Commentary: The role of inflammation in idiopathic intracranial hypertension

The manuscript titled “Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as inflammation markers in patients with papilledema due to idiopathic intracranial hypertension” investigates the role of inflammation in the pathogenesis of idiopathic intracranial hypertension (IIH).[1] It has also provided a novel and a simple method of using hemogram as a marker of inflammation in IIH.

IIH, otherwise known as pseudotumor cerebri, is a chronic debilitating condition seen predominantly in overweight individuals particularly in women of reproductive age group. It is characterized by elevated intracranial pressure (ICP) in the absence of any space-occupying lesion in the brain and in the presence of normal cerebrospinal fluid (CSF) composition. Diagnosis is made by using the modified Dandy's criteria.[2] The primary pathogenesis of IIH remains unknown but several mechanisms have been proposed to explain the raised CSF pressure such as increased CSF production,[3] impaired CSF absorption at arachnoid granulations and or lymphatics,[4] cerebral edema[5] , and elevated cerebral venous pressure[6] from aberrant venous pressure gradients.[7]

It has been hypothesized that inflammation may play a role in IIH.[8,9,10] Obesity is proposed as a risk factor for IIH; thus, adiposity might have a causative role in IIH, but the mechanisms by which obesity predisposes to the condition have not been fully elucidated. Human fat is an active endocrine tissue, secreting numerous neuroendocrine molecules that could potentially play a role in IIH. Few studies have evaluated the mechanisms by which hormones and adipokines exert their effects on ICP regulation in IIH.

Obesity is known to cause a chronic proinflammatory state in the body,[11,12,13] and this may be strongly associated with IIH development.

Several mechanisms have been proposed by which an inflammatory process could be involved in IIH pathogenesis, partly to explain the strong association of obesity and IIH. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11b-HSD1)), a modulator of glucocorticoids, may have a potential role in IIH by regulating CSF secretion. It has been shown to be dysregulated with increased activity in both obesity and IIH.[14] In humans, 11b-HSD1 increases local cortisol levels. Long-standing high cortisol levels have been shown to increase secretion of pro-inflammatory mediators[15] and possibly to increase the production of CSF by affecting sodium transporters in the choroid plexus.[14] Weight loss and lower ICP values have been shown to reduce 11b-HSD1-levels in IIH patients.[14]

A first phase II randomized controlled trial in IIH evaluated the in vivo efficacy of 11b-hydroxysteroid dehydrogenase type 1 inhibitor AZD4017 compared with placebo. They demonstrated reduction in serum cortisol: cortisone which correlated with decreased intracranial pressure.[16]

The possible role of proinflammatory cytokines and apokines such as leptin, IL-2, IL-10, IL-12, IL-17, and TNF-α have been studied in IIH. Several studies have demonstrated increased or decreased levels of these inflammatory mediators indicating again that proinflammatory activation could plausibly be involved in the pathogenesis of IIH.[9,17,18,19] Adipokines such as leptin, could act directly on the choroid plexus or arachnoid granulation tissue, or indirectly via peripheral mechanism with consequent secondary central effects that modify CSF secretion and absorption. But the role it may have in disease development requires further investigation.

Chronically increased circulating or CSF cytokines in an obese individual may result in fibrotic changes or lead to a hypercoagulable state causing blockage of the arachnoid granulations and, therefore, reducing drainage of CSF.

Exposure to an infectious or inflammatory disorder in the year preceding IIH diagnosis was significantly associated with increased odds of developing IIH supporting the hypothesis that a major inflammatory activation could act as a trigger factor to IIH development.[20]

The authors of this paper looked at the neutrophil-to-lymphocyte ratio NLR (neutrophil count divided by lymphocyte count) and platelet-to-lymphocyte ratio PLR (platelet count divided by lymphocyte count) as inflammatory markers in IIH. This is because platelets and neutrophils are mediators of inflammatory responses. The NLR and PLR have been studied as inflammatory markers in other systemic and ocular inflammatory diseases and also in non-arteritic anterior ischemic optic neuropathy.[21] But has not been studied in IIH previously, hence this seems like a novel concept that has thrown additional perspective on the role of inflammation in IIH. Interestingly this paper found that NLR and PLR were higher in patients with IIH than controls (P < 0.05), higher in patients with papilledema (P < 0.05) in the IIH group and were found to be associated with worse visual acuity. The authors certainly have provided a simple and easy to obtain blood test that could be further explored prospectively as an inflammatory marker in IIH. As cited in their manuscript, prospective studies are needed to study the correlation of NLR and PLR with the previously defined inflammatory markers in IIH to truly understand their role in ICP regulation.