INTRACRANIAL PRESSURE AND
CEREBROSPINAL FLUID DYNAMICS IN IDIOPATHIC INTRACRANIAL
HYPERTENSION
Erik Martoma Thesis
Medicine
University of Eastern Finland / Faculty of Health Sciences
School of Medicine / Neurosurgery April 2020, Kuopio
UNIVERSITY OF EASTERN FINLAND, Faculty of Health Sciences School of Medicine, Medicine
MARTOMA, ERIK: Intracranial pressure and cerebrospinal fluid dynamics in idiopathic intracranial hypertension
Thesis, 29 pages
Tutors: HUUSKONEN TERHI; MD, specialist, ELOMAA ANTTI-PEKKA; MD, registrar April 2020
Background: Idiopathic intracranial hypertension (IIH) is a rare disease mostly seen in young obese women. Diagnosis of IIH is based on the presence of papilledema and/or raised intracranial pressure (ICP) without any secondary causes. The diagnosis is contributed by unremarkable neurological examination, radiologic imaging findings and cerebrospinal fluid (CSF) composition. The etiology and pathogenesis of IIH are unclear, but there are multiple theories about the origin of IIH. Disturbed hormonal factors and obesity may contribute to the development of the condition, but most of the causative mechanisms suggest a role for CSF hypersecretion, increased venous sinus pressure and in parallel, obstruction in the CSF outflow.
Objective: To characterize the nature of the altered CSF dynamics in IIH we performed a meta-analysis to determine how invasive CSF infusion tests have been utilized in these populations.
Methods: In this systematic review we used computerized Pubmed search to establish robust knowledge of the studies concerning IIH and CSF dynamics to identify prospective or retrospective cohorts or case series of patients with IIH studied with CSF infusion tests between January 1980 and December 2016.
Results: A total of 178 IIH patients were included in ten studies. Majority of the studies were done in the end of 20th century and the cohorts were rather small (range 6-67 IIH patients). Half of the studies were case series and the rest case-control studies. Only one was a prospective study. The IIH patients were relatively young (range 2-63 years) and majority were female, which supports earlier knowledge. All studies measured ICP invasively either intracranially or via lumbar way. Studies reported CSF dynamics such as CSF opening pressure, CSF formation rate, resistance/conductance of CSF outflow, continuous pressure values, and sagittal sinus pressure. CSF and sagittal sinus pressure were elevated in most of the studies, but only the CSF pressure decreased during the CSF drainage. Resistance of CSF outflow was increased, and there was also a positive linear relationship between resistance and the ICP. In one study CSF formation rate tended to decrease on IIH patients with higher than average ICP values. One study illustrated so called B waves during the continuous CSF monitoring, present for at least 50% of the time.
Conclusion: Patient populations diagnosed with IIH illustrate consistently altered CSF dynamics. Increased CSF pressure, resistance of the CSF outflow and sinus sagittalis pressure were the most common findings in IIH patients. Most of the studies were old and the diagnosis of IIH altered from modern standards. Further research is warranted on the subpopulations diagnosed with IIH as the deranged CSF hydrodynamics is key factor in its pathogenesis.
KEY WORDS: idiopathic intracranial hypertension • cerebrospinal fluid dynamics • infusion test • intracranial pressure • sinus sagittalis pressure
ITÄ-SUOMEN YLIOPISTO, Terveystieteiden tiedekunta Lääketieteen laitos, Lääketieteen koulutusohjelma
MARTOMA, ERIK: Intracranial pressure and cerebrospinal fluid dynamics in idiopathic intracranial hypertension
Opinnäytetutkielma, 29 sivua
Tutkielman ohjaajat: HUUSKONEN TERHI; LT, erikoislääkäri, ELOMAA ANTTI- PEKKA; LT, erikoistuva lääkäri
Huhtikuu 2020
Tausta: Idiopaattinen intrakraniaalinen hypertensio (IIH) on harvinainen tauti, jota tavataan tyypillisesti nuorilla ylipainoisilla naisilla. Taudin diagnoosi perustuu näköhermon pään turvotukseen ja/tai kohonneeseen kallonsisäiseen paineeseen, jonka taustalla ei ole muuta syytä. Diagnoosia tukee näennäisen normaali neurologinen status, pään kuvantamislöydös ja likvorin koostumus. IIH:n etiologia ja patofysiologia ovat edelleen epäselvät, mutta sen synnylle on esitetty lukuisia teorioita.
Hormonaalisten tekijöiden ja ylipainon arvellaan myötävaikuttavan tautiin, mutta vaikuttavimmiksi tekijöiksi on arveltu eri syistä johtuvaa kohonnutta laskimosinuspainetta, ja likvorin liikatuotantoa tai sen poistumisesteitä.
