Delayed development of a de novo contralateral middle cerebral artery aneurysm in a patient with hyperimmunoglobulin E syndrome: A case report

Abstract

A 50-year-old female patient with hyperimmunoglobulin E syndrome (HIES) presented initially at the age of 48 years with subarachnoid hemorrhage (SAH) from a ruptured left middle cerebral artery (MCA) bifurcation aneurysm, which was treated successfully with coiling and microsurgical clipping. Angiography and cross-sectional imaging did not indicate evidence of any additional intracranial aneurysm. However, the patient presented two years later with SAH secondary to a new ruptured right MCA bifurcation aneurysm, which was treated successfully with microsurgical clipping. This case provides further evidence that HIES places the cerebral vasculature at increased risk for cerebral aneurysm formation and that special considerations are indicated in managing and monitoring these patients.

Introduction

Hyperimmunoglobulin E syndrome (HIES), also known as Job syndrome, is a rare genetic disorder occurring in approximately one out of one million births. HIES is associated with an increased risk of vascular abnormalities of the cerebral, carotid, coronary and aortic vasculature.^1–5 Although the specific causes and incidence of vascular abnormalities in patients with HIES are unclear, aneurysm formation in HIES may be related to weakening of the vascular wall as a consequence of infection, autoimmune vasculitis and/or genetic factors.^6,7 In this report, we present a case of a female patient who, two years after being treated for a ruptured left middle cerebral artery (MCA) bifurcation aneurysm, developed a second MCA aneurysm with subarachnoid hemorrhage (SAH) on the right side. This case report provides further evidence that HIES places the cerebral vasculature at increased risk for cerebral aneurysm formation, and special considerations are indicated in managing and monitoring these patients.

Case report

A 50-year-old female with previously diagnosed autosomal dominant HIES initially presented to our facility in June 2016 after a syncopal episode, experiencing acute dizziness, diaphoresis, and loss of consciousness for five minutes, followed by a severe headache (Hunt and Hess grade 2 at presentation). Previous medical history indicated recurrent sinus infections attributed to HIES that were cared for longitudinally by a pulmonologist and recurrent superficial skin infections. A non-contrast computed tomography (CT) of the head showed diffuse Fisher grade 4 SAH, suggesting a ruptured aneurysm (Figure 1). Angiogram confirmed a 4.4 mm × 3.0 mm × 2.4 mm bi-lobed, broad-based, laterally directed aneurysm at the left MCA bifurcation, arising primarily from the posterior division origin. The aneurysm was partially coiled for dome protection, with subsequent completion treatment with microsurgical clipping via a pterional craniotomy. At the time of surgery, the Sylvian fissure was opened laterally down to the M1 segment, which was traced to the middle cerebral bifurcation where a fair amount of thick clot was found and removed. The neck of the aneurysm was identified, and a temporary clip was placed on the M1 segment. A clip was applied across the aneurysm neck, coming across the very base of the coils, crushing the coils, and obliterating the majority of flow into the aneurysm. Below this, a second curved clip was used to gather the bulbous origin of the M2 branch. Gore-Tex was wrapped around the construct, and papaverine-soaked Gelfoam was placed over the exposed vasculature. Despite the potential risk of using foreign material in an immunocompromised patient, we decided to use Gore-Tex because of the abnormal appearance of the MCA bifurcation, which could not be clipped completely without compromising the parent artery. Indocyanine green videoangiography and intraoperative catheter angiography confirmed aneurysm closure and patency of the parent vasculature. The dura was closed with a patch, and the bone flap was replaced with titanium mesh cranioplasty. The patient recovered well initially following the procedure. Routine follow-up angiography showed no evidence of recurrent aneurysm. In particular, there was no evidence of an aneurysm at the right MCA bifurcation, which was well visualized (Figure 1(f)).

Figure 1.

Initial ruptured aneurysm at the left middle cerebral artery (MCA) bifurcation. (a) Non-contrast computed tomography showing diffuse subarachnoid hemorrhage throughout the cisterns and the frontal lobe sulci, mostly on the left side; (b) pre-operative 3D angiogram showing the left MCA bifurcation aneurysm; (c) pre-operative angiogram showing a small, bi-lobed, broad-based, laterally directed aneurysm at the left MCA bifurcation, arising primarily from the posterior division of the M2 segment; (d) post-coil angiogram; (e) post-clip angiogram, showing no evidence of parent vessel compromise; (f) routine follow-up angiogram showing no evidence of aneurysm at the right MCA bifurcation.

