Correlation between Diagnostic Magnetic Resonance Imaging Criteria and Cerebrospinal Fluid Pressure in Pediatric Idiopathic Intracranial Hypertension

<jats:p>Purpose: Idiopathic intracranial hypertension (IIH) is a clinical syndrome that mimics brain tumors with increased intracranial pressure. The present study is designed to investigate the diagnostic criteria of magnetic resonance imaging (MRI) and the severity of cerebrospinal fluid (CSF) pressure to understand the relationship and frequency of these criteria with the level of CSF pressure.Methods: The present cross-sectional study was conducted on children diagnosed with IIH between the years 2011 and 2020, who were admitted to the pediatric neurology department of Ghaem Hospital, Mashhad, Iran. Clinical manifestations and imaging findings of the patients were recorded through a checklist. Results: Forty-nine patients were included in the study; 27 (55.1%) were male, and 22 (44.9%) were female. The average CSF pressure was 40.64±20.63 cmH&lt;sub&gt;2&lt;/sub&gt;O. The mean diameter distension of the perioptic subarachnoid space was 6.02±1.21 mm. Six (10.8%) patients had unilateral transverse sinus stenosis with an average CSF pressure of 20.47±36.80 cmH&lt;sub&gt;2&lt;/sub&gt;O and 11 (21.4%) patients had bilateral transverse sinus stenosis with an average pressure of 48.22±21.04 cmH&lt;sub&gt;2&lt;/sub&gt;O. In 22 (44.89%) patients, flattening of the posterior globe with the CSF pressure of 48.80±17.94 cmH&lt;sub&gt;2&lt;/sub&gt;O was reported. Twenty-four (49%) patients had optic nerve tortuosity, with an average CSF pressure of 46.52±20.33 cmH&lt;sub&gt;2&lt;/sub&gt;O. Among the diagnostic criteria, the pressure had a significant relationship with the flattening of the posterior globe (&lt;i&gt;P&lt;/i&gt;&lt;0.022).Conclusion: Since MRI is a non-invasive method for examining IIH, the findings of this study may aid in diagnosing and monitoring these patients.</jats:p>

section_content: Idiopathic intracranial hypertension (IIH), also known as Bpseudomotor cerebri^and Bbenign intracranial hypertensionî s characterised by headaches associated with raised cerebrospinal fluid (CSF) pressure in absence of any intracranial abnormality, normal spinal fluid composition, papilloedema and normal level of consciousness [1] [2] [3]. The term Bidiopathic intracranial hypertension^was eventually coined due to the condition not always being benign [4] Children as young as 4 months can be affected with equal sex distribution [5]. In the general population, female predominance is noted [1]. There are several theories as to the origin of intracranial hypertension. These include increased venous sinus pressure, decreased spinal fluid absorption, increased spinal fluid secretion, increased blood volume and cerebral oedema [6, 7]. In this review, we analyse and summarise the current updates in the literature for the diagnosis, pathophysiology and management of intracranial hypertension.
section_name: Introduction

section_content: A narrative review was decided because of the heterogeneity of the qualitative research literature. A review of studies published on the topic of IIH in the literature between 1st January 2000 and 31st December 2015 and indexed within PubMed and Google Scholar. Searches were conducted looking within 'titles' and 'general', using the search terms 'idiopathic, intracranial hypertension, headaches, cerebrospinal fluid, familial, ventriculoperitoneal shunt, pseudomotor cerebri'. 

The searches revealed 72 studies that were assessed, including systematic reviews, cohort studies, case-control studies, randomised control trials and case-studies. This is an extraordinarily small body of peer-reviewed research papers given the importance and contentiousness of the topic. The studies in this paper have limitations that should be acknowledged, such as their small size and limited scope. As this is not a systematic review and few articles were found, evaluations of methodological quality were not used to exclude papers from the study. Once the searches were collated for a final review of the chosen articles, their bibliographies were also reviewed, looking for papers that may have been omitted by the stratifications of the primary searches.
section_name: Method

section_content: The incidence of IIH is well recorded in the literature as steadily increasing [8, 9]. The incidence of IIH is documented as being 1-2 per 100,000 population [4, 8]. A study in Sheffield, UK showed that the incidence was 1. 56/100,000/year for men and 2. 86/100,000/year for women [9]. 

