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With advancements in our understanding of the relationship between venous sinus pressures and intracranial pressures, the term ‘idiopathic intracranial hypertension’ no longer adequately describes the disease process for which it is named, nor does it help stratify the heterogenous group of patients that suffer from it. Venous manometry in patients with this condition clearly demonstrates elevated intracranial venous pressures as the cause of elevated intracranial pressures. I propose the term ‘chronic intracranial venous hypertension syndrome’ as a better descriptor for the disease and then present a potential classification scheme for patients based upon the pathophysiology causing the venous hypertension.
Introduction
Idiopathic intracranial hypertension (IIH) was first described as pseudotumor cerebri by Dandy in 1937 as a clinical syndrome composed of headaches and visual obscurations combined with elevated intracranial pressure and no obvious mass lesion.1 This nomenclature later would be changed to ‘benign intracranial hypertension,’ however IIH clearly does not always have benign behavior as patients may present with visual loss that can progress to fulminant blindness.
According to the Oxford Medical Dictionary, “idiopathic” is defined as:
“Relating to or denoting any disease or condition which arises spontaneously or for which the cause is unknown.” Through history, afflictions that had no clear inciting or contributing cause (and therefore were perceived to develop spontaneously) were labeled with the term ‘idiopathic.’ Often times these diseases were diagnoses of exclusion, whereby the disease was defined by a subset of observed clinical criteria but more importantly by the absence of other, more common, better understood pathologies. The ‘wastebasket’ that is the diagnosis of exclusion is therefore a summation of ‘unknowns’ that may, in fact, represent separate, clinically-distinct entities beyond the resolving power of current medicine. The endless goal of medical research is to further understand disease to reduce the suffering it causes. It is only natural that, as time progresses, the number of diseases termed ‘idiopathic’ will decrease.
In this commentary, I propose a new nomenclature and classification scheme for IIH to better describe the disease process and to categorize patients based on objective phenotypes that have important treatment considerations.
IIIH is not idiopathic: cerebral venous hypertension causes intracranial hypertension
The relationship between cerebral venous pressures and cerebrospinal fluid (CSF) resorption via the arachnoid granulations is well described.2 A number of studies have demonstrated that unidirectional flow of CSF through arachnoid granulations requires a 3–5 mmHg pressure gradient from subarachnoid space to venous sinus.3–5 In conditions where cerebral venous hypertension is present, intracranial CSF pressures (ICP) will concomitantly be elevated.
Previous studies have investigated the impact of intra-abdominal pressure (commonly elevated in obesity) on central venous pressure (CVP) and jugular venous pressure and found significant, positive associations between the two measurements.6 7 This relationship is further suggested by the effectiveness of bariatric surgery and aggressive weight loss in improving IIH symptoms.8 In our recent series of more than 100 IIH patients who underwent cerebral venography and manometry,9 only 11% of patients were normal weight (body mass index (BMI) less than 25) and 75% had elevated CVP (defined as 9 mmHg or higher based on convention of a normal CVP being 3–8 mmHg) at time of measurement. Further, BMI was highly correlated to CVP.
Recently, venous sinus outflow obstruction has been identified as an additional contributing factor in anywhere from 30%–70% of patients with IIH.10 11 In the presence of venous sinus stenosis, IIH is sometimes referred to as “secondary intracranial hypertension.” Two separate groups conducted stenting with concomitant ICP monitoring and showed an immediate reduction in ICP following stenting of symptomatic venous sinus stenosis.12 13 Importantly, reductions in ICP following treatment are independent of weight loss or acetazolamide dosages.14
The recognition of intracranial venous outflow obstruction as a contributing factor in a subset of patients with IIH has dramatically improved our understanding of the relationship between intracranial venous hypertension and ICP elevation. Specifically, we are now routinely performing cerebral arteriography and venography with venous manometry in patients with IIH to evaluate for symptomatic venous sinus stenosis by measuring physiologic pressure differentials (gradients) across regions of angiographic narrowing. The venous pressure measurements have been integral in understanding the relationship between CVP and intracranial venous pressures and allowing for comparison with ICP.
