Neurological outcomes of untreated brainstem cavernous malformations in a prospective observational cohort and literature review

Patient population

Patients diagnosed with brainstem CMs in our institute from January 2009 to December 2015 were registered and enrolled in the consecutive prospective cohort according to the inclusion and exclusion criteria. The inclusion criteria were (1) a definitive diagnosis of an untreated brainstem CM and (2) provision of informed consent. Patients were excluded if they met one of the following criteria: (1) the diagnosis was questionable/undefined; (2) they did not consent to follow-up; (3) they received treatment (radiation or surgery) before enrolment; (4) they had severe comorbidities involving the eloquent location, which might potentially influence the accuracy of neurological evaluation; (5) they were pregnant or breast feeding; and (6) they underwent surgery immediately following diagnosis. Surgical indications have been described in prior studies,15–19 22 23 and stereotactic radiosurgery (SRS) was not recommended. Surgical treatment was recommended if as follows: (1) multiple haemorrhages and poor or progressively aggravated neurological status; (2) lesion size ≥2 cm or enlarged with a significant mass effect; and (3) lesion grew exophytically or became abutting the pial surface after haemorrhagic ictus. All clinical data were obtained from a prospective clinical trial (no. ChiCTR-POC-17011575). Written informed consent was obtained from all participants and their parents or caregivers.

Procedures and neurological evaluation

The inception point of the study was the date of the first medical consultation or clinical visit that led to the diagnosis of a brainstem CM at our institute. Two neuroradiologists independently reviewed the MRI scans to verify the diagnosis according to the accepted criteria (online supplemental figure 1).13 In patients with MRI scans obtained more than 2 weeks prior, MRI re-examination was prescribed at enrolment to check the radiological features because haematomas evolve over time. The characteristics of MRI, including (but not limited to) an equivalent lesion size, crossing the axial midpoint,16 the Zabramski classification13 and developmental venous anomalies (DVAs), were extensively reviewed. If there were multiple CMs involving the brainstem, the symptomatic haemorrhagic CM took precedence for analysis; otherwise, the larger CM was preferred since both were postulated to be predictors of haemorrhage or FND.2 Brainstem CMs often encompassed different compartments, and we classified each CM only to one compartment according to the location of the maximal axial cross-sectional area of the lesion regardless of the number of anatomical compartments involved by the lesion (online supplemental figure 2). If the maximal axial cross-sectional area of a CM was located in the thalamus, the lesion would be classified as a thalamic CM even if it concurrently encompassed the midbrain. Neither the anatomical compartment within the brainstem nor the number of compartments involved by a brainstem CM had been proven to be related to the worsened outcome that had been observed in prior studies.15 16 18–22 Our classification was easily understandable, practicable and repeatable in clinical practice that conformed to the gross anatomy of the brainstem and facilitated statistical analysis.

The initial presentation, number of prior haemorrhages, and symptoms and neurological status following each ictus were collected and identified according to the medical records combined with available radiographic evidence that facilitated judgement of the presence of haemorrhagic events. Cranial nerve palsy, long tract deficits (motor and sensory abnormalities) and/or extrapyramidal symptoms specifically pertinent to the anatomical location of the lesion were classified as FNDs. Headache, dizziness, nausea, vomiting and/or other symptoms not directly associated with the lesion were classified as non-FNDs (non-specific symptoms). The definition of haemorrhage according to that advocated by Al-Shahi Salman et al 24 is as follows: a clinically symptomatic event (an acute or subacute, new-onset or worsening FND corresponding to the anatomical location of the brainstem CM, impaired consciousness, or severe headache) with recent overt haemorrhage within or outside the lesion leading to changes in lesion size and/or signal intensity based on serial radiographs.2 22 The first 3 days since onset of a clinically symptomatic event was defined as acute, and after that the interval ranging from the fourth day to 3 weeks was defined as subacute. Symptomatic events, provided by patients’ impression, recall or only medical records but without concomitant radiographs, were not enough to conclude a haemorrhagic event, which was considered uncertain to reduce recall bias and to avoid overestimating prior haemorrhages. Acute-onset symptoms or worsened deficits, anatomically consistent with the CM location, likely raised the suspicion of a haemorrhage, but other causes (ischaemic attack, infarction or secondary perilesional oedema) were not precluded in the absence of timely radiographs.

Follow-up

At enrolment, at least three phone numbers from the patients and their relatives were registered, along with information on home address, email address and social media account (Tencent Messenger and WeChat) if available. Two authors (PPL and ZYW), blinded to the results of the radiographs and haemorrhagic status, independently evaluated the neurological status at enrolment using modified Rankin Scale (mRS) scores and then completed the scheduled follow-up by clinical revisits (in person) 3, 6 and 12 months after enrolment and then annually after that or by telephone interviews, with visual contact according to structured question approaches or mailed questionnaires with digital photos sufficient for clinical evaluation. Home visits or connections with family doctors from community health services or community hospitals were alternative approaches to obtain follow-up information, with any discrepancy resolved by the senior author (JTZ). Since 2009, with the economic development, few patients would change their phone numbers, and these three phone numbers were less likely to change at the same time. These phone numbers and information for contacting the patients would be updated at each scheduled clinical revisit, and if clinical revisits were unavailable telephone interviews were performed annually to check the availability of these contact methods. MRI was recommended at the same time, but MRI at any time was necessary once the patient perceived severe headache or new/worsened pre-existing symptoms. Provided changes in neurological function, we were fully aware of a new haemorrhage, but it would be noted as questionable without radiological evidence.

The follow-up duration began at enrolment and ended on the date of surgery, SRS, death or the most recent evaluation, whichever occurred first. The cause of death was enquired from their relatives if the patient has passed away.

Statistical analysis and literature review

The clinical and baseline data stratified by neurological outcomes were compared (table 1). The risk factors for worsened outcomes were evaluated by univariate and multivariate binary logistic regression (method: Enter). Statistical analyses were performed using SPSS statistical package software (V.25.0), with significance set at p<0.05. A systematic review of the literature was performed regarding neurological outcomes in untreated brainstem CMs. Studies were reviewed and screened by two independent review authors using the terms ‘cavernoma’, ‘cavernous malformation’ and ‘cavernous hemangioma’ in the following databases from January 1984 to December 2019: EMBASE, PubMed, Cochrane, Ovid/Medline, Web of Science and EBSCO. We further reviewed all of the references provided in the identified studies and incorporated all pertinent citations. Studies that did not provide neurological outcomes were excluded.