Prospective studies have shown that females are more affected than males. Of the patients with IIH, 90% are females [1, 10, 11]. IIH has been significantly associated with conditions related to increased intra-abdominal, visceral fat and elevated body mass index (BMI), such as elevated levels of adipose tissue-derived retinol-binding protein, polycystic ovarian disease in women and androgen deficiency in men [8, 9, 12]. A relationship has been shown between female sex, a higher BMI and a resultant greater risk of IIH [12, 13]. 

The first report of IIH in children was in 1967. Children as young as 4 months can be affected with equal sex distribution. Other than symptomatic manifestation, this condition tends to present with loss of school improvement [5]. 

Albeit its rarity, familial IIH has been recorded in the literature. A study by Karaman et al. [14] noted a consistent history of ICH in multiple members of the same family. These observations were also noted in reports by Kharode et al. [15], where multiple families were recorded as having intracranial hypertension in successive generations. Corbett [16] showed an intracranial hypertension relationship occurring between parent and child in 7 out of 11 families studied and siblings in 4 out of 11 families. Cheber et al. [17] noted significant association of IIH in siblings. All the above-mentioned studies describe obesity has being a common factor in most cases.
section_name: Epidemiology

section_content: Diagnostic process for IIH is one of exclusion based on clinical symptoms: neurological, ophthalmic, radiological and CSF findings from a lumbar puncture [5, 18]. 

Headaches, predominantly frontal, worse on lying down, are the most common presenting symptom. It is sometimes associated with back pain or radicular pain [19, 20]. Other symptoms include visual disturbances, including diplopia commonly secondary to abducens nerve palsy, visual loss, photophobia and shimmering lights due to papilloedema. Rarely, IIH can present with migrainous features without papilloedema [4]. Visual disturbances are documented as being present in up to 10% of patients with diplopia occurring in one-third to two-thirds of patients [21] [22] [23]. Similarly patients can present with other sensory disturbances such as olfactory dysfunction and tinnitus [24] [25] [26]. Pulsatile tinnitus can present as unilateral or bilateral [27]. 

Other symptoms include lethargy, dizziness, depression for IIH (replaced 'mood changes'), cognitive impairment, sleep and behaviour disturbances [5, 19, 28]. 

The primary role of neuroimaging in IIH is to exclude other pathologies, with magnetic resonance imaging (MRI) being the modality of choice. Pathologies noted on MRI in the case of long-standing IIH include an empty sella, flattening of posterior globes, protrusion of the optic nerve head, optic nerve sheath distention, optic nerve tortuosity, herniation of the cerebellar tonsils, meningoceles, CSF leaks and transverse venous sinus stenosis [18]. Imaging is also necessary to exclude any space occupying lesions [22]. 

A guide for diagnosis of IIH is the Dandy Criteria, developed in 1937 and further modified by Smith [3] in 1985, coining them the BModified Dandy Criteria^ [2, 18]. Due to the advances in imaging, new criteria have been developed by Wall et al. [20] and Ligouri et al [ 29]. In our diagram (Fig. 1 ) we aim to identify the key similarities and differences between these three criteria. 

A second mandatory test is a lumbar puncture to record the opening pressure for CSF. A CSF sample is sent for various tests, including microscopy, protein measurement, glucose, cytology, culture and xantochromia [22]. One major diagnostic result from this test is the opening pressure. The current guidelines allow different pressure measures. The IIHTT Criteria (2014), allow a pressure of 200 mm H 2 O as a diagnostic factor. The Friedman Criteria (2013) and the traditional Modified Dandy Criteria (1985) both accept a higher threshold: 250 mm H 2 O [3, 18, 22, 29].
section_name: Diagnosis

section_content: The current understanding is that IIH occurs due to dysregulation of the physiology of CSF flow, causing CSF to accumulate intracranially. In the traditional model, CSF is secreted by the choroid plexus, then flows through the subarachnoid space and leaves through the arachnoid granulations [30]. As a result, the pathophysiology of intracranial hypertension is unclear but proposed mechanisms include increased production or reduced absorption of CSF, causing a significantly raised central venous pressure (CVP). Recently, the involvement of inflammatory factors has been proposed [4]. Excessive CSF production has been recently put under question due to a normal or decreased ventricular size in IIH patients [4]. 

