Neuro-ophthalmic manifestations of Polyarteritis Nodosa
PAN is a medium vessel vasculitis that may affect the eye and the CNS. Ocular findings may include inflammatory episcleritis, scleritis, keratitis, retinal vascular occlusions, and ocular ischemic syndrome. Retinal (e.g., cotton wool patches) and choroidal (e.g., choriocapillaris) ischemia may be present and fluorescein angiogram may be helpful. Neuro-ophthalmic manifestations from CNS vasculitis may include afferent (optic neuropathy, homonymous hemianopsia) or efferent presentations depending on the location of the inflammatory process. Ophthalmologists should be aware of the clinical manifestations of PAN and consider the diagnosis in patients with vasculitis.
Polyarteritis nodosa (PAN) is a rare multisystem vasculitis of medium-sized arteries . Arteries in any part of the body may be affected by PAN including the cardiovascular, nervous, and Gastrointestinal systems. The renal arteries are the most affected arteries in PAN. Weakening central nervous system (CNS) arteries may result in aneurysms and have a higher likelihood of rupture, leading to hemorrhagic infarcts. Arteries may also become stenotic due to chronic inflammation resulting in thrombosis. Intermixed aneurysms and thrombosis are classic findings on angiography in patients with PAN [1,2,3].
The annual incidence and prevalence of biopsy proven PAN were 0.7 and 6.3 per 100,000, respectively . The incidence of PAN with ocular involvement is 10 to 20 percent and most often presents with vasculitis of the retinal and choroidal arteries . PAN has a male predominance and typically presents in aged patients 40 to 60. It is often associated with Hepatitis B, and HBV-PAN has a frequency of 7 to 10 percent . PAN occurs most frequently in areas that are endemic for HBV . There is overlapping classification systems of PAN between the American College of Rheumatology (ACR), Chapel Hill Consensus Conference (CHCC), and the Lanham criteria which influences incidence and prevalence . There are ongoing efforts to develop a validated algorithm with high sensitivity and specificity for differentiating between various forms of microscopic vasculitis using the previous criteria sequentially .
The pathophysiology of PAN is not completely understood. It is believed to be an underlying genetic predisposition that is triggered by an environmental stimulus. In a subset of patients, PAN is associated with a mutation in “cat eye syndrome” critical region protein 1 (CECR1) which leads to a deficiency of adenosine deaminase-2 (DADA2) . DADA2-PAN presents at a younger age, with most patients coming to clinical attention before age 10. This mutation is also associated with more severe symptoms and a higher rate of stroke .
The exact etiology of the inflammatory cascade in PAN is unknown. However, it is assumed that an inciting triggering event of the inflammatory cascade results in endothelial damage of medium sized arteries. Endothelial dysfunction may be due to direct damage or be cytokine or antibody mediated process, the latter of which is supported by high levels of IL-2, IL-8, and interferon-gamma documented in PAN . This inflammatory milieu recruits’ leukocytes to the arterial media with subsequent disruption of the internal elastic lamina leading to thickening of the intima, edema, or thrombosis eventually causing arterial occlusion [5,7].
PAN is associated with hepatitis B (HBV) or hepatitis C (HCV) infections, with the onset of PAN most commonly occurring within 6 months of HBV infection [1,5,8]. Serum immune-complex levels suggest that HBV-PAN is mediated by the deposition of immune complexes and consumption of complement leading to arterial inflammation . A temporal relationship between HBV and PAN, with both having decreased in incidence since the implementation of widespread vaccination against HBV, which accounts for the frequency of HBV-PAN falling from 36% to 7% since the 1970s [5,8]. However, HBV or HCV serologies are not positive in all patients, nor are immune complexes isolated frequently in cases that are not associated with HBV. Therefore, their role in the pathogenesis of idiopathic PAN remains unclear . However, the positive response to immunosuppressive therapies, may support an immunologic underlying mechanism .
PAN is a multi-system disease, and initially constitutional, nonspecific symptoms may occur, including fever, sweats, weight loss, and severe muscle/joint ache and pain. These symptoms may present over several weeks to months and can spread to any part of the body. Interestingly, testicular pain is a highly suggestive complaint in the setting of these constitutional symptoms for PAN. Another common feature of PAN is hypertension [1,2].
The illness script for PAN would be a previously healthy young man who presents with hypertension, neuropathy, and rash after insidious onset weight loss, myalgia, and abdominal pain. A review of symptoms does not typically reveal any lung complaints.
|Peripheral Nerves||Peripheral neuropathy, mononeuritis multiplex||50-70|
|Kidney||Renal artery vasculitis with subsequent proteinuria, hypertension, and renal failure||70|
|Skin||Palpable purpura, ulcers, livedo nodules, gangrene||50|
|Gut||Abdominal pain, nausea/vomiting, gastrointestinal bleeding, hemorrhage, bowel infarction, and perforation are rare but may be serious.||30-35|
|Heart||Myocardial infarction and congestive heart failure||Low|
|CNS||Seizures and stroke||Low|
|Genitals||Testicular infarction, Unilateral orchitis||20|
|Eye||Retinal, choroidal, or optic nerve hemorrhage or ischemia||Low|
The physical exam in PAN can be unremarkable and patients may present as other more common conditions such as essential hypertension. Peripheral neuropathy is often the earliest and most common symptom, present in 75% of cases [2,5]. Abdominal tenderness, rash (e.g., lower extremity purpura)[1,3,7], or murmur due to left heart failure may be present .
