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ReplyCorrespondence

Dr. Varaprasad and Dr. Agrawal reply

IRLAPATI R. VARAPRASAD and SUMEET AGRAWAL
The Journal of Rheumatology April 2012, 39 (4) 871; DOI: https://doi.org/10.3899/jrheum.111483
IRLAPATI R. VARAPRASAD
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SUMEET AGRAWAL
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  • For correspondence: sumeet.drsumeetagrawal@gmail.com
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To the Editor:

It is an interesting proposition made by Dr. Park, et al regarding the pathogenesis of posterior reversible encephalopathy syndrome (PRES) in systemic lupus erythematosus (SLE)1. The report by Dr. Ortiz, et al points to the occurrence of PRES in various autoimmune conditions in which endothelial dysfunction might play a central role2.

Various factors responsible for PRES in SLE include disease activity (mostly with associated nephritis), renal failure, hypertension, and drugs such as cyclophosphamide and steroids3. There are not enough data to understand the exact pathogenesis of PRES but it depends on 2 vital factors, hypertension and endothelial dysfunction, with variable contributions by each4. Severe hypertension can cause endothelial dysfunction and endothelial dysfunction per se can lower the threshold of cerebral autoregulation, deranging the blood-brain barrier and ultimately leading to vasogenic edema, with or without cytotoxic edema, depending on the severity. Immune-mediated endothelial dysfunction may play an important role in normotensive patients with PRES5.

Many molecules are involved at different stages of vasogenic edema, such as vascular endothelial growth factors (VEGF), angiopoietins, aquaporins, and matrix metalloproteinases6. Aquaporin-4 autoimmunity is considered to predispose to PRES in neuromyelitis optica7. Reports of PRES in normotensive patients with thrombotic thrombocytopenic purpura with severe renal involvement also point to endothelial dysfunction and altered cerebral autoregulation. Altered function of P-glycoprotein, an adenosine triphosphate export pump, in proximal convoluted tubules and brain capillaries is implicated8. A similar role may be the cause for PRES in patients with postinfectious glomerulonephritis who have neurological manifestations before nephritis9.

VEGF has an important role in angiogenesis and capillary permeability, and elevated levels are seen in various autoimmune diseases secondary to endothelial activation. Elevated VEGF levels (by inducing nitric oxide synthesis) are required for repair of glomerular endothelium in various nephropathies including lupus nephritis10.

Patients with active lupus have elevated VEGF levels, and postmortem studies in PRES showed VEGF upregulation in the biopsy specimens10,11. But there are reports of occurrences of PRES in patients treated with bevacizumab, an IgG1 monoclonal antibody against VEGF used in the treatment of colorectal and renal cell carcinomas12. VEGF-A and angiopoietin-2 are important in the initial stages of edema, and antagonizing this by VEGF-A receptor chimeric protein and angiopoietin-1 administration in rodent models showed a decrease in edema size13. In contrast, VEGF-B and angiopoietin-1 are important for maintenance of the blood-brain barrier after an initial breach6.

With the available data it is difficult to say whether elevated VEGF levels indicate a cause or a consequence in PRES. An imbalance between various isoforms of VEGF and their receptors may be crucial and accordingly, the targeted therapy might be complex.

REFERENCES

  1. 1.↵
    1. Park SJ,
    2. Pai KS,
    3. Kim JH,
    4. Shin JI
    . Could increased vascular endothelial growth factor induced by interleukin 17 be the cause of posterior reversible encephalopathy syndrome in systemic lupus erythematosus? [letter]. J Rheumatol 2012;39:870.
    OpenUrlFREE Full Text
  2. 2.↵
    1. Ortiz A,
    2. Roverano S,
    3. Paira S
    . Posterior reversible encephalopathy syndrome [letter]. J Rheumatol 2012;39:869–70.
    OpenUrlFREE Full Text
  3. 3.↵
    1. Varaprasad IR,
    2. Agrawal S,
    3. Prabu VN,
    4. Rajasekhar L,
    5. Kanikannan MA,
    6. Narsimulu G
    . Posterior reversible encephalopathy syndrome in systemic lupus erythematosus. J Rheumatol 2011;38:1607–11.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Bartynski WS
    . Posterior reversible encephalopathy syndrome, part 2: Controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol 2008;29:1043–9.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Abbott NJ,
    2. Mendonça LL,
    3. Dolman DE
    . The blood-brain barrier in systemic lupus erythematosus. Lupus 2003;12:908–15.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Nag S,
    2. Manias JL,
    3. Stewart DJ
    . Pathology and new players in the pathogenesis of brain edema. Acta Neuropathol 2009;118:197–217.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Magaña SM,
    2. Matiello M,
    3. Pittock SJ,
    4. McKeon A,
    5. Lennon VA,
    6. Rabinstein AA,
    7. et al.
    Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology 2009;72:712–7.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Burrus TM,
    2. Mandrekar J,
    3. Wijdicks EF,
    4. Rabinstein AA
    . Renal failure and posterior reversible encephalopathy syndrome in patients with thrombotic thrombocytopenic purpura. Arch Neurol 2010;67:831–4.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Aeby A,
    2. David P,
    3. Fricx C,
    4. Jissendi P,
    5. Blecic S,
    6. Van Bogaert P
    . Posterior reversible encephalopathy syndrome revealing acute post-streptococcal glomerulonephritis. J Child Neurol 2006;21:250–1.
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Navarro C,
    2. Candia-Zúñiga L,
    3. Silveira LH,
    4. Ruiz V,
    5. Gaxiola M,
    6. Avila MC,
    7. et al.
    Vascular endothelial growth factor plasma levels in patients with systemic lupus erythematosus and primary antiphospholipid syndrome. Lupus 2002;11:21–4.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Horbinski C,
    2. Bartynski WS,
    3. Carson-Walter E,
    4. Hamilton RL,
    5. Tan HP,
    6. Cheng S
    . Reversible encephalopathy after cardiac transplantation: Histologic evidence of endothelial activation, T-cell specific trafficking, and vascular endothelial growth factor expression. AJNR Am J Neuroradiol 2009;30:588–90.
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Glusker P,
    2. Recht L,
    3. Lane B
    . Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006;354:980–2.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Van Bruggen N,
    2. Thibodeaux H,
    3. Palmer JT,
    4. Lee WP,
    5. Fu L,
    6. Cairns B,
    7. et al.
    VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 1999;104:1613–20.
    OpenUrlCrossRefPubMed
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The Journal of Rheumatology
Vol. 39, Issue 4
1 Apr 2012
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Dr. Varaprasad and Dr. Agrawal reply
IRLAPATI R. VARAPRASAD, SUMEET AGRAWAL
The Journal of Rheumatology Apr 2012, 39 (4) 871; DOI: 10.3899/jrheum.111483
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