SHORT COMMUNICATION

Cerebral vasospasm in acute porphyria

P. Olivier , L. Defreyne and D. Hemelsoet
, D. Van Melkebeke, P.-J. Honore

Ghent University Hospital, Ghent, Belgium

Keywords: Background and purpose: Porphyrias are a group of inherited metabolic disor-

EUROPEAN JOURNAL OF NEUROLOGY

acute porphyria,
vasospasm
Received 2 February 2017
Accepted 22 May 2017
European Journal of
Neurology 2017, 24:
1183–1187
doi:10.1111/ene.13347
ders resulting from a specific deficiency along the pathway of haem biosynthe-
sis. A clinical classification distinguishes acute from non-acute porphyrias
considering the occurrence of life-threatening neurovisceral attacks, presenting
with abdominal pain, neuropsychiatric disturbance and neuropathy. Vaso-
spasm is a very rare complication that can occur in all major types of acute
porphyria.
Methods: We describe a porphyric crisis with vasospasm in a woman with
previously undiagnosed acute porphyria. Furthermore we performed a sys-
tematic review by searching the electronic database Pubmed/MEDLINE
for additional data in published studies of vasospasm in acute porphyria.
Results: Overall, 9 case reports reporting on 11 patients who suffered
vasospasm during an exacerbation of acute porphyria were identified. All
of the reported patients were women and the mean age was 29.4 years.
When brain MRI was performed, T2-hyperintense lesions, consistent with
ischaemic changes, were observed in most patients (10/11, 91%). Although
the genetic pathogenesis of the disease is well understood, the precise mech-
anisms to explain neurologic involvement in acute porphyria remain
unclear.
Conclusion: Acute porphyria is an unusual and rare cause of vasospasm.
However, considering porphyria in patients with unexplained cerebral vaso-
spasm, especially in women of childbearing age, is crucial given the severity of
possible complications and the available treatment options.

neuropsychiatric disturbance, abdominal pain and a

Introduction
Porphyrias are predominantly inherited metabolic
disorders, resulting from a specific deficiency of one
of the eight enzymes along the pathway of haem
biosynthesis. A clinical classification distinguishes
acute from non-acute porphyrias, considering the
potential occurrence of life-threatening acute neuro-
visceral attacks. The acute porphyrias are further
classified into acute intermittent porphyria (AIP),
variegate porphyria (VP), hereditary coproporphyria
(HCP) and d-aminolevulinic acid dehydratase
(ALAD) deficiency porphyria [1]. An acute por-
phyric attack typically presents with a triad of
Correspondence: P. Olivier, Ghent University Hospital,
De Pintelaan 185, 9000 Ghent, Belgium (tel.: 09 332 21 11; fax 09
332 38 00; e-mail: pieter.olivier@ugent.be).
motor-predominant neuropathy, but a variety of
symptoms can occur.
Materials and methods
We present a case of vasospasm secondary to an exa-
cerbation of AIP and a literature review.
Two reviewers (P.O. and D.H.) performed an inde-
pendent PUBMED/MEDLINE search of relevant stu-
dies written in English and published before December
2016. The following key words were used in relevant
combinations: “acute intermittent porphyria”, “acute
porphyria”, “vasospasm” and “stroke”. The search
was restricted to articles on vasospasm in acute por-
phyria. Full-text versions of published reports were
obtained and the references were searched for addi-
tional studies.

