Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions

doi:10.1016/S1474-4422(15)00298-7

The Lancet Neurology

Volume 15, Issue 1, January 2016, Pages 78-91

https://doi.org/10.1016/S1474-4422(15)00298-7 Get rights and content

Summary

Idiopathic intracranial hypertension is a disorder characterised by raised intracranial pressure that predominantly affects young, obese women. Pathogenesis has not been fully elucidated, but several causal factors have been proposed. Symptoms can include headaches, visual loss, pulsatile tinnitus, and back and neck pain, but the clinical presentation is highly variable. Although few studies have been done to support evidence-based management, several recent advances have the potential to enhance understanding of the causes of the disease and to guide treatment decisions. Investigators of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) reported beneficial effects of acetazolamide in patients with mild visual loss. Studies have also established weight loss as an effective disease-modifying treatment, and further clinical trials to investigate new treatments are underway. The incidence of idiopathic intracranial hypertension is expected to increase as rates of obesity increase; efforts to reduce diagnostic delays and identify new, effective approaches to treatment will be key to meeting the needs of a growing number of patients.

Introduction

Idiopathic intracranial hypertension is characterised by signs and symptoms of raised intracranial pressure (ICP) with no established pathogenesis. The disorder is strongly associated with obesity, and patients are mostly female and typically of reproductive age. Common symptoms of idiopathic intracranial hypertension include headaches, visual loss, pulsatile tinnitus, and back and neck pain, but the clinical presentation is highly variable, which can lead to delays in diagnosis. If left untreated, the disorder can lead to substantial visual morbidity. Diagnosis is usually based on the updated modified Dandy criteria,¹ which require the presence of raised ICP, typically papilloedema, and no identifiable secondary causes. Previously, little evidence existed to guide the management of idiopathic intracranial hypertension, but important prospective studies have considerably advanced understanding of the disorder, including the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), which investigated the effects of acetazolamide in patients with mild visual loss,² and a study of the effect of low calorie diet (resulting in weight loss) on intracranial pressure and symptoms and signs of idiopathic intracranial hypertension.³

In this Review, we highlight progress made during the past decade, providing an update on the pathogenesis, diagnosis, and management of adult idiopathic intracranial hypertension. We do not consider the practical management of the disorder in detail here,⁴ but we draw on the latest findings and local expertise (ie, in the authors' institutions) to suggest an approach to the acute management of idiopathic intracranial hypertension. Finally, we briefly discuss factors that might have a bearing on prognosis and consider future directions for research.

Section snippets

Epidemiology

Idiopathic intracranial hypertension is typically seen in women who are obese and of childbearing age, with a worldwide incidence of around 12–20 per 100 000 people per year in this group,5, 6, 7 but only 0·5–2 per 100 000 people per year in the general population (table 1).5, 6, 7, 10, 12, 14 Owing to an absence of large epidemiological studies, prevalence is poorly documented in male and paediatric populations.¹⁵ Obesity rates are reportedly lower in children with idiopathic intracranial

Pathogenesis

The pathogenic mechanisms of idiopathic intracranial hypertension are still unclear and although no single unifying theory exists for the development of the disorder, dysregulation of ICP is an important focus of investigation. Three main intracranial mechanisms have been suggested to result in raised ICP, including disordered CSF dynamics such as CSF hypersecretion and outflow obstruction, and increased venous sinus pressure (figure 1). Historically, case series have implicated weight as a

Clinical presentation

The clinical presentation of idiopathic intracranial hypertension (table 2) is highly variable, which can lead to substantial delays in diagnosis. Headaches are a predominant feature of the disease, reported by around 75–94% of patients,65, 66, 68, 70, 71 and are highly heterogeneous.69, 72 Idiopathic intracranial hypertension-associated headaches are described as pressure-like, holocranial, frontal or retro-orbital, worse on waking or with Valsalva-type manoeuvres, and improved with CSF

Nomenclature

Idiopathic intracranial hypertension was initially known as serous meningitis, but rapidly became known as pseudotumour cerebri.⁹⁰ In the 1950s, it was renamed benign intracranial hypertension as medical diagnostics improved and secondary causes began to be ruled out. The term idiopathic intracranial hypertension arose when the disorder was no longer regarded as benign:⁷¹ 68% of patients have chronic headache 1 year after diagnosis despite ICP normalisation,⁷¹ and up to 24% of patients have

Management

No consensus exists on the best management strategy for idiopathic intracranial hypertension, mainly due to an absence of robust evidence. A Cochrane review in 2002¹⁰² showed an absence of good-quality randomised controlled trials to assess the effectiveness of available treatments. In 2005, a revised review¹⁰³ drew the same conclusions. But an evidence-based approach can start to be taken in view of recent trials that have assessed the effectiveness of acetazolamide and weight loss in patients

