencephalopathy syndrome (PRES). The patient subsequently developed multiorgan involvement with an axonal sensorimotor neuropathy, vascular cutaneous lesions and multiple bilateral renal and splenic infarcts. Based on the 2012 Revised International Chapel Hill Consensus Criteria, a diagnosis of polyarteritis nodosa (PAN) with secondary PRES was made. The patient was given intravenous methylprednisolone, followed by a prolonged course of oral prednisolone, and tenofovir antiviral therapy to target HBV seroconversion. He made a good neurological recovery with resolution of imaging changes. This case highlights the importance of a low threshold for systemic screening for young patients presenting with PRES secondary to uncontrolled hypertension and the importance of viral screening, particularly for HBV.
Background
Here, we report a case of polyarteritis nodosa (PAN) presenting with seizures. Central nervous system involvement and posterior reversible leukoencephalopathy syndrome (PRES) is a rare manifestation of PAN and is seldom reported in the literature. Nevertheless, it is an important differential to consider in patients presenting on the acute medical take with refractory hypertension and/or PRES. A low threshold for hepatitis B (HBV) serology should be considered in these patients. PAN is a treatable condition but if left unattended can result in multiorgan failure.
Case presentation
A male in his 20s presented to the accident and emergency department following a generalised tonic–clonic seizure. He reported a 6-week history of worsening pains in his lower limbs. More recently, he had lost half a stone in weight and become increasingly unsteady on his feet. He also reported a non-specific headache and had noticed some mild ankle swelling over the few days prior to his presentation. His medical history was unremarkable, except for mild childhood asthma that did not require inhalers. He smoked 10 cigarettes per day, occasionally drank alcohol and admitted to frequent cannabis use. He had previously used cocaine, although not recently, and denied any other illicit drug use.
On examination, he was noted to be pale and cachexic and was encephalopathic with fluctuating level of consciousness. Systemically, he was found to have non-tender cervical and groin lymphadenopathy and had a several, small, irregular, well-demarcated lesions over the dorsum of his feet and lateral malleoli. On neurological examination, he had impaired dorsiflexion of both feet and walked with a high-stepping gait. Sensation to pin prick was reduced to the ankles, with impaired proprioception to the distal interphalangeal joints bilaterally. Reflexes were retained and Rhomberg’s test was negative.
The patient had been hypertensive since admission, with initial blood pressure readings at 180/115 mm Hg. At one point, a labetalol infusion had been required to gain blood pressure control and he was requiring three oral antihypertensives to main systolic readings of 160 mm Hg. On admission, his white cell count (WCC) was raised with a neutrophilia and elevated C-reactive protein (CRP) (table 1). The patient also had mildly elevated liver enzymes with preserved synthetic function. Electrolytes were also low with potassium plateauing at 2.5 mmol/L. In addition, the patient had a positive PCR nasopharyngeal swab for COVID-19 on admission, but he was asymptomatic and did not recall any recent contacts. A lumbar puncture, performed 3 days into admission, showed normal CSF: WCC<0.001 ×109/L, protein 0.29 g/L, glucose ratio>60% and viral PCR negative.
Basic haematology and biochemistry results taken on day 1 of admission
| Investigation | Result on admission | Reference range |
| WCC | 41.9×109/L | 4–11 |
| Neutrophils | 37.7×109/L | 1.9–8 |
| Haemoglobin | 135×109/L | 140–180 |
| Platelets | 407×109/L | 140–450 |
| CRP | 65 mg/L | 0–10 |
| Erythrocyte sedimentation rate (ESR) | 18 mm in 1 hour | 1–7 |
| Urea | 7.8 mmol/L | 2.5–7.8 |
| Creatinine | 81 µmol/L | 0–135 |
| eGFR | >90 | |
| Alanine aminotransferase | 72 µ/L | 11–55 |
| Alkaline phosphotase | 208 µ/L | 30–130 |
| Gamma-glutamyl transferase | 243 µ/L | 0–60 |
| Bilirubin | 12 µmol/L | 0–21 |
| Na+ | 130 mmol/L | 133–146 |
| K+ | 3.0 mmol/L | 3.5–5.3 |
| Activated partial thromboplastin time | 20.3 s | 20.5–33.4 |
| Partial thromboplastin time | 9.8 s | 9–12.7 |
| B12 | 694 ng/L | 200–770 |
| Folate | 2.60 µg/L | 3.9–26.8 |
| Thyroid-stimulating hormone | 1.73 mU/L | 0.4–4.5 |
Initial CT imaging of the head was reported as showing non-specific hemispheric hypodensities bilaterally suspicious of encephalitis. An electroencephalogram (EEG) showed fluctuating generalised slow activity with variable consciousness throughout the recording and intermittent alpha rhythm. There was no epileptiform activity noted during the recording. Nerve conduction studies revealed reduced amplitude for both distal lower limb sensory and motor responses in keeping with large fibre sensorimotor axonal polyneuropathy, with some asymmetry evident in the sural sensory responses. There were fibrillations and positive sharp wave suggesting active denervation. Full neurophysiology results can be found in the online supplemental appendix. MRI at presentation showed multiple areas of predominantly subcortical white matter T2 signal hyperintensity in the frontal, parietal and occipital lobes, as well as along the corticospinal tracts, in the cerebellum and pons (figure 1). The majority of signal abnormality was distributed along both a watershed pattern and a superior frontal sulcus pattern. Almost all areas of signal abnormality showed facilitated diffusion in keeping with vasogenic oedema. An MRI performed 5 days later showed a small focus of diffusion restriction in the left centrum semiovale consistent with a lacunar infarct.