© 2017 EAN 1183

1184 P. OLIVIER ET AL.
Figure 1 Left: MRI-TOF shows generalized vasospasm of the posterior circulation. Middle: Conventional angiography of the left ver-
tebral artery shows narrowing of the basilar and posterior cerebral circulation. Right: Follow-up MRI, 3 years after initial complaints,
shows T2-weighted hyperintensities in both occipital lobes, marking old infarction and gliosis.
Results
Case
A 43-year-old woman presented with colicky abdomi-
nal pain, following a viral syndrome. Due to her
medical history of ectopic pregnancy, dysmenorrhoea
and presumed – but never confirmed – endometriosis,
she was admitted to the department of gynaecology.
Diagnostic laparoscopy, gastroscopy and colonoscopy
showed no cause for the abdominal pain. Postopera-
tively she developed malignant hypertension
(SBP > 200 mmHg). Brain computed tomography
(CT) showed no abnormalities. Because no apparent
cause was found, abdominal complaints were attribu-
ted to pseudo-obstructive colon or menorrhagia and
the patient was discharged with antihypertensive
treatment.
A few days later she presented at our hospital with
confusion, vision loss and vertigo. Laboratory findings
showed hyponatraemia [132 mmol/L (136–145)] and
negative urinary toxicological screening. Initial brain
magnetic resonance imaging (MRI) revealed bilateral
occipital hyperintense lesions on T2-weighted images.
Time-of-flight (TOF) 3D-angiography showed bila-
teral generalized vasospasm of the great arteries, pre-
dominantly of both posterior cerebral arteries (PCA)
with secondary brain infarction (Fig 1). Vasospasm
was confirmed with cerebral digital subtraction
angiography (DSA). Considering the history of unex-
plained abdominal pain episodes, screening for por-
phyria was performed. Urinary porphobilinogen
(PBG) screening was positive and further analysis
showed elevated levels of coproporphyrins [172 lg/
24h (0–60)], uroporphyrins [29 lg/24h (0–20)] and d-
aminolevulinic acid [69 lmol/L (<35)]. Despite a nega-
tive family history of porphyria, molecular analysis of
the porphobilinogen deaminase gene revealed a patho-
genic missense mutation (c.517C>T, p.Arg173Trp),
confirming a diagnosis of AIP [2].
The patient was treated with saline infusion and
intravenous human haemin. Within the next days the
colicky abdominal pain regressed and her mental state
ameliorated. Although her visual acuity initially
improved, it never fully recovered. During 3 years of
follow-up, she has only been readmitted once with a
stress-induced exacerbation of AIP without cerebro-
vascular involvement. Symptoms resolved quickly with
intravenous haemin and supportive treatment.
Literature review
The PUBMED search yielded 11 articles, of which 9
relevant, reporting on 11 patients with suspected
vasospasm secondary to an exacerbation of acute por-
phyria. The gold standard for diagnosing cerebral
vasospasm is cerebral angiography. Hence we discri-
minate between patients with probable vasospasm
(n = 8), when DSA was not performed or reported,
and patients with confirmed vasospasm (n = 3), when
cerebral vasospasm was confirmed with DSA. Patient
characteristics are detailed in Table 1.
Discussion
The porphyrias are a group of rare metabolic dis-
orders that are underdiagnosed, mostly due to their
low prevalence and often aspecific symptoms that may
© 2017 EAN
 Table 1 Characteristics of acute porphyria patients with probable or confirmed vasospasm

Porphyria Etiologic and

Study Sex Age classification Main symptoms Hypertension Serum sodium Treatment exacerbating factors Reference

© 2017 EAN
Probable vasospasm
CW. Lai et al. F 21 AIP Abdominal pain, constipation, Yes Hyponatraemia Supportive therapy Family history of 19
vision loss and paraplegia porphyria
P. King et al. F 20 AIP Abdominal pain, seizure, Yes Hyponatraemia Supportive and haem Post-operatively 20
confusion and visual (128 mmol/L) therapy (gastrostomy)
hallucinations
H. Kupferschmidt F 35 AIP Vision loss, seizures and – – Supportive and haem Family history of 21
et al. tetraplegia therapy porphyria
F 32 AIP Abdominal pain, vision loss, Yes – Supportive and haem Post-operatively
seizures and tetraplegia therapy (hysterectomy)
S. Susa et al. F 29 AIP Abdominal pain, vomiting, No Hyponatraemia Carbohydrate loading, – 22
constipation, lethargy, (94 mmol/L) supportive and haem
seizures and tetraplegia therapy
A. Soysal et al. F 22 AIP Abdominal pain, confusion, Yes – Carbohydrate loading Post-operatively 23
visual hallucinations, and supportive therapy (appendectomy)
seizures and tetraplegia
F 22 AIP Abdominal pain, nausea, No Hyponatraemia Carbohydrate loading Post-operatively
vomiting and confusion and supportive therapy (appendectomy) and
exposure to
porphyrinogcnic drugs
S. Mullin et al. F 29 HCP Abdominal pain, vomiting, – Hyponatraemia Removal of implanted Exposure to 24
seizures, confusion and (121 mmol/L, oestrogen and porphyrinogeni c
tetraplegia 137–144) progesterone drugs (rifampicin)
contraceptive device
and haem therapy
Confirmed vasospasm
K. Black et al. F 33 AIP Abdominal pain, seizure – Hyponatraemia Haem therapy Family history of 5
and confusion (121 mmol/L) porphyria and
post-operatively
(appendectomy)
B. Maramattom et al. F 18 AIP Abdominal pain, Yes Hyponatraemia Supportive and – 6
constipation, confusion, haem therapy
visual hallucination
and seizures
A. Webb et al. F 49 VP Abdominal pain, vomiting, – Hyponatraemia Supportive therapy Exposure to 7
lethargy and confusion (117 mmol/L) porphyrinogenic
drugs (trimethoprim)
Current report F 43 AIP Abdominal pain, vertigo, Yes Hyponatraemia Supportive and Viral infection
VASOSPASM IN PORPHYRIA

vision loss and confusion (132 mmol/L, haem therapy

136–144)

