Abstract
Abstract
Background
Idiopathic intracranial hypertension is characterized by increased intracranial pressure without any pathological findings on neuroimaging, except for signs of high intracranial pressure. Before diagnosing idiopathic intracranial hypertension secondary causes of increased intracranial pressure should be excluded.
Objective
to characterize the phenotype of patients with secondary intracranial hypertension and to identify possible risk factors for secondary intracranial hypertension.
Methods
We have systematically searched the PubMed database. The publications were analyzed according to the patient phenotype, age, gender, comorbidities, body mass index/weight status, and additional medication. The results are summarized in four categories: medication, infection, hormonal induced intracranial hypertension and miscellaneous groups of diseases related to sIH.
Results
We identified 105 eligible papers which included 272 cases. There were 49.6% pediatric cases. Among the adult group,70.9% were women. A total of 40.4% of all cases were obese or overweight, 27% among adults and 13.4% among pediatric cases. Increased BMI and recent weight gain, anemia, renal diseases and hypertension were the most frequent comorbidities related to sIH.
Conclusion
Among sIH patients, 40.4% were obese or overweight; two thirds were women. We recommend that even patients with a typical IIH phenotype should be screened for secondary causes.
Introduction
Idiopathic intracranial hypertension (IIH), also known as pseudotumor cerebri and benign intracranial hypertension, is a neuroophthalmological disorder characterized by increased intracranial pressure without any pathological findings on neuroimaging, except for signs of increased intracranial pressure (ICP) (1). IIH is diagnosed according to the ICHD-III criteria and revised Friedman criteria (2,3).
In patients with a typical phenotype (obese women of childbearing age) with qualifying criteria, a diagnosis of IIH can be established. In atypical cases (women or men with normal weight), additional work-up is needed to exclude secondary cases of intracranial hypertension (sIH) (1,3).
In the definition of increased ICP, the lumbar puncture (LP) opening pressure (OP) must be measured to or above 25cm H2O, and the cerebrospinal fluid (CSF) composition should be normal (1,3).The neurological examination should be normal except for sixth cranial nerve palsy and papilledema (1,3).The ophthalmological examination may confirm and assess the degree of the papilledema, which is one of the hallmarks of IIH (1,3).
However, LP OP, neuroimaging, neurological-, ophthalmological- and biochemistry/blood examinations cannot be interpreted in isolation when diagnosing IIH, rather they all contribute together. Thus, IIH is a diagnosis of exclusion and all secondary causes of increased ICP should be excluded before diagnosing IIH.
In terms of the clinical presentation, secondary intracranial hypertension (sIH) and IIH are similar, and in both cases, patients will often suffer from headache, visual disturbances, tinnitus and nausea (4,5). The two conditions cannot be differentiated on a clinical basis, and sometimes it is difficult to identify a secondary reason for increased ICP, but as the treatment is widely different it is crucial to identify patients with sIH.
The aim of this article is to try to characterize the phenotype (gender and weight) of patients with sIH and to identify possible risk factors that could be linked to sIH by literature review of published cases.
Methods
Search strategy and selection of studies
We systematically reviewed research articles that assessed the possible risk factors for sIH. We searched PubMed on 21 February 2020 for the following search string. It should be noted that we both used the abbreviation and the full text of the words such as
But only the abbreviations are written below :
First, one investigator (KK) independently screened articles by title and abstracts. If an association between a secondary reason/disease/medication and IH was illustrated in the title and abstract, the full-text was screened with use of the revised Friedman criteria. If the cases in the full-text fulfilled the revised Friedman criteria they were designated as included otherwise as excluded. VVC subsequently reassessed a sample of excluded articles and all included publications. Final inclusion was decided by consensus between KK and VVC. An initial consensus regarding the included articles was reached for approximately 90% of records. An independent investigator was available (RHJ) to make the final decision if a consensus was not achieved. The articles, that were published before the revised Friedman criteria, used the modified Dandy criteria for diagnosing IIH/pseudotumor cerebri. The challenge of using modified Dandy criteria as an inclusion criterion is that they exclude secondary reasons for raised intracranial hypertension due to the last criterion: “no other explanation for the raised intracranial pressure”. In our systematic review we have also screened articles published according to the Dandy criteria but used revised Friedman criteria for the inclusion of cases for the final analysis. The first database search resulted in a total of 802 articles. The included articles were exported to the reference manager Mendeley, and all the duplicates were excluded. After duplicates were removed there were 754 articles, which were screened by title and abstract and this yielded 59 articles. The second database search resulted in 2235 articles, after removal of duplicates there were 2206 articles, which were screened by title and abstract and this yielded 78 articles. The third database search resulted in 297 articles, after removal of duplicates there were 263 articles, which were screened by title and abstract and this yielded 29 articles.
