Spontaneous cerebrospinal fluid (sCSF) leaks occur in the presence of lateral or anterior skull base bone defects in addition to holes in the dura with or without encephalocele. Clinically, lateral leaks lead to hearing loss, persistent ear effusions with or without chronic otorrhea, while anterior leaks lead to chronic clear rhinorrhea. Most importantly, sCSF leaks predispose patients to meningitis, thus prompting surgical repair. It is a spontaneous disease which occurs in patients without known cause related to trauma, prior skull base surgery, or intracranial tumor . sCSF leaks are most prevalent in middle-aged (average age 45–65 years) and obese (average BMI = 35–38 kg/m2) females (female : male ratio = 70 : 30) [2▪,3,4]. Comorbid condition associated with obesity such as elevated intracranial pressure (ICP) and obstructive sleep apnea (OSA) are also common in sCSF leak patients [3,5▪,6,7▪,8–10,11▪]. The rate of sCSF leaks continues to increase over recent decades, mirroring the increasing obesity during this time period, but the pathophysiology and mechanism of sCSF leak are not well understood [3,7▪,12,13].
Increased ICP, whether chronic or intermittent, is suspected to be one of culprits in thinning the skull base and ultimately leading to a defect in the bone and dura. Studies have shown that sCSF leak patients demonstrate isolated skull base defects along with global calvarial thinning, but do not typically have thinning of extracranial bones (zygoma), supporting the notion that an intracranial process is responsible for sCSF leak [2▪,14▪▪]. Recent studies have investigated the role of obesity, idiopathic intracranial hypertension (IIH), and OSA in causing transient and chronic elevations in ICP which can lead to skull thinning over time [5▪,6,7▪,14▪▪,15▪▪]. These studies have noted that obesity alone does not account for the development of sCSF leaks; rather, obesity-related factors such as IIH and/or OSA play a more integral role in the pathophysiology of sCSF leaks [2▪,14▪▪]. The role of OSA has been investigated recently given its association with obesity and its transient effects on ICP. Here we review the recent literature on the association of obesity, ICP, and sleep apnea with the development of sCSF leaks.
The effect of obesity in the development of sCSF leak has been extensively studied in the past and studies have shown that most patients who undergo sCSF leak repair are obese [7▪,8,10,13,16–18]. Studies have also demonstrated an association between elevated BMI and elevated ICP [6,10,16,18]. Nonetheless, recent data have begun to suggest that obesity-related factors, rather than obesity itself, are implicated in the development of sCSF leak.
Prevalence of obesity among spontaneous cerebrospinal fluid leak repair patients
Virtually all studies that have investigated sCSF leak have noted that most patients are obese. A recent retrospective 10-year review of the University HealthSystem Consortium national database found that, of those undergoing craniotomy for CSF leak repair, all patients were overweight (BMI > 25 kg/m2) and the majority of patients were obese (average BMI = 37.8 kg/m2) [7▪]. In addition, this study found that sCSF leak repair was twice as common in regions of the country with high obesity rates (Midwest) when compared with regions with lower obesity rates (West) [7▪]. Other studies in recent years have reported that the average BMI among sCSF leak patients ranges between 32 and 37 kg/m2[8,10,13,17,19]. These studies have conclusively established that obesity is strongly associated with sCSF leak, prompting further studies on the underlying mechanism of this relationship.
Skull base thickness in obese and nonobese patients
Numerous studies have investigated skull base thickness in obese and nonobese patients. A recent retrospective review compared sCSF leak patients with obese and nonobese controls and measured tegmen thickness in each of these groups; 97 patients were measured overall . The study found that sCSF leak patients had significantly thinner tegmen compared with obese and nonobese controls, and obese patients had thinner tegmen than nonobese patients; BMI was inversely related to tegmen thickness . A similar study compared the tegmen's bone mineral density among obese, nonobese, and sCSF leak patients and concluded that there were no significant differences between the three groups [21▪]. Yet another recent study measured the superior semicircular canal and the lateral skull base among obese and nonobese patients and found that BMI did not correlate with lateral skull base thickness [22▪].