Supplementary data
Top row: Axial imaging (initial to latest follow-up, left to right) shows multiple subcortical and white matter T2 signal hyperintensities in the superior frontal and parietal lobes, which show improvement over time. Bottom row—left: fluid attenuated inversion recovery (FLAIR) imaging show multiple subcortical white matter signal hyperintensities in the superior frontal lobes in addition to signal hyperintensities along the corticospinal tracts bilaterally, in the left insula and in the right side of the pons. Bottom row—middle and right: Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) map, respectively, show a small focus of diffusion restriction (high signal on DWI, low signal on ADC map) in the left centrum semiovale in keeping with a small infarct (arrow).
We went on to perform an extensive panel of investigations (table 2), which identified an elevated urine protein: creatinine ratio, elevated urinary electrolytes and an elevated random troponin without a dynamic rise. Extended vasculitis screen, including cryoglobulins, was negative. HBV serology was positive, showing acute active infection with a high viral load of 17 300 000 copies IU/mL (table 3).
Results from extended autoimmune, hypertension and vasculitis screen
| Investigation | Result | Reference range |
| Lactate dehydrogenase (LDH) | 471 µ/L | 0–250 |
| Troponin | 79 ng/L | 0–14 |
| Anti-myelin oligodendrocyte glycoprotein (MOG) | Negative | |
| Anti-aquaporin 4 antibody | Negative | |
| Paraneoplastic antibodies | Negative | |
| Aldosterone/renin ratio | 0 | <80 |
| Complement C4 | 0.21 g/L | 0.18–0.58 |
| Complement C3 | 1.47 g/L | 0.70–1.70 |
| Cryoglobulins | Not detected after 72 hours | |
| Antinuclear antibodies | Negative | |
| Cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) | Negative | |
| perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) | Negative | |
| Anti-cyclic citrullinated peptide | Negative | |
| Extractable nuclear antigen antibodies | Negative | |
| Serum osmolality | 279 mOsm/kg | 275–295 |
| Urine sodium | 32 mmol/L | <20 |
| Urine osmolality | 157 mOsm/kg | 50–850 |
Virology results including hepatitis B serology
| Hepatitis B sAg | Positive |
| Hepatitis B core Ab | Positive |
| Hepatitis B core IgM | Weakly positive |
| Hepatitis B eAb | Negative |
| Hepatitis B eAg | Positive |
| Hepatitis B viral load | 173 000 000 copies IU/mL |
| Hepatitis C Ab | Negative |
| HIV Ag/Ab | Negative |
| Cytomegalovirus (CMV) IgM | Negative |
| CMV IgG | Negative |
| Epstein-Barr Virus viral capsid antigen (EBV VCA) IgM | Negative |
| EBV VCA IgG | Positive |
| Toxoplasma IgM | Negative |
| Toxoplasma IgG | Negative |
| Syphilis | Negative |
A CT angiogram of the thorax, abdomen and pelvis was performed and showed multiple small intrarenal aneurysms (figure 2). The portal venous phase scan of the abdomen showed bilateral wedge-shaped low attenuation areas in both kidneys in keeping with multiple bilateral renal infarcts.