F indicates female; AIP, acute intermittent porphyria; HCP, hereditary coproporphyria; VP, variegate porphyria.
1185
1186 P. OLIVIER ET AL.
hamper early recognition and diagnosis. Despite their
rarity, the genetic basis of these conditions is well-
defined but the precise etiopathogenetic mechanisms
are not yet well understood. Attacks can be precipi-
tated by several triggers, like porphyrinogenic drugs,
alcohol intake, infections or psychological stress [3,4].
Our literature review identified 9 reports presenting
11 patients who were suspected of suffering vasospasm
during an exacerbation of acute porphyria. Diagnosis
of acute porphyria was always made based upon
qualitative or quantitative analysis of urinary PBG.
Two-thirds (8/12) of patients were treated with intra-
venous haemin.
Brain MRI abnormalities during an acute porphyric
attack were observed in most (10/11; 91%) patients.
Black et al. [5] were first to report transient cerebral
vasospasm in porphyria, demonstrated by both MR
angiography and conventional angiography. Proof of
cerebral vasospasm was further applied by Maramat-
tom et al. [6], who correlated reversible MRI lesions
with vasospasm demonstrated by cerebral angiogra-
phy. Webb et al. [7] were first to demonstrate reversi-
ble cerebral vasoconstriction by cerebral angiography,
despite normal brain MRI, in a case of VP. Our case
report is fourth to confirm vasospasm in acute por-
phyria but documents the most elaborate cerebral
vasospasm of all reported cases. In all other patients
T2 hyperintense lesions were reported, consistent with
ischaemic changes, but DSA to confirm vasospasm
was not performed or reported. Vasospasm in por-
phyria tends to be predominant in the posterior circu-
lation. Similar findings may be encountered in
eclampsia and posterior reversible encephalopathy
syndrome where an increased sensitivity or altered
vascular reactivity to circulating pressor agents (e.g.
prostaglandins), endothelial dysfunction and impaired
autoregulation of the posterior circulation compared
to the anterior circulation have been suggested to
explain this posterior predominance [8,9]. In few
patients the lesions observed on MRI during por-
phyric crises resolved or reduced in the months fol-
lowing recovery, suggesting an initial degree of
reversibility and possible vasospasm. Remarkably, the
complication seems to be exclusive to young females
(100% women, mean age 29.4 years), which may be
explained by a key role for sex hormones in the
expression and exacerbation of acute porphyria [10].
Oestrogen and progesterone have been shown to
increase porphyrin precursors by inducing the first
enzyme (5-aminolevulinic acid (ALA) sythase) of the
haem biosynthesis [11].
The leading hypothesis to explain the neurovisceral
symptoms in acute porphyria is that porphyric
metabolites such as ALA, that are overproduced by
the liver, are neurotoxic [3,4,12]. Vasospasm has now
been reported in all major types of acute porphyria.
This association of elevated levels of porphyrins and
vasospasm begs the question whether or not there is a
causative relationship between acute porphyric attacks
and vasospasm. One suggested mechanism is a defi-
ciency of nitric oxide synthase (NOS), a haem-depen-
dent isoenzyme catalyzing the production of nitric
oxide (NO). NO is a key molecule of vascular home-
ostasis by regulating smooth muscle tone and platelet
activation. Reductions in NO plasma levels with sub-
sequent reduction in guanylate cyclase activity lead
to platelet activation/aggregation as well as smooth
muscle dystonias, resulting in hypertension, gastroin-
testinal contractions and erectile dysfunction [13–16].
During a porphyric crisis, impaired supply of NOS
owing to insufficient haem substrate could reduce
available NO, causing vasoconstriction [12]. Pro-
longed cerebral vasoconstriction could provoke the
ischaemic brain lesions but prolonged mesenteric
vasospasm and gastrointestinal contractions could
also explain the colicky abdominal pain during a cri-
sis of acute porphyria. Few cases have been described
where intestinal angina was suggested as a cause of
abdominal pain during an exacerbation of acute
porphyria [17,18].
Conclusion
Acute porphyria is an unusual and rare cause of
vasospasm. However, considering porphyria in
patients with unexplained cerebral vasospasm, espe-
cially in women of childbearing age, is crucial given
the severity of possible complications and the avai-
lable treatment options.
Disclosure of conflict of interest
The authors declare no financial or other conflicts of
interest.
References
1. Lip GY, McColl KE, Moore MR. The acute porphyr-
ias. Br J Clin Pract 1993; 47: 38–43.
2. Pischik E, Mehtala S, Kauppinen R. Nine mutations
including three novel mutations among Russian patients
with acute intermittent porphyria. Hum Mutat 2005; 26:
496.
3. Puy H, Gouya L, Deybach JC. Porphyrias. Lancet 2010;
375: 924–937.
4. Stein PE, Badminton MN, Rees DC. Update review of
the acute porphyrias. Br J Haematol 2017; 176: 527–
538.
5. Black KS, Mirsky P, Kalina P, et al. Angiographic
demonstration of reversible cerebral vasospasm in
© 2017 EAN