Unfortunately, one month after the procedure, the patient developed a left-sided wound infection with subgaleal, epidural, and subdural loculated fluid collections, and acute cerebritis secondary to methicillin-resistant Staphylococcus aureus infection, which was successfully treated with surgical drainage and intravenous vancomycin. The bone flap and all hardware were removed. After prolonged antibiotic therapy, the patient came back for an artificial cranioplasty at a later date.

In September 2018, approximately 15 months after her left MCA aneurysm, the patient returned to our facility with sinus pressure, headache, and neck pain. The patient had been experiencing these symptoms for the past week with posterior nasal drainage. A CT of the head revealed mild to moderate SAH; angiography confirmed a new, ruptured, laterally directed 1.9 mm × 2.4 mm × 2.5 mm aneurysm at the right MCA M1/M2 junction (Figure 2). This aneurysm was treated with a similar microsurgical clipping procedure, and vancomycin powder was used to cover the bone flap prior to scalp closure in an attempt to avoid another infection. The patient awoke in good condition and recovered well. Approximately one month postoperatively, the patient was readmitted with minimal drainage from the surgical site, but MRI and additional workup did not show evidence of infection. The patient continues to be monitored closely for potential development of infection. The patient also will be followed closely with angiography for potential delayed formation of a de novo aneurysm.

Figure 2.

Second ruptured aneurysm of the right middle cerebral artery (MCA). (a) Non-contrast computed tomography showing mild to moderate subarachnoid hemorrhage along the right Sylvian fissure; (b) 3D angiogram showing the MCA aneurysm at the right M1/M2 junction; (c) pre-operative angiogram; (d) post-clip angiogram showing no evidence of parent vessel compromise.

Discussion

This is the first known case of a patient with HIES presenting with a delayed, metachronous, contralateral, ruptured MCA aneurysm, highlighting the increased risk for initial and/or recurrent cerebral aneurysms with HIES. Also, this case serves to alert neurovascular surgeons of the need for careful management and vigilant monitoring for recurrent aneurysms among patients with HIES.

The mechanism of aneurysm formation and rupture in HIES patients remains largely undefined but is thought to be due to three primary factors, which may occur individually or in combination: (a) infection; (b) autoimmune vasculitis; or (c) genetic predisposition. Immunocompromised patients, such as those with HIES, are predisposed to systemic and local recurrent bacterial and fungal infections, which may be chronic or recurrent.^8–11 Chronic infection results in a systemic inflammatory state that may weaken vascular walls by degrading the endothelium, thereby inducing aneurysm development.¹² Previous work by Freeman et al. found focal cerebral hyperintense lesions via MRI in 35/50 (70%) studied HIES patients, potentially representing manifestations of small vessel degeneration that are more typically found in the elderly.¹³ Additionally, invasive fungal infections may lead to local mycotic aneurysm formation,^8,10,12 which otherwise is exceedingly rare in immunocompetent patients.

HIES also affects connective tissue, which may further contribute to an increased risk of aneurysms, presumably due to structural compromise in vascular integrity.¹⁴ In a review by Sowerwine et al., 71% of studied patients with autosomal dominant HIES had minimal trauma fractures and 68% reported hyperextensibility, both of which are hallmarks of connective tissue dysfunction.¹⁵ In autosomal recessive HIES patients, connective tissue manifestations are less frequent, with only 1/13 (8%) patients having mild joint hyperextensibility and none having minimal trauma fractures, as noted by Renner et al.¹⁶ Cerebral aneurysms have been documented in both autosomal dominant and recessive HIES patients.¹⁷ Thus, it is recommended that HIES patients receive follow-up vascular imaging every five years to exclude aneurysmal dilation.¹⁸

