Cerebral vasospasm and anterior circulation stroke secondary to an exacerbation of hereditary corproporphyria
- 1Department of Clinical Neurosciences, Royal Free Hampstead NHS Trust, London, UK
- 2Department of Neuroradiology, Royal Free Hampstead NHS Trust, London, UK
- 3North West Thames Regional Genetics Centre, Northwick Park Hospital, London, UK
- Correspondence to Dr Stephen Mullin, Department of Clinical Neurosciences, Royal Free Hampstead NHS Trust, Pond Street, London NW3 2GQ, UK;
- Received 27 March 2012
- Accepted 7 June 2012
Acute porphyria, though rare, has well-known neurological sequelae. Vasospasm rarely complicates exacerbations of acute intermittent porphyria, but has not been previously reported in hereditary coproporphyria. We describe a porphyric crisis in a woman with previously undiagnosed hereditary coproporphyria (triggered by rifampicin), leading to vasospasm and stroke.
A 29-year-old Pakistani woman presented with abdominal pain, nausea and vomiting, 2 days after having taken rifampicin as prophylaxis following tuberculosis exposure. She developed three self-terminating generalised seizures, treated with gabapentin and clobazam. Investigations showed that she was hyponatraemic (serum sodium 121 mmol/l (137–144)). Urinary porphobilinogen was 25.5 mol/mmol creatinine (reference range <1.5) and aminolevulinic acid was 30.4 mol/mmol creatinine (reference Range <3.8), consistent with active acute porphyria. Her faecal porphyrin excretion level was also high, giving a porphyrin pattern consistent with hereditary corproporphyria. Subsequent genetic analysis confirmed this, with a previously described mutation in the coproporphyrinogen oxidase (CPOX) gene (542G>T, p.Trp181Leu in exon 1).1 She started a standard course of intravenous haem arginate therapy and an implanted oestrogen and progesterone contraceptive device was removed. One day later, she developed confusion, incompetent swallow and a predominately right-sided paroxysmal onset asymmetrical tetraparesis. At this stage, she was transferred to our care.
MR scan of brain showed asymmetrical signal change and restricted diffusivity (figures 1 and 2). There was extensive T2 hyperintensity within the left posterior frontal lobe and parietal lobe involving the cortex and adjacent subcortical white matter, with medial extension into the corpus callosum. There was also reduced diffusivity bilaterally in the frontal cortical white matter and in the right posterior frontal subcortical white matter, compatible with an acute ischaemic stroke. MR angiogram showed severe stenoses of the proximal anterior cerebral vessels (circulation) extending from the supraclinoid segment of the internal carotid arteries to involve both anterior (A1) and middle cerebral (M1) arteries. The posterior circulation was spared (figure 3). Repeat imaging 2 days later showed improved diameter in the anterior cerebral arteries with an otherwise unchanged pattern of vessel narrowing and diffusivity (figure 4).
Nerve conduction studies were normal. Cerebrospinal fluid was colourless, with normal opening pressure, protein and glucose content, and there were no cells or organisms. She received intensive physiotherapy and was fed continuously via a nasogastric tube until her swallow became normal. Subsequent urinary porphyrin precursor measurements showed complete resolution of the porphyric crisis. Four months later, she could walk independently with a stick.
Genetic analysis and family history
There was no family history of porphyria or of porphyric-like episodes, although the family pedigree was highly consanguineous. Despite this, her presentation and genetic result were consistent with autosomal-dominant hereditary coproporphyria. We are continuing to investigate and counsel family members.