While many diseases have definite histopathological features, there is little documentation about the histopathological changes in the literature. Mollan et al. [22] stated that cerebral venography sheds light on anatomical abnormalities of cerebral venous sinuses. These imaging abnormalities tend to present in most patients with IIH [22, 31]. The two main types of venous stenotic changes are the extrinsic and intrinsic types. Intrinsic stenosis tend to present due to arachnoid granulations or fibrous septae. Extrinsic stenosis occurs secondary to a smooth, tapered stenosis. The literature however suggests that these changes present secondary to raised intracranial pressure (ICP) as reducing ICP with the various methods described below, tend to resolve these changes described on imaging [22]. 

Obesity is heavily documented in the literature as being associated with IIH [12]. A theory that has been suggested includes increased intra-abdominal pressure, which in turn causes reduced cerebral venous drainage [4]. Obesity is also considered as a pro-inflammatory state due to increased expression of adipokines and cytokines. Elevated levels of the cytokine leptin was noted in IIH patients in both CSF and serum samples [4, 32, 33]. IL-17 and IL-12 were also found within significant levels in the CSF of IIH patients, therefore implying an inflammatory process occurring in obese patients [34]. 

Another hypothesis outlined by Tabassi et al. [34] and Warner et al. [35] is abnormal vitamin A metabolism [12]. Both studies recorded elevated retinol levels in the CSF [12, 35]. Warner et al. [35] demonstrated lower levels of retinol binding protein in the CSF. No further major studies have been published on the topic. A current trial on the topic is the Nordic Idiopathic Intracranial Hypertension Treatment Trial (IIHTT), which can shed some light on the significance of vitamin A and leptin in IIH [36]. 

Another hypothesis documented in the literature is sex hormone imbalance. Patients with PCOS have been reported to Fig. 1 A diagram comparing and contrasting the current diagnostic criteria available in the literature [3, 18, 29] have a significant level of admission with IIH. As hormonal imbalance is related to obesity, this might be an explanation. However, there is no study outlining the pathophysiological pathway [18]. 

Anomalous distal transverse sinuses can occur, resulting in bilateral transverse sinus stenosis-a condition possible in obesity, hypercoagulable state, medications and OSA [37, 38]. Stenosis of a dominant transverse sinus or stenoses of both transverse sinuses can impair venous drainage, resulting in cerebral venous hypertension and CSF malabsorption with resulting accumulation [12]. Similarly Juguner et al. [39] and O'Brien et al. [40] showed a significant relation between traumatic brain injury and a resultant defect in blood-brain barrier permeability. 

Similarly, microthrombosis secondary to thrombophilia within the cerebral veins can occur, resulting in impaired CSF absorption. However, routine hypercoagulation studies in presumed IIH patients are not warranted, unless there is a demonstrated clot within the cerebral venous sinuses, or a strong personal or family history of thrombophilia [12]. 

Aquaporins are cell membrane proteins which allow transport of water in and out of cells [4]. These are present in large amounts at the blood-brain barrier and the brain-CSF interface. Deficiency of aquaporin-4 used for transmembrane osmotic movement of water has been noted to cause IIH in transgenic mice [41]. However, these findings have not shown any extrapolation to human diseases [12, 42, 43]. Aquaporin-1 is another protein of the aquaporin family and is predominantly located in the choroid plexus, therefore allowing water secretion into the subarachnoid space. In this case, hyperexpression of aquaporin-1 can occur due to medications such as retinoids and steroids, therefore explaining a possible pathogenetic factor for IIH [4, 44]. 

Another recent study by Skau et al. [45] suggested the involvement of natriuretic peptide as a regulatory factor of ICP due to dysregulation of the vascular tone. The study suggests the use of antriuretic peptides as markers of the disease. The study highlights the use of C-type natriuretic peptide, which is released from endothelial cells and relaxes vascular tone. High levels of the propeptide form of the C-type natriuretic peptide has been noted in IIH patients [4].
section_name: Pathophysiology

section_content: The management of IIH includes two cardinal points: alleviation of symptoms while preserving vision and elimination of any contributing factors. 

