Isoflavones and gastrointestinal infection: Two potential triggers for reversible cerebral vasoconstriction syndrome

Abstract

Background

Reversible cerebral vasoconstriction syndrome (RCVS) is an important differential diagnosis of singular or recurrent thunderclap headache. Prognosis is generally good, however complications of the transient segmental vasospasms of cerebral arteries such as stroke, subarachnoidal hemorrhage and brain edema may worsen the clinical outcome. Although the exact pathomechanism is still unclear, various vasoactive substances and conditions (e.g. post partum) have been identified as triggering RCVS.

Cases

We report on the clinical course and management of two cases of typical RCVS that were associated with two different precipitants previously not described: A gastrointestinal infection and isoflavones, which are phytoestrogens used for menopausal vasomotor symptoms.

Discussion

In the case of gastrointestinal infection, either systemic inflammatory processes might lead to disturbances of vascular tone, or the repetitive vomiting that resembles Valsalva manoeuvers known to trigger RCVS. In the case of isoflavone intake, it may be their estrogenic potential that induces dysregulation of cerebral arteries, a mechanism known from other states of hormonal change such as post-partum angiopathy. However, the association of both precipitating factors with RCVS in our two cases is not a proof for a causal relationship, and there may have been additional potential triggers for RCVS.

Conclusion

In patients with (gastrointestinal) infection and concomitant thunderclap headache, RCVS should be considered as an important differential diagnosis due to its major complications. Since RCVS may be triggered by various vasoactive substances, taking the medical history should always include over-the-counter drugs and dietary supplements (such as the isoflavones) beside the regular medication.

Introduction

Reversible cerebral vasoconstriction syndrome is characterized by singular or recurrent thunderclap headache, multifocal vasoconstriction of cerebral arteries, and subsequently transient or persistent neurological deficits due to subarachnoid/intracerebral hemorrhage or ischemic events (1–3). In contrast to its major differential diagnosis –primary angiitis of the central nervous system (CNS) – RCVS is usually self-limiting within a period of three months and of good prognosis, which is however dependent on the occurrence of vascular complications such as stroke (4,5). The pathophysiology is still unclear, but certainly a transient disturbance of the regulation of cerebral arterial tone must be responsible for the sudden vasoconstriction and vasodilatation of cerebral arteries. This is supported by the identification of typical vasoactive triggers in more than half the cases of RCVS, i.e. sexual activity, physical exertion, stressful or emotional situations, bathing, various Valsalva maneuvers (defecation, coughing, sneezing) as well as vasoactive drugs such as serotonergic antidepressants, triptans, herbal products like licorice and ephedra, corticosteroids and different illicit substances like amphetamines, cocaine and cannabis (3–7).

Here, we report on two cases of RCVS with typical clinical and radiological course, provoked by two independent triggers that have not been associated with RCVS before: a) isoflavones, which are phytoestrogens used as dietary supplements for menopausal vasomotor symptoms, and b) a gastrointestinal infection.

Case 1

A 55-year-old woman working in her garden without heavy physical exercise experienced an acute bifrontal thunderclap headache of maximal intensity. In an outpatient clinic, she was prescribed analgetics and the headaches consecutively remitted within two hours to a bearable level. Back home on Day 2, the acute thunderclap headache recurred and the patient was referred to our hospital. Beside the headaches, she presented with nausea and vomiting. Past medical history was blank. She was not taking any regular medication apart from a dietary supplement for menopausal symptoms that she had started five days before. It contained (per capsule) 50 mg of soybean isoflavones, 50 mg of red clover blossom extract and 300 mg of Mexican wild yam extract. Neurological examination was normal, as were the immediate CT brain scan, CSF analyses and basic laboratory studies. Blood pressure at admission was 150/90 mmHg. Since analgesia with ibuprofen and metamizole did not improve the headaches, the patient was admitted to the neurological ward. She later received an MRI brain scan including MR angiography, revealing a small sulcal subarachnoid hemorrhage over the right parietal lobe and multifocal narrowing of cerebral arteries in a “string of beads” pattern affecting both anterior, middle and posterior cerebral arteries and distal parts of the basilar artery (Figure 1). Stenoses were confirmed by Duplex sonography of the brain-supplying arteries. The patient stopped taking the dietary supplement and received nimodipine 60 mg four-hourly. Headaches subsided over the following two weeks. Blood pressure at discharge was 130/80 mmHg. The MR angiography at a follow-up six weeks later showed complete resolution of the initial multifocal vasoconstriction of cerebral arteries. Consecutively, nimodipine treatment was discontinued and the patient remained free of headaches, as reported at a follow-up examination six months later.

Figure 1.

MR imaging of the brain including MR angiogram in the patient taking isoflavones. (a) Initial T2* weighted image showing convexal subarachnoid hemorrhage over the right parietal lobe . (b) Initial time-of-flight MR angiogram illustrating multifocal narrowing in almost all the intracranial brain supplying arteries (arrows). Note the typical string-of-beads pattern, pronounced in the right anterior cerebral artery. (c) Follow-up MR angiogram six weeks later demonstrating complete resolution of the initial multifocal vasoconstriction.