Obesity is unlikely to be independently responsible for skull thinning. A study examining calvarium thickness in patients undergoing cochlear implant surgery sought to examine skull thickness in age-matched obese (BMI ≥ 30 kg/m2) and nonobese (BMI < 30 kg/m2) patients in which they measured the squamous temporal bone (Fig. 1) [2▪]. The calvarial thickness was not significantly different when comparing the obese with nonobese cochlear implant patients. When comparing both the obese and nonobese cochlear implant cohort to patients with lateral skull base sCSF leaks, there was a significant thinning of the calvarium in the sCSF leak patient population (Fig. 1). The extracranial zygoma bone thickness was then used as a control in this study to control for nonintracranial systemic diseases, such as osteopenia. Utilizing the ratio of the squamous temporal bone thickness to the extracranial zygoma thickness, they showed that sCSF leak patients had a significantly lower ratio than both the obese and nonobese cochlear implant patients; and again no difference was found among the two cochlear implant cohorts. These data implicate an intracranial process that causes isolated skull thinning and is independent of obesity in the development of sCSF leaks. Thus, it is hypothesized that additional obesity-related factors, such as IIH and OSA, are implicated in the development of sCSF leak, rather than obesity alone [2▪,3,14▪▪,15▪▪]. The varying data from the aforementioned studies highlights the potential that obesity alone does not completely account for the development of sCSF leak.
Studies investigating the association between BMI and ICP in the past have identified a positive linear relationship between BMI and ICP, with an increase of 0.24 mmHg in CSF pressure per unit of BMI . The mechanism of this linear relationship has been postulated as follows: increased abdominal adiposity can increase intraabdominal and intrapleural pressures and lead to increased cardiac filling pressures and cerebral venous retention, ultimately causing chronically elevated ICP. This in turn is theorized to lead to skull and skull base thinning [6,9,10,16,18,23].
Relationship between intracranial pressure and spontaneous cerebrospinal fluid leaks
It has been postulated that sCSF leaks result from chronic or intermittently elevated ICP and may be a type of IIH [23,24]. Epidemiological studies have revealed obesity as a risk factor for IIH and have identified a relationship between fluctuations in weight and the development of IIH [5▪,11▪,23,25,26▪,27–30]. Furthermore, numerous studies have shown that weight loss, whether by surgical or nonsurgical methods, leads to resolution of elevated ICP in the vast majority of patients with IIH [25,31,32▪,33–35,36▪,37].
Chronic pressure-like forces acting on the skull base and skull are predicted to thin the bone, ultimately leading to dural exposure and tearing. Elevated ICPs have been found on preoperative ICP measurements in anterior skull base sCSF leaks, with a reported average opening pressure of 33.0 cmH2O . The nature of anterior skull base CSF leak repair generally warrants the placement of a lumbar drain, whereas this is not generally routine practice in the commonly performed middle cranial fossa approach for lateral skull base leaks [3,38]. Among those presenting for evaluation and management of sCSF leak, elevated ICP has been observed in 10–66% of patients in studies that were able to perform lumbar puncture [5▪,11▪,39]. Lumbar puncture takes only a single measure of the ICP and it is known that ICP varies with time of day and patient positioning. In addition, there are some risks of bleeding, infection, and persistent leak with lumbar puncture and many patients defer testing . This makes it difficult to truly know the transient or chronic ICP in many patients with these pathologies.
Imaging findings in idiopathic intracranial hypertension
Computed tomography (CT) scan findings in intracranial hypertension include thinning or attenuation of the skull base and calvarial bone, demonstration of arachnoid pits , and the presence of multiple skull base defects in up to 31% . When examining the squamous temporal bone, it was shown that patients with sCSF leak had on average 22% thinner squamous temporal bone thickness than age and BMI-matched controls [2▪] (Fig. 1). A similar study examined the relationship between skull thickness and ICP recorded on lumbar punctures; it was revealed that in patients with low or normal ICP, the calvarium thickness increased with aging; while the calvarium thickness decreased with aging in patients with high ICP [42▪▪] (Fig. 2). The patient cohort was then split into two groups of high and low-normal ICP, revealing a significant difference in squamous temporal bone thickness. Extracranial zygoma thickness was measured and utilized as a control which revealed no effect from ICP. Furthermore, the skull base was measured above the internal auditory canal revealing decreased thickness in patients in this same cohort with elevated ICP. As with this study and many others, the limitation remains that the methods in which the ICP was measured is at a single timepoint rather than over multiple timepoints or a distinct time period. This highlights the notion that patients with sCSF leaks may not have chronically elevated ICP; transient spikes in ICP may also be implicated. OSA is known to cause transient elevations in ICP during apnea overnight and thus is central to this discussion [43▪,44].
