A. Any headache fulfilling criterion C
B. Idiopathic intracranial hypertension (IIH) has been diagnosed, with CSF pressure >250 mm CSF (measured by lumbar puncture performed in the lateral decubitus position, without sedative medications, or by epidural or intraventricular monitoring)
C. Evidence of causation demonstrated by at least two of the following:
1. Headache has developed in temporal relation to IIH, or led to its discovery
2. Headache is relieved by reducing intracranial hypertension
3. Headache is aggravated in temporal relation to increase in intracranial pressure
D. Not better accounted for by another ICHD-3 diagnosis
Table 18.2
Diagnostic criteria for Idiopathic Intracranial Hypertension (IIH) Established by the International Headache Society (ICHD-3 beta) (Cephalalgia 2013; 33(9): 629–808)
A. Any headache fulfilling criterion C |
B. Low CSF pressure (<60 mm CSF) and/or evidence of CSF leakage on imaging |
C. Headache has developed in temporal relation to the low CSF pressure or CSF leakage, or has led to its discovery |
D. Not better accounted for by another ICHD-3 diagnosis |
Research efforts have therefore focused recently on venous outflow and CSF absorption abnormalities as the possible mechanism behind IIH. In this context it is hypothesized that an obstruction in venous outflow elevates cerebral venous pressure affecting the rate of CSF absorption. The hypothesis is fueled by the strong association between IIH and obesity, which is present in up to 80 % of adult IIH patients [17–19] with clinical studies indicating a direct correlation between the body mass index (BMI) and CSF opening pressure [19–21]. The proposed rationale behind this association suggests that the obesity-related increase in intra-abdominal and intra-thoracic pressure may lead to an increase in cerebral venous pressure, a decrease in CSF absorption and finally an elevation in ICP [22]. The fact that a weight reduction reduces CSF opening pressure as well as clinical symptoms proves the pathophysiological importance of obesity in IIH [23–30]. In this context is has been suggested that the effect of acetazolamide in the treatment of IIH may be, at least in part, the result of the associated weight loss [31].
However, despite the clear relationship between obesity and IIH, the proposed mechanistic rationale behind this association has been questioned as it does neither explain female preponderance nor the fact that IIH patients tend to be obese in lower parts of the body rather than in abdominal parts [32, 33]. The distinct body fat distribution in IIH is even more pronounced in women than in men [33]. Therefore, other factors such as hormonal influences may contribute to the relationship between obesity and IIH [34]. Clinical data suggest that substances secreted by adipose tissue may be involved in the pathogenesis of IIH. For example, aromatase has been discussed in this context as aromatase is involved in the production of estrogens from androstenedione and its distribution correlates with the female distribution of body fat [35]. Recently, vitamin A has also been associated with IIH. It is converted in adipose tissue to retinoic acid, its active metabolite. The exact mechanism of action that relates retinol to increased ICP remains largely unknown. However, studies indicate that excessive vitamin A concentrations in plasma and CSF, which have been demonstrated in IIH [36–38], may impair CSF absorption. However, as vitamin A may induce the synthesis of progesterone and activate the mineralocorticoid receptor [39], the functional basis of the relationship of vitamin A and elevated ICP may be much more complex than initially suspected. The fact that hypovitaminosis may also increase ICP adds to the complexity of the association [40]. Further research is needed to elucidate further the mechanisms behind the association between vitamin A and ICP.
Beside the mechanistic hypothesis that suggests an outflow reduction resulting from an increase in an obesity-related elevation of intra-abdominal pressure and the hormonal hypothesis that suggests a reduced CSF absorption which may be based on structural changes in the arachnoid villi [41], stenotic transverse sinuses (TSS) have been proposed to play a significant role in impairing CSF absorption as they can be observed in up to 90 % of IIH patients [42]. However, if the observed TSS are cause or consequence of the elevated ICP in IIH has not been entirely clarified [10, 43, 44]. In this context, it has been hypothesized that a primary TSS may impair venous outflow affecting the pressure gradient over the arachnoid granulations and thereby reducing CSF absorption [43]. Another hypothesis suggests that the observed TSS are secondary to increased ICP [43, 44]. This rationale is supported by the observations that high ICP may lead to a collapsing of the transverse sinuses causing an additional increase in venous pressure in the superior sagittal sinus and that CSF diversion procedures may reverse previously identified TSS [44–50]. Regardless of the question if observed TSS are primary or secondary, the location and degree of the TSS does not seem to affect the clinical course of IIH [51].