From the first and second and third database search a total of 166 articles were assessed with the use of the revised Friedman criteria and this yielded 105 articles, which were included in the final result.
In 20 of the 105 publications there were missing data on either the LP OP, MRI, or the ophthalmological assessment, but these publications have been included due to the association between the exposure to a risk factor and the onset of symptoms indicating raised intracranial hypertension e.g., papilledema or bulging fontanels in infants. These 20 publications are highlighted with: “*” in Tables 1–4. In neuroinfection induced sIH, the CSF composition was not normal, which was the only criterion that was not fulfilled for sIH related to neuroinfections.
Medication induced sIH.
*patients do not fulfill Friedman’s criteria.
Infection induced sIH.
*patients do not fulfil Friedman’s criteria.
Hormonal disease induced sIH.
*patients do not fulfil Friedman’s criteria.
Miscellaneous group of diseases related to sIH.
*patients do not fulfil Friedman’s criteria.
** the number after a term in the colon comorbidities and treatment refers to the number of cases
Abbreviations related to the tables:
Ac: acute
AML: Acute myeloid leukemia
ANE: anemia
BMI: body mass index
SLE antiphospholipid sy: Systemic lupus erythematosus secondary antiphospholipid
antibody syndrome
CC: corticosteroid treatment
Cong: congenital
CR: case-report
CS: case-series
Dis: disease
DRPC: Double-blind, randomized, placebo-controlled trial
F: female
FQ: fluoroquinolones
HT: hypertension
M: male
MC: minocycline
Mo: months
N: normal
NAION: Non-artertitic anterior ischaemic optic neuropathy.
NM: not mentioned
O: obese
OC: oral contraceptives
OW: overweight
PTEN mutation: Phosphatase and Tensin Homolog on chromosome TEN (PTEN) mutation
RCA: retrospective case analysis
RO: renal osteodystrofi
Sec: secondary
Sy: syndrome
TC: tetracycline
Th: therapy
T-LAAL: T-lymphoid/myeloid bilineal acute leukemia
Vit A: vitamin A
Vit D: vitamin D
Eligibility criteria
The searches were limited to articles published in English and to studies with human subjects. We also reviewed the reference lists for relevant primary articles and reviews in the search for studies that we might have missed in the initial search process. The full eligibility criteria are presented in Figure 1.
Search process.
We have excluded conditions such as dural venous sinus thrombosis, subarachnoid hemorrhage, space occupying lesions, hydrocephalus, Chiari malformation, tumor processes that may compress parts of the venous outflow system, glomus tumor on the basis that these conditions are identifiable on imaging and rarely mistaken for IIH. It is beyond the scope of this systematic review to include conditions and diseases that are not mistaken for IIH and that can be easily identified on MR or CT-C with contrast, which are the diagnostic procedures according to the revised Friedman criteria.
Data extraction and synthesis of included literature
For each study, KK recorded data on the total number of subjects with sIH, patient phenotype, age, gender, comorbidities, body mass index (BMI)/weight status, and additional medication. Patient characteristics (age, gender, comorbidities) were then related to possible triggers for sIH.
Regarding BMI, we also included patients where the BMI was mentioned as high or normal. In articles where the height and weight were mentioned but the author did not calculate the BMI, we calculated the BMI from the given information.
