Idiopathic intracranial hypertension
The veno glymphatic connections

We thank Drs. Kronenberg and Kunte for their comments and interest in our Medical Hypothesis.¹ Several authors have suggested that most patients with idiopathic CSF leaks have underlying idiopathic intracranial hypertension (IIH).^2,3 Several clinical and radiologic arguments support this. First, there is the common clinical pattern in which the disease occurs (young obese women), then the high prevalence of radiologic signs of IIH in patients with idiopathic CSF leaks,⁴ the development of IIH symptoms following CSF leak repair, as well as the high rate of recurrence after surgery.⁵ We, therefore, suggest that the leaks are directly caused by overflow from the overburdened lymphatic CSF outflow pathway in these cases. The chronic excess of increased CSF pressure in the sheaths of the cranial nerves, and especially the olfactory bulbs, would lead to the progressive erosion of the bone and the dura matter at the level of the skull base (e.g., the cribriform plate), eventually resulting in CSF leaks. The leak will immediately relieve the headache and the IIH symptoms experienced by the patient, since it is a “natural” CSF diversion procedure. However, its surgical repair may result either in the development of IIH symptoms or in a recurrence of a leak. This recognition of this entity is important in clinical practice, when facing a patient with a CSF leak caused by IIH, since the treatment of the leak should be performed in conjunction with treatment of IIH, which is the often the underlying cause of the leak.

1. Lenck S, Radovanovic I, Nicholson P, et al. Idiopathic intracranial hypertension: The veno glymphatic connections. Neurology 2018;91:515–522.
2. Pérez MA, Bialer OY, Bruce BB, Newman NJ, Biousse V. Primary spontaneous cerebrospinal fluid leaks and idiopathic intracranial hypertension. J Neuroophthalmol 2013;33:330–337.
3. Bialer OY, Rueda MP, Bruce BB, et al. Meningoceles in idiopathic intracranial hypertension. AJR Am J Roentgenol 2014;202:608–613.
4. Martínez-Capoccioni G, Serramito-García R, Martín-Bailón M, García-Allut A, Martín-Martín C. Spontaneous cerebrospinal fluid leaks in the anterior skull base secondary to idiopathic intracranial hypertension. Eur Arch Otorhinolaryngol 2017;274:2175–2181.
5. Teachey W, Grayson J, Cho DY, Riley KO, Woodworth BA. Intervention for elevated intracranial pressure improves success rate after repair of spontaneous cerebrospinal fluid leaks. Laryngoscope 2017;127:2011–2016.

For disclosures, please contact the editorial office at [email protected].

We thank Drs. De Simone and Ranieri for their comments and interest in our paper.¹

Our hypothesis doesn't support a dysfunction of aquaporin 4 (AQP-4) in idiopathic intracranial hypertension (IIH); rather, an unknown type of AQP (e.g., aquaglyceroporin) may be involved at the venodural junction and may trigger the hydrodynamic cascade of IIH. We agree that a direct discharge of glymphatic fluid into the venous blood has not been documented in studies of CSF hydrodynamics;² however, the techniques used to demonstrate the existence of the glymphatic and lymphatic systems of the brain were not able to detect any venous CSF outflow, leading some to question even the existence of a venous CSF outflow pathway in the brain.³ Based on our clinical experience (i.e., cerebral venous thrombosis) and on previous experimental studies, we feel that a direct discharge of glymphatic fluid into venous blood seems highly likely.⁴

It may seem hazardous to extrapolate the physiology of CSF excretion from animals to humans, since the venous physiology and anatomy of quadrupedal animals are very different from those of bipedal humans.⁵ We agree that the discovery of an arachnoid granulation (AG) may be incidental and that the prevalence of AG in the lumen of the sinuses increase with age; however, pathologic and radiologic studies have described a specific type of AG, mostly observed in the transverse sinus and particularly at the junction between the vein of Labbé and the transverse sinus (e.g., lateral sinus stenoses in IIH). These granulations are centered on a vein and associated with the point of entry of a cortical vein into the dural sinus. We named them "vascular AGs" to differentiate from avascular granulations which allow the pressure-dependant transport of CSF from the subarachnoid space to the venous blood of the dural sinuses. These vascular AGs may allow a connection between the perivascular spaces of large cortical veins to the venous blood of the dural sinuses and may be involved in the discharge of interstitial fluid (CSF) from the glymphatic system to the venous blood of the dural vessels.⁶

Several arguments support the hypothesis that extrinsic stenoses are caused by the compression of the lateral sinus by the congested brain and CSF (and not by the increased intracranial pressure [ICP]), including the radiologic aspect of such stenoses on MRI, the propensity of such stenoses to reoccur outside the stented portion of the sinus, the fact that the radial force of the stent is usually enough to reopen the sinus with no need for balloon angioplasty, and their disappearance after CSF removal.^7,8 We agree that the venous sinus stenosis is the main precipitating factor in IIH symptoms since it makes the venous outflow pathway ineffective for the glymphatic reabsorption and the direct reabsorption, which aims to balance the ICP. Stent placement allows reestablishment of the direct reabsorption of the CSF from the subarachnoid space to the venous blood of the dural sinuses, thus regulating the ICP and resolving IIH symptoms.