Up to 10%-20% of PAN patients have ophthalmic or neuro-ophthalmic findings. Branch and central retinal artery occlusion, ischemic retinopathy, proptosis, papilledema, papillitis, anterior or posterior ischemic optic neuropathies, episcleritis, scleritis, interstitial keratitis, and peripheral ulcerative keratitis have all been described in PAN [4,7,8,9,10,11]. Choroidal vasculitis is the most common ocular finding and multifocal acute ischemia of the choriocapillaris is highly suggestive of vasculitis including PAN in young patients [4, 9,10,11]. Retinal cotton wool spots may be seen secondary to ischemia from retinal arteriole obstruction [1,7]. Neuro-ophthalmic manifestations of CNS vasculitis may be present depending on the location of the ischemia (e.g. homonymous hemianopsia).
PAN is a clinical diagnosis supported by laboratory, imaging, and pathology. In individuals with high suspicion of PAN, a biopsy of an artery may be performed [1,2]. The predictive value of a biopsy from any give tissue is often directly proportional to the clinical signs and symptoms of involvement .
Biopsy specimens in PAN may show a patchy, pan-mural fibrinoid necrosis of a medium artery with predominant neutrophil inflammation [1,2,5]. Chronic lesions may show lymphocytes and macrophages with angiogenesis. The combination of necrosis and fibrosis, and juxtaposed microaneurysm and thrombosis are typical of PAN. Intimal hyperplasia is typically present due to vascular remodeling [1,2].
Evidence of vascular inflammation is seen in 80% of symptomatic patients found to have PAN with combined muscle and nerve biopsy, compared to 65% in muscle biopsies alone . Providers may consider prioritizing biopsies from easily accessible areas such as skin, muscle, or sural nerve. Biopsies of the testicle, kidney, or liver can be reserved for when these organs are symptomatic, and all primary biopsies have returned negative in the setting of high clinical suspicion .
There is no single confirmatory lab test for PAN. A common constellation of lab findings includes elevated ESR, CRP in the setting of chronic anemia, thrombocytosis, and mild leukocytosis. Serologies for HBV, HIV, HCV may be positive. ANCA and cryoglobulinemia and evaluation for alternative forms of vasculitis are usually negative [1,3]. In the case of ocular PAN, fluorescein angiography may demonstrate multifocal acute ischemia of the choriocapillaris .
Magnetic resonance imaging (MRI) of the head may show findings suggestive for vasculitis including multiple disseminated lesions across grey and white matter of different ages located in the cortical and subcortical regions. Concurring small hemorrhagic lesions and multiple infarcts that are present across gadolinium enhancement and FLAIR can raise suspicion for PAN . MR angiogram (MRA) or computed tomography (CT) angiography (CTA) may reveal multiple coexisting stenotic lesions with microaneurysms found predominantly in the mesenteric, renal, or hepatic arteries [1,2]. Visceral angiography of abdominal, renal, or cardiac arteries can be performed if biopsies are negative or if the symptoms are primarily visceral. Classic findings include multiple 1–5 mm saccular or fusiform arterial microaneurysms intermixed with stenotic lesions. These findings, in the proper clinical picture, can be diagnostic even in the absence of histologic findings [2,3].
A positive ANCA makes PAN much less likely. Other findings that make PAN less likely include the presences of cryoglobulinemia, glomerulonephritis, small vessel involvement, asthma, hypereosinophilia, or alveolar hemorrhage. If granulomas or giant cells are present on biopsy, other etiologies are more likely than PAN to be the cause of the vasculitis .
- Vasculitides: Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (eGPA), Microscopic Polyangiitis, Mixed cryoglobulinemia
- Infectious: Subacute endocarditis, HBV, HCV, HIV, EBV, Parvovivus B19
- Inflammatory: systemic lupus erythematosus
- Iatrogenic (e.g., side effect of ergot use)
- Connective tissue disorder: Fibromuscular dysplasia
- Neoplastic: Left atrial myxoma
The management of PAN is determined by context, with treatment being directed at the comorbidity if present . For HBV-PAN: antivirals directed at HBV and plasma exchange may help to clear immune complexes [1,3,8]. For DADA2-PAN: symptomatic management is with tumor necrosis factor (TNF) inhibitors . In other cases of PAN, steroids and cyclophosphamide are the cornerstones of treatment [2,7]. In most cases of PAN, it is appropriate to induce remission with 1 to 3 intravenous pulses of cyclophosphamide in combination with steroids. Once remission is achieved, maintenance therapy with methotrexate or azathioprine can be considered. Mycophenolate mofetil is the third-line maintenance therapy in those with contraindications to methotrexate or azathioprine .
The Factor Five Score (FFS) is a prognostic framework developed for PAN. The FFS is based on renal insufficiency defined as creatininemia >150 μmol/L; cardiomyopathy; GI manifestations; age greater than 65 years old; and of ear, nose, and throat involvement. One point is given for each finding present [1,3,12]. The FFS has significant prognostic value with FFS at diagnosis = 0, 1, or >/= 2, correlating to a 5-year mortality of 9%, 21%, or 40% respectively [1,3,12]. Untreated PAN has a 5-year survival rate of 13%. The 5-year survival rate with treatment on average is over 80% [1,10]. PAN recurrence has been noted in 10-40% of cases but this risk can be lowered with careful monitoring of new symptoms and regular lab testing. HBV-PAN has a poor prognosis with a 5-year survival of 35% . ENT manifestations are associated with a better prognosis .
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