Treatment commences with the use of a diagnostic lumbar puncture which often resolves the symptoms transiently or in some cases, a complete remission [24]. The current understanding involves an understanding that the lumbar puncture draining will reduce the CSF pressure below a given threshold for the unstable equilibrium. As a result, the ICP will settle at a lower pressure. Many times, however, these patients might require serial lumbar punctures done when they become symptomatic [46]. 

In common practice, the treatment of the patient is coordinated by a neurologist or neuro-ophthalmologist. The factors which are playing a key role to the treatment planning are the presence and severity of symptoms, i. e. headache, visual disturbance, one detectable underlying cause (e. g. Chiari malformation, medication aetiology) and identification of known factors for their prognosis (phylogenetics, male sex, puberty age, high-grade papilloedema with macular involvement) [47]. Basic goal of every treatment is keeping the vision safe. To our knowledge there are no randomised prospective trials yet which assess the efficacy of the treatments of IIH.
section_name: Current advances in management of intracranial hypertension

section_content: Obesity is a common causative factor of IIH documented in the literature [8, 9, 12]. Weight loss is, therefore, critical in overweight patients. Patients with a BMI greater than 40 is predictive of a greater visual impairment [48]. A study by Johnston et al. [49] explains that 6% weight loss is associated with resolution of marked (Grade 3) papilloedema. Wong et al. [48] described successful stopping of systemic treatment in patients who underwent weight loss after 24 months of follow-up. However, the study mentions that absolute body mass is better than BMI to calculate likelihood of resolution of ICH. 

Loss of 5-10% of total body weight usually alleviates symptoms. In some patients one might consider the use of bariatric surgery. The beneficial effects of bariatric surgery in IIH patients are weight reduction, resolution of papilloedema, and return of ICP to normal as documented in the literature [46, 50]. Further randomised controlled trials are, however, required in order to confirm this seemingly successful method of management.
section_name: Treatment of risk factors

section_content: The most appropriate medical therapy is achieved when the symptom to be treated is headache exclusively. Caution should be applied to some preparations as either they cause gain of weight (tricyclic antidepressants, valproate) or fluid retention (channel blockers of Ca ions).
section_name: Medication (diuretics carbonic anhydrase inhibitors/acetazolamide, topiramate, steroids, rest diuretics)

section_content: Acetazolamide resembles the most frequently used drug and has a double function as inhibitor of CSF production and mild diuretic. Acetazolamide inhibits the carbonic anhydrase in the choroid plexus, leading to a decreased CSF production and flow by reducing transport of sodium ions through the choroid plexus epithelium [12, 51, 52]. It has been shown to reduce CSF production in humans by up to 50% [52]. 

According to the IIHTT randomised controlled trial of the NORDIC consortium, acetazolamide is especially efficient on: mild visual loss, severity of papilloedema and quality of life but is not clear if it is efficient on headache control [52]. Acetazolamide's effectivity is supported by the only systematic review present to date [53]. The common practice has suggested commencing acetazolamide in adults generally by beginning at a dose of 1 g/day given in divided doses of either 250 mg 4 times a day or 500-mg sequels twice a day. Lower doses usually have no effect and should not be considered. 

An attempt to increase the dosage amount of acetazolamide to 2. 5 mg/day from 1-2 mg/day, which was used previously, has shown a modest effect on the visual loss [54]. In a subgroup analysis of the same article, a higher efficacy of acetazolamide was found in patients with severe papilloedema. Moreover, when the indication was mild visual loss, then acetazolamide combined with weight loss was the treatment of choice. Common side effects are fatigue, tingling of hands. 

In summary, the IIHTT describes improved perimetric mean deviation (PMD), papilloedema, weight loss, quality of life and CSF opening pressure. No proof has been given for treating visual acuity or headache relief [53]. 

Data from an unmasked randomised controlled trial by Ball et al. [55] have proved effective change of headache existence (presence vs absence), transient visual obscuration, visual loss and binocular contrast sensitivity. However, there was no significant effect difference on papilloedema, headache severity, improved visual acuity and visual fields Common topics of both randomised controlled trials is the lack of evidence for effectiveness of the drug to the visual acuity and for the ability to manage the headache severity. Disharmony appeared regarding papilloedema as the NORDIC Idiopathic Intracranial Hypertension Study Group Writing Committee [53] described reduction of the papilloedema, in contrast to Ball et al. [55], who could not find any evidence for it. 