Prognosis

Visual prognosis is generally good in idiopathic intracranial hypertension, but a risk of permanent visual loss exists for a subset of male patients.⁸³ For most patients, headache is increasingly recognised as the predominant, long-term disability.¹²⁷ In the IIHTT study,² treatment failed in seven patients, six of whom were in the placebo-diet group and one of whom was in the acetazolamide group. These seven patients had high-grade papilloedema, which suggests that this feature of the disorder

Conclusions and future directions

Idiopathic intracranial hypertension was first recognised as a disorder more than 100 years ago. Progress has since been gradual, with little evidence to guide management. However, the past decade has seen advances in understanding of idiopathic intracranial hypertension and improvements in diagnosis. An increase in incidence is expected in the future because of the rising levels of obesity. In response, a greater drive towards elucidating the pathophysiology of idiopathic intracranial

Search strategy and selection criteria

We searched MEDLINE and PubMed between January, 1946, and July, 2015, for articles published in English using the search terms “idiopathic intracranial hypertension”, “pseudotumour cerebri”, “benign intracranial hypertension”, and “IIH”. Reference lists of articles identified were reviewed for any further important papers. The final reference list was generated on the basis of relevance of topics covered in this Review, with a focus on papers published within the past 5 years.

References (131)

K Radhakrishnan et al.
Epidemiology of idiopathic intracranial hypertension: a prospective and case-control study
J Neurol Sci
(1993)
SM Standridge
Idiopathic intracranial hypertension in children: a review and algorithm
Pediatr Neurol
(2010)
I Johnston
Reduced C.S.F. absorption syndrome. Reappraisal of benign intracranial hypertension and related conditions
Lancet
(1973)
S Beri et al.
Familial idiopathic intracranial hypertension with variable phenotype
Eur J Paediatr Neurol
(2011)
F Umenishi et al.
Induction of human aquaporin-1 gene by retinoic acid in human erythroleukemia HEL cells
Biochem Biophys Res Commun
(2002)
V Biousse et al.
Anemia and papilledema
Am J Ophthalmol
(2003)
P Jennum et al.
Intracranial pressure and obstructive sleep apnea
Chest
(1989)
CJ Glueck et al.
Changes in weight, papilledema, headache, visual field, and life status in response to diet and metformin in women with idiopathic intracranial hypertension with and without concurrent polycystic ovary syndrome or hyperinsulinemia
Transl Res
(2006)
A Ducros et al.
Headache arising from idiopathic changes in CSF pressure
Lancet Neurol
(2015)
MA Fard et al.
Quantification of peripapillary total retinal volume in pseudopapilledema and mild papilledema using spectral-domain optical coherence tomography
Am J Ophthalmol
(2014)

KM Kulkarni et al.

Differentiating mild papilledema and buried optic nerve head drusen using spectral domain optical coherence tomography

Ophthalmology

(2014)

DI Friedman et al.

Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children

Neurology

(2013)

M Wall et al.

Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial

JAMA

(2014)

AJ Sinclair et al.

Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study

BMJ

(2010)

SP Mollan et al.

A practical approach to, diagnosis, assessment and management of idiopathic intracranial hypertension

Pract Neurol

(2014)

N Raoof et al.

The incidence and prevalence of idiopathic intracranial hypertension in Sheffield, UK

Eur J Neurol

(2011)

K Radhakrishnan et al.

Idiopathic intracranial hypertension (pseudotumor cerebri). Descriptive epidemiology in Rochester, Minn, 1976 to 1990

Arch Neurol

(1993)

FJ Durcan et al.

The incidence of pseudotumor cerebri. Population studies in Iowa and Louisiana

Arch Neurol

(1988)

A Carta et al.

Idiopathic intracranial hypertension (pseudotumor cerebri): descriptive epidemiology, clinical features, and visual outcome in Parma, Italy, 1990 to 1999

Eur J Ophthalmol

(2004)

JJ Craig et al.

Idiopathic intracranial hypertension; incidence, presenting features and outcome in Northern Ireland (1991-1995)

Ulster Med J

(2001)

VM Asensio-Sánchez et al.

Epidemiology of pseudotumor cerebri

Arch Soc Esp Oftalmol

(2007)

A Kesler et al.

Epidemiology of idiopathic intracranial hypertension in Israel

J Neuroophthalmol

(2001)

T Idiculla et al.

The incidence and prevalance of idiopathic intracranial hypertension in south Sharaqiah region, Oman

Oman J Ophthalmol

(2013)

A Kesler et al.