Hereditary coproporphyria is an autosomal dominant acute hepatic porphyria with incomplete penetrance and is due to partial deficiency of CPOX enzyme activity, caused by mutations in the CPOX gene. Acute attacks in susceptible patients involve increased demand for hepatic haem-dependent enzymes, such as cytochrome P450; these are required to metabolise medication such as the rifampicin. Where reduced enzyme activity becomes rate limiting, the increased haem requirement cannot be met and leads to upregulation of the pathway, with a consequent large surge in δ-aminolevulinic acid (ALA), porphobilinogen and coproporphyrin, released from the liver. Further precipitants include starvation and other inducers of the P450 system, as well as factors that directly activate ALA synthase, the rate-limiting step. Hereditary coproporphyria classically presents in adults with abdominal pain without peritonism, nausea, vomiting, tachycardia, hypertension, a predominately motor neuropathy and neuropsychiatric disturbance. Hyponatraemia with a picture of the syndrome of inappropriate antidiuretic hormone secretion is often a feature and some also suffer bullous photosensitivity. Females are more likely to be affected than males, and symptoms may be exacerbated by endogenous or prescribed sex hormones, particularly progesterone. The acute management is with intravenous haem arginate, a high carbohydrate diet and avoidance of known precipitants.2 The presentation here was that of non-specific abdominal symptoms with vomiting and seizures (which may have been secondary to cerebral ischaemia or hyponatraemia or both) but without other neurological features—in particular neuropathy. The temporal relationship between taking rifampicin and the symptom onset suggests that this precipitated this attack; however, an oestrogen/progesterone contraceptive device probably contributed, particularly as its removal may have caused a progesterone surge. Treatment of her seizures was problematic given the spectrum of interactions between first-line anticonvulsants (in particular phenytoin, valproate and carbamazepine) and the P450 system. Similarly, given her suspected latent tuberculosis infection, she will probably need future treatment with careful consideration of the effect of antituberculosis medications on hepatic haem biosynthesis.
Recognising porphyria as the cause for her presentation with abdominal pain, nausea and seizures with associate hyponatraemia was essential for her appropriate management. In addition, this is the first reported case of acute cerebral vasospasm in an attack of hereditary coproporphyria. Vasospasm is a rare but acknowledged complication of acute intermittent porphyria, the more common acute hepatic porphyria caused by porphobilinogen deaminase deficiency. Most of these cases presented with reversible posterior circulation vasospasm: in one case this was accompanied by an acute encephalopathy.3–5 Although there was some resolution in the anterior cerebral arteries in this case, the stenosis was largely unchanged at 2 days and spared the posterior circulation. Further imaging may have revealed resolution over a longer time frame.
The mode of action of vasospasm in acute porphyria remains unclear; however, the pathogenesis of acute attacks is believed to be identical. A suggested cause is that there is deficiency of nitric oxide synthase, a haem-dependent isoenzyme catalyzing the conversion of-arginine to the vasodilator, nitric oxide. In porphyric crisis, impaired supply of this enzyme owing to insufficient haem substrate could, in theory, reduce available nitric oxide, causing vasoconstriction.6 When the liver from a patient with active acute intermittent porphyria was transplanted, it caused acute porphyria in the recipient.7 This suggests that toxic liver metabolites are the main cause of neurological sequelae in acute porphyrias, although their ability to cross the blood–brain barrier remains to be proven.6
We have described a patient with a crisis of hereditary coproporphyria, precipitated by rifampicin who suffered a novel complication of anterior circulation vasospasm and stroke. The diagnosis and appropriate management depended on rapid clinical suspicion of the diagnosis in the context of paroxysmal onset nausea, abdominal pain and hyponatraemia following rifimpicin treatment. Prompt administration of haem arginate, together with appropriate and continuous nutrition via a nasogastric tube and removal of the rifampicin trigger probably reduced the vasospasm and so limited the extent of resultant disability. The neurological sequelae of acute porphyrias are highly variable and often begin with non-specific systemic symptoms. The limited penetrance of these predominately autosomal dominant conditions means that there is often no family history. Clinicians should consider a porphyria in atypical acute neurological presentations, especially when drugs that interact with the P450 system could be a trigger.
Acute porphyrias classically present with nausea and severe abdominal pain, without peritonism.
Hyponatraemia from the syndrome of inappropriate antidiuretic hormone secretion is common in porphyria.
Starvation and exposure to P450-inducing drugs and hormones commonly trigger porphyric crises.
The most common neurological manifestation is a predominantly motor neuropathy, which may be symmetrical, assymetrical or focal.
There may be an autonomic neuropathy leading to tachycardia, excessive sweating, bladder dysfunction and hypertension.
There may be central manifestations, including agitation, paranoia, confusion, encephalopathy and occasionally seizures.
Vasospasm is a rare but well-described complication of acute porphyria.
Although predominately inherited in an autosomal-dominant fashion, the limited penetrance of porphyria means there may be no relevant family history.
We thank Dr Mike Badminton, Department of Medical Biochemistry, University Hospital of Wales and Dr Emma Wakeling, North West Thames Regional Genetics Centre, Northwick Park Hospital for their invaluable advice and assistance. We also thank Dr John Rohrer and Dr Tom Wellings, Department of Clinical Neurosciences, Royal Free Hospital, London, UK.
Contributors SM and AP drafted and revised the manuscript. KR and PW revised the manuscript.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed. This paper was reviewed by George Elder, Cardiff, UK.