The BMI in adult patients was interpreted by using the BMI guidelines published by the World Health Organization (6). The BMI in pediatric patients was interpreted by using the BMI guidelines from the Danish Pediatric Society (7).We have subdivided the pediatric patients in age categories (0-14 years and 15-17 years) as children/teenagers from the age of 15 generally have entered puberty, and therefore their bodies, hormonal systems and diseases resemble that of adults.
Our intention was to extract BMI and weight information from all of our included cases, but one of the main challenges in data extraction was missing data. Unfortunately a large number of authors do not mention the BMI or weight of the cases in their publications. If we excluded all the studies that did not have informed the BMI or weight we would have missed lot of cases and therefore data regarding secondary reasons for IH. Furthermore, some publications did not specify the age and sex of the cases, they only mentioned the mean age and the mean distribution of the sexes, which could not be used in the data analysis in our systematic review due to missing precise data. It was important that we obtained the most basic information of the cases such as gender and age. Therefore we excluded all the publications that did not specify the gender and age with the exception of a nested case-control study about oral fluoroquinolones, because it is the only nested-case control study we found stating oral fluoroquinolones as a secondary reason for IH.
Based on our research criteria, we summarized the results into four categories of possible triggers for sIH: medication, infection, hormonal, and miscellaneous diseases related to sIH for both children and adults (Tables 1–4). We analyzed the articles according to the patient phenotype, age, gender, comorbidities, BMI/weight status, and additional medication. Patient characteristics (age, gender, comorbidities) were then related to possible triggers for sIH.
Results
Among the 105 included articles, we found 76 case-reports; 18 studies reported on case series, 9 were retrospective case analyses, 1 was a case-control study and 1 was a double-blinded, randomized placebo-controlled trial with collected data on sIH.
The most frequent comorbidities related to sIH in our population were renal diseases 11/272 (4%), hypertension 8/272(2.9%) and anemia 7/272 (2.6%). Furthermore, anemia was the underlining cause of sIH in 42/272 (15.4%) cases.
BMI or an interpretation of the BMI was mentioned in 141/272 (51.8%) cases. Among patients with mentioned BMI, 84 (59.6%) had normal weight, 13 (9.2%) had gained weight recently and 57 (40.4%) were obese or overweight, of these 77.2% were females.
We found that 12/19 (63.2%) pediatric cases had increased BMI in the age group 0–14 years, and 7/19 (36.8%) in the age group 15–17. There was a predominance 14/19 (73.7%) of girls among the pediatric patient cases with overweight or obese.
Medication induced sIH
We found 43 articles with a total of 104 cases: 47 pediatric cases and 57 adult cases (Table 1). Seventeen publications referred to antibiotics and antiviral medications (8–24), 10 referred to vitamin A and its derivatives (25–34), and eight to hormonal treatment (35–42). We found three additional publications referring to medication used for gastrointestinal diseases (43–45), two referred to psychotropic agents (46,47), two to immunosuppressive treatments (48,49) and one to the consumption of herbs (50).
In the age group 0-14 years there were 8/27 (29.6%) girls and in the age group 15-17 years there were 6/10 (60%) girls. Furthermore, there were 25/30 (83.3%) women in the adult group; 1/104 was a transgender male. The gender was not mentioned in 10/104 (9.6%) infants and 26/104 (5.8%) adults.
Infection induced sIH
We found 11 articles with 29 cases: 17 pediatric and 12 adults (Table 2). The most common infections were meningitis in two, Lyme disease in three and panencephalitis in two publications, respectively. In addition, other infections were syphilis in two, acute HIV in one and mucormycosis in one publication, respectively (51–61).
The age distribution among the children was as follows: in the age group 0–14 years 4/15 (26.6%) girls and in the age group 15–17 years 1/2 (50%) girls. In the adult group there were 5/12 (41.6%) women.
Hormonal disease induced sIH
We found nine articles with 34 cases: 23 pediatric cases and 11 adult cases (Table 3) (62–70). There were 28/34 (82.4%) cases with endocrine metabolic dysfunction including primary or secondary aldosteronism. The less common hormonal diseases were ACTH deficiency, partial pituitary deficiency, primary hypothyroidism and pituitary hyperplasia, Addison’s disease, Cushing’s disease and secondary panhypopituitarism (62–70).
