Multiple brain cavernomas and pregnancy: Risk of seizures during obstetrical management

Cerebral cavernous malformations (CCMs), or cavernous angiomas or cavernomas, are vascular abnormalities in the brain characterized by dilated sinusoidal vessels made up of endothelial cells and lacking intervening connective tissue [1]. The natural history of CCMs carries a potential risk of hemorrhage and may present as seizures in untreated cases, thereby increasing the risks associated with pregnancy and labor. Despite ongoing controversies in the literature, most studies suggest that pregnancy does not significantly elevate the risk of hemorrhages resulting from pre-existing CCMs during gestational and obstetric management [2]. Observations indicate that pregnancy may heighten the threshold for seizure risk due to hormone-induced changes, with maternal seizures posing significant threats to fetal well-being [3]. This situation presents a substantial clinical challenge, especially considering the limited literature concerning the risks and management of epilepsy in patients with pre-existing CCMs during the peri-gestational period [3],[4],[5]. This report examines a case involving multiple brain cavernomas in a patient who experienced epileptic seizures during delivery without any accompanying intracranial hemorrhage. This report aims to investigate the management of CCMs during the gestational period, particularly focusing on the risks of seizures during both pregnancy and the puerperium.

A 25-year-old female patient presented with vomiting, dizziness, diplopia, and difficulty ambulating persisting for a week. She had a significant medical history of surgical intervention (Rastelli repair) for truncus arteriosus during childhood. The physical examination revealed a right eye deviation accompanied by impaired adduction, as well as impairment in both adduction and abduction of the left eye, along with left facial palsy. Notably, the tandem gait test yielded a positive result, and an impaired nose-to-finger test on the right was observed. A differential diagnosis of posterior fossa mass lesion was suspected. Magnetic resonance imaging disclosed multiple small brain lesions located in the left paracentral pons, right central pons, right cerebellar lobe, and left parieto-occipital region. One lesion identified in the left pons exhibited a fluid level indicative of intra-lesional hemorrhage with perifocal edema, consistent with multiple brain cavernomas (Figure 1 and Figure 2). The patient was managed conservatively, and her symptoms resolved within four months. Two years after the initial presentation, the patient became pregnant. Considering the high-risk nature of her condition, she was closely monitored by a multidisciplinary team (MDT) that included her neurosurgeon, obstetrician, and cardiologist. The MDT diligently observed both her health and that of the fetus throughout the pregnancy, during which she remained asymptomatic with no complications reported. She opted for a lower-segment cesarean section performed under regional anesthesia, and both her obstetric and puerperal periods were uneventful. Following the first pregnancy, the patient experienced mild symptoms such as headaches, dizziness, and blurred vision; these symptoms resolved spontaneously. Serial annual MRI assessments revealed stable supra- and infratentorial cavernomas, except for an increase in the size of the posterior pontine cavernoma from 10 × 6.7 mm to 14.5 × 10 mm. Two years later, during the second trimester of her second pregnancy, she manifested right eyelid drooping, facial numbness, headache, and vomiting. The physical examination was within normal limits, and a repeat MRI indicated stable cavernomas (Figure 3). The symptoms subsided spontaneously after a few days. The patient opted for a cesarean section. Postoperatively, she experienced two brief generalized tonic-clonic seizures. A computed tomography (CT) scan confirmed the presence of multiple brain cavernomas, with no change in size and no evidence of intracranial hemorrhage (Figure 4). Treatment with levetiracetam was initiated, resulting in no further seizures noted during her last follow-up, which occurred 18 months later post-pregnancy.

Cerebral cavernous malformations represent approximately 10–15% of all vascular malformations within the central nervous system [6],[7]. These malformations may manifest as singular or multiple lesions; multiple cavernous malformations may be of familial origin or arise sporadically [1],[6]. The most prevalent clinical presentations associated with CCM include seizures (4–6%) and intracranial hemorrhages (0–6%), which may or may not correlate with focal neurological deficits [1],[7].

In approximately 70–80% of cases, these malformations are identified supratentorially; however, a significant percentage of symptomatic patients present with seizures as the primary clinical manifestation [6].