Tavoite: Selvittääksemme IIH-taudin likvorin dynamiikkaa teimme meta-analyysin ja raportoimme miten likvortiloja testaavia infuusiotestejä on sovellettu IIH-potilaissa.
Metodit: Tässä systemaattisessa kirjallisuuskatsauksessa etsimme eri hakusanayhdistelmin Pubmedistä tietoa IIH-potilailla tehdyistä likvorin infuusiotesteistä saadaksemme kattavan kuvan jo tehdyistä tutkimuksista mukaan lukien prospektiiviset, retrospektiiviset sekä tapausselostustutkimukset, joissa on tutkittu IIH:ta ja aivo-selkäydinnesteen dynamiikkaa.
Tulokset: Löysimme kymmenen artikkelia, joissa oli yhteensä 178 potilasta. Suurin osa tutkimuksista oli 1900-luvun lopulta ja niiden kohortit olivat pieniä (6-67 IIH- potilasta). Puolet tutkimuksista oli tapausselostuksia ja puolet tapaus- verrokkitutkimuksia. Vain yksi tutkimuksista oli prospektiivinen. IIH-potilaat olivat suhteellisen nuoria (2-23 vuotta) ja suurin osa oli naisia, mikä tukee aiempaa tietoa.
Kaikissa tutkimuksissa kallonsisäistä painetta mitattiin invasiivisesti joko kallonsisäisesti tai lumbaalisesti. Tutkimuksissa seurattiin monia likvorin dynamiikan suureita, kuten likvorin avauspainetta, syntynopeutta, ulosvirtauksen konduktanssia ja resistenssiä, jatkuvia painearvoja sekä sinus sagittaliksen painetta. Suurimmassa osassa tutkimuksista sekä likvorin että sinus sagittaliksen paine olivat koholla, mutta näistä ainoastaan likvorin paine laski likvoria poistettaessa. Likvorin ulosvirtauksen resistenssi oli kohonnut, ja sen sekä kallonsisäisen paineen välillä todettiin positiivinen lineaarinen yhteys. Yhdessä tutkimuksessa likvorin syntynopeus laski niillä IIH- potilailla, joiden kallonsisäinen paine oli keskiarvoa korkeampi. Lisäksi yhdessä tutkimuksessa todettiin ns. B-aaltoja vähintään 50% mittausajasta.
Päätelmä: IIH-potilailla todettiin johdonmukaisia muutoksia likvorin dynamiikassa.
Kohonnut likvorin paine, ulosvirtauksen resistenssi ja sinus sagittaliksen paine olivat yleisimmät löydökset IIH-potilailla. Suurin osa tutkimuksista oli vanhoja ja IIH:n diagnostiikka niissä oli erilaista, kuin nykyään. Lisää tutkimusta tarvitaan IIH- potilailla, sillä häiriintynyt aivo-selkäydinnestekierto on avainasemassa IIH:n patogeneesissä.
Contents
1 BACKGROUND 5
1.1 Idiopathic intracranial hypertension 5
1.1.1 Rationale for research 5
1.1.2 Epidemiology 5
1.1.3 Pathogenesis 6
1.1.4 Clinical presentation and diagnosis 7
1.1.5 Treatment 9
1.2 Intracranial pressure 10
1.3 Cerebrospinal fluid 11
1.4 Cerebrospinal fluid dynamics 12
1.5 Infusion techniques 14
1.6 Aim of the study 15
2 MATERIALS AND METHODS 15
3 RESULTS 16
4 DISCUSSION 22
5 CONCLUSION 25
REFERENCES 26
1 BACKGROUND
1.1 Idiopathic intracranial hypertension 1.1.1 Rationale for research
Idiopathic intracranial hypertension (IIH) is a rare disease that is mostly seen among young and obese women. Main symptoms of IIH are headache and momentary visual symptoms. However, if IIH is not treated well, it may lead to total loss of vision. Almost all IIH patients have papilledema and increased intracranial pressure (ICP), which are included in the diagnostic criteria. The patients are described by unremarkable findings in neurological examination, radiologic imaging and cerebrospinal fluids (CSF) chemical and cytological composition. Nevertheless, the first line treatment of IIH is weight loss, medical treatment, and in selected severe cases, surgical.1,2
The pathophysiology of IIH is still unclear. The suggested mechanisms include increased venous sinus pressure, CSF hypersecretion and CSF outflow obstruction.