The age and gender distribution among the children were as follows: in the age group 0-14 years 16/20 (80%) girls, and in the age group 15-17 years there were 3/3 (100%) girls. In the adult group 8/11 (72.7%) were women. In total there were 79.4% females in this group.
Miscellaneous group of diseases
This group included hematological, oncological, rheumatologic and genetic diseases related to sIH
We found 42 articles with 105 cases: 48 pediatric and 57 adult (71–112), Table 4. The distribution was as follows: hematological diseases (N = 16) (90–93,95–104,106,107), rheumatologic diseases (N = 7): Behçet’s disease and systemic lupus erythematosus (SLE) (71,72,83,94,105,108,109), different genetic diseases (N = 5) (73,74,110–112), oncological disorders (N = 3) (75–77). The most common diseases in this group were anemia (N = 42), leukemia (N = 17) (75–77), Behçet’s disease (N = 7) SLE (N = 7) (94,105,108,109), head trauma (N = 7) (78,79), obstructive sleep apnea syndrome (N = 5) (80,81) and sickle cell disease (N = 5) (104,106). Cases related to sIH induced by genetic diseases were distributed as following: cystic fibrosis (N = 2), Gitelman’s syndrome (N = 1), Phosphatase and Tensin Homolog on chromosome TEN (PTEN)mutation (N = 1) Turner syndrome (N = 1) (73,74,110–112).
The gender distribution among the children was as follows: in the age group 0-14 years there were 20/34 (58.8%) girls and 9/14 (64.3%) girls in the age group 15-17 years. In the adult group there were 40/57 (70.2%) women.
BMI information and interpretation in our patient case population
Medication induced sIH
We had information about weight, BMI, or an interpretation of these measures in 37/104 (34.6%) of the cases: 22 were adults, and 15 were pediatric cases. Among the adult cases 14/22 (63.6%) were overweight or obese: 12/22 (54.5%) were obese or overweight adult women, 1/22(4.5%) overweight men and 1/22(4.5%) was an overweight transgender male. Among the pediatric patient cases 3/15 (20%) were obese or overweight.
Infection induced sIH
In 10/29 (34.5%) cases (2 adults and 8 pediatric cases), weight, BMI, or an interpretation of these measures was mentioned: both adults were obese or overweight. Among the pediatric cases 3/8 (37.5%) were obese or overweight.
Hormonal disease induced sIH
We had information about the weight, BMI, or an interpretation of these measures in 16/34 (47.1%) cases. BMI was mentioned/calculated in 4/16 (25%) cases, and 6/16 (37.5%) cases were categorized as obese with weight gain 18 months before the onset of headache and visual disturbances and six cases were categorized as overweight or obese without further specification (62,63). In one case weight loss of 10 kg was recorded one year prior to the sIH diagnosis (65). All seven pediatric cases (100%) (girls) were obese. In the adult group 2/3 (66.6%) were obese or overweight (females).
Miscellaneous group of diseases including hematological, oncological, rheumatological and genetic diseases related to sIH
The exact BMI, or interpretation of the BMI was known in 78/105 (74.3%) of cases. Of these 31/78 (39.7%) were pediatric cases and 47/78 (60.3%) were adult cases. The gender distribution of 22/47 was not specified with regards to BMI, but 16/22 cases were obese or overweight, while six cases were normal weight. Therefore, we have focused on the BMI interpretation of the adult group as follows: 16/25 (64.4%) female cases were obese, or overweight and 4/25 (16%) male cases were obese. Only 6/31 (19.4%) pediatric cases were obese or overweight in this category.
Discussion
Increased intracranial pressure, if untreated, is a serious condition which in severe cases can even lead to death. Thus, it is very important to search for the multiple potential differential diagnoses for IIH, identify the causes of sIH and treat the underlying condition. To the best of our knowledge, this is the first time that possible risk factors for sIH have been summarized in four categories in a review to analyze the patient phenotype in different groups.
Our results show that the published sIH cases have a similar phenotype to IIH. Among the adult group, we have identified 70.9% females. Regarding BMI, 40.4% were obese or overweight, and of these 77.2% were females.
