Abstract
Postpartum cerebral angiopathy (PCA) is an infrequent cerebral vasoconstriction syndrome, occurring within 30 days of delivery. It can affect large, medium and small arteries of the brain (1). The patients present with refractory headache, focal neurological deficits, and sometimes seizures. Although benign in most cases, PCA can result in ischaemic and haemorrhagic stroke, and even fatal cases have been reported (1). Affected cerebral blood vessels occasionally show signs of inflammation on histological investigation. These inflammatory changes seem to be mainly chronic and secondary to prolonged vasoconstriction, suggesting functional vasoconstriction as the primary pathophysiological process (1–3). So far, treatment with oral nimodipine, magnesium sulphate, steroids and cyclophosphamide has been reported with varying success (4), but established therapy is non-existent. Here, we report a patient with clinically progressive PCA who was successfully treated with intra-arterial and intravenous nimodipine.
Case report
A previously healthy 32-year-old patient, gravida two, para two, presented with persisting severe global headache 4 days after uncomplicated spontaneous vaginal delivery of a healthy child. The headache had begun abruptly, developing over a few minutes. Neurological examination on admission revealed left-sided homonymous hemianopia. Shortly after admission, the patient had two generalized tonic-clonic seizures with deviation of gaze to the right. Eclampsia and haemolysis, elevated liver enzymes, and low platelets syndrome were ruled out: liver function tests were normal and neither haemolysis nor thrombocytopenia was detected. Proteinuria was not present and the patient did not suffer from pedal oedema. Blood pressure on admission was 140/70 mmHg. The patient did not complain of nausea, vomiting, photophobia or phonophobia. She had not previously suffered from headaches. Diffusion weighted magnetic resonance imaging (MRI) showed bilateral frontal and parieto-occipital ischaemic lesions (Fig. 1a). Cerebrospinal fluid was without pathologic findings (1 cell/μl, protein 37 mg/dl, glucose 56 mg/dl). The patient was treated with nimodipine (60 mg six times per day p.o.) and phenytoin (100 mg three times per day p.o.). Headache intensities slightly declined and new seizures were not observed. Blood pressure was stable at 120–130/70 mmHg. However, on day 3 after admission, she developed weakness of the right arm. MRI revealed new cortical ischaemic lesions (Fig. 1b), a magnetic resonance angiogram (MRA) showed vasospasms of both anterior cerebral (ACA) and both middle cerebral arteries (MCA). Vasoconstriction was more severe in the left cerebral arteries, which correlated to the localization of the aggravation of cerebral ischaemia. Digital subtraction angiography (DSA) was performed which confirmed the MRA findings (Fig. 2a,c). Using a 5F-Envoy catheter, 2 mg of nimodipine was administered into the left proximal internal carotid artery for 1 h. Shortly thereafter, cerebral vasoconstrictions diminished (Fig. 2b,d). The paresis of the right arm resolved completely and the headaches improved. Significant changes of blood pressure were not observed. Due to the obvious success of the intra-arterial treatment, nimodipine therapy was continued intravenously (2 mg/h) for seven and orally (60 mg six times per day) for eight further days. Control MRI 7 and 15 days after admission showed no new ischaemic lesions (Fig. 1c,d), and the vasospasms had resolved. The patient was discharged without focal neurological deficits.
Diffusion weighted (a–c) and fluid-attenuated inversion recovery (FLAIR) (d) magnetic resonance imaging (MRI). On admission (a), left parieto-occipital hyperintensities are found on diffusion weighted MRI, suggestive of ischaemia. Three days later (b), additional diffusion restrictions are visible in the white matter of the left hemisphere indicating new ischaemic infarcts. Fifteen days after admission (c) and after intra-arterial and intravenous therapy with nimodipine, lesions have not progressed. Accordingly, the FLAIR sequence (d) shows a manifest ischaemic lesion comparable in size to the diffusion weighted hyperintensities 3 (b) and 15 days after admission (c).
Digital subtraction angiography (DSA) reveals narrowing of multiple branches of the left (a) and right (c) middle cerebral artery (MCA) and anterior cerebral artery (ACA) with significant stenosis of the left M1 segment (a, insert). After infusion of 2 mg nimodipine into the left internal carotid artery for 1 h, stenosis of the M1 segment (b, insert) and narrowing of peripheral MCA and ACA branches on the left side lessen (b). Furthermore, narrowing of MCA and ACA branches on the contralateral right side has diminished (d).