Simply put, the CSF dynamics is based on three components: production, circulation and absorption of CSF, which can be tested with CSF infusion protocols. Such CSF infusion tests have been be used to investigate mechanisms of IIH pathogenesis, also, but comprehensive reviews on their utilization and findings in IIH patients are lacking.1,2 1.1.2 Epidemiology of IIH
Idiopathic intracranial hypertension is a disease that has been reported since late 1890s.1 Patient with IIH is typically a young obese woman and has an increased ICP but no established pathogenesis.2 The term benign intracranial hypertension has been rejected as the disease can result in loss of vision if it is not treated properly or early enough.1
As mentioned, women are more likely to have IIH than men, as the female:male ratio varies from 3:1 to 18.5:1.1,2 For IIH it is typical that it occurs mostly among obese women – the prevalence is approximately 1 case/100000 women but increases to 13 cases/100000, as women of ages from 20 to 44 with a body weight 10% above the ideal, are observed.1 Among obese (body weight more than 20% above ideal) women the prevalence is already 19 cases/100000.1 The prevalence of the IIH among men and pediatric patients has not been studied that well due to a lack of large
epidemiological studies.2 The incidence among men has been reported to be approximately 0.3 cases/100000 men and it increases when obese men are observed.1 In pediatric population, the female preponderance disappears.1 As the obesity rates have grown and continue to grow according to WHO reports, the incidence of the IIH is approximated to grow.2
1.1.3 Pathogenesis of IIH
The pathogenesis of IIH is still unclear but there are plenty of different theories trying to describe why does ICP increase among the patients with IIH. Mostly suggested mechanisms are intracranial: CSF hypersecretion and outflow obstruction along with increased venous sinus pressure.2 The hypersecretion has been studied for instance by initial infusion and magnetic resonance imaging (MRI) studies but findings have not been significant,2 except for some cases that has involved plexus choroid papilloma.1,2 Increased cerebral blood volume or brain water content have also been investigated, but the evidence has not been strong.1,2 The obstruction of CSF outflow is not proved to be a significant pathogenic mechanism as the absorption mechanism of CSF is still rather unclear.2 Some studies have suggested that IIH is a result of increased venous pressure that respectively has an impact to CSF absorption.1 Also increased sinus pressure caused by sinus stenosis has been suggested, but it has been turned out that sinus stenosis is more like a result from IIH than a cause of the disease.2, Figure 1.
In addition to these theories, obesity and hormonal factors have been considered.
Majority of studies suggest that increase in weight and obesity both are associated with IIH.2 Some clinical studies and observations support this suggestion as the loss in weight has a positive influence in signs and symptoms of IIH according to the prospective cohort study.2 Despite these findings the mechanism is still unknown – there have been suggestions that raised abdominal mass results in increased intrathoracic pressure and therefore in increased sinus pressure, but this theory doesn’t explain why IIH is observed mainly in women.2 Thus, the hormonal factors have been considered: the effects of female hormone have been researched as well as the possible effects of glucocorticoids.2
1.1.4 Clinical presentation and diagnosis in IIH
The IIH is a disease that has a plethora of symptoms that varies between patients, and may complicate and delay making the right diagnosis.2 Headache is the most dominant symptom of the IIH as the incidence is approximately 75-94%.1,2 In addition to headache, momentary visual symptoms such as blurring or horizontal double visions have been reported.1,2 Other symptoms include tinnitus, dizziness, numbness, impairments in smelling and problems in cognition.1,2
Basically all IIH cases include papilledema and thus the ophthalmoscopic examination has a crucial role in diagnosing IIH.1 Nevertheless, it is important to be aware of the fact that papilledema is not manifested or recognized in all patients.1 In IIH cases increased ICP causes swelling of the intraocular part of the optic nerve head, which results in an ischemia in it and may lead to optic atrophy and hence cause a total loss of vision.2 Papilledema can be unilateral or bilateral, although the latter is more
Figure 1. Mechanism involving elevated intracranial pressure on IIH. Obesity, female sex and venous sinus stenosis are suggested to increase venous sinus pressure and hence affect reduction in drainage of CSF across subarachnoid villi.
Moreover, obesity and female sex may result in elevated inflammatory and thrombophilia factors. Both increased CSF formation rate and impaired lymphatic drainage have an influence on raised ICP. (Image adopted from: Markey KA, Mollan SP, Jensen RH, Sinclair AJ. Understanding idiopathic intracranial hypertension: Mechanisms, management, and future directions. Lancet Neurol. 2016;15(1):78-91).
common. 2, Figure 2. Usually papilledema develops gradually but occasionally the development can be quick.2 First it has a negative impact to the peripheral vision and thus patients may not notice any changes in vision and therefore they may be careless when it comes to vision testing.1 This may be fateful as the central visual acuity can stay unaltered, while permanent damages already occur in the optic nerve head.1
Current diagnostic criteria rest on Dandy criteria that were brought out in 1937.3 Since then these criteria have been revised as both imaging techniques and understanding of the disease have improved.2 MRI and computer tomography (CT) provide a possibility to rule out the secondary causes, e.g. venous sinus thrombosis or tumors.2, Figure 3.