Data obtained in an in vivo study suggest that the hemodynamic consequences of a unilateral TSS do not suffice to affect CSF absorption while a bilateral TSS does lead to an elevation of ICP [52]. Clinical, in particular interventional studies, have therefore aimed at investigating the consequences of an endovascular treatment in patients that show bilateral TSS in MR imaging. Based on existing data it seems clear that endovascular treatment can be effective in alleviating IIH-associated symptoms in most patients with bilateral TSS [45, 53–60] supporting a causality between TSS in IIH, at least in some patients. However, this observation does still not clarify whether bilateral TSS are primary or secondary as a beneficial effect on elevated ICP is feasible in both cases.
Taken together, based on the available literature it seems unlikely that the commonly observed IIH-associated TSS are primary stenoses as this mechanism would not explain the observed female preponderance and the fact that TSS are common in the general population [42, 61, 62]. The uni- and bilateral TSS rather appear to be secondary to the elevated ICP triggering a vicious cycle that further increases ICP due to a reduced venous outflow and consecutively reduced CSF absorption.
18.2.2 Clinical Syndrome and Diagnosis
The headache associated with IIH lacks of any specific features and may vary substantially in its clinical presentation. It is commonly described as a daily occurring diffuse headache with a frontal, retro-orbital localization that may be aggravated by physical activity and even be accompanied by nausea. IIH-associated headache can occasionally even show similarities to primary headaches including migraine [63–65] and tension-type headache [66] that may hamper its clinical distinction to these syndromes, in particular if IIH presents without an accompanying papilledema or visual abnormalities. Despite the fact that headache is usually the symptom that leads affected patients to seek medical advice, cases of probable IIH without headache have been described [67].
Visual disturbances described in IIH include a reduction in visual acuity, visual field losses, and photopsia [2]. Ophthalmoscopic examination reveals a papilledema in 40–95 % of patients [11, 63, 68] which occasionally may be asymmetric or even unilateral [69, 70]. Ophthalmoscopic examination is therefore mandatory if IIH is suspected. Nevertheless, the presence and extent of an observed papilledema does not correlate with headache frequency and intensity [68]. Horizontal diplopia occurs in about one-third of IIH patients and is in most cases a result of a sixth nerve palsy [3].
In addition to headache and visual disturbances, olfactory disturbances and a pulse-synchronous tinnitus are commonly observed in IIH [71, 72].
In contrast to its clinical features, IIH is associated with characteristic structural abnormalities that can be identified using magnetic resonance imaging (MRI) techniques [11, 71, 73–75]. The most reliable signs observed in MRI scans are the morphometric changes of the pituitary gland (partial or complete empty sella) and the optic nerve sheath (ONS) [11, 73–76]. The commonly observed posterior flattening of the optic globe is highly specific for the presence of IIH but its low sensitivity limits its use as a diagnostic criterion for the initial diagnosis of IIH. In contrast, the size of the lateral ventricles is not affected in IIH [73, 76, 77]. In addition to the described structural abnormalities, uni- or bilateral stenoses of the transverse sinuses (TSS) are commonly observed in IIH with reported prevalence rates of up to 90 % [42, 78]. Therefore, the diagnostic workup should always include a MR venography to exclude a venous sinus thrombosis and to identify the presence of a uni- or bilateral TSS.
Nevertheless, due to their variability as well as their specificity and sensitivity with respect to IIH, imaging abnormalities observed in MRI can only serve as supportive for the diagnosis of intracranial hypertension in IIH. Lumbar puncture with a measurement of CSF opening pressure is therefore still required for the initial diagnosis and the evaluation of treatment effects. According to the criteria established by the IHS, an elevated CSF opening pressure is diagnosed if pressure exceeds 250 mm CSF [8]. Occasionally the elevation of ICP may occur intermittently, hampering the diagnosis of the syndrome, in particular in cases of IIH without accompanying papilledema. In this case continuous monitoring of CSF pressure by lumbar catheter may be considered if IIH is suspected but CSF opening pressure remains within normal range.
18.2.3 Treatment
The principal aim in the treatment of IIH is the preservation of visual acuity followed by the relief of the associated headache. An appropriate treatment strategy should therefore include a consequent reduction of body weight, complemented by an adequate pharmacological treatment. Invasive interventions such as endovascular treatments, CSF diversion procedures, and optic nerve sheath fenestration should be reserved exclusively for treatment refractory cases with a high risk of partial or complete visual loss.