The incidence of idiopathic intracranial hypertension in Israel from 2005 to 2007: results of a nationwide survey

Eur J Neurol

(2014)

A Kesler et al.

Idiopathic intracranial hypertension in the pediatric population

J Child Neurol

(2002)

BB Bruce et al.

Idiopathic intracranial hypertension in men

Neurology

(2009)

Global Database on Body Mass Index

B Newborg

Pseudotumor cerebri treated by rice reduction diet

Arch Intern Med

(1974)

HF Cserr

Physiology of the choroid plexus

Physiol Rev

(1971)

HW Davson et al.

Physiology and pathophysiology of the CSF

(1986)

JO Donaldson

Cerebrospinal fluid hypersecretion in pseudotumor cerebri

Trans Am Neurol Assoc

(1979)

J Malm et al.

CSF hydrodynamics in idiopathic intracranial hypertension: a long-term study

Neurology

(1992)

HM Eisenberg et al.

Cerebrospinal fluid overproduction and hydrocephalus associated with choroid plexus papilloma

J Neurosurg

(1974)

HH Damkier et al.

Cerebrospinal fluid secretion by the choroid plexus

Physiol Rev

(2013)

M Johnston et al.

Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species

Cerebrospinal Fluid Res

(2004)

DI Friedman et al.

Diagnostic criteria for idiopathic intracranial hypertension

Neurology

(2002)

BD Riggeal et al.

Clinical course of idiopathic intracranial hypertension with transverse sinus stenosis

Neurology

(2013)

JO King et al.

Manometry combined with cervical puncture in idiopathic intracranial hypertension

Neurology

(2002)

RJ Joynt et al.

Brain swelling of unknown cause

Neurology

(1956)

M Wall et al.

Idiopathic intracranial hypertension. Lack of histologic evidence for cerebral edema

Arch Neurol

(1995)

P Gideon et al.

Increased brain water self-diffusion in patients with idiopathic intracranial hypertension

AJNR Am J Neuroradiol

(1995)

ME Bastin et al.

Diffuse brain oedema in idiopathic intracranial hypertension: a quantitative magnetic resonance imaging study

J Neurol Neurosurg Psychiatry

(2003)

HJ Sugerman et al.

Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri

Neurology

(1997)

J Hannerz et al.

The relationship between idiopathic intracranial hypertension and obesity

Headache

(2009)

AB Daniels et al.

Profiles of obesity, weight gain, and quality of life in idiopathic intracranial hypertension (pseudotumor cerebri)

Am J Ophthalmol

(2007)

MW Ko et al.

Weight gain and recurrence in idiopathic intracranial hypertension: a case-control study

Neurology

(2011)

MJ Kupersmith et al.

Effects of weight loss on the course of idiopathic intracranial hypertension in women

Neurology

(1998)

W Whiteley et al.

CSF opening pressure: reference interval and the effect of body mass index

Neurology

(2006)

CJ Lyon et al.

Minireview: adiposity, inflammation, and atherogenesis

Endocrinology

(2003)

AK Ball et al.

Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance?

Clin Endocrinol (Oxf)

(2009)

Cited by (310)

Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus
2024, Toxicology and Applied Pharmacology
Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues.
Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA.
Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands.
These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.
Establishing continuum in Transcranial Doppler characteristics of IIH, migraine and healthy controls- An exploratory study
2024, Clinical Neurology and Neurosurgery
IIH is a severe form of headache that often has superimposed migraine and often it is very difficult to distinguish the two forms of headache. Intracranial hemodynamics is a relatively unexplored means of distinguishing between the two forms of headache.
We aimed to study intracranial flow dynamics using Transcranial Doppler in patients with IIH, migraine, and normal controls.
It was a hospital-based observational study that included 51 people with IIH, 87 people with migraine, and 101 healthy controls and all were subjected to TCD study after detailed clinical examination. Results: Mean age of patients in three groups were similar with the mean age in IIH being 33.41 ± 10.75 (age in years ± SD). Vision loss was present in 66.67% of patients with IIH, and most common field defect was generalized constriction (27.5%). Neuroimaging was abnormal in 94.11% of patients of IIH with mean CSF pressure was 31.27±5.32 cm of water. Of all the TCD-measured velocities, mean flow velocity (MFV) showed a significant difference in all three groups with (p-value <0.001). The pulsatility index, both for middle cerebral arteries as well as ophthalmic arteries showed a significant difference in the three groups with the highest values in IIH patients (p-value<.001). The mean VMR in IIH (1.11±0.32) was lower than the mean VMR in migraine (1.34±0.43) as well as controls (1.49±0.46).
TCD parameters like MFV and PI are useful parameters that show considerable variation and can be used to differentiate between IIH and migraine.
Venous sinus stenting for idiopathic intracranial hypertension: An updated Meta-analysis
2024, Journal of the Neurological Sciences
Idiopathic intracranial hypertension (IIH) is characterized by elevated intracranial pressure and primarily affects obese women of reproductive age. Venous sinus stenting (VSS) is a surgical procedure used to treat IIH, but its safety and efficacy are still controversial.
A systematic review and meta-analysis were conducted following PRISMA guidelines. Multiple databases were searched for studies evaluating the safety and efficacy of VSS in IIH patients and meta-analysis was performed to pool the data.
A total of 36 studies involving 1066 patients who underwent VSS were included. After VSS, a significant reduction in trans-stenotic gradient pressure was observed. Patients also showed significantly lower cerebrospinal fluid (CSF) opening pressure. Clinical outcomes demonstrated improvement in tinnitus (95%), papilledema (89%), visual disturbances (88%), and headache (79%). However, 13.7% of patients experienced treatment failure or complications. The treatment failure rate was 8.35%, characterized by worsening symptoms and recurrence of IIH. The complications rate was 5.35%, including subdural hemorrhage, urinary tract infection, stent thrombus formation, and others.
VSS appears to be a safe and effective treatment option for IIH patients who are unresponsive to medical therapy or have significant visual symptoms. However, long-term outcomes and safety of the procedure require further investigation.
The “Wrinkle Sign” in Time-of-Flight Magnetic Resonance Venography is a Hallmark of Idiopathic Intracranial Hypertension
2024, World Neurosurgery
Idiopathic intracranial hypertension (IIH) is usually caused by sinus stenosis, which manifests in magnetic resonance venography (MRV) as occlusion or intraluminal webbing. We present the case of a 27-year-old patient with IIH, and time-of-flight (TOF) MRV only exhibited a rare “wrinkle sign,” which was eventually proved to indicate sinus obstruction. The patient received venting and recovered. The TOF MRV provides a nonradioactive approach to identify IIH patients who potentially need intervention.
Obstructive sleep apnea in those with idiopathic intracranial hypertension undergoing diagnostic in-laboratory polysomnography
2024, Sleep Medicine
The association of obstructive sleep apnea (OSA) with idiopathic intracranial hypertension (IIH) remains unclear, and few studies have used objective in-laboratory polysomnography (PSG) data. Thus, we used PSG data to examine the: 1) association between OSA, and its severity, with IIH and 2) sex differences in OSA severity in those with and without IIH.
We retrospectively analyzed diagnostic PSG data from January 2015 to August 2023 for patients who were diagnosed with IIH by a neuro-ophthalmologist using the modified Dandy criteria. We selected three age, sex, and body mass index (BMI) matched controls for each IIH patient. We examined potential associations of IIH with OSA using regression. Sex differences were analyzed using ANOVA.
Of 3482 patients who underwent PSG, we analyzed 78 IIH patients (16 males) and 234 matched controls (48 males). Five (6.4 %) IIH and 39 (16.7 %) control patients had OSA, defined as AHI≥15. After adjusting for age, sex, BMI, and comorbidities, IIH was negatively associated with the presence of OSA (OR 0.29, 95%CI 0.10–0.87, p = 0.03). However, models that adjusted for acetazolamide use, with or without comorbidities, showed no significant relationship with OSA (OR 0.31, p = 0.20). Males with IIH had a significantly higher age (p = 0.020), OSA severity (p = 0.032), and arousal index (p = 0.046) compared to females with IIH.
IIH treated with acetazolamide was not an independent risk factor for OSA presence or severity. The presence of IIH treated with acetazolamide likely does not warrant routine screening for OSA, but related risk factors may identify appropriate patients.
Effectiveness and Safety of Ventriculoperitoneal Shunt Versus Lumboperitoneal Shunt for Idiopathic Intracranial Hypertension: A Systematic Review and Comparative Meta-Analysis
2024, World Neurosurgery
Idiopathic Intracranial Hypertension (IIH) is a condition characterized by elevated intracranial pressure. Although several mechanisms have been proposed as underlying causes of IIH, no identifiable causative factor has been determined for this condition. Initial treatments focus on weight or CSF reduction, but severe cases may require surgery. This study compares outcomes in IIH patients treated with lumboperitoneal shunts (LPSs) versus ventriculoperitoneal shunts (VPSs).
This systematic-review and meta-analysis follows Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines and includes studies about VPS and LPS patients, reporting one of the outcomes of interest. We conducted searches on PubMed, Embase, Web of Science, and Cochrane Library.
Our analysis involved twelve studies, comprising 5990 patients. The estimated odds ratio (OR) for visual improvement was 0.97 (95% CI 0.26–3.62; I² = 0%) and for headache improvement was 0.40 (95% CI 0.20–0.81; I² = 0%), favoring LPS over VPS. Shunt revision analysis revealed an OR of 1.53 (95% CI 0.97–2.41; I² = 77%). The shunt complications showed an OR of 0.91 (95% CI 0.68–1.22; I² = 0%). The sub-analyses for shunt failure uncovered an OR of 1.41 (95% CI 0.92–2.18; I² = 25%) and for shunt infection events an OR of 0.94 (95% CI 0.50–1.75; I² = 0%).
The interventions showed general equivalence in complications, shunt failure, and other outcomes, but LPS seems to hold an advantage in improving headaches. Substantial heterogeneity highlights the need for more conclusive evidence, emphasizing the crucial role for further studies. The findings underscore the importance of considering a tailored decision between VPS and LPS for the management of IIH patients.