The diagnosis of IIH is nevertheless based on the following criteria: (1) papilledema, (2) no significant deviances in neurological examination excluding abducens and facial palsies as well as false localizing neurological signs, (3) normal imaging findings and no signs of a dural sinus thrombosis, (4) the chemical and cytological composition of
Figure 2. Papilledema. (A): Mild papilledema; burring & elevation of nasal disc margin (arrow), (B): Moderate papilledema: vessel obscuration caused by oedematous nerve fibre layer, (C, D, E): Severe papilledema: cotton wool spots, nerve fibre layer haemorrhage (arrows C and D), venous
engorgement and tortuosity (arrow E), (F): Papilledema & secondary optic atrophy.(Image adapted from: Mollan SP, et al. Pract Neurol 2014;14:380–
390. doi:10.1136/practneurol-2014-000821)
the CSF is normal (CSF can contain some protein) and (5) the lumbar opening pressure is raised and is more than 250mmH2O in lateral decubitus.1,2
1.1.5 Treatment of IIH
Currently, there is no consensus on the optimal treatment of IIH.2 IIH can be managed by either conservative or by surgical methods. Conservative methods include weight loss and medical treatment. Dieting has a significant role in treatment on ground of several studies claiming that weight loss results in reduced ICP and alleviating of headaches and papilledema.2 The most used drug is acetazolamide that is a carbonic anhydrase inhibitor and affects mainly papilledema by influencing the CSF production that takes place at the choroid plexus.2 For those who cannot use acetazolamide, furosemide may be an alternative, although it has only a little impact on CSF production.1,2 Topiramate and octreotide are possible drugs in treatment but further studies are needed.2
Surgical treatment needs to be considered or is necessary when the conservative treatment is insufficient, the loss of vision is progressive or patient has pertained difficult headaches.1,2 Optic nerve sheath fenestration (ONSF), CSF shunting, venous sinus stent placement and bariatric surgery are invasive treatment options in IIH.2
Figure 3. Radiologic imaging findings in IIH. The radiologic imaging should be by definition normal (left), but unorthodox findings such as empty sella (middle top), optic nerve oedema (middle bottom), and sinus stenosis (left) have been documented. (Image adopted from: Degnan AJ, Levy LM. Pseudotumor cerebri: brief review of clinical syndrome and imaging findings. AJNR Am J Neuroradiol. 2011 Dec;32(11):1986-93. doi:
10.3174/ajnr.A24Epub 2011 Jun 16. Review. PubMed PMID: 21680652)
1.2 Intracranial pressure
Intracranial pressure (ICP) is simply a pressure that prevails inside the skull. This pressure consists of three components: (1) an arterial vascular component, (2) cerebrospinal fluid (CSF) circulatory component and (3) a venous outflow component.
4,5 The normal ICP varies from 5 to 15 mmHg, 6 whereas the dangerous values of ICP are from 20-25 mmHg upwards.5 Increased ICP can be, for instance, a consequence of a pathological process, a head injury or an intracerebral bleed.5 Elevated ICP interferes normal blood flow and may cause secondary ischemia.4 ICP is an invasively measurable value that can be measured via intraventricular catheter, intraparenchymal probe or lumbar puncture.5 ICP is usually measured continuously after head injury, subarachnoid hemorrhage, hydrocephalus, intracerebral hemorrhage, meningitis and hepatic encephalopathy.6
Dynamic changes occur when ICP is measured. These changes result from normal variations in cerebral blood volume (CBV), resulting in different ICP waveform components.4 In a normal situation it has been postulated that there are two types of waveforms; (1) small pulsations transmitted by systemic blood pressure into intracranial compartment and (2) blood pressure pulsations that are superimposed on slower respiratory variations.7 The pulse waveform follows the heart rate (50-180 beats/minute), as the respiratory waveform has a frequency of 8-20 cycles/minute.4 Cardiac cycle causes alterations in arterial CBV, which results in pulse pressure waveforms. Respiratory waves are induced by the venous CBV changes that are caused by alterations in the pressure of the intrathoracic space. During expiration, the pressure in the superior vena cava increases, which reduces venous outflow from cranium resulting in increased ICP.7
In the case of increased ICP, the cerebral compliance decreases, the venous components disappear and the arterial pulses become more pronounced. In right atrial cardiac insufficiency, the central venous pressure increases and the ICP waveform takes more rounded appearance. There are three pathological waveform types with a peculiar frequency that can be observed by spectral analysis described by Lundberg;
8 (1) A waves: also called as plateau waves, are noted as ICP elevated ≥ 50mmHg for 5-20 minutes accompanied by increase in mean arterial pressure, (2) B waves:
pressure pulses of an amplitude of 10-20 mmHg lower than A waves with duration of
30 seconds to 2 minutes, (3) C waves: low amplitude waves with a frequency of 4-8 minutes and may be seen in the normal ICP waveform.