18.2.3.1 Weight Reduction
The consequent reduction of body weight in obese patients has been demonstrated to reduce ICP, papilledema, and consecutive visual loss as well as the IIH-associated headache [23, 79]. Even minor weight losses of about 6 % have been demonstrated to be effective [26, 28]. A weight gain should be avoided, even after successful treatment, as it increases the risk of recurrence [80] and may even increase the risk of IIH in non-obese individuals highlighting the importance of weight reduction and maintenance of a normal BMI in the treatment of IIH [17, 72, 81, 82]. If an effective weight reduction is not achieved, bariatric surgery may represent an effective treatment strategy in these exceptional cases [29, 30].
18.2.3.2 Lumbar Puncture
Repeated therapeutic lumbar punctures may provide a treatment option for a short period of time. The withdrawal of CSF through a lumbar puncture probably improves IIH-associated headache although no trials exist to confirm this hypothesis [83, 84]. Since ICP is restored within hours, it remains unclear why the relief of IIH-associated symptoms, in particular the headache, may persist for a prolonged time [15]. It may be speculated that the transient reduction in ICP reduces secondary TSS improving venous outflow and CSF absorption restoring a stable equilibrium with adequate CSF dynamics [12, 85–87].
18.2.3.3 Pharmacological Treatment
The pharmacological treatment of IIH is mainly based on the use of carbonic anhydrase inhibitors. The carbonic anhydrase plays a significant role in the production of CSF as it regulates the synthesis of hydrogen carbonate (HCO3 −) [88–91]. The enzyme is located in epithelial cells of the choroid plexus. In addition to the cytosolic form, extracellular membrane-associated isoforms exist [92]. Carbonic anhydrase inhibitors such as acetazolamide may inhibit CSF secretion [93–95] and reduce ICP [96, 97]. If this effect is mediated through an action on the intra- or extracellular isoforms of carbonic anhydrase or both, has not been entirely clarified.
Acetazolamide represents the most widely used carbonic anhydrase inhibitor for the pharmacological treatment of IIH. It is generally used in a dose ranging between 500 and 2000 mg per day. Despite the widespread use of acetazolamide, until recently evidence on its clinical efficacy was scarce and mainly based on small open-label studies [98, 99]. A randomized controlled trial that was conducted in 2011 did not show a convincing efficacy, probably due to the small number of participants and the high discontinuation rate of acetazolamide. In addition, this trial did not include a placebo group [98]. In 2014, the NORDIC Idiopathic Intracranial Hypertension Study Group published data from the first multicenter, randomized, double-masked, placebo-controlled study of acetazolamide with 165 participants which demonstrate that acetazolamide is effective in improving visual function, papilledema, and headache disability [100]. Interestingly, participants also experienced a significant weight reduction that may have contributed to the clinical efficacy of this pharmacological approach [31, 100]. In the trial participants were treated with up to 4 g of acetazolamide per day. The most commonly observed unwanted side effects were fatigue and gastrointestinal symptoms including diarrhea, dyspepsia, nausea, and vomiting.
The anticonvulsant topiramate is increasingly used for the treatment of IIH, in particular in cases in which the effect of acetazolamide does not suffice to normalize ICP and stop the progression of visual deficits or in which acetazolamide has to be discontinued due to intolerable side effects. Topiramate is commonly used in a dose ranging between 50 and 200 mg per day. Treatment with topiramate is frequently accompanied by unwanted side effects that may include dysesthesias, mood changes, and decline in cognitive abilities [101]. The effect of topiramate is thought to be based on its ability to inhibit carbonic anhydrase and the reduction of body weight. Despite its common use in clinical routine, up to date no randomized, placebo-controlled trial has been conducted to verify its efficacy in treating IIH. In an open-label study, topiramate has been demonstrated to be as effective in improving visual field grades as acetazolamide [99]. Another small study conducted by Shah et al. largely confirmed the findings [102] but results have to be taken with caution as the study was based on an open-label design and did not include a control group. As in the case of acetazolamide, it is not entirely clear if the beneficial effect is mainly the result of topiramate-induced weight loss, rather than an effect on carbonic anhydrase [28]. Further studies, in particular a randomized, placebo-controlled trial, are required to clarify if topiramate is beneficial in the treatment of IIH and which mechanism is responsible for its efficacy.
The use of diuretic substances for the treatment of IIH has been debated since Jefferson et al demonstrated beneficial effects for several diuretic compounds [103]. In this context, furosemide has been demonstrated to inhibit carbonic anhydrase [104–108] and to lower ICP [109]. Given its widespread use in clinical routine, the effect on carbonic anhydrase led to its increasing use for the treatment of IIH. For the relief of IIH-associated symptoms it is generally used in a dose ranging between 30 and 80 mg per day. However, up to date no randomized placebo-controlled trials exist that may demonstrate its efficacy in IIH.