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ReviewUnderstanding idiopathic intracranial hypertension: mechanisms, management, and future directions

Summary

Introduction

Section snippets

Epidemiology

Pathogenesis

Clinical presentation

Nomenclature

Management

Prognosis

Conclusions and future directions

Search strategy and selection criteria

J Neurol Sci

Pediatr Neurol

Lancet

Eur J Paediatr Neurol

Biochem Biophys Res Commun

Am J Ophthalmol

Chest

Transl Res

Lancet Neurol

Am J Ophthalmol

Ophthalmology

Revised diagnostic criteria for the pseudotumor cerebri syndrome in adults and children

Neurology

Effect of acetazolamide on visual function in patients with idiopathic intracranial hypertension and mild visual loss: the idiopathic intracranial hypertension treatment trial

JAMA

Low energy diet and intracranial pressure in women with idiopathic intracranial hypertension: prospective cohort study

BMJ

A practical approach to, diagnosis, assessment and management of idiopathic intracranial hypertension

Pract Neurol

The incidence and prevalence of idiopathic intracranial hypertension in Sheffield, UK

Eur J Neurol

Idiopathic intracranial hypertension (pseudotumor cerebri). Descriptive epidemiology in Rochester, Minn, 1976 to 1990

Arch Neurol

The incidence of pseudotumor cerebri. Population studies in Iowa and Louisiana

Arch Neurol

Idiopathic intracranial hypertension (pseudotumor cerebri): descriptive epidemiology, clinical features, and visual outcome in Parma, Italy, 1990 to 1999

Eur J Ophthalmol

Idiopathic intracranial hypertension; incidence, presenting features and outcome in Northern Ireland (1991-1995)

Ulster Med J

Epidemiology of pseudotumor cerebri

Arch Soc Esp Oftalmol

Epidemiology of idiopathic intracranial hypertension in Israel

J Neuroophthalmol

The incidence and prevalance of idiopathic intracranial hypertension in south Sharaqiah region, Oman

Oman J Ophthalmol

The incidence of idiopathic intracranial hypertension in Israel from 2005 to 2007: results of a nationwide survey

Eur J Neurol

Idiopathic intracranial hypertension in the pediatric population

J Child Neurol

Idiopathic intracranial hypertension in men

Neurology

Global Database on Body Mass Index

Pseudotumor cerebri treated by rice reduction diet

Arch Intern Med

Physiology of the choroid plexus

Physiol Rev

Physiology and pathophysiology of the CSF

Cerebrospinal fluid hypersecretion in pseudotumor cerebri

Trans Am Neurol Assoc

CSF hydrodynamics in idiopathic intracranial hypertension: a long-term study

Neurology

Cerebrospinal fluid overproduction and hydrocephalus associated with choroid plexus papilloma

J Neurosurg

Cerebrospinal fluid secretion by the choroid plexus

Physiol Rev

Evidence of connections between cerebrospinal fluid and nasal lymphatic vessels in humans, non-human primates and other mammalian species

Cerebrospinal Fluid Res

Diagnostic criteria for idiopathic intracranial hypertension

Neurology

Clinical course of idiopathic intracranial hypertension with transverse sinus stenosis

Neurology

Manometry combined with cervical puncture in idiopathic intracranial hypertension

Neurology

Brain swelling of unknown cause

Neurology

Idiopathic intracranial hypertension. Lack of histologic evidence for cerebral edema

Arch Neurol

Increased brain water self-diffusion in patients with idiopathic intracranial hypertension

Review
Understanding idiopathic intracranial hypertension: mechanisms, management, and future directions