The pulse amplitude (AMP) is mostly used when the pulse pressure waveforms need to be assessed. The AMP can be measured by two apparently equal methods – using either time or frequency domain.4 The AMP gives information about the dynamics of the cerebrospinal pressure as it depends on mean ICP.6 Hence, it can be used as a diagnostic tool for instance for normal-pressure hydrocephalus.4
The morphological structure of the cardiac-derived pulse wave of ICP can also be a helpful indicator for some pathological conditions.4 Without any undergoing pathological processes, the shape of the waveform is based on three different peaks.
4,6,7 Peak one (P1) is so-called percussion wave that is associated with arterial pulsation. The following peak (P2) – the tidal wave – denotes the intracranial compliance and lastly the P3 is the dicrotic wave that indicates the aortic valve closure.
If ICP increases, pressure pulse becomes more smoothed as the tidal wave (P2) becomes dominant while percussion wave (P1) and dicrotic wave (P3) vanish.4 1.3 Cerebrospinal fluid
Cerebrospinal fluid (CSF) is colorless liquid that can be found from the ventricles in the brain and from the subarachnoid spaces both around the brain and the spine.
Compared to plasma, CSF has a lower concentration of glucose, protein, and potassium while having a higher concentration of chloride. The lower protein content reflects the degree of impermeability of the blood-CSF barrier to macromolecules.9 It provides central nervous system (CNS) a physical shelter from injuries through buoyancy.5 In addition, CSF has a function in deposing metabolites and toxins. It also operates in homeostatic hormonal signaling, chemical buffering, circulation of nutrients and neurodevelopment.10-13
CSF is formed mainly in the choroid plexus within the ventricles and around 30% of CSF comes from the interstitial fluid exudate from the pia from vessels. Production of CSF can be measured, although imprecisely, due to the lack of direct measuring methods.5 As the CSF is produced in the lateral and third ventricles, it starts to flow to the fourth ventricle through the aqueduct called Sylvius. After the fourth ventricle, CSF flows through the central hole called Magendie and bilateral holes called Luschka, into
the subarachnoid space. After these foramina CSF continues its way through the subarachnoid cisterns. From the subarachnoid space CSF travels over the cortical convexities and skull base until it is reabsorbed at the dural venous sinuses.14
CSF is absorbed mostly to the superior sagittal sinus through so-called subarachnoid granulations that are located in the subdural space. There is a pressure difference between the subarachnoid space and the sagittal sinus, which causes the absorption of the CSF. The ICP of subarachnoid space is greater than the pressure in the superior sagittal sinus and if this pressure gradient changes, the drainage of CSF stops.5 Especially in pathology some alternative CSF absorption mechanisms, such as intraparenchymal and periventricular absorption, have been presented.5 Small part of CSF flows towards the lumbar subarachnoid space, which compensates pressure- volume and is an important factor for fluid exchange.5
1.4 Cerebrospinal fluid dynamics
CSF dynamics is based on three components: production, circulation and absorption of cerebrospinal fluid, from which the undisturbed circulation is probably the most important factor assuring good circumstances for the CNS.5 The production rate of CSF has been reported to be about 0.35ml/min and almost constant.15 According to Marmarou’s theory,16 the CSF formation is equal to its storage and absorption in equilibrium condition:
𝐼𝑓= 𝐼𝑠+𝐼𝑎 (1.1)
where 𝐼𝑓, 𝐼𝑠 and 𝐼𝑎 are formation, storage and absorption rates, respectively with ml/min as an unit. Intracranial compliance is characterized pressure-volume index (PVI), dural sinus pressure (𝑃𝑑), resistance to absorption (𝑅), and an external input rate of fluid summed up with the intrinsic CSF formation rate. Compliance (C) represents brains’ capabilities to response to external volume addition to CSF space or internal pressure fluctuations. This compliance or elasticity is formulated as volume change per unit pressure difference, ∆𝑉 ∆𝑃⁄ . The compliance curve has an exponential feature and it varies mobbing along the curve. Hence, plotting the same data on a semilog scale exhibits a linear behavior and yields constant values as obtained from the slope of the line. The inverse slope is called PVI (ml), which is defined as the extra fluid volume necessary to increase the CSF pressure 10-fold.
