Clinical/Scientific
Notes

N. Chatterjee, MD
K. Domoto-Reilly, MD
P.E. Fecci, MD, PhD
L.H. Schwamm, MD
A.B. Singhal, MD

LICORICE-ASSOCIATED REVERSIBLE
CEREBRAL VASOCONSTRICTION WITH PRES

The reversible cerebral vasoconstriction syndromes
(RCVS) are a group of conditions characterized by
reversible segmental constriction and dilatation of cerebral arteries, typically associated with recurrent
thunderclap headaches, and often complicated by
ischemic or hemorrhagic strokes.1,2 The posterior reversible encephalopathy syndrome (PRES) is another
clinical–radiologic syndrome characterized by reversible, posterior-predominant brain edema, usually associated with headache, altered mental status,
seizures, and visual symptoms.3 These entities may
share pathophysiologic elements.1-3 We report a patient with RCVS-PRES overlap syndrome associated
with excessive licorice consumption. Knowledge of
the pharmacologic effects of licorice may offer insights into the pathophysiology of RCVS and PRES.
Case report. A 49-year-old woman developed a severe headache reaching peak intensity within seconds. Similar thunderclap headaches recurred twice
over the next 2 days and were associated with intermittent loss of central vision. On day 4 after symptom onset, she developed a generalized seizure. She
was hypertensive (230/130 mm Hg), and her neurologic examination showed hyperreflexia. Urinalysis
and toxicology screen were unremarkable. Brain
MRI showed vasogenic edema in the bilateral
parieto-occipital regions (figure, A), with underlying
regions of brain hemorrhage detected on gradient
echo sequences (not shown). Head CT angiogram
(CTA) showed smooth, segmental narrowing of
multiple intracranial arteries (figure, B), which was
confirmed on gold standard transfemoral cerebral angiography (figure, C). Oral nimodipine was initiated.
On day 5, her headache recurred. Repeat CTA revealed worsening cerebral vasoconstriction.
A diagnostic evaluation for etiologies of secondary
hypertension showed elevated morning serum cortisol
(12.3 ␮g/dL, normal ⬍10 ␮g/dL), elevated urine free
cortisol (260.4 mcg per 24 hours, normal 17– 47 mcg
per 24 hours), serum renin below the reference range
(⬍0.6 ng/mL), and serum aldosterone below the reference range (⬍21 ng/dL). Urinary metanephrines were

normal. She was not taking any medications known to
perturb the renal-angiotensin-aldosterone system. She
denied taking any vasoconstrictive medications, illicit
drugs, or over-the-counter agents. However, the medical team discovered a package of licorice at her bedside.
Further inquiry revealed that she had been eating 1
pound per day for 4 months. She was instructed to discontinue licorice consumption.
By hospital day 8, the headaches had resolved, repeat
morning cortisol level was normal at 5 ␮g/dL, and 24hour urine free cortisol level had decreased to 61 mcg
per 24 hours. Nimodipine was transitioned to longacting oral verapamil before discharge. At 1- and
2-month follow-up visits, she was noted to be asymptomatic; blood pressure and neurologic examination
were normal. Repeat tests showed normal serum and
24-hour urine free cortisol levels. CT/CTA performed
after 3 months showed resolution of the lobar hemorrhages, edema, and vasoconstriction (figure, D).
Discussion. The onset of symptoms with recurrent
thunderclap headaches, bilateral lobar hemorrhages,
and reversible cerebral angiographic abnormalities
are consistent with RCVS. However, the patient also
had severe transient hypertension and reversible
brain edema, consistent with PRES. This case exemplifies an increasingly recognized overlap between
these 2 syndromes, and supports the hypothesis that
they share pathophysiologic elements.1-3
Excessive licorice consumption was the only identified precipitating factor. Licorice is derived from the
root of the herb Glyzerrhiza glabra. The biologically active component, glycyrrhizic acid, inhibits 11␤hydroxysteroid dehydrogenase (11␤-HSD). Excessive
ingestion leads to a glucocorticoid and functional mineralocorticoid excess in the setting of low serum renin
and aldosterone. This syndrome of apparent mineralocorticoid excess is characterized by metabolic alkalosis,
hypokalemia, volume expansion, and hypertension.4
Inhibition of 11␤-HSD via licorice in rat models is associated with hypertension, potentiation of vasoconstrictor activation, impaired vasorelaxation, and
endothelial damage.5 These actions might explain the
occurrence of PRES in our patient. Licorice derivatives,
including glycyrrhetinic acid and carbenoxolone, have
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Figure