Pathophysiology of venous sinus stenosis
Although the exact mechanism is still debated, there is a growing literature supporting a relationship between ICP, extramural sinus compression, and venous congestion.12 13 Concerning this current hypothesis, increased ICP causes extramural compression of the venous sinuses, leading to progressive outflow obstruction and resulting in venous congestion, which then leads to further elevations in ICP in the fashion of a positive-feedback loop. The degree of stenosis necessary to cause a significant trans-stenosis gradient is lower than would be predicted: studies have shown that development of a significant pressure gradient can be found with angiographic stenoses of only 30%–35%.10 Eventually, once the trans-stenosis pressure gradient is severe enough, intramural venous pressures resist further extramural compression and an equilibrium is reached where high venous pressures and ICPs co-exist (figure 1).15 This feedback loop is disrupted with stenting or shunting, with a number of reports detailing the resolution of venous sinus stenosis with lowering of ICP by CSF diversion.16 17 In fact, isolated changes in end-tidal carbon dioxide concentration (and resultant ICP changes) may have immediate and pronounced effects on not only venous sinus caliber but also venous sinus pressures.18 These studies further support the causal relationship between elevated venous sinus pressures and ICP.
Hypothesized feedback loop resulting in progressive sinus stenosis and elevations in intracranial pressure.
Venous pressures in IIH patients
In our recent series of more than 100 IIH patients who underwent venous manometry,9 we provided nomenclature for defining the relationships between measurements at different locations throughout the venous system. Most notably, we defined and calculated adjacent anatomical and summative gradients across patients both with and without pathological venous outflow obstruction.
In brief, patients exhibited an approximate stepwise pressure decrease of 1 mmHg between each anatomical location as the microcatheter is withdrawn more caudally during manometry, for a median total cranial pressure gradient of about 3 mmHg in those without venous sinus stenosis and a median of 19 mmHg in those with venous sinus stenosis. The median extracranial gradients, measured from the jugular bulb to the right atriocaval junction, was 2 mmHg. When accounting for both cranial and extracranial gradients (the total pressure decrease from superior sagittal sinus (SSS) to CVP), the “overall pressure gradient” was a median 4 mmHg in those with normal ICP and no venous sinus stenosis and 15 mmHg across all IIH patients.
Several important conclusions can be drawn from this data: first, CVP forms the foundation through which intracranial venous pressures arise; second, SSS pressures are higher than CVP by 4 mmHg in patients with low ICP and without stenosis, indicating that intracranial venous pressures are probably always normally higher than CVP; and third, significant additional intracranial venous pressure elevation may be present when stenosis exists. In this series, over half of patients exhibited venous sinus stenosis with pressure gradients in excess of 7 mmHg.
In our analysis, SSS pressures most closely correlated to ICP, as measured by the most recent opening pressure (OP) on lumbar puncture (LP), compared to other measured venous sinus pressures (ρ= 0.44; P < 0.001). SSS pressures in mmHg can be predicted by OP in cm of water using the formula: SSS = 6.80 + 0.69*OP (figure 2). There are obvious individual temporal and technical variabilities between OP on LP and venous sinus pressure measurements that limit the validity of these comparisons. A prospective study of patients undergoing stenting with an ICP monitor in place showed a similar close correlation between maximum pre-stent venous pressures and intracranial pressures.12 There are a number of individual factors that are still poorly understood that may influence the relationship between OP and SSS pressures, such as anatomic variability in the distribution of arachnoid villi, postural outflow variability19 and the role of intracranial lymphatics, which are known to contribute to cerebrospinal fluid clearance especially in the setting of elevated intracranial pressure.20 21 Even in light of these factors, there remains a strong and direct association between SSS pressures and OP.
Relationship between opening pressure and SSS pressures.
Venous sinus pressures in patients with normal intracranial pressures
To date, there have been no studies specifically designed at reporting on venous sinus pressures measured via catheterization in patients with normal OP. A few studies decades ago calculated SSS pressures from lumbar catheter infusion protocols, suggesting that SSS pressures exist below 11 mmHg in most patients.22 23 Other studies of patients undergoing craniotomy24 or ventriculography for brain tumor diagnosis25 with direct venous catheterization showed the vast majority of mean awake (control) SSS pressures to be less than 15 mmHg. There are surprisingly little data reporting on these pressures measured via venous catheterization in normal physiologic states particularly given that these pressures form the basis for selecting patients for stenting. However, we can infer some data from both our series and a large multicenter series by Levitt et al.26 In the Levitt series, none of the 11 patients with intracranial pressures of 24 cm H20 or less had pathological pressure gradients at time of venography, although specific venous sinus pressures were not provided. In our series,9 we selected 3 patients with OP of 20 cm H20 or less and all adjacent pressure gradients of 4 mmHg or less in an attempt to capture patients on the milder end of the IIH disease spectrum that may have venous pressure measurements approximating (or at least closer to) those in normal individuals. While limited by the small sample size, the data from these 3 patients suggests that in normal individuals SSS pressures should probably be less than 18 mmHg with overall pressure gradients of less than 8 mmHg and total cranial gradients less than 5 mmHg.