Thus, our results indicate that being overweight may also play a role in sIH.
There were 13 cases in our study with remarkable weight gain in a period of 12-18 months prior to being diagnosed with sIH (20,37,51,62). This indicates a possible association between recent weight gain and onset of sIH related symptoms.
The exact pathophysiology of IIH and sIH are still unknown, but obesity seems to play a significant role. In certain cases, medications listed in Tables 1–4 are possible co-factors that may trigger a cascade of events leading to sIH in the predisposed patient.
We can speculate that sIH is induced more easily in overweight patients taking specific medication that then triggers the syndrome.
Ezequiel et al. have reported that obesity is a more common finding in pubertal patients, but is rare in prepubertal children (55). This is in contrast with our findings: we found that 12/19 pediatric cases had increased BMI in the age group 0–14 years, and 7/19 in the age group 15–17. There was a predominance, 14/19 (73.7%), of girls among the pediatric patient cases who were overweight or obese.
Due to the fact that we had information about weight in only 43.7% of our pediatric population, we are not able to confirm a significant association between BMI and the development of sIH.
Distelmaier et al. reported that the frequency of IIH is equal in a pediatric population and there is no clear correlation with obesity (75). Although our study focused on sIH, this is in line with our results: in our study the frequency of sIH among girls and boys is almost equal.
It has been observed that sIH often presents with the same clinical picture as IIH, but the treatment of IIH and sIH differs markedly (109).While the treatment of sIH is focused on eliminating the underlying causes of sIH, the treatment of IIH is mainly based on medical treatment with acetazolamide and weight loss. The treatment of both groups requires a multidisciplinary team of healthcare professionals such as neurologists, neuro-ophthalmologists, neuroradiologists, dieticians, neurosurgeons, and physiotherapists. Furthermore, in sIH patients, specialists such as endocrinologists and infectious disease specialists should also be engaged to give the patient an individualized treatment.
The identified difference of phenotype between IIH and sIH in published cases has led us to investigate whether there are other phenotypical differences. In the following, the four categories of risk factors for sIH are summarized and discussed.
Medication induced sIH
We have observed that antibiotics such as tetracycline, doxycycline, minocycline, nalidixic acid and fluoroquinolones, although used for different purposes, could induce sIH (8,10,12–14,19–24).
High consumption of vitamin A or hypervitaminosis A has been reported to induce sIH by a number of researchers (25–32). Interestingly, vitamin A deficiency has also been reported to induce sIH (33,34). This indicates that it is more likely that the imbalance of vitamin A rather than the vitamin A itself induces sIH.
We have observed that there was a higher frequency of low vitamin A induced sIH among boys in prepubertal age, possibly due to malnutrition. The use of vitamin A and tetracycline was higher among girls in pubertal age, probably related to acne treatment.
Treatment with corticosteroids was more often associated with sIH than other hormonal treatments. It has been well documented that corticosteroid withdrawal can induce sIH (35–37,77). Eight of the 15 cases with a hormonal drug induced sIH, were induced by corticosteroids. Only one case of the eight was an adult, while the other cases were children.
Methotrexate and cyclosporine A have also been described to induce sIH, as well as oncological treatments such as cytarabine hydrochloride and cytosine arabinoside A (Ara-C) (48,113–115). However, it is disputable to conclude an association between sIH and a particular oncological drug because cancer patients are simultaneously taking multiple medications. It is more likely that it was the combination of different cancer treatments and possibly the disease itself that induced sIH (48,113–115). Due to the lack of proven association between specific cancer treatments and sIH in these publications, we have not included them in our results.
Infection induced sIH
There are several infectious diseases, especially neuroinfections that may present with signs and symptoms of IH (51–61). However, there is a main clinical difference between IIH and sIH: the CSF analysis in IIH should be normal, while the CSF analysis (white cell count, protein, glucose) is abnormal in the presence of a neuroinfection. Although doxycycline is a known risk factor for sIH, the patients in the case-series by Ramgopal et al. achieved symptom resolution upon treatment with doxycycline (56). This implies that Lyme disease was the causative factor for the development of sIH (56).
