A 5-year outcome of propranolol for the treatment of paediatric intracranial cavernoma: case report and a review of the literature

We describe a case of a young male patient with KRIT1-driven familial cavernous malformation syndrome who developed multiple brain cavernomas, intracranial bleeding, and persistent seizures. Due to the relentless growth of cavernous malformations and recurrent intracranial bleeds, it was decided to enrol the patient in the “Propranolol for Intracranial Cavernoma” (PICC) pilot trial at our institution. Over the 5-year treatment period with 20 to 40-mg oral propranolol three times daily (TDS), we noted the near-complete arrest of the growth of cavernous malformations with no further evidence of intracranial bleeding or any further seizures. The observed outcome is consistent with the extremely limited published literature on the topic; thus, this case provides important evidence that supports the use of propranolol as a prophylactic treatment for paediatric intracranial cavernomas. We strongly encourage and recommend future prospective randomised controlled trials to definitively assess and characterize the therapeutic utility of propranolol in this patient population.


Introduction
Cavernous malformations, also known as cavernomas or cavernous angiomas, are low-flow vascular malformations of the brain and spinal cord that consist of clusters of dilated blood vessels lined with endothelial cells harbouring structurally defective tight junctions [1]. While most cavernomas are identified sporadically as a single-isolated lesion, multiple recurrent cavernomas are often suggestive of familial cavernous malformation syndrome. The recommended management is focused on regular monitoring with brain MRI scans, as well as timely and appropriate treatment of acute manifestations. Bleeding into the cavernoma and mass compression requires surgical removal of the lesion, while seizures, headaches, and other neurological symptoms are best managed with appropriate pharmacological therapy and neurorehabilitation [2,3]. Currently, there is a lack of prophylactic pharmacological treatments that act to arrest the growth of cavernomas and prevent intracranial bleeding.
In this case report, we present a case of a young male patient with an early presentation of multiple brain cavernomas, recurrent intracranial bleeding, and persistent growth of cavernomas evidenced by MRI imaging. Following enrolment in the PICC pilot trial at our institution, the patient was started on 20 to 40mg oral propranolol Three times daily (TDS). The treatment resulted in the near-complete arrest of cavernoma growth and the absence of bleeding over the follow-up period of 5 years, with no significant medication side effects.

Case presentation
In June 2006, a 9-month-old male presented to the Emergency Department at the Royal Hospital for Kids and Young People in Edinburgh, Scotland, with seizures, nausea and vomiting, tachycardia, and bulging fontanelles (Fig. 1). His past medical history included pseudo-squint, gastroesophageal reflux disease, and a recent episode of gastroenteritis. At the time of admission, his only regular medication was omeprazole, while his family history was unremarkable. Physical examination revealed good neurodevelopmental progress, with no neurological deficits or cerebellar signs. The fontanelles were soft and enlarged, measuring 2.5 by 2.5 cm. The CT scan showed significant intracranial bleed and increased intracranial pressure, likely secondary to multiple intracranial angiomatous formations.
Given the patient's presentation and investigation findings, a working diagnosis of intracranial bleeding into cavernoma, seizure disorder, and acute hydrocephalus was established. A surgical procedure for left frontal bleeding of frontal giant cavernoma was carried out. Pharmacological therapy with carbamazepine 80 mg twice daily was started to address recurrent seizures, along with a "rescue" therapy of buccal midazolam 0.24 ml and paraldehyde 3 ml in 3 ml of olive oil. Following the eventual discharge from the hospital, the patient's seizures significantly reduced in frequency, while a battery of genetic tests relieved a KRIT1 mutation in him and his father.
Over the next 7 years, the patient experienced relentless growth of cavernous malformations and recurrent intracranial bleeds as evidenced by MRI imaging. This required two separate surgical procedures for the removal of left frontal and left cerebellar cavernomas. He was eventually enrolled in the PICC trial-a single-centre clinical trial aiming to evaluate the benefit of 0.66-mg/kg TDS propranolol in children aged 2-16 presenting with intracranial cavernoma at our institution (i.e. RHCS).
A baseline MRI scan was obtained in February 2017, and the patient commenced on the propranolol 20 mg TDS. A regular ECG, blood pressure measurement, and blood sugar monitoring were arranged. On a 3-month follow-up, the MRI scan showed no increase in the size of the angiomatous formations. Propranolol was well tolerated by the patient, with the only side effect being mildly cold hands. A subsequent MRI scan in March 2018 showed no change in the size of cavernomas, with a possible reduction in the size of left frontal cavernoma. As the patient reported no side effects at this visit, it was decided to increase the propranolol dose to 40 mg TDS.
The most recent MRI scan, performed in March 2022, showed very minor enlargement in the largest cavernoma cantered within the left parasagittal frontal lobe with other numerous supra-and infratentorial cavernomas remaining unchanged (Fig. 2).

Discussion
The available evidence for the use of propranolol in the treatment of paediatric cavernous malformations is extremely limited but convincing. A recently published study by Oldenburg et al. reported increased cell-cell junctions and thickened endothelial-pericyte basal membrane in a propranolol-treated mice model of cerebral cavernous malformation [4]. These changes are correlated to the higher integrity of the vascular wall and provide a compelling explanation for the therapeutic benefit of propranolol. Furthermore, a few anecdotal reports have been published  over the last 10 years reporting arrest or regression of paediatric brain cavernomas with propranolol therapy (Table 1) [5][6][7]. Similar therapeutic benefits have been observed in the adult population; a number of reports noted regression of cavernous malformation, [8,9] while a retrospective study by Zuurbier et al. identified an association between the use of beta-blockers and reduced risk of intracranial haemorrhage [10]. Two large multicentre European trials (i.e. Treat_CCM, CARE) are currently collecting data and planning to publish their results as early as 2024 [11][12][13].
The findings presented in this report are in line with the literature. The unique aspect of this case report is the length and consistency of follow-up. In contrast to previously published reports, we followed the patient for 5 years. Propranolol treatment almost completely arrested cavernous malformations, as well as prevented further intracranial bleeding and seizures. While this is highly indicative of a significant therapeutic effect, many important questions regarding the efficacy of propranolol remain unanswered [14]. We, therefore, strongly recommend further prospective randomised controlled trials to definitively assess and characterise the therapeutic benefits of propranolol in the treatment of paediatric cavernomas.