Neuroimaging at admission and 3-month follow-up

(A) Brain MRI, axial fluid-attenuated inversion recovery image showing bilateral parieto-occipital vasogenic edema (arrows). These
lesions did not show restricted diffusion and are consistent with the posterior reversible encephalopathy syndrome. The hyperintense
dots in the sulcal spaces (arrowheads) suggest the presence of dilated cortical surface arteries and have been reported in patients
with the reversible cerebral vasoconstriction syndrome. (B) Head CT angiogram, sagittal maximum intensity projection images, and (C)
transfemoral cerebral angiogram show smooth, segmental narrowing and dilatation of multiple cerebral arteries (arrows). (D)
Follow-up head CT angiogram performed after 3 months shows reversal of the cerebral vascular abnormalities.

been shown to directly and indirectly enhance vasoconstriction within vascular smooth muscle.6 Furthermore,
in vitro evidence of serotonin reuptake inhibition by
licorice suggests a potential serotonin-mediated cerebral
vasoconstrictive effect.7 RCVS has been previously associated with serotonin-enhancing drugs.1,2
Despite the relatively long (4 months) interval between the start of excessive licorice consumption and
onset of symptoms, the effects of licorice intake described above support a mechanistic relationship between licorice consumption and RCVS/PRES.
Similarly, other drugs (e.g., sumatriptan, chemotherapeutic agents) are implicated in RCVS/PRES based on
their mechanism of action and do not always have a
close temporal relationship. These drugs may lower the
threshold for developing RCVS/PRES or act in concert
with other factors that ultimately precipitate these cerebrovascular syndromes.
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This case suggests that RCVS and PRES represent
syndromes along a spectrum of vascular dysregulation and endothelial dysfunction. Hormonal and serotonergic mechanisms appear to be important. In
addition to prescription and illicit drugs, overexposure to common dietary products such as licorice
may be a risk factor and should be explicitly reviewed
in the medical history.
From the Departments of Neurology (N.C., K.D.R., L.H.S.,
A.B.S.) and Neurosurgery (P.E.F.), Massachusetts General Hospital, Boston; and Department of Neurology (K.D.R.), Brigham and
Women’s Hospital, Boston, MA.
Disclosure: Dr. Chatterjee reports no disclosures. Dr. Domoto-Reilly
has received research support from the Alzheimer’s Association
(IIRG-09-133560). Dr. Fecci has served as a consultant for Campbell Alliance. Dr. Schwamm serves as chair of the American Heart
Association GWTG Steering Committee; serves on scientific advisory
boards for CoAxia, Inc., Phreesia, and Lundbeck Inc.; serves on the
editorial board of Neurocritical Care; may accrue revenue on a
patent re: Imaging system for obtaining quantitative perfusion indi-

ces; his wife receives royalties from publishing Obstetric Anesthesia
(Cambridge Pocket Clinicians, 2007); serves/has served as a consultant to CryoCath® Technologies Inc., Research Triangle Inc., Massachusetts Department of Public Health, and the Canadian Stroke
Network; and receives research support from Lundbeck Inc., the
NIH (NINDS P50 NS051343-01 [Coinvestigator], NINDSU01
NS052220 IMS-3 [Site PI], NCRR 1 UL 1 RR025758-01 [CRC
Staff]), and the Department of Health and Human Services (CDC
5U13 DP001176-02 [PI]); and has provided expert medical opinions in malpractice lawsuits [re: stroke treatment and prevention].
Dr. Singhal has received research support from the NIH/NINDS
(R01NS051412 [PI], P50 NS051343 [PI, Project 1], P01
NS035611 [Coinvestigator], R01NS059775 [Coinvestigator],
R01NS38477 [Coinvestigator], and R21NS061119 [Coinvestigator]); has provided expert medical opinions in malpractice lawsuits;
and his wife is an employee of, and owns stock and stock options in,
Vertex Pharmaceuticals.

1.

2.

3.

4.

5.

Received March 17, 2010. Accepted in final form June 17, 2010.
Address correspondence and reprint requests to Dr. Kimiko DomotoReilly, Massachusetts General Hospital, Department of Neurology,
WACC 835, 15 Parkman Street, Boston, MA 02114; KDomotoReilly@partners.org
Copyright © 2010 by AAN Enterprises, Inc.

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Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB.
Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007;146:34 – 44.
Ducros A, Boukobza M, Porcher R, Sarov M, Valade D,
Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome: a prospective series of
67 patients. Brain 2007;130:3091–3101.
Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. Am J Neuroradiol 2008;29:447– 455.
White PC, Mune T, Agarwal AK. 11␤-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev 1997;18:135–156.
Ruschitzka F, Quaschning T, Noll G, et al. Endothelin 1
type a receptor antagonism prevents vascular dysfunction
and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide. Circulation
2001;103:3129 –3135.
Dobbins KR, Saul RF. Transient visual loss after licorice
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Ofir R, Tamir S, Khatib S, Vaya J. Inhibition of serotonin
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