The precise mechanism for sIH in patients with infectious diseases is not established. However, it has been suggested that increased intracranial pressure is related to reduced CSF absorption due to meningeal inflammation/changes in arachnoid and thus accumulation of CSF (55,56).
Hormonal disease induced sIH
Androgen related hormonal diseases such as primary and secondary aldosteronism were the most predominant (82.4%) in this group as mentioned in the results section. These diseases can be associated with the predominance of overweight and obesity among the patients (93.8% were obese or overweight in our study group) (116–118). The proposed association between adrenal cortex and adipose tissue is related to adipocytes, which produce mineral corticoid releasing factors, whose function is to induce aldosterone and cortisol production. An increased number of adipocytes increases mineralocorticoid activity through the aldosterone sensitive mineralocorticoid receptors in the epithelial cells of the choroid plexus, and thereby increases the activity and a number of Na/K ATPase pumps in the apical membrane of the epithelial cells of the choroid plexus. This induces secretion of sodium ions into the cerebral ventricular system leading to increased CSF secretion through an osmotic gradient (62).
It has also been postulated that estrogen produced through aromatization of androstenedione by adipocytes is one of the factors that links obesity with IH, and that it could induce an increased production of CSF (119).
Miscellaneous group of diseases related to sIH
Hematological diseases
According to the World Health Organization anemia is more common in women than in men globally. Anemia is most prevalent in non-pregnant women while men have the lowest prevalence of anemia globally (120). sIH related anemia in the miscellaneous group of diseases that had an important role. Furthermore, two publications with a total of 173 anemia cases were not included in the table and statistic calculation because the gender and age of the individual cases were not specified (121,122), but this high number of cases indicate how important anemia is as a risk factor for sIH. Anemia alone has been described as a risk factor for sIH by increasing the brain blood flow (109): anemia and tissue hypoxia change the cerebral hemodynamics, which increase the brain capillary permeability, and thereby increasing the ICP causing sIH (92). We have not found a consensus in this literature review to how severe the anemia must be if it was regarded as a cause for sIH or was possibly an additional risk factor. This is due to the fact that different laboratories have different machines and thereby different thresholds for anemia. The most common type of anemia was iron deficiency anemia and hemolytic anemia and the hemoglobin level ranged from 3.7–10.2 in the included articles.
Rheumatological diseases related to sIH
A higher prevalence of sIH among SLE patients has been observed (109). SLE has been reported to have IIH resembling symptoms in a case series of 53 SLE patients with sIH (108).
Several theories regarding the association between SLE and sIH have been suggested: systemic inflammation, deposition of immune complexes and thrombosis, all compromising the blood-brain barrier and reducing CSF absorption via the arachnoid villi (94,123). In some predisposed SLE patients steroid withdrawal could be the trigger factor for the development of sIH, while in others a hypercoagulable state and consequent micro-obliteration of the cerebral arteriolar and venous systems and subsequent reduction in CSF absorption could be the mechanism for development of sIH (94,123).
Pseudotumoral neuro Behçet’s disease (PNBD) is a rare and life-threatening condition compared to the classical form of neuro Behçet’s disease (NBD). PNBD is associated with severe neurological involvement, while NBD is associated with more extracerebral manifestations such as uveitis, joint and venous involvement. However, there are no differences between these two conditions with regard to three factors: gender ratio, age-onset or HLA-B5 type (83).
Oncological diseases related to sIH
sIH-related symptoms can complicate the diagnosis and disease course in haemato-oncological diseases. sIH symptoms such as headaches, visual disturbances, and papilledema can mimic anemia, stress, or other cancer-related complications (75,77).
Genetic diseases related to sIH
Cystic fibrosis (CF) is an autosomal-recessive genetic disease characterized by heterogeneous clinical manifestations. Up to 10% of infants with newly diagnosed CF develop IH. The underlying etiology of IH in cystic fibrosis patients has not been clarified; vitamin A deficiency, hypervitaminosis and concurrent anemia or replacement therapy with pancreatic enzymes have been suggested (110,111).
Other conditions related to sIH
It is well known that severe head trauma can induce sIH. However, the development of sIH after a mild trauma should not be dismissed (78,79).