Absorption rate (𝐼𝑎) is defined as the gradient of pressure between the venous system of the dural sinus (𝑃𝑑) and CSF space (𝑃) divided by the resistance to absorption (𝑅):
𝐼𝑎 = (𝑃−𝑃𝑑)
𝑅 (1.2)
Storage rate (𝐼𝑠) means the rate of change of CSF volume stored:
𝐼𝑠 = 𝑑𝑉
𝑑𝑡 (1.3)
There are alternative ways to define the previously described compliance (𝐶):
𝐶 = 𝑑𝑉
𝑑𝑃 (1.4)
As the compliance curve grows exponentially, the compliance can also be as follows:
𝐶 = 1
𝐾𝑃 (1.5)
where 𝐾 stands for a constant determining the steepness of compliance curve. Hence, when the (1.4) and (1.5) are combined, they form:
𝑑𝑃
𝑑𝑡 = 𝐾𝑃𝑑𝑉
𝑑𝑡 = 𝐾𝑃𝐼𝑠 (1.6a)
thus, the storage rate 𝐼𝑠 can be defined as follows:
𝐼𝑠 = 1
𝐾𝑃 𝑑𝑃
𝑑𝑡 (1.6b)
As the new terms for absorption (𝐼𝑎) and storage (𝐼𝑠) rates have been formed, they can be used as substitutes in the very first equation (1.1):
𝐼𝑓 = 1
𝐾𝑃 𝑑𝑃
𝑑𝑡 + (𝑃−𝑃𝑑)
𝑅 (1.7)
The standard differential equation can be simplified by rearranging the terms:
𝑑𝑃 𝑑𝑡+ 𝐾
𝑅𝑃2− 𝐾 (𝐼𝑓+𝑃𝑑
𝑅) 𝑃 = 0 (1.8)
A specific mathematical transformation can be used to form the general analytical time-dependent solution of (1.8) for pressure:
𝑃(𝑡) = 𝜓(𝑡)
[1
𝑃0+(𝐾𝑅) ∫ 𝜓(𝜏)𝑑𝜏0𝑡 ] (1.9) where 𝜓 (𝑡) = 𝑒𝐾 ∫ 𝐼(𝜏)𝑑𝜏0𝑡 is the integration factor.
The model shows that at the steady-state condition the CSF pressure (𝑃) depends on dural sinus pressure (𝑃𝑑) as well as on the formation rate (𝐼𝑓) and resistance to absorption (𝑅):
𝑃 = 𝑃𝑑+ 𝐼𝑓𝑅 (1.10)
1.5 Infusion techniques
Constant flow infusion and constant pressure infusion are gradual infusion mechanisms. In these methods, adding of fluid and monitoring of the time course of CSF pressure are done simultaneously. Constant flow infusion method is based on the uninterrupted infusion of fluid that occurs on top of the natural production speed.
In this method, the pressure depends on time and rises quickly, but later gradually stabilizes eventually reaching a balance (or plateau) with a steady-state pressure (𝑃𝑠𝑠).
This technique provides many possible ways to solve the outflow resistance (𝑅). A simply and static way is as follows:
𝑅 = 𝑃𝑠𝑠−𝑃𝑜
∆𝐼 (1.11)
where the 𝑃𝑜 stands for the resting pressure as the ∆𝐼 symbolises the infusion rate.17-
19 According to Juniewicz, 20 a slight increase in the resting pressure occurs after a constant infusion test.
Constant pressure infusion is the other technique that has been originally suggested by Ekstedt in 1977.21 In this method the pressure is continuously kept at the same level as the artificial CSF flow. Requirements of constant pressure infusion are a peristaltic infusion pump, two needles (one for infusion, one for measuring) and a computer-based system that regulates feedback system. In this method the CSF pressure increases gradually in a stepwise fashion, and on each level the CSF pressure and flow rate needs to be recorded. At the end of the infusion the resting
pressure is restored.22 This technique provides also a possibility to estimate the outflow resistance (𝑅) and it is a modification of a constant flow infusion. In constant pressure infusion, the CSF pressure is measured with the increments of small offset values.
Figure 4.
1.6 Aim of the study
Aim of this study was to establish known literature of all studies done on IIH patient population using CSF infusion analyses. An extensive and systematic literature review was performed by reviewing all the literature concerning CSF dynamics and ICP waveform analytics in IIH. The aim was to create more accurate CSF hydrodynamics hypothesis for further research in IIH.
2 MATERIALS AND METHODS
A computerized search of studies concerning IIH and CSF dynamics from PubMed was conducted between January 1980 and December 2016 using the following search terms: (“pseudotumor cerebri” OR “benign intracranial hypertension” OR “idiopathic
Figure 4. Infusion study on non-shunted IIH patient. (Image adapted from:
https://icmplus.neurosurg.cam.ac.uk/wp-content/uploads/2017/08/IIH.png; Cambridge, M.
Czosnyka)
intracranial hypertension” OR “IIH”) AND (“cerebrospinal fluid” OR “CSF”) AND (“absorption” OR “circulation” OR “dynamics” OR “homeostasis” OR “hydrodynamics”
OR “infusion study” OR “secretion” OR “resorption”)). Furthermore the following search terms were used: (“pseudotumor cerebri” OR “benign intracranial hypertension” OR “idiopathic intracranial hypertension” OR “IIH”) AND (“intracranial pressure waveform” OR “lumbar infusion”)). The search was limited to articles in English, and all case reports and reviews were excluded, as well as the animal studies.
Figure 5. Flow chart showing illustrating selection criteria.