Of note are some side effects such as paraesthesias of the extremities, lethargy and altered taste sensation. As an alternative, methazolamide (Neptazane) may be used and is sometimes better tolerated than acetazolamide [56].
section_name: Carbonic anhydrase inhibitors

section_content: Topiramate has shown positive results in reducing ICP. It represents the antimigraine drug of choice because of weight loss and mild carbonic anhydrase activity. A comparison study of topiramate and acetazolamide by Celebisoy et al. [57] describes that at the end of 12 months of pharmacological management the two groups showed similar efficacy in the management of IIH. Side effects include angle-closure glaucoma, distal paraesthesia and concentration difficulties. Caution must be exercised onto combination with acetazolamide for risk of metabolic acidosis [57].
section_name: Topiramate

section_content: The use of oral steroids in IIH is questionable due to the well-known side effects such as weight gain. As acute treatment, high-dose IV steroids may be against fulminant IIH with severe visual loss [58]. Despite the acute lowering of ICP, caution should be exercised with the routine use of corticosteroids as it produces a rebound increase in ICP. In addition, classic side effects as fluid retention and weight gain shall always be taken into account as the latter is a common cause of IIH [18].
section_name: Steroids

section_content: Furosemide and chlorthalidone are occasionally used to treat pseudotumour cerebri. In general, they are not as effective as either acetazolamide or topiramate. Potassium sparing diuretics such as spironolactone and triamterene can be considered in patients who have allergy to acetazolamide or other sulphonamide-containing diuretics. The combination of diuretics alone or with carbonic anhydrase inhibitors may cause hypokalaemia and should be done extremely carefully [18].
section_name: Rest diuretics

section_content: The exact effectiveness mechanism of the intervention is still uncertain. Nevertheless selected cases seem to profit, especially pregnant patients. There are several approaches. The high volume approach suggests removing equal to or more than 20 mL CSF, while the normal-range approach (target, 140-180 mm H 2 O) reduces the likelihood of post-lumbar-puncture headaches [18].
section_name: Lumbar puncture

section_content: Surgery is performed according to underlying disease, i. e. when Chiari malformation then decompression. Absolute indication for surgery is only the severe optic neuropathy or failure to treat visual loss conservatively.
section_name: Surgery

section_content: Optic nerve sheath fenestration (ONSF) is the intervention of choice, having replaced the older subtemporal decompression. ONSF (also called Boptic nerve sheath decompression^) is the operation of exposing the optic nerve through several slits in dura and arachnoid mater posterior to the globe, hence CSF is drained from the slits. It is indicated when the main symptom is visual disturbance by papilloedema and medications are ineffective or there is induced tolerance, a fact about which Mukherjee and Bhatti [47] and Bidot et al. [18] agree. ONSF seemed to stabilise or improve vision. Feldon et al. [59] found a 72% success in improvement of visual fields and a 50% success in improvement of visual acuity. On the other hand, Moreau et al. [60] add neutral and positive clinical outcome results. They mention 96. 9% stabilisation or improvement of visual fields and 95. 8% stabilisation or improvement of visual acuity

In some of the first observation trials, the patients post ONSF have shown improved headaches by two-thirds and some developed headaches which could get managed with LPs [61, 62]. Various scientists such as Corbett et al. [61], Spitze et al. [64] and Brazis et al. [70] describe a 50% resolution, Sergott et al. [62] describe 76% resolution, Banta and Farris [63] 31% and Thuente and Buckley [65] 41%-. 

There has been no proven effect of ONSF on ICP and the temporary clinical improvement is attributed to a focal rather than general ICP impact. On that basis, major indications for ONSF are the visual disturbances and not the headaches. More frequent risks are: infection, transient or permanent diplopia, and transient or permanent loss of vision from central retinal artery occlusion or ischaemic optic neuropathy [47].
section_name: Optic nerve sheath fenestration