Cervical dural arteriovenous fistulas (dAVF) can induce venous congestion and/or increase venous sinus pressure resulting in increased ICP due to the reduced re-absorption of CSF. Thereby dAVF will resemble IIH due to the development of papilledema and clinical signs (82,84).
Methodological considerations
There are certain limitations in our study: we identified 272 cases, however, our search strategy may have been incomplete. The following should be taken into consideration: the articles that used the modified Dandy criteria did not include as many secondary cases as is the case after Friedman criteria from 2013 were published and widely accepted. The selected cases and case reports are clinically identified and published, whereas the real prevalence of sIH is yet unknown. There is a general lack of population control studies on possible secondary causes for IH, therefore our research was based predominantly on case reports. Furthermore, due to a difference in diagnostic criteria, some of the older papers could have been excluded. A certain bias in the inclusion of studies for our final analysis was probably present. The cause-effect relation is also unknown and prospective large-scale studies are needed. Furthermore, although we tried to group different diseases and treatments into categories, in some publications it was difficult to separate the disease and the treatment for the disease. Especially oncological cases are difficult to analyze, as these patients are complex and a definitive cause or an additive risk factor in some cases could not be clarified. However, we believe that the number of cases in either of the groups gives cause for them to be classified as a possible secondary cause for IH.
Furthermore, we had data on BMI or an interpretation of BMI in 141/272 (51.8%) of the cases. In all of these cases a secondary cause for IH was suspected, but it is unknown how much obesity actually plays a role in these cases, as the pathophysiology of IIH and sIH is not fully understood.
Conclusions
To the best of our knowledge, this is the first time that these four categories of risk factors for sIH have been summarized in a review to analyze the patient phenotype in different groups. Among sIH patients, 40.4% were obese or overweight and two thirds were women.
We have shown that in 40.4% of the cases obesity could be a risk factor that plays a significant role in the development of sIH. We strongly recommend that both atypical cases and patients with a typical IIH phenotype should be carefully screened for secondary causes. Due to a small sample size of included cases in each sIH category in our search, we cannot provide the evidence level of how strong the association is between different factors and sIH.
It is important as a clinician to be aware of different risk factors for sIH because the clinical symptoms and even phenotype (obesity) of IIH and a subgroup among sIH patients resemble one another. This observation is especially important because misdiagnosing sIH patients as IIH means that this group of patients will not undergo the diagnostic work-up necessary to find and treat the secondary cause of IH.
Our study has shown that it is difficult to use the BMI as a phenotypical distinction between IIH and sIH. Therefore, we would recommend that further studies highlight phenotypical differences between IIH and sIH more clearly and investigate this possible overlap. By increasing the awareness of possible risk factors related to secondary IH among clinicians, the treatment in both patient groups will hopefully be improved.
Clinical Implications
MRI, CT angiography (venous sequences) to exclude sinustrombosis, lumbar puncture with pressure measurements, ophthalmological examination as well as routine blood tests are the milestones of diagnostic work-up for all suspected IIH patients. In atypical phenotype patients (men, normal weight young women/men, elderly patients, non-responsive to initial treatment or in cases where a secondary cause is suspected), the following tests are recommended: X-ray of the chest To exclude rheumatological diseases: ANA, ANCA, anti-dsDNA, anti-cardiolipin antibody, lupus anticoagulant, rheuma factor, interleukin 2 To exclude Metabolic/hormonal diseases: s-peptidyltransferase, TSH, PTH, Ca2+ To exclude infectious diseases: Coxiella B, Borrelia B, Entyerovirus, Herpes simplex virus 1 og 2, varicella-zoster virus, treponema pallidum (Syfilis), HIV test. In the case of suspected but not CT verified sinustrombosis the coagulation blood tests are recommended. Our list of recommended investigations should be broadened in particular cases, according to the clinical picture
Footnotes
Declaration of conflicting interests
The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RHJ is or has been principal investigator in studies sponsored by Lundbeck, Eli Lilly and ATI and has given lectures for Novartis, Lundbeck, Allergan, TEVA and ATI. VVC has given lectures for Novartis.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.