porphyric encephalopathy. AJNR Am J Neuroradiol
1995; 16: 1650–1652.
6. Maramattom BV, Zaldivar RA, Glynn SM, Eggers SD,
Wijdicks EF. Acute intermittent porphyria presenting as
a diffuse encephalopathy. Ann Neurol 2005; 57: 581–584.
7. Webb AJ, Ingale H, Irani SR, Hu MT. Acute variegate
porphyria presenting with reversible cerebral vasocon-
striction. Clin Neurol Neurosurg 2016; 146: 102–104.
8. Hinchey J, Chaves C, Appignani B, et al. A reversible
posterior leukoencephalopathy syndrome. N Engl J Med
1996; 334: 494–500.
9. Stevens CJ, Heran MK. The many faces of posterior
reversible encephalopathy syndrome. Br J Radiol 1020;
2012: 1566–1575.
10. Andersson C, Innala E, Backstrom T. Acute intermittent
porphyria in women: clinical expression, use and experience
of exogenous sex hormones. A population-based study in
northern Sweden. J Intern Med 2003; 254: 176–183.
11. Granick S. The induction in vitro of the synthesis of
delta-aminolevulinic acid synthetase in chemical por-
phyria: a response to certain drugs, sex hormones, and
foreign chemicals. J Biol Chem 1966; 241: 1359–1375.
12. Meyer UA, Schuurmans MM, Lindberg RL. Acute por-
phyrias: pathogenesis of neurological manifestations.
Semin Liver Dis 1998; 18: 43–52.
13. Rother RP, Bell L, Hillmen P, Gladwin MT. The clini-
cal sequelae of intravascular hemolysis and extracellular
plasma hemoglobin: a novel mechanism of human dis-
ease. JAMA 2005; 293: 1653–1662.
14. Cannon RO 3rd, Schechter AN, Panza JA, et al. Effects
of inhaled nitric oxide on regional blood flow are consis-
tent with intravascular nitric oxide delivery. J Clin Invest
2001; 108: 279–287.
15. Schafer A, Wiesmann F, Neubauer S, Eigenthaler M,
Bauersachs J, Channon KM. Rapid regulation of
© 2017 EAN
VASOSPASM IN PORPHYRIA 1187
platelet activation in vivo by nitric oxide. Circulation
2004; 109: 1819–1822.
16. Vanhoutte PM, Zhao Y, Xu A, Leung SW. Thirty years
of saying no: sources, fate, actions, and misfortunes of
the endothelium-derived vasodilator mediator. Circ Res
2016; 119: 375–396.
17. Lithner F. Could attacks of abdominal pain in cases of
acute intermittent porphyria be due to intestinal angina?
J Intern Med 2000; 247: 407–409.
18. Budhoo MR, Mitchell S, Eddlestone J, MacLennan I.
Sickle cell trait and acute intermittent porphyria leading
to small bowel infarction. J R Coll Surg Edinb 1999; 44:
130–131.
19. Lai CW, Hung TP, Lin WS. Blindness of cerebral origin
in acute intermittent porphyria. Report of a case and
postmortem examination. Arch Neurol 1977; 34: 310–
312.
20. King PH, Bragdon AC. MRI reveals multiple reversible
cerebral lesions in an attack of acute intermittent por-
phyria. Neurology 1991; 41: 1300–1302.
21. Kupferschmidt H, Bont A, Schnorf H, et al. Transient
cortical blindness and bioccipital brain lesions in two
patients with acute intermittent porphyria. Ann Intern
Med 1995; 123: 598–600.
22. Susa S, Daimon M, Morita Y, et al. Acute intermittent
porphyria with central pontine myelinolysis and cortical
laminar necrosis. Neuroradiology 1999; 41: 835–839.
23. Soysal A, Dogan P, Dayan C, Caliskan BG, Arpaci B.
Reversible MRI findings of porphyric encephalopathy.
A report of two cases. Neuroradiol J 2008; 21: 655–
659.
24. Mullin S, Platts A, Randhawa K, Watts P. Cerebral
vasospasm and anterior circulation stroke secondary to
an exacerbation of hereditary corproporphyria. Pract
Neurol 2012; 12: 384–387.