IIH is a spectrum with different sensitivities to elevated pressure
Classically, patients meeting Dandy’s diagnostic criteria for IIH have an OP greater than or equal to 25 cm H20. However, there is a population of patients with OP less than 25 cm H20 that have signs and symptoms of elevated ICP, including headaches, visual obscurations, and even papilledema, and benefit from pressure-lowering therapies. These patients are often classified as having IIH when they technically do not meet criteria for diagnosis.
In reality, intracranial venous pressures and ICP range across a wide spectrum. Approaching IIH using a 25 cm H20 threshold fails to recognize a population of individuals that have higher OP than normal and as a result, harbor significant impairment in quality of life from disabling symptoms. In most individuals, symptoms are absent or minor when OP ranges from 5-20 cm H20, but symptoms of hypotension or hypertension result when pressures fall below or above this range, respectively. In other individuals that are more sensitive to pressure extremes, the asymptomatic pressure window may be substantially narrower. In my experience, the narrower asymptomatic range may be found in patients with connective tissue diseases, where OP of 17 or 18 cm H20 may cause disabling symptoms (figure 3). Some authors have demonstrated a population of patients with transverse sinus stenosis with symptoms of IIH at OP at, or even less than, 20 cm of water (sometimes referred to as “IIH without papilledema”).27 In our prior series,9 patients with OP of 24 or less accounted for approximately 15% of the patients evaluated. The current diagnostic criteria of IIH fail to identify these patients as having a true disease process and may lead to mismanagement and continued patient suffering.
Example of varying symptom severity that may be present at different pressures based on sensitivity.
The etiologies of intracranial venous hypertension in IIH are highly variable
The fundamental pathologic process that defines IIH is the presence of intracranial venous hypertension, which directly causes elevated ICP. However, the causes and degrees of intracranial venous hypertension are variable among patients (figure 4). For example, some patients are morbidly obese and have extreme elevations of CVP that directly cause elevated intracranial venous pressures. Others are normal weight but have heart failure or pulmonary hypertension which causes similar venous pressure elevations. Others may have normal CVP but severe venous sinus stenosis. Another subset have elevated venous sinus pressures secondary to both elevated CVP and venous sinus stenosis. These patients suffer from different pathologies that would be best treated based on the causative etiology of their venous hypertension, yet there is no mechanism in the current IIH diagnostic paradigm in differentiating separate pathologies. As it stands right now, all IIH patients are considered equally, and those with substantial symptoms but an OP less than 25 cm H20 on a spinal tap are not considered at all.
Example of four separate IIH patients that all have SSS pressures of 25 mmHg and similar OP on LP but different etiologies of intracranial venous hypertension.
A proposal for changing the nomenclature
The International Nomenclature of Diseases (IND), a joint project of the Council for International Organizations of Medical Sciences and the WHO, defines the main criteria for selecting a disease name. The IND states that disease names should be specific, unambiguous, self-descriptive, simple, and based on cause.28 The term idiopathic intracranial hypertension, while simple, fails to meet the remaining criteria, as it lacks specificity, is not self-descriptive, is ambiguous, and is not based on cause.
Chronic intracranial venous hypertension syndrome
I propose changing the name from IIH to Chronic Intracranial Venous Hypertension Syndrome (CIVHS). The proposed nomenclature is specific, self-descriptive, simple, and explains the cause of the symptoms. Additionally, we propose a change to the diagnostic criteria in which diagnosis requires opening pressure on lumbar puncture or intracranial pressure monitor >25 cm H20 and elevated superior sagittal sinus pressures (>18 mmHg) in the absence of an intracranial mass lesion. Additionally, I propose to define a CIVHS-spectrum disorder, which includes patients with an OP of 15–24 cm H20 with symptoms of CIVHS that respond to pressure-lowering therapies, most notably CSF drainage following LP.
This nomenclature and classification excludes acute causes of venous hypertension, most notably acute sinus thrombosis or traumatic injuries, which are distinct and separate entities.
Proposed subtype classification
Type 1: Pathologic venous sinus stenosis, low-moderate CVP, absence of arteriovenous shunting (table 1).
Proposed subtype classification for CIVHS
Type 2: High CVP, absence of venous sinus stenosis or arteriovenous shunting.
Type 3: Pathologic venous sinus stenosis, moderate-high CVP, absence of arteriovenous shunting.
Type 4: Post-venous sinus thrombosis, with or without venous sinus stenosis, normal or elevated CVP, with or without arteriovenous shunting.
CIVHS-spectrum disorder: Patients with ICP of 15 to 24 cm H20 but have symptoms of CIVHS that are relieved with pressure-lowering therapies.