1. Lenck S, Radovanovic I, Nicholson P, et al. Idiopathic intracranial hypertension: The veno glymphatic connections. Neurology 2018;91:515–522.
2. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 2012;4:147ra111.
3. Murtha LA, Yang Q, Parsons MW, et al. Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats. Fluids Barriers CNS 2014;11:12.
4. Boulton M, Young A, Hay J, et al. Drainage of CSF through lymphatic pathways and arachnoid villi in sheep: measurement of 125I-albumin clearance. Neuropathol Appl Neurobiol 1996;22:325–333.
5. Aurboonyawat T, Suthipongchai S, Pereira V, Ozanne A, Lasjaunias P. Patterns of cranial venous system from the comparative anatomy in vertebrates. Part I, introduction and the dorsal venous system. Interv Neuroradiol 2007;13:335–344.
6. Trimble CR, Harnsberger HR, Castillo M, Brant-Zawadzki M, Osborn AG. "Giant" arachnoid granulations just like CSF?: NOT!! AJNR Am J Neuroradiol 2010;31:1724–1728.
7. Baryshnik DB, Farb RI. Changes in the appearance of venous sinuses after treatment of disordered intracranial pressure. Neurology 2004;62:1445–1446.
8. Lenck S, Vallée F, Labeyrie MA, et al. Stenting of the Lateral Sinus in Idiopathic Intracranial Hypertension According to the Type of Stenosis. Neurosurgery 2017;80:393–400.

For disclosures, please contact the editorial office at [email protected].

The Medical Hypothesis paper by Lenck et al.¹ provided an exciting new angle on recent findings concerning CSF circulation in the brain. The authors succinctly summarized clinical and radiologic evidence supporting their hypothesis that dysfunction of veno glymphatic connections lies at the heart of idiopathic intracranial hypertension (IIH). In particular, the authors speculated that chronic overflow of CSF in the sheaths of the olfactory bulbs may result in CSF rhinorrhea by eroding the cribriform plate.¹ Olfactory dysfunction, especially a marked impairment in olfactory threshold levels, is an even more common yet under-recognized presentation of IIH.^2,3 Indeed, as early as 2008, Dr. Kapoor speculated that dysfunction of the extensive lymphatic network around the olfactory nerves might be causally linked to IIH, making hyposmia a more sensitive predictor of IIH than other clinical features.⁴

1. Lenck S, Radovanovic I, Nicholson P, et al. Idiopathic intracranial hypertension: The veno glymphatic connections. Neurology 2018;91:515–522.
2. Kunte H, Schmidt F, Kronenberg G, et al. Olfactory dysfunction in patients with idiopathic intracranial hypertension. Neurology 2013;81:379–382.
3. Bershad EM, Urfy MZ, Calvillo E, et al. Marked olfactory impairment in idiopathic intracranial hypertension. J Neurol Neurosurg Psychiatry 2014;85:959–964.
4. Kapoor KG. Do patients with idiopathic intracranial hypertension suffer from hyposmia? Med Hypotheses 2008;71:816–817.

For disclosures, please contact the editorial office at [email protected].

We read the interesting idiopathic intracranial hypertension (IIH) pathogenetic Medical Hypothesis by Lenck et al.¹ We agree that the lymphatic interstitial/cerebrospinal fluid (ISF/CSF) outflow is increased by intracranial hypertension and may explain part of IIH symptoms. However, the asymptomatic primary impairment of ISF/CSF outflow proposed by the authors—mediated by a putative acquaporine 4 (AQP4) dysfunction at the vascular arachnoid granulations (VAG) interface with the dural sinuses and followed by the secondary sinus stenosis with symptomatic shift—is exceedingly weak and possibly misleading. In fact, the AQP4-glymphatic existence as a convective vs diffusive ISF/CSF outflow route has been very recently questioned.² ISF/CSF containing intraventricular administered tracers do not drain through venous sinus, as proposed, but through nasal lymphatic.³ The VAG are very common in subjects without intracranial vascular pathology,⁴ while IIH is rare. The sinus wall should bear CSF pressure much higher than that possibly associated with an asymptomatic stage of lymphatic dysfunction.⁵ Finally, after sinus stenting, the intracranial pressure returns to fully physiologic values in responders.⁶ Therefore, the hypothesis of an asymptomatic primary CSF hypertension by glymphatic impairment leading to a secondary symptomatic sinus stenosis is highly unlikely.

1. Lenck S, Radovanovic I, Nicholson P, et al. Idiopathic intracranial hypertension: The veno glymphatic connections. Neurology 2018;91:515-522.
2. Abbott NJ, Pizzo ME, Preston JE, et al. The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system? Acta Neuropathol 2018;135:387-407.
3. Murtha LA, Yang Q, Parsons MW, et al. Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats. Fluids Barriers CNS 2014;11:12.
4. Gailloud P, Muster M, Khaw N, et al. Anatomic relationship between arachnoid granulations in the transverse sinus and the termination of the vein of Labbe: an angiographic study. Neuroradiology 2001;43:139-143.
5. Martins AN, Kobrine AI, Larsen DF. Pressure in the sagittal sinus during intracranial hypertension in man. J Neurosurg 1974;40:603-608.
6. Patsalides A, Oliveira C, Wilcox J, et al. Venous sinus stenting lowers the intracranial pressure in patients with idiopathic intracranial hypertension. J NeuroInterv Surg Epub 2018 Jun 5.

For disclosures, please contact the editorial office at [email protected].