3 RESULTS
As the Figure 5 shows above, the search gave 499 hits, and after extracting all the 272 duplicates, 227 unique abstracts were studied. Accordingly 201 abstracts were excluded: 36 were in Non-English language, three were case reports, eight were reviews, four were animal studies and 142 did not analyse CSF hydrodynamics in IIH.
Eight abstracts were published before January 1980, and therefore excluded. There were 26 articles evaluated, from which one was a case report, one was an animal study and one was a review. In addition, 13 articles were excluded, as those did not analyse CSF hydrodynamics in IIH. In the end, ten relevant cohorts were found and included in this review. The relevant cohorts are summarized below in Table 1.
Table 1.
AuthorsData collectionNo of IIH patients (% were females)Meanage & age range of IIH patients (years)
CSFdynamics test (study set up)VariablesstudiedCSF dynamics findings / results in IIH patients Pickard et al.2008Case series•9 patients (89 %)•41 •22-55•Invasive ICP monitoring (lumbar infusion test) •DRCV (intracranial)
Pcsf, Pss, sex, age•Pcsf slightly exceeded Pss •CSF infusionprovoked rises in Pcsf and Pss •CSF drainage decreased Pcsf compared to Pss Karahalios et al. 1996Case series•10 patients (70 %)•24 •2-40Invasive ICP monitoring (lumbar/intracranial)Pcsf,Pss, CVP,sex, age•Pcsf elevated •CVP elevated •Pss elevated Gideonet al. 1994Case-control study•12 patients (67 %) •10 healthycontrols•38 •12-61Invasive ICP monitoring (lumbar infusion test)ICP, R, sex, age•Increased R •Increased CSF volume amplitude Malm et al.1992Prospective case-control study
•13 clear IIH patients (69%) •45 controls•35 •16-59Invasive ICP monitoring (lumbar infusion test)Pcsf, Gop, F, Pdop, Pss•Pcsf increased •Gop significantlyreduced •Pdopincreased •Pss was elevated Hayashi et al. 1991Case series•8 IIH pts (NA %) •mixed cohort•NAContinous invasive ICP monitoring (lumbar infusion test and intracranial)
C, plateau waves (B and C waves), F•C reduced Lundar et al. 1990Case series•6 patients (50 %) •16 •3-39Invasive ICP monitoring (lumbar infusion test andintracranial)ICP, R, Po, Pp, sex, age, EPD•ICP increased •R from upper normal to pathologically increased •EPD labile but increased with a number of B waves Shakhnovich et al. 1990Case-control study•67 IIH patients (86%) •mixed cohort•NA •14-63Continous invasive ICP monitoring (lumbar infusion test)EL, F, R, Pis•EL increased •R significantly increased •No correlation between Pis and R Borgesenet al. 1987Case-control study•23 IIH patients (NA %) •mixed cohort•NAContinous invasive ICP monitoring (intracranial)ICP,R, F, duration of symptoms, Evans ratio, sex, age•ICP increased with R •Fdecreased in the higher ICP values •The Evans ratio was higher in patients with low or normal ICP •Higher ICP in patients with a short duration of symptoms •R was lower in patients with a long duration of symptoms Gjerriset al. 1985Case series•14 patients (71 %)•34 •12-61Continous invasive ICP monitoring (intracranial)ICP, C, CBF, plateau waves, B waves, sex, age•ICP borderline elevated or increased •C decreased •All had B waves > 50% of the time Janny et al.1981Case-control study•16 patients (50 %) •6 controls•25 •2-56Continous invasive ICP monitoring (intracranial)ICP, Pcsf, Pss, pressure gradient between Pcsf-Pss, Evans ratio, R•ICP was elevated •R was elevated Abbreviations: IIH= idiopathic intracranial hypertension;CSF= cerebrospinal fluid; ICP= intracranial pressure;DRCV= direct retrograde cerebral venography;Pcsf= CSF pressure;Pss= sagittal sinus pressure; CVP= central venous pressure; R= CSF outflow resistance; Gop= conductance of outflow pathways; F= CSF formation rate; Pdop= pressure differenceacross outflow pathways; NA = datanot available; C= conductance of CSF outflow; Po= opening pressure; Pp= plateau pressure; EPD= epidural intracranial pressure ; EL= elasticity of the CSF system; Pis= intrasinus pressure; CBF= cerebral blood flow
The most recent case series presented nine IIH patients of whom 89% were female.23, Table 1. The mean age of the patients was 41 years (range 22-55). ICP was monitored invasively by lumbar infusion test and direct retrograde cerebral venography. In this study CSF pressure (Pcsf) and sagittal sinus pressure (Pss) were measured, and both of them were increased during the CSF infusion (R=0.97, p<0.0007). In addition, Pcsf slightly exceeded Pss (27.0 ± 2.3 mmHg vs. 25.2 ± 7.5 mmHg; p=0.026, correlation R=0.97, p=0.0032). In eight cases drainage of CSF resulted in decreased Pcsf values compared to Pss values (-3.26 ± 3.9 mmHg; p=0.0097). Moreover, a strong correlation was found between slow waves of Pcsf and Pss (mean R=0.9), as well as between baseline pulse amplitudes of those pressures (R=0.91; p=0.03).23, Table 1. Another small case series studied ten IIH patients of whom 70% were female.24, Table1. The mean age of the patients was 24 years (range 2-40). ICP was monitored invasively via lumbar and intracranial ways. Age, sex, venous outflow, associated clinical condition, CSF pressure, superior sinus sagittalis (SSS) pressure, possible endovascular or surgical treatment and central venous pressure (CVP) from right atrial were studied.