Case 2

In the morning of Day 1, a 59-year-old woman developed nausea, vomiting, diarrhea and shivering together with febrile temperatures (38.5℃). In the afternoon, she experienced an acute thunderclap headache (“as if my head explodes”), holocephalic with an intensity of 10/10 measured by visual analogue scale (VAS). The headache subsided in the evening but persisted at a lower intensity level (VAS 5/10). Over the following three days, the symptoms of gastrointestinal infection remitted completely whereas headaches persisted at VAS 5-7/10 and were transiently exaggerated by two recurrent attacks of the severe thunderclap headache. Still suffering from moderate headaches, on Day 6 the patient experienced a sudden weakness and numbness of her right arm that completely resolved after 20 minutes. This transient sensory-motor deficit recurred twice within the next 48 hours. After contacting her GP, the patient was admitted to our hospital on Day 9. On admission, she was reporting headaches VAS 6/10. The neurological examination was completely normal, blood pressure within normal limits. Past medical history included diagnosis of arterial hypertension, diabetes mellitus type II, and polymyalgia rheumatica (pANCA and MPO antibodies positive), the latter being treated with prednisolone (10 mg/day) and methotrexate (20 mg/week). CT brain scan and subsequent MRI brain scan revealed convexal subarachnoid haemorrhage (SAH) over the left hemisphere; MR angiography showed multifocal narrowing of the cerebral arteries, most prominently at the distal internal cerebral artery and proximal middle cerebral artery on the left and the distal basilar artery. Basic laboratory studies (especially CRP and blood count) were normal, as were the CSF analyses apart from a few hemosiderophages. The patient received nimodipine 60 mg four-hourly. At discharge on Day 18 after symptom onset, the headaches had completely resolved and no further transient ischemic attacks had recurred.

Discussion

Various precipitants can provoke RCVS (see (4) for an extensive review). However, an infection, like that in our latter patient 2, has not been associated with typical RCVS so far. Only posterior reversible encephalopathy syndrome, a syndrome that shows some overlap with RCVS, has been described in critically-ill patients with septic shock (4,8). Patient 2 clearly had gastroenteritis due to the typical clinical presentation, and the RCVS occurred within a few hours after manifestation of the infection. Moreover, the benign clinical course, laboratory and radiological findings argue against an angiitis of the central nervous system despite her rheumatological past medical history. This patient had additional vasoactive risk factors for RCVS including arterial hypertension, steroids and methotrexate treatment, but it was the acute gastrointestinal infection that eventually precipitated the RCVS. We do not know, however, whether the multifocal vasoconstriction in this RVCS was caused by inflammatory processes at the endothelium of brain-supplying arteries due to the infection itself or as consecutive spasms induced by repetitive heavy vomiting, which would resemble the Valsalva maneuvers known to trigger RCVS (4).

In patient 1, the only identifiable trigger was a dietary supplement that included isoflavones from soybeans and red clover as well as wild yam extract. Isoflavones are yellow plant pigments, produced by higher plants of the Fabaceae family such as soybeans and red clover. They are referred to as phytoestrogens because their chemical structure is related to the human body’s 17β-estradiol, which enables them to act as agonists at estrogen receptors (especially ER- β) in mammals, though with a lower binding affinity (9). Due to their estrogenic effects on the central nervous system and blood vessels, isoflavones are used as dietary supplements for peri- and postmenopausal vasomotor symptoms (e.g. hot flushes), although their efficacy is still questioned while earlier safety concerns have been ruled out by a systematic review of the European Food Safety Authority (10,11). Wild yam extract, the other ingredient of the dietary supplement, contains diosgenin, a phytosteroid with strong structural similarities to progesterone and dehydroepiandosterone (12).

Taking their potential estrogenic and steroidal influence on the vascular system into account, it seems reasonable that an intake of isoflavone and diosgenin may trigger an RCVS, as in our patient 1. Support for this hypothesis comes from a report on RCVS provoked by hormonal ovarian stimulation (13) and from various studies on post-partum RCVS, where fluctuations in concentrations of estrogens and progesterones are assumed to be the major pathophysiological mechanism (3,4,14).

We emphasize that the association of both gastrointestinal infection and isoflavones with RCVS in our two cases is not a proof for an independent and causal relationship. Furthermore, there may have been additional triggers for RCVS in both patients.

We still convey two important conclusions for clinical practice: (1) physicians should explicitly ask their headache patients about dietary supplements, alternative medicine and other drugs obtained over the counter beside the regular medication and (2) RCVS is one important differential diagnosis if headaches occur together with gastrointestinal and other infections, especially when the onset resembles a thunderclap.

Clinical implications

Reversible cerebral vasoconstriction syndrome (RCVS) is an important differential diagnosis of (recurrent) thunderclap headache.

RCVS may be elicited by both a gastrointestinal infection and intake of isoflavones as dietary supplements.

Taking the patient’s medical history should always include dietary supplements and over-the-counter drugs beside the regular medication.