Steroids have been used for the treatment of IIH in the past [110]. Due to their significant side effects, which may include a substantial weight gain, long-term treatment of IIH with steroids has become obsolete. In addition to the substantial side effects, long-term treatment with steroids bear the risk of a rebound when treatment is terminated. However, in exceptional cases with an imminent risk of a complete visual loss, short-term treatment may be considered to bridge a preoperative period prior to a CSF diversion procedure.
18.2.3.4 Endovascular Treatment
Endovascular treatment has been shown to be effective in the treatment of IIH in the majority of patients with TSS [45, 53–60, 111]. The mechanism behind this beneficial effect is believed to be based on an improvement of venous outflow that leads to an improved CSF absorption and a decrease in ICP [43, 112]. However, endovascular treatment may be accompanied by severe complications which include an in-stent thrombosis, stent migration, sinus perforation, and subdural hemorrhage. Due to the potential complications that may arise in the context or as a consequence of endovascular treatment, the lack of studies investigating the long-term efficacy and safety of this treatment in IIH and the fact that most patients benefit significantly from weight loss and pharmacological treatments, the procedure remains controversial and is currently not recommended for the routine treatment of IIH [113].
18.2.3.5 Surgical Treatment
CSF diversion procedures include the surgical implantation of a ventriculoperitoneal or lumboperitoneal shunt [114]. Clinical data suggest, that ventriculoperitoneal shunts should be preferred in contrast to lumboperitoneal shunts as the latter are associated with a higher risk of complications that require surgical shunt revision [115]. Studies that address the long-term efficacy and safety of these procedures remain scarce [54]. Given the lack of conclusive data and due to the fact that these procedures may suffer complications such as a shunt infection, shunt failure, or over-shunting, that may occasionally require a surgical shunt revision, these interventions should only be considered in treatment refractory cases or in case of an imminent risk of complete visual loss [116].
18.2.3.6 Optic Nerve Sheath Fenestration
Optic nerve sheath fenestration should be considered if papilledema and visual disturbances represent the primary symptom or if pharmacological treatment has not been effective in preventing visual deterioration. The intervention is performed through an incision in the meninges surrounding the optic nerve. The technique is highly effective in stabilizing and improving papilledema and visual loss [117–121]. Nevertheless, as with endovascular treatment options and CSF diversion procedures, future studies will need to clarify long-term efficacy and safety as current studies still provide inconclusive results [118, 121].
A recommendation on which interventional technique, CSF diversion procedure or optic nerve sheath fenestration, should be preferred if surgical treatment is indicated is currently not possible based on the existing literature [113].
18.3 Spontaneous Intracranial Hypotension
Spontaneous intracranial hypertension (SIH) is a rare headache syndrome with an estimated annual incidence of 5 cases per 100,000 people and a prevalence of 1 case per 50,000. Although it may occur at any age, the typical age of incidence ranges between 40 and 60 years. The syndrome shows a female sex predilection with a female to male ratio of 2:1 [122].
The clinical syndrome has been initially described by Schaltenbrand in 1938 [123] and is now defined in the IHS classification [8] (Table 18.2). It is characterized by an orthostatic headache that is usually the result of a spontaneous CSF leak. The underlying cause of the CSF leaks, in particular the reasons for the observed age distribution and sex predilection, remain largely unknown.
18.3.1 Pathophysiology
In contrast to earlier hypotheses that suggested a decrease in CSF production or an increase in CSF absorption [124], clinical evidence indicates that SIH is the result of a spontaneous CSF leak which causes a reduction of CSF pressure. Most of the CSF leaks causing SIH are located in the cervicothoracic junction or along the thoracic spine and occasionally multiple simultaneous CSF leaks may be observed [122]. In contrast, cranial leaks are not associated with the clinical syndrome of SIH [125]. The underlying cause of the development of CSF leaks has not been entirely clarified. Clinical evidence suggests that traumatic events which may include trivial increases in ICP during coughing or physical exercise, as well as a genetic predisposition that may induce tissue abnormalities increasing the likelihood of spontaneous dural ruptures and CSF leaks, have been hypothesized [8, 126–130]. While evidence for traumatic events can be identified in about one-third of SIH patients, evidence for an underlying generalized connective tissue disorder, which among others may include Marfan [131–134] and Ehlers-Danlos [135] syndromes, can be observed in up to two-thirds of SIH patients [130, 135–139]. These associated connective tissue disorders may be underdiagnosed as their clinical manifestations may be subtle [135].
< div class='tao-gold-member'>
Only gold members can continue reading. Log In or Register to continue
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