Discussion
Patients with PCA usually present with headaches and sometimes seizures and/or fluctuating motor and sensory deficits (1). The bilateral headaches are typically severe with a reported duration of 5 min to 2 weeks (5). In PCA, neuroimaging of cerebral blood vessels by DSA reveals narrowing of one or more intracranial arteries, which is known to be located bilaterally in approximately two-thirds of patients. In severe cases, these lead to cerebral infarctions (1). Accordingly, the patient presented here showed all typical features of PCA. Four days after delivery, she suffered from (i) headaches; (ii) focal neurological deficits; (iii) seizures; and (iv) constriction of both MCA and ACA, documented by DSA. Other possible neurological complications of the postpartum period such as postpartum eclampsia (6), sinus or venous thrombosis (7) or haemorrhage (8) were excluded.
Currently, the best therapeutic option seems to be the use of calcium channel blockers (9). Small case series on its use have been studied in patients with reversible cerebral vasoconstriction syndrome (RCVS). This is a unifying term for disorders characterized by reversible segmental and multifocal vasoconstriction of cerebral arteries, severe headaches with or without focal neurological deficits or seizures. Besides PCA, RCVS also includes benign acute cerebral angiopathy, Call–Fleming syndrome, benign angiopathy of the central nervous system (CNS), CNS pseudovasculitis, drug-induced cerebral angiopathy, and thunderclap headache (5). Recently, Ducros et al. have reported 67 patients with RCVS. In that study, 61 patients received treatment with oral (n = 50) or intravenous (n = 11) nimodipine. Of these, 59% were symptom-free after nimodipine treatment was started, 41% had recurrent headaches, and only 8% developed transient ischaemic attacks or stroke (5). However, RCVS is considered a benign disease with spontaneous reversibility in most cases (10). Thus, a possible benefit of nimodipine cannot be concluded from the study (5). Here, we were able to document angiographically a dilating effect of nimodipine on the vasoconstriction in PCA. Interestingly, intra-arterial nimodipine also had an instantaneous dilating effect on contralateral cerebral arteries not directly exposed to intra-arterial nimodipine. This indicated a strong systemic nimodipine effect. Therefore, intravenous treatment was continued for another week and no new symptoms such as headaches or paresis were observed. In conclusion, the instant dilating nimodipine effect that correlated with clinical improvement is strongly suggestive of a benefit of intra-arterial/intravenous therapy with nimodipine in PCA. However, since PCA is usually benign and most patients recover spontaneously after development of transient neurological deficits, it cannot be confirmed with absolute certainty that the persistent clinical improvement of our patient was attributable to the therapy with nimodipine.
Worsening of neurological symptoms during PCA is alarming because in a few cases, residual neurological deficits and death have been reported (1). Our patient deteriorated under conservative therapy, developing new paresis of the right arm that was associated with strong generalized vasospasms and progression of cerebral ischaemia. This directed us to invasive therapy. So far, only a few patients have been reported with intra-arterial treatment after worsening of PCA. These patients received intracranial balloon angioplasty, which led to persistent dilation of the vessel (11, 12). The advantage of intra-arterial nimodipine application is the possibility of also treating distal vasospasms and not only localized constrictions of larger arteries. At present, only small case series and reports on intra-arterial use of nimodipine in vasospasms after subarachnoid haemorrhage have been published, but there are no studies that have investigated intra-arterial nimodipine therapy in RCVS (13). However, in cases with PCA (and possibly also other subtypes of RCVS) with worsening of the disease under full conservative therapy, its use should be considered.
One major side-effect of intra-arterial and intravenous nimodipine therapy is a drop in systemic arterial blood pressure (14, 15). This is crucial in patients who are suffering from cerebral vasospasms. Thus, intra-arterial blood pressure control and quick appropriate treatment are essential during intravascular nimodipine therapy. Furthermore, the procedure carries a certain risk of reperfusion injury. In rare cases this may even lead to intracerebral haemorrhage. Also, general complications of intra-arterial catheterization such as arterial dissection have to be considered. Nimodipine therapy has recently been evaluated in comparison with magnesium sulphate in severe preeclampsia (16). Patients with severe preeclampsia who were treated with nimodipine were more likely to suffer from seizures than those receiving magnesium sulphate, showing the importance of excluding preeclampsia before treatment with nimodipine should be considered. As a matter of course, close surveillance of patients during and after nimodipine therapy is mandatory.
In summary, we report a patient with PCA who benefited from intra-arterial and subsequent intravenous nimodipine therapy after worsening of symptoms under conservative treatment.