Vascular Endothelial Growth Factor and Neuropathy

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: VEGF is elevated in the serum and plays a role in the pathogenesis of neuropathies associated with monoclonal gammopathies.

Source: Briani C, Fabrizi GM, Ruggero S, et al. Vascular endothelial growth factor helps differentiate neuropathies in rare plasma cell dyscrasias. Muscle Nerve http://www.ncbi.nlm.nih.gov/pubmed/21082697

Can measurement of serum vascular endothelial growth factor (sVEGF) aid in the diagnosis of neuropathy and predict disease course? sVEGF is increased in POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes), less so in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (in spite of a similar demyelinating pathology), and is not significantly elevated in multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). sVEGF levels in amyloidosis have not been systematically studied.

To evaluate sVEGF levels in amyloidosis and its response to treatment, 25 patients (18 men and 7 women, mean age 66.8 years) with biopsy-proven amyloidosis were evaluated, including 17 (10 men and 7 women) with primary amyloidosis (AL-A), 7 men with transthyretin amyloidosis (TTR-A), and 1 man with senile systemic (wild-type TTR) amyloidosis. TTR-A was diagnosed by molecular analysis and confirmed with sural nerve biopsy. TTR-positive immuno-histochemistry confirmed the diagnosis of senile (wild-type TTR) amyloidosis, whereas primary AL-A was diagnosed by the presence of monoclonal light chain protein in urine or serum, abnormal serum free light chain ratio, or monoclonal plasma cells in bone marrow with negative immuno-histochemistry for TTR and absence of TTR mutation on DNA analysis. Seven TTR-A patients and 3 AL-A patients had an axonal sensory polyneuropathy, and 6 TTR-A patients had autonomic polyneuropathy. sVEGF levels were measured by ELISA (enzyme-linked immunosorbent assay). Statistical analysis included the Mann-Whitney U-test and the Kruskal-Wallis test, with significance set at P < 0.05.

sVEGF levels were significantly lower in patients with AL-A (median 420 pg/ml) and TTR-A (median 179 pg/ml) compared to those with POEMS syndrome (median 2580 pg/ml). Multiple myeloma median sVEGF level, 260 pg/ml, was also significantly lower than seen in POEMS syndrome. Presence or absence of neuropathy in AL-A did not affect sVEGF level and it did not vary with disease status or therapeutic response. sVEGF measurement can assist in differentiating POEMS from CIDP, MGUS-neuropathy, and amyloidosis, and should be measured in patients with plasma cell dyscrasias and neuropathy.

Commentary

Angiogenesis and lymphangiogenesis, critical processes during embryogenesis, tissue growth, wound healing, and disease pathogenesis, are regulated via activation of three receptor tyrosine kinases, VEGFR-1, 2, and 3, by vascular endothelial growth factors (VEGFs). Vascular permeability and vessel dilatation are regulated by these receptors, and VEGF also has, both in vivo and in vitro, direct trophic effects on neuronal cells. Demyelinating neuropathy in POEMS may result from blood-nerve barrier dysfunction mediated by increased levels of circulating VEGF. Yet the mechanism for POEMS remains a puzzle. It is unclear why lambda light chain predominates in POEMS, as opposed to kappa light chain that predominates in MGUS, though both present similar demyelinating neuropathies. Vascular leakage is suggested by the presence of hepatomegaly and splenomegaly in POEMS, attributed to elevated circulating VEGF levels, but other factors, including interleukin-1β, interleukin-6, and tumor necrosis factor α, are also elevated in POEMS and may play a role in pathogenesis.