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Candelaresi et al. Vessel Plus 2018;2:11 I http://dx.doi.org/10.20517/2574-1209.2018.09 Page 3 of 4

the brainstem. Persistent disability and life-threatening complications such as severe cerebral hemorrhage,
cerebellar herniation and refractory status epilepticus have been described. Likewise, an increasing number
of different inciting entities have been identified, such as haemodialysis, glomerulopathies and other
autoimmune disorders, sepsis, neoplastic disease, and drugs. Among the latter, increasing attention is
being directed to antineoplastic therapies. The syndrome has been described in association with induction
chemotherapy in childhood acute lymphoblastic leukaemia, specifically with oxaliplatin, L-asparaginase,
gemcitabine, bevacizumab, and sunitinib. Multiple myeloma, a neoplastic proliferation of an aberrant
colony of plasma cells, has historically been difficult to treat with remission rates as low as 5%. Recent
research identified the ubiquitin-proteasome pathway as a potential target for chemotherapeutic agents as
its inhibition blocks cellular growth and division, ultimately leading to a proapoptotic state. Bortezomib is
a potent, specific and reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, leading
to the inhibition of NF-kB. NF-kB acts as a transcription factor, turning on genes implicated in cell growth,
surface molecules expression and vascular endothelial growth factor (VEGF)-mediated angiogenesis. By
inhibiting NF-kB, bortezomib leads to the inhibition of cell growth, tumor-associated angiogenesis, and
the promotion of apoptosis. The most common adverse events reported in patients receiving bortezomib
include thrombocytopenia, fatigue, peripheral neuropathy and neutropenia. To date, only 6 cases of
bortezomib-induced PRES have been reported. The exact mechanisms of vasogenic brain oedema in such
patients have not been completely delineated. In all cases, imaging studies show prominent posterior poles
involvement. Local more sparse posterior circulation sympathetic innervation, compared to that in the
anterior circulation, may explain the increased susceptibility of the posterior circulation to haemodynamic
[8]
stress. Furthermore, as it happens in cases of granulomatous vasculitis and capillary leak syndrome ,
endothelial cell damage and perivascular lymphomononuclear infiltration may further contribute to the
development of brain oedema. There have been several cases of anti-VEGF agent induced PRES reported so
[9]
far . Bortezomib induces decreased transcription of cellular growth factors, including VEGF. Therefore,
bortezomib might indirectly alter the integrity of the vascular endothelium through the NF-kB pathway.

In our case, as in other 4/6 cases of bortezomib-induced PRES, only a small increase in blood pressure levels
has been detected, suggesting that in bortezomib-treated patients hypertension might be a contributor but
not the originator of the cascade leading to brain oedema.

[10]
The concomitant use of melphalan is to be considered. In a case series , 9/451 of high-dose melphalan
treated patients developed acute encephalopathy. Eight of them developed changes in mental status ranging
from drowsiness and confusion to loss of consciousness, while one patient had tonic-clonic seizures. Only
one patient had imaging abnormalities compatible with posterior reversible encephalopathy syndrome.
Melphalan-induced encephalopathy is usually associated with renal impairment. It is not the case in our
patient, who was treated with low-dose melphalan and did not experience renal impairment. However, we
cannot completely rule out a minor contribution of melphalan in the development of PRES. Our patient
received a short course of dexamethasone, which should theoretically improve vasogenic edema, even
though robust evidence for their use is lacking.

In conclusion, PRES must be considered when a bortezomib-treated patient develops altered mental status
associated with other neurological signs, such as visual alterations or language impairment as in our case,
even in the absence of an excessive rise in blood pressure levels, particularly if concomitant potentially
neurotoxic drugs are used. Brain MRI scan is the preferred imaging modality to diagnose vasogenic oedema,
and posterior poles seem to show a particular susceptibility.

Prompt withdrawal of the offending drug and control of blood pressure are associated with neurological
recovery in all cases of bortezomib-induced PRES reported so far.