New insight into the cranial nerve pathology secondary to elevated CSF pressure

In an innovative case-control study, Becker and colleagues investigated whether lumbar puncture with CSF drainage improves olfactory function in patients with idiopathic intracranial hypertension (IIH) (1). In this study, a semi-quantitative olfactory function test, Sniffin’ Sticks, was conducted and compared between IIH patients and two groups of control subjects, age-, sex-, and body mass index (BMI) matched healthy controls and neurological controls; that is, patients with other neurological disorders who underwent a lumbar puncture. After the lumbar puncture and CSF drainage, the olfactory scores improved within 24 hours exclusively in IIH patients but not in the neurological controls. This study exhibited a particular importance to the understanding of the mechanism of hyposmia in patients with IIH.

The concept of olfactory dysfunction in IIH is relatively new. Kunte and colleagues in 2013 reported that hyposmia exists in patients with IIH in comparison to healthy controls (2). Additionally, the presence of hyposmia probably reflects the disease activity – patients with active IIH were more likely to report hyposmia compared to those who had been treated (2). Interestingly, patients with idiopathic normal pressure hydrocephalus (iNPH), another disease relevant to the dysfunction of CSF homeostasis, also showed hyposmia and even pertinent structural changes – reduced olfactory bulb volume (3). However, it remains unknown where and what the pathology is behind an olfactory dysfunction in regard to the dysfunction of CSF homeostasis. The current study provides a strong argument for a functional basis of olfactory dysfunction, at least in the case of IIH. A follow-up period of less than 24 hours is too short to allow certain structural reorganization, which renders a functional dysfunction the only possibility. The exact mechanism behind the improvement is still unclear. One of the possibilities for a rapid restoration of olfactory sensitivity is an altered glymphatic pathway – spontaneous CSF drainage into the perivascular space (4), specifically CSF efflux via the olfactory bulb in IIH (5): Certain IIH patients developed spontaneous CSF rhinorrhea, which possibly in part affects the olfactory function (6). The mechanism for how the CSF dysregulation leads to an olfactory nerve (or bulb) pathology may not be limited to the olfactory nerve but also to other cranial nerves, including the visual nerve (7), which is associated with the most dreadful complication of IIH – visual loss.

While the study provides clues as to how intracranial hypertension leads to the dysfunction of the olfactory nerve, and possibly other cranial nerves, the etiology of intracranial hypertension in the first place (the cause of IIH) cannot be answered in the study design. Another limitation in the current study is the high prevalence of hyposmia in the neurological controls. We do not know yet whether the olfactory test in this study, the Sniffin’ Sticks, is too sensitive but not specific, or the olfactory dysfunction as such is rather common in neurological disorders but has been for a long time under-recognized. Therefore, we still need validation studies not only for IIH, but also validation of the olfactory (dys)function in other neurological diseases. In the end, olfactory examination, in comparison to the other neurological examination, has long been the relatively neglected neurological examination, except in certain diseases, for example, Lewy body diseases. We now start to recognize the olfactory dysfunction in IIH, but it could be more than just IIH.

Despite the authors’ best efforts, it remains of question, are the neurological controls in the study good enough? There is an inherent difference in the IIH cohort and the neurological control in regard to the lumbar puncture. In IIH, the lumbar puncture serves as a diagnostic tool and a therapeutic trial, thus usually an average of 20–30 ml of CSF is drained until the CSF pressure normalizes. However, in the control group, most patients received a diagnostic tapping, in which only small amount of CSF was removed with minimal change in the CSF pressure before and after the lumbar puncture. In this case, we still do not know whether an improvement of the olfactory function is “IIH” specific, or “pressure-reduction” specific. An alternative is to use patients with iNPH as a control group. These patients usually undergo a diagnostic and therapeutic tapping, in which a large amount of CSF, up to 30 ml, is removed. Nevertheless, this group bears other confounding factors. The patients with iNPH are usually older and show no obvious sex predominance, unlike the female predominance seen in IIH. Both factors render the comparison between IIH and iNPH difficult.

The understanding of IIH pathophysiology has improved over the last few years thanks to the progress on its association with obesity, adipose tissue distribution/dysregulation, and androgen sex hormones (4). Despite the limitations, the current study adds to the evidence on how CSF dysregulation as seen in IIH could lead to cranial nerve pathology such as hyposmia. Such a study plays a critical role in our understanding of a disease mechanism and serves as a potential paradigm shift from empirical treatments toward mechanism-based treatments in the future.