Left: Coronal maximum intensity projection (MIP) image of a CT angiogram of the abdomen shows multiple small intrarenal aneurysms (example arrowed) as well as wedge shaped areas of hypoenhancement. Right: Coronal image of the portal venous phase scan of the abdomen confirming multiple wedge-shaped hypoenhancing areas in both kidneys in keeping with bilateral renal infarcts (example arrowed).
Investigations
Full blood count on admission demonstrated significantly elevated WCC with a neutrophilia. This was accompanied by an elevated CRP and ESR. Liver enzymes were also elevated. Renal function tests were normal with low potassium and sodium.
Extended screen demonstrated no evidence of autoimmune or paraneoplastic encephalitis and extended vasculitic screen was negative. Of note, LDH and troponin were elevated. Investigations for hyponatraemia identified raised urinary sodium in the context of normal serum osmolality. This was felt to be secondary to excess renal losses.
HBV serology results demonstrated chronic active infection with a high viral load. There was no evidence antibodies to surface or e-antigens signalling the patient has not yet seroconverted. There was evidence of previous EBV infection and no evidence of additional viral infections.
Treatment
Based on these findings, a diagnosis of PAN was made; in accordance with the 2012 Revised International Chapel Hill Consensus Criteria.1 It was felt that his initial presentation of seizures was secondary to a posterior reversible leukoencephalopathy (PRES) resulting from his renal involvement. The patient was given antiviral treatment with tenofovir and given pulsed intravenous methylprednisolone 1 g for 3 days, followed by a tapering dose of oral prednisolone. Further immunosuppression with cyclophosphamide was avoided due to active HBV infection, but could be considered if his symptoms persist following seroconversion.
Outcome and follow-up
Follow-up imaging at 4 months showed improvement in multiple lesions with resolution of some lesions. There was no pathological enhancement following the administration of intravenous gadolinium. A whole-spine MRI was also performed and showed normal appearances with no cord signal abnormality or pathological enhancement. Repeat serology has demonstrated significant improvement of viral load at 11 311 IU/mL. The patient remains on tenofovir.
Discussion
Background
PAN is a medium-vessel and small-vessel necrotising arteritis that is characterised by the absence of glomerulonephritis or a positive ANCA.2 3 Estimated incidence in Europe is 0–1.6 per million per year, with it becoming increasingly uncommon in the developed world.2 The pathophysiology of PAN remains largely unknown, with the majority of cases described as idiopathic. A small proportion is associated with an HBV infection. HBV-associated PAN usually occurs within the first 4 months of infection and has been postulated to be secondary to immune complex deposition. This mechanism has been disputed by some due to the absence of glomerulonephritis. A mixed inflammatory vessel wall infiltrate and fibrinoid necrosis is seen on histopathology, with a predilection for arterial branch points. This process leads to microaneurysm formation, thrombosis and tissue ischaemia. Biopsy of affected tissues can be a useful aid but is not specific. Alternatively, angiographic findings demonstrating microaneurysms, typically 1–5 mm in diameter, coexisting with stenotic lesions can be supportive.2 4
High-dose immunosuppression with corticosteroids and cyclophosphomide, is often required in patients with PAN-associated end-organ involvement.2 Commonly patients will need prolonged courses to avoid relapse. Management of PAN-associated with HBV differs in that focus of treatment is on achieving seroconversion, which is associated with complete remission and almost 0% risk of relapse. Extended course of corticosteroids in this group has been associated with failure to seroconvert and increased risk of fulminant liver failure. This has led to some using regular courses of plasma exchange to avoid this.5
Clinical presentation of PAN is variable,2 but the peripheral nervous system is commonly involved in up to 50%–75% and is often the initial presenting feature.6 7 Inflammatory infiltrate into the vasa narvorum leads to ischaemia and commonly results in a mononeuritis multiplex, most commonly involve both motor and sensory nerves.8 With disease progression, this can evolve into a more confluent distal symmetric sensorimotor neuropathy.8–10 More rarely, a symmetrical axonal sensorimotor is observed from the outset as in presented case. In addition, a variant of PAN exclusively affecting the peripheral nervous system has been observed in some.10
Renal and gastrointestinal manifestations occur at a high frequency.2 Renal involvement with multiple intrarenal aneurysms and resultant infarction is the most common manifestation.11 12 Renal hypoperfusion and infarction results in activation of the Renin–Angiotensin–Aldosterone System leading to hypertension.2 With renal disease, hypertension usually develops quickly.11 Proteinuria is often seen but with relatively preserved renal function. Gastrointestinal involvement can be severe in the form of pancreatitis or gastrointestinal haemorrhage or mesenteric ischaemia.2
Central nervous system involvement
Central nervous system (CNS) involvement is much rarer than peripheral; approximately seen in 2%–10% of patients; but, when present, is associated with a poor prognosis.7 The most frequently described CNS manifestation is a diffuse encephalopathy.6 PRES is associated with various autoimmune diseases, including PAN, which has been previously described in a small number of cases.13–16 The distribution of signal abnormalities seen in our case were consistent with the two primary patterns described in PRES.17 18 Navinan et al reported a case of PAN-associated PRES in a woman in her 20s presenting with seizures and visual disturbance on a background of known young-onset hypertension.14 Further case reports by Arai et al 15 and Stanzani et al 16 propose PAN-associated PRES as the underlying the aetiology in patients presenting with PRES. There is some doubt about the diagnosis of PAN in these latter two cases. The case by Arai et al had a positive p-ANCA and Stanzani’s patient had positive type 2 cyroglobulins. However, both teams felt that PAN was the most likely unifying diagnosis. All three cases exhibited complete clinical and radiological resolution of PRES, suggesting that the natural history is the same in PAN-associated PRES.