Subclassification A: Presence of acute or fulminant symptoms, including rapidly progressive visual loss or decreased mental status/coma. For example, a type 1 patient that presents with acute and rapid visual decline would be denoted CIVHS type 1A.
CIVHS type 1 (craniocervical origin)
These patients have elevated venous sinus pressures with an associated venous sinus stenosis and pressure gradient but proximal to the stenosis they have roughly normal CVP and jugular pressures. In these patients, treatment of the offending stenosis with stenting may normalize intracranial venous sinus pressures and is likely to be highly effective (and potentially curative) given the more normal CVP values, which are indicative of little or no physiologic venous congestion from more proximal causes. Weight loss or loop diuretics are unlikely to be of benefit in these patients.
CIVHS type 2 (central origin)
This subset of patients have elevated ICP secondary to isolated elevations in CVP without an associated venous sinus stenosis. In these patients, stenting is not an option as there is no focal pathology amenable to treatment. Treatments which decrease CVP (weight loss or correction of heart failure) may lead to reductions in ICP. From a surgical standpoint, only CSF diversion, bariatric surgery, or ON fenestration will provide benefit.
CIVHS type 3 (mixed origin)
Patients in type 3 demonstrate mixed pathology wherein elevated venous sinus pressures are secondary to both a pathologic trans-stenosis pressure gradient as well as elevated CVP. In these patients, resolution of the trans-stenosis gradient by stenting will result in a reduction in ICP but this treatment alone will fail to reduce pressures to normal due to the presence of systemically high venous pressures and resultant high intracranial venous pressures. These patients are probably more prone to relapse following stenting alone.
CIVHS type 4 (post-venous thrombosis)
A small percentage of patients with chronic venous sinus thrombosis (previously diagnosed or highly suspected based on imaging) present with symptoms of elevated intracranial pressure due to venous outflow impairment. Often these patients have a history of transverse sinus, sigmoid sinus or jugular vein thrombosis which do not fully recanalize on anticoagulants. Patients occasionally develop stenosis of the contralateral, patent sinus pathway. Other patients may have more diffuse thromboses with generalized impairment of outflow. These patients may have normal or elevated CVP. Some patients may develop dural arteriovenous fistulae which may also contribute. Treatment of choice in these individuals may include sinus stenting if stenosis is present or CSF shunting.
CIVHS-Spectrum Disorder
These patients have an OP of 15 to 24 cm H20 but have symptoms of CIVHS that impair quality of life and are relieved with pressure-lowering therapies. In my experience, these patients usually have OP in the low 20’s or high teens but have temporary relief of CIVHS symptoms following lumbar puncture with CSF drainage. There is very little published evidence supporting the incidence of this condition and/or the role of surgical treatment in this patient population. In my experience, patients in this population usually are not candidates for stenting (<25%)9 but often pursue CSF shunting to improve quality of life.
Hydrocephalus is not CIVHS
Chronic hydrocephalus may present with elevated OP on LP and symptoms of headache or cognitive dysfunction. Hydrocephalus, unlike CIVHS, is defined by discordant ICP and venous sinus pressures. Venous manometry reveals lower than expected venous sinus pressures compared with OP. These patients harbor a fundamental impairment of CSF resorption unrelated to the subarachnoid-venous sinus pressure differential and therefore suffer from a disease process that is distinctly different from CIVHS. Ventricular size is usually larger than that classically seen in IIH and patients usually have a history of craniotomy, intracranial hemorrhage, or bacterial meningitis. In those patients without a clear diagnosis of hydrocephalus but have elevated OP with low (dissociated) SSS pressures, the disease truly may best be described as “idiopathic” and IIH may remain a suitable nomenclature for classification.
Conclusion
With advancements in our understanding of the relationship between venous sinus pressures and intracranial pressures, the term ‘idiopathic intracranial hypertension’ no longer adequately describes the disease process for which it is named nor does it help stratify the heterogenous group of patients that suffer from it. I propose the term ‘chronic intracranial venous hypertension syndrome’ as a better descriptor for the disease and then present a potential classification scheme for patients based on the pathophysiology causing the venous hypertension. As with any established but outdated norm in medicine, there will be resistance to change that must be overcome by solid evidence, open-mindedness, and time. Future research is necessary to define more definitive thresholds for CVP, SSS and intracranial pressures based on larger patient series and studies in patients without elevated intracranial pressure. This proposal, subgroups and individual diagnostic criteria represent a first attempt at better defining and classifying this disease through our modern understanding of intracranial venous hypertension. As our knowledge grows, we will have the opportunity to refine the way we classify and treat patients with this condition.
References
Footnotes
Contributors The primary author conceived and composed all portions of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.