section_content: CSF diversion is indicated when the predominant symptom is headache. This is accepted by the majority of contemporary literature [18, 47, 66]. There is little outcome difference whether CSF diversion occurs through a ventriculoperitoneal (VP)shunt or lumboperitoneal (LP) shunt, with VP shunts having a slightly longer survival period [66]. Given the very poor literature only one study has compared LP and VP shunting on the same symptoms management. Thus, Tarnaris et al. [66] found that when treating headache, LP shunting had a resolution rate of 71%, whereas VP shunting gave a rate of 60%. With regards to visual acuity, the LP shunts were 42% successful and the VP shunts 40%. Another study describes 18. 2% resolution of headaches and 27. 3% improvement, way below what Tarnaris et al. mention. Regarding visual disturbances, there was a 5. 9% resolution and 29. 5% improvement on the LP shunt group, with no input for a VPS group to compare. Regarding papilloedema, Feldon [59] found a 22. 7% resolution and 15. 9% improvement of papilloedema when doing an LP shunting, whilst the VP shunting was fully successful at 100% on resolution. 

In time, VP and LP shunts have gained ground against the traditionally used lumbar punctures. Standard complications are excessively low pressure, spontaneous obstruction of the proximal or distal ends of the shunt, and migration of the distal end of the catheter causing chest or abdominal pain and infection. A higher complication rate is associated with LP shunting than with VP shunting.
section_name: Cerebrospinal fluid diversion

section_content: This method is an efficient and low complication treatment when a venous sinus thrombosis is radiologically confirmed. The indications for the procedure are not absolute. While Matloob et al. [67] and Mukherjee and Bhatti [47] agree that only condition for stenting is the presence of a sinus stenosis, Bidot et al. [18] suggest that stenting is indicated after bilateral stenosis and previous unsuccessful conservative treatment. Single contraindication for stenting is a dural sinus stenosis [68]. 

With regards to clinical outcome, Puffer et al. [71] found a headache resolution in 88% of patients while Radvany et al. [69] found headache resolution in 17% of patients and improvement in 42%. 

In visual disturbances such as visual fields and visual acuity, Puffer et al. [71] found resolution or improvement of results in 87% of cases, whereas Radvany et al. [69] described resolution or improvement of visual fields on 79% and improvement of visual acuity on 91% of patients. Finally, in terms of papilloedema Puffer et al.
section_name: Transverse venous sinus stenting

section_content: There is undoubtedly a correlation between increased ICP and occlusion of the cerebral venous sinuses. However, it is still unclear whether venous occlusion is the cause or the effect of increased ICP.
section_name: described resolution of 97% and Radvany et al. 91%.]

section_content: Until now there is no class I evidence guideline to which our decision-making can be based on for the diagnosis and management of IIH. A lack of systematic reviews and randomised control trials has been noted. If we focused our research on that, we could develop a standardised treatment protocol. 

VA and VP shunts seem to be more effective than ONSF in treating headache and equally effective to ONSF in treating vision disturbances. Therefore, ONSF is not considered as a first-line treatment any more. In our attempt to compare symptom-based treatment methods, we came across harmonical clinical outcome results among different studies, with only two exceptions: the headache improvement rate of Feldon [59] (45. 5%) and Tarnaris et al. [66] (71%) after LP shunt and the headache improvement rate of Puffer et al. [71] (88%) and Radvany et al. [69] (61%) after venous sinus stenting. Of course sample size always plays a huge role in the shaping of results. Nevertheless an attempt to compare the different treatment methods is confounded by the retrospective nature of the data, different surgical techniques, and undetailed reporting of their outcomes and adverse effects. 

We suggest that all patients with IIH undergo a venogram proactively and that patients are subsequently divided into simple and complicated IIH. Simple IIH would require a one-off management with a therapeutic lumbar puncture. On the other hand, a complicated IIH patient would require multiple interventions [68]. In diagnosis and monitoring of the IIH, we should take optical coherence tomography into account [18]. 

We believe that future studies should look into testing efficiency of programmable CSF diversion devices, success rate and positive outcomes of each surgical procedure, development of indication guidelines for venous sinus stenting through a new randomised controlled trial and clinical trials on the subgroup of patients with severe visual loss [49]. 

Finally, every case should be referred to a specialist centre where multi-disciplinary teams are operating [68].
section_name: Discussion

section_content: Funding No funding was received for this research. 

Conflict of interest All authors certify that they have no affiliations with or involvement in any organisation or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript. 

Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. 

Informed consent For this type of study formal consent is not required.
section_name: Compliance with ethical standards