OBSTRUCTIVE SLEEP APNEA
Sleep apnea has a strong association with obesity [45,46] and is known to cause transient intracranial hypertension during apneic episodes when patients are asleep [43▪,44]. Recent studies examining the relationship between OSA, sCSF leak, and calvarium and skull base thickness have identified OSA as an important factor strongly associated with this clinical pathology.
Prevalence of obstructive sleep apnea in spontaneous cerebrospinal fluid leak patients
The first prospective study to investigate the prevalence of OSA among sCSF leak patients has been published. This was performed by obtaining level 1 polysomnography (PSG) on every patient who presented for repair of sCSF leak during a 3-year period [15▪▪]. A total of 21 sCSF leak patients (average BMI 35.3 kg/m2) presented for evaluation, and 18 of them ultimately obtained a PSG; 15 of 18 patients were found to have OSA (83.3%) [15▪▪]. This prevalence is much higher than expected based on previously reported retrospective studies [6,7▪,47,48]. This study established a strong association between OSA and sCSF leak, prompting further research into skull and skull base findings in OSA patients.
Calvarial and skull base thickness in obstructive sleep apnea and spontaneous cerebrospinal fluid leak patients
Numerous studies have investigated skull measurement findings in obese and nonobese patients, as detailed above, but until recently no studies had examined these variables in those with sleep apnea. A recent study helped fill this gap in the literature by investigating calvarial and skull base findings in OSA, non-OSA, and sCSF leak patients [14▪▪].
The study first identified over 1000 non-sCSF leak patients who had obtained high-resolution CT scans and level 1 PSG studies at a large academic institution in the past decade [14▪▪]. Non-OSA patients [Apnea–Hypopnoea Index (AHI) < 5] and moderate–severe OSA patients (AHI > 25) were then matched for age, BMI, and hemoglobin A1c [14▪▪]. Skull calverium, skull base, and zygoma thickness were measured in a consistent and reproducible manner (Fig. 3a and b). Patients with OSA were found to have thinner mean (SD) calvaria and thinner skull bases than non-OSA patients (Fig. 3c) [14▪▪]. OSA and non-OSA patients in this same cohort were compared with previously identified sCSF leak patients. sCSF leak patients had significantly thinner calvaria than non-OSA patients, with a 17.9% difference in thickness; while calvarial thickness was not significantly different between OSA patients and sCSF leak patients (Fig. 3c). The extracranial zygoma thickness was not different between the three groups (Fig. 3d). The tegmen mastoideum was dehiscent in nearly twice as many patients with OSA as those without (37 vs. 20%).
Overall, this study showed that, in a cohort of obese non-sCSF leak patients, those with moderate–severe OSA have thinning of the squamous portion of the temporal bone and skull base when compared with non-OSA patients, a relationship independent of age, BMI, sex, and multiple comorbidities [14▪▪].
Though there is an association of OSA with thinning of the calvarium and skull base, the potential mechanism of this remains under study. We hypothesize that OSA, when left untreated in the long term, plays a role in a progressive thinning of intracranial bones through its transient effects on ICP during apneic episodes. When patients are apneic overnight, they have transient hypercarbia, resultant cerebral vasodilation and impairment of venous drainage, and this can lead to spikes in ICP [43▪,44]. Over time, this progressive thinning can lead to sCSF leak, especially in inherently thin areas of the skull base such as the tegmen and cribriform plate, where erosion of bone to a magnitude of 1 mm can lead to CSF otorrhea and/or rhinorrhea [7▪].
The pathophysiology of sCSF leak has been extensively studied in recent years, and the current literature suggests that a multifactorial process involving obesity and its related factors is responsible for the development of sCSF leak. The sCSF leak patient is typically obese, middle-aged, and more often female than male. The interplay between obesity, ICP, and OSA over time is likely what leads to tegmen dehiscence and resultant sCSF leak. There are inherent limitations to studying ICP in these patients, but the current literature strongly suggests that transient and chronic elevations of ICP play a role in skull base dehiscence and ultimately sCSF leaks.
Financial support and sponsorship
The work was supported by the Department of Otolaryngology – Head and Neck Surgery, Indiana University, Indianapolis, IN, USA.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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