A unique case of cabergoline-induced reversible cerebral vasoconstriction

PRACTICAL IMPLICATIONS

Consider RCVS in the differential diagnosis of an acute thunderclap headache on dose escalation of cabergoline as an unrecognized trigger after long-term use.

A 47-year-old right-handed Hispanic man presented to the emergency department reporting the worst headache of life, complicated by emesis with minimal improvement despite ibuprofen. The patient reported numbness in his left hand and face, and transient slurred speech. His blood pressure was 202/101, necessitating admission to neuroscience ICU for IV nicardipine drip and close monitoring. Neurologic examination was normal, lacking meningeal signs and papilledema. Noncontrast CT head demonstrated acute right fronto-parieto-occipital convexity consistent with trace SAH. Brain MRI redemonstrated right SAH and hemispheric leptomeningeal enhancement favored to represent reactive SAH changes. Diffusion-weighted imaging revealed small acute infarcts involving the right lateral occipital, posterior temporal, and parietal lobes. MRA showed high-grade right distal MCA irregular narrowing with concurrent postcontrast vessel wall enhancement (figure 1), raising concern for stenosis, vasospasm, or vasculitis. There was no evidence to suspect cerebral venous thrombosis during the review of venous phase images within MRA study acquisition. Transcranial Doppler was without evidence of vasospasm. Bilateral carotid ultrasound revealed no clinically significant stenosis. Cerebral angiography showed focal stenosis of right MCA, without AVM, aneurysm, or vasculitis (figure 2).

Figure 1. MRI.

(A and B) Coronal and axial views of MRI T1 postcontrast sequence suggestive of associated vessel wall enhancement in the region of right M1 middle cerebral artery stenosis.

Figure 2. Cerebral angiogram.

(A and B) Sagittal and coronal views of cerebral angiogram showing narrowing irregularity of the distal portion of the right M1 middle cerebral artery.

The patient with a history of macroprolactinoma (2001 diagnosis), initially treated with bromocriptine, transitioned to cabergoline 0.5 mg weekly with few treatment interruptions. One week before presentation, he increased the dosing to 1.5 mg to enhance sexual function. The patient's headache improved during hospitalization while off cabergoline with complete resolution on day 3 in the setting of nimodipine initiation. Blood counts, chemistries, A1C, LDL, ESR, and CRP were normal. ANA and ENA (for anti dsDNA, SSA, SSB, Sm, RNP, Chromatin, Scl-70, Centromere-B, Ribosomal-P, and Jo-1 Ab) returned negative. The patient was discharged on verapamil 240 mg daily to be taken for a total of 6 months for suspected reversible cerebral vasoconstriction syndrome (RCVS). Aspirin and Atorvastatin were started for secondary stroke prevention. Head CTA after 1 month demonstrated stable right M1 stenosis without additional cerebrovascular abnormalities.

Discussion

RCVS is a syndrome of transient, segmental constriction of cerebral arteries without inflammation, first described by Call et al. in 1988. It is characterized by acute, recurrent thunderclap headaches with or without neurologic deficit, typically over 1–4 weeks. More than half of RCVS cases are secondary, mainly from exposure to vasoactive substances. Major complications of RCVS include cortical subarachnoid hemorrhages and strokes. Vessel imaging and cerebral angiography classically show segmental vasoconstriction with irregular caliber size affecting both anterior and posterior circulations. Because of the dynamic nature of RCVS, angiography may be normal if completed early (within 4–5 days of symptoms) or late (vasoconstriction is at maximum 2–3 weeks) and therefore could be missed.^1–4 Depending on clinical presentation, alternative differential to consider may include primary angiitis of the CNS (PACNS), migraine, cerebral venous thrombosis, posterior reversible vasoconstriction syndrome, hypertensive emergency, arterial dissection, spontaneous intracranial hypotension, pituitary apoplexy, and meningitis.⁵

In our case, both brain MRA and cerebral angiography performed lacked characteristics of RCVS-related vascular changes. However, because our patient presented within 5 days of symptomatic onset, these negative studies could not rule out RCVS. Patient was found to have a significant proximal MCA stenosis, but this etiology is unlikely to cause the patient's ischemic findings, considering multifocal distribution of punctate-to-small infarcts, characteristics better explained by RCVS.⁵ Given the patient's clinical presentation with acute onset and recurrent thunderclap headaches, evidence of multifocal cortical infarcts, symptomatic improvement after withdrawal of offending medication, complete resolution after calcium channel blocker initiation, and negative workup for alternative vascular cause, this case is most consistent with RCVS.^5–7 PACNS is an inflammatory disease affecting small-sized and medium-sized intracranial vessels with angiographic similarities to RCVS.⁶ Given the lack of deep/brainstem infarcts, angiographic vessel segmental abnormalities, inflammation, or blood vessel destruction, PACNS was satisfactorily ruled out.^5–7

Cabergoline treats prolactinomas through pituitary D2 receptor-binding inhibiting prolactin synthesis. Cabergoline also has agonism toward D4 and 5-HT1a receptors, but most importantly, it has been shown to exhibit pronounced agonism toward 5-HT2b receptors compared with bromocriptine.⁴ Our patient most likely experienced vascular side effects following increased cabergoline dosing in the setting of chronic use. Therefore, providers should educate and monitor patients taking cabergoline for serotonergic vascular side effects, and given appropriate context, should suspect and evaluate for RCVS early to avoid possible life-threatening complications.

Appendix. Authors

Study funding

No targeted funding reported.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.