Importantly, stroke is a common CNS manifestation in PAN, reported to occur in 13%–17%.6 19 The majority of insults are lacunar infarcts secondary to deep vessel thrombotic microangiopathy. Incidence is highest in 6 months following initial presentation of PAN and is not related to disease activity. Postulated mechanisms include accelerated atherosclerosis and increased production of thromboxane A2 leading to platelet aggregation.19 The latter was proposed to result from an observed association between corticosteroid treatment induction and stroke. Despite this observation, there is no current guidance as to whether antiplatelets should be initiated as primary prevention in patients with PAN on corticosteroid treatment.
There have been a few cases of biopsy-confirmed cerebral vasculitis in patients with PAN, but these were prior to the revised diagnostic criteria and discovery of ANCA.20 Despite systemic microaneurysms and vessel stenosis being virtually pathognomonic of PAN, these are not usually seen within the cerebral vasculature,7 though there are isolated case reports.21
Finally, there are a few case reports in the literature proposing other CNS manifestations of PAN, but these associations are not confirmed and there is diagnostic doubt around PAN in all. These include a case of bilateral optic neuropathy,22 a patient presenting with pachymeningitis23 and a woman in her 30s with a 20-year history in keeping with clinical and radiological appearances of relapsing-remitting multiple sclerosis.24
Conclusions
Given the rarity of PAN it is difficult to accurately depict the range of potential neurological manifestations or the risk of developing CNS complications. Nevertheless, our case clearly demonstrates why it is important to be aware of these presentations and have a high index of suspicion. The majority of cases described in the literature are patients with pre-existing PAN who developed secondary neurological complications. Our case differs in that the initial presentation was with central neurological manifestations. We therefore wish to raise awareness of the importance of systemic screening in young patients with uncontrolled hypertension and PRES. The threshold for testing for HBV infection should be low in these patients. Furthermore, the presence of proteinuria should prompt consideration of renal angiogram where there is no clear explanation.
Learning points
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Polyarteritis nodosa is a rare but important differential in patients with multisystem involvement and positive hepatitis B (HBV) serology.
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A high index of suspicion, and a low threshold for systemic screening, should be taken when managing young patients with posterior reversible leukoencephalopathy syndrome and unexplained severe hypertension.
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Screening for HBV should be considered in patients presenting with severe hypertension in absence of an alternative cause.
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The presence of proteinuria should prompt investigation for a renal cause of hypertension, even in the absence of impaired creatinine clearance. Renal angiographic imaging should be considered in the diagnostic workup where initial screening is negative.
Ethics statements
Patient consent for publication
Footnotes
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Contributors RH wrote the initial draft of the manuscript and the literature review. MN summarised the neurophysiology results and performed a literature search and review of the peripheral nerve manifestations. MN also provided additional contributions with editions to subsequent drafts. AB reviewed and analysed all imaging, created the corresponding figures and summarised the imaging with corresponding literature review. RH provided the main contribution to subsequent editions of the manuscript and formatting as well as the submission process. SA was the responsible clinician for the patient during their admission. SA was the principal author to proof read and edit the manuscript.
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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.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
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Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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References
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