Despite the notable occurrence of intracranial aneurysms in patients with HIES, the magnitude of risk in this population is undetermined, partly because there are few published reports of intracranial aneurysms in HIES patients, given their relatively short average lifespan (26.5 years).⁷ A review of the literature for cerebral aneurysms in HIES yielded reports of 11 total patients; 7 (64%) were female, 9 (82%) had ruptured aneurysms, 3 (27%) had bilateral aneurysm, and 5 (45%) died from hemorrhage due to aneurysm rupture.^7,16,19–22 Among 9 aneurysms in which the location was reported, 3 (33%) were located in the MCA, 3 (33%) in the internal carotid artery, 1 (11%) in the anterior cerebral artery, 1 (11%) in the basilar trunk, and 1 (11%) in the anterior temporal artery. Table 1 presents a review of the source, patient demographics, HIES subtype, aneurysm location, rupture status, treatment approach and outcome in these 11 cases.

Table 1.

Literature review of cerebral aneurysms in patients with hyperimmunoglobulin E syndrome.

Author, year	Age (years)/ Sex	HIES subtype	Location	Size	Ruptured?	Treatment	Outcome
Renner, 200416	8/F	Recessive	N/A	N/A	Yes	N/A	Died from SAH
Renner, 200416	2/F	Recessive	N/A	N/A	Yes	N/A	Died from SAH and sepsis
Freeman, 20077	40/F	Not specified	Bilateral ICA	N/A	Yes	Clipped	Died from pulmonary hemorrhage
Freeman, 20077	24/F	Not specified	Left MCA	N/A	Yes	None	Died from Aspergillus pneumonia
Freeman, 20077	29/F	Not specified	Anterior temporal artery (mycotic) +  left MCA occlusion	N/A	Yes	None	Died from SAH
Kim, 201519	12/M	Dominant	Right ICA	25 mm × 24 mm	No	Clipped	Recovered
Chandesris, 201220	38/M	Dominant	Right MCA	7 mm	No	Coiled	Recovered
Chandesris, 201220	39/M	Dominant	Basilar trunk	17 mm × 19 mm	Yes	None	Died from SAH
Takeuchi, 201221	61/M	Not specified	Left A1-A2 junction of the ACA, multiple others noted	N/A	Yes	Clipped	Recovered
Fathi, 201122	29/F	Dominant	Left MCA	5 mm	Yes	None	Died from SAH
Fathi, 201122	35/F	Dominant	ICA bifurcation	N/A	Yes	Clipped	Recovered

ACA: anterior cerebral artery; HIES: hyperimmunoglobulin E syndrome; ICA: internal carotid artery; MCA: middle cerebral artery; N/A: data not available; SAH: subarachnoid hemorrhage.

Given that this patient had no history of aneurysm or SAH during her initial 48 years of life, the de novo development and rupture of a second, contralateral MCA aneurysm within two years after the initial SAH is noteworthy and warrants considering potential causative factors. Both the literature and details of this patient's history suggest possible intrinsic and extrinsic etiologies of the de novo aneurysm, including genetic factors related to HIES, increasing age, hormone imbalance and postinfection vasculopathy. As described previously, physiologic effects of HIES can weaken vascular walls, causing vulnerability to aneurysm.^6,7 Studies also document increased incidence of metachronous cerebral aneurysms and SAH among women compared with men.^23,24 The effects of declining estrogen during menopause, such as diminishing collagen deposition in cerebral arteries, may be causally associated with the increased incidence of SAH among women of this age.²⁵ Lastly, various opportunistic infections, including S. aureus infection, have been associated with aneurysms attributed to vascular abnormalities.^8–12,26 Each of these factors could have contributed, independently or additively, to the etiology of this patient's second, de novo, contralateral MCA aneurysm and SAH.

Conclusion

In conclusion, this is the first reported case of a delayed, de novo, contralateral MCA aneurysm in a patient with HIES. Given the notable vascular abnormalities and risk for multiple ruptured aneurysms in patients with HIES, neurovascular surgeons treating patients with this condition should monitor them closely for recurrent aneurysms. Also, in providing postoperative care to these patients, surgeons should be aware of the increased propensity for infection.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AMG contracts with Superior Medical Experts.

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: the Regions Hospital Medical Staff Research, Education, and Development Fund.