Cerebral cavernous malformations can occur or be diagnosed at any age, with a higher prevalence in females due to hormonal factors. Both sporadic and familial forms have been reported, showing an incidence rate of 0.4–0.8% in the general population [1],[6],[7]. The literature documents a wide variety of clinical presentations, with common symptoms including headaches, seizures, focal neurological deficits, and intracranial hemorrhage [1],[6],[7]. In our case, the patient exhibited a fluctuating clinical course characterized by focal neurological deficits, worsened by seizures immediately following delivery. Cerebral cavernous malformations are generally considered benign, with 20% of patients remaining asymptomatic and 50% diagnosed incidentally. The natural history indicates a hemorrhage risk of 1.6% per patient-year and 0.9% per cavernoma year in asymptomatic patients [1],[6],[7],[8]. Cavernomas with dot-like patterns on imaging have an annual bleeding rate of 0.7% per lesion-year [7],[9]. Among symptomatic patients, seizures are the most common clinical manifestation [3],[10]. Some researchers have linked the occurrence of epileptic seizures during gestation to elevated serum estrogen concentrations in pregnant patients [11]. Studies show estrogen receptors are prominent in key brain regions associated with epileptogenesis, including the hypothalamus, hippocampus, and amygdala. Estrogens reduce the activity of gamma-aminobutyric acid (GABA) channel receptors in the pyramidal layers of cortical layers V and VI while enhancing the excitatory effects of glutamate on pyramidal neurons. Additionally, estrogens boost the rate of spontaneous neuronal secretion, especially in the medial amygdala, and stimulate excitatory responses to acetylcholine [3],[12]. Furthermore, the physiologically elevated levels of progestogens during pregnancy are known to decrease the seizure threshold [12].

Furthermore, angiogenic processes stimulated by growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), or placental growth factor, play a critical role in the enlargement of cavernomas [3],[12]. Significant levels of angiogenic growth factors, including VEGF, bFGF, and transforming growth factors, are expressed in these conditions. Cerebral cavernous malformations promote angiogenesis and cellular proliferation in arteriovenous malformations [12]. Hyperdynamic circulation, coupled with increased extracellular fluid volume and cardiac output, intensifies turbulent blood flow within sinusoids characterized by thin walls, thus elevating the risk of cavernoma rupture [2],[3].

In a population-based study conducted in Scotland by Joseph et al. [10] found that the five-year risk of experiencing a first seizure among adults with CCMs was low, regardless of whether these individuals initially presented with intracerebral hemorrhage (ICH) or focal deficits (6%, 95% CI 0–14%) or if the CCMs were discovered incidentally (4%, 95% CI 0–10%). In contrast, for CCMs not associated with any intracranial hemorrhage or focal neurological deficits, the five-year risk of developing epilepsy after a first seizure was significantly heightened, estimated at 94%. The same study revealed that two-fifths of patients began treatment with antiepileptic medications following their first seizure, with a 47% chance of achieving seizure freedom for two years [10]. The patient in question was prescribed levetiracetam and experienced seizure freedom for 18 months until her most recent follow-up. An additional concern in managing these patients is the consideration of early lesionectomy, which involves the excision of the perifocal epileptogenic hemosiderin ring in pursuit of seizure remission. However, multiple brain cavernomas complicate the decision-making process regarding the surgical approach [13],[14],[15]. A surgical alternative was proposed in this case, but the patient opted to pursue medical management instead of treatment.

The ongoing debate about the delivery method for pregnant women diagnosed with CCMs remains contentious. Recent evidence suggests that the risk of hemorrhage associated with CCMs does not significantly vary throughout pregnancy, during delivery, or in the postpartum period [6],[9]. Regarding the development of seizures in neurosurgical conditions, prophylactic antiepileptic medications are not recommended for alert and conscious patients; instead, these medications are administered only after the onset of seizures in cases with a high propensity for epileptogenic activity [1],[3],[4],[6],[9],[10],[11],[12],[13]. Key factors linked to the onset of epileptic seizures in CCMs include lesion multiplicity and the cortical location of the CCMs [1],[2],[9]. In this specific scenario, after consulting an epileptologist, we decided not to initiate prophylactic antiepileptic treatment until the patient experienced a seizure.

The current evidence regarding the risks of intracranial hemorrhages and epilepsy during pregnancy, labor, or the postpartum period remains insufficient. Furthermore, the published data on other risks linked to the delivery method is limited. Hormonal changes throughout pregnancy may lower the seizure threshold, thereby increasing the risk of seizures in individuals with preexisting CCM. Therefore, it is essential to gather robust evidence from clinical trials to enhance the management of pregnancy-related cases of CCM in the future.