CSF pressure, SSS pressure and CVP were elevated in all ten patients. SSS pressure was 16.6 mmHg (range 13-24). Some of the patients had dural venous outflow obstruction and endovascular techniques were used to ameliorate this obstruction but this did not alleviate clinical symptoms.24, Table1. Another small case series presented six IIH patients.25, Table 1. The mean age was 16 years (range 3-39), and half of the patients were women. ICP was measured by lumbar puncture in a steady state infusion test in five of six patients. Moreover, epidural intracranial pressure (EDP) was measured in three patients. Sex, age, presenting symptoms, clinical signs of IIH, medication, shunt treatment, opening pressure (Po), plateau pressure (Pp), ICP and CSF outflow resistance (Ro) were collected in this study. ICP and Po (range 13-48 mmHg) were increased in all patients, whereas Ro was increased either slightly or pathologically (range 8-19 mmHg/ml/min). The three patients, whose EDP was measured, had an increased and labile EDP. Furthermore, a number of B waves were detected among those patients.25, Table 1. Gjerris and colleagues conducted a case series of 14 IIH patients, of whom 71% were female.26, Table 1. The mean age was 34 years (range 12-61). ICP, conductance to CSF outflow (Cout), plateau and B waves, sex, age and cerebral blood flow (CBF) were studied. ICP was measured by an epidural transducer except for one patient that had a lumbar puncture performed. A lumbo-lumbar perfusion method was used to measure Cout, whereas a 133Xe inhalation
and a single photon emission computer tomography was used to measure CBF. This study revealed that all patients except one had either a borderline elevated or clearly increased ICP (mean steady-state ICP was 22.5 mmHg, range 8-45). All patients had B waves for over half of the monitored time, while only six patients had plateau waves.
Conductance (Cout) was significantly decreased in all patients (0.042 ± 0.004 mm·mmHg-1min-1) apart from the patient that had a normal ICP. In addition, 11 patients underwent CBF studies that were performed before and after treatment, and there was no significant difference in CBF measurements.26, Table 1.
We found only one prospective case-control study that included 13 IIH patients and 45 controls.27, Table 1. The mean age of the IIH patients was 35 years (range 16-59), and 69% of them were female. ICP was measured via invasive lumbar infusion test.
CSF pressure (Pcl), sagittal sinus pressure (Pss), conductance of outflow pathways (Gop), CSF formation rate (qf), pressure difference across outflow pathways (Pdop), clinical symptoms, diagnosis and treatment were studied. This study found that Pcl was increased (3.0 vs. 1.4 kPa, p<0.0001), Gop was significantly reduced (10.4 vs. 18.0 mm3kPa-1s-1, p<0.0001), Pdop was increased (0.9 vs. 0.4 kPa, p<0.001) and Pss was elevated (2.1 vs. 1.0 kPa, p<0.0001) in IIH patients as compared with healthy controls.
However, qf was not significantly different (6.8 vs. 6.9 mm3s-1, p was not studied) between the IIH patients and the controls.27, Table 1.
Gideon et al. conducted a case-control study with 12 IIH patients and ten healthy controls.28, Table 1. The mean age of the IIH patients at presentation was 38 years (range 12-61) and 67% of them were female. An invasive lumbar infusion test was performed to measure ICP, and the variables included in the study were the following;
age, sex, duration of the symptoms, ICP and CSF outflow resistance (Rout). Nine of the patients (75%) had an increased Rout. Moreover, compared to the healthy controls, the IIH patients had elevated CSF volume amplitudes. In addition, Gideon et al. found that there was a significant correlation (p<0.05) between Rout and CSF volume amplitude. The mean supratentorial CSF production rate was calculated in both IIH patients (0.79 ml/min) and healthy controls (0.70 ml/min), however, this difference between the CSF production rates was not statistically significant. This study included also MRI measurements, where the following was found: in the superior sagittal sinus the mean blood flow was lower in IIH patients (mean 345 ml/min) than in healthy controls (mean 457 ml/min). MRI measurements also showed CSF hypersecretion in
