Neurol Sci DOI 10.1007/s10072-015-2071-y
ORIGINAL ARTICLE
The laboratory profile in idiopathic intracranial hypertension Lea Pollak • Efrat Zohar • Yoseph Glovinsky Ruth Huna-Baron
•
Received: 15 September 2014 / Accepted: 9 January 2015 Ó Springer-Verlag Italia 2015
Abstract While overweight and female gender play an undisputable role in the pathogenesis of idiopathic intracranial hypertension (IIH), the contribution of other factors is still unclear. We have evaluated the laboratory findings of patients with IIH in an attempt to find the influence of abnormalities on the disease course. Included were 82 females after menarche and males older than 18 years who were followed up for at least 1 year. A wide range of laboratory parameters were examined at the time of presentation. The most frequent abnormal laboratory findings were elevated C reactive protein (CRP) (51 %), thrombophilia (31 %), increased plasma cortisol levels (29 %) and elevated lactate dehydrogenase (LDH) (20 %). Patients with elevated CRP and patients with thrombophilia had an unfavorable visual outcome. Increased cortisol levels and abnormal calcium correlated with a higher rate of recurrence. The visual outcome of patients with elevated LDH was better than those with normal LDH. It seems that certain metabolic, inflammatory and coagulation abnormalities may influence the course of IIH. If confirmed in further studies, these findings could contribute to elucidation of the etiology and prognosis of IIH.
L. Pollak E. Zohar Y. Glovinsky R. Huna-Baron Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel L. Pollak (&) Kibutz Galuyot 4, 74012 Nes Ziona, Israel e-mail: [email protected] Y. Glovinsky R. Huna-Baron Goldschleger Eye Institute, Sheba Medical Center, Tel-Hashomer, Israel
Keywords Idiopathic intracranial hypertension Laboratory findings Prognosis
Background Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure in the absence of an identifiable pathology related to the rise in CSF pressure [1, 2]. Its prevalence is about 1–2/100,000 in the general population, but up to twenty times more among young obese women [1, 2]. The entity is one of the most commonly encountered diseases at neuroophthalmological clinics and may lead to blindness. While overweight and female gender play an undisputable role in the pathogenesis of IIH, the contribution of other clinical factors, previously considered to be strongly associated with this condition, is still unclear [3, 4]. Various medications have been presumed to cause or precipitate IIH, but only a few of them, such as tetracycline, have been shown to be of probable significance [1]. The theory of increased intracranial venous pressure due to increased abdominal pressure has also been abandoned. Similarly, oral contraceptives have been implicated in the pathogenesis of IIH, probably only due to their concomitant use by young women with IIH. Stenosis of the distal portion of the transverse cerebral sinuses leading to impaired venous drainage and resulting in decreased CSF absorption and increased intracranial pressure could offer a plausible explanation for the pathogenesis of IIH, but this is still controversial [3, 4]. Therefore, until the etiology of IIH is definitely established, reports about other common findings associated with IIH might be of value. We have comprehensively evaluated the laboratory findings of patients with IIH in an attempt to find the influence of distinct abnormalities on the disease outcome.
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Materials and methods The medical records of patients with IIH who were treated at the Neuro-Ophthalmology service center and were prospectively recruited during the years 1995–2008 were reviewed. Amongst them were patients who presented for the first time and patients who came to the clinic for follow-up. The diagnosis of IIH was established according to the Modified Dandy Criteria: (1) Symptoms and signs, if present, reflect only increased ICP; (2) Documented elevated ICP ([250 mm H2O) during lumbar puncture. Patients with a characteristic clinical picture (headache and papilledema) and with ICP [200 mm H2O were also included in this study [5]; (3) Normal cerebrospinal fluid composition; (4) Normal neuroimaging including the cerebral venous sinuses. Included were females after menarche and males older than 18 years who were followed up for at least 1 year. Blood tests were performed during the first visit. A wide range of laboratory parameters including complete blood count, biochemical profile, hormone levels, lipid profile, clotting functions, and inflammatory and immunological markers were examined by routine laboratory methods. The demographic, clinical and ophthalmological data of the patients were collected and analyzed in respect to the laboratory findings. The number of drugs or surgical interventions needed as well as the number of recurrences was registered. Improvement was judged according to the resolution of papilledema and improvement of the visual fields. Recurrence was defined as the return of papilledema, usually accompanied by recurrence of symptoms during tapering off or after discontinuation of treatment. No time frame was used to assess recurrences. Statistical methods We used the Chi square test for comparing categorical variables. The paired sample t test was applied to compare means between variables with normal distribution, while the Mann–Whitney test served for comparison of nonparametric variables. Pearson’s correlation coefficient was used to evaluate interrelations between quantitative values with normal distribution and Spearman’s rank correlation coefficient was applied for nonlinear distribution. A p value of \0.05 was considered statistically significant. SPSS version 18 (SPSS Inc. Chicago, Il, 2008) was used for the analyses.
according to the principles of the Helsinki Declaration. In view of the retrospective nature of the study, a signed consent was not required.
Results Demographics, presentation and treatment Eighty-two patients with a mean age of 30.2 ± 12 years were included [73 (89 %) were women (Table 1)]. Eightytwo percent of the patients were overweight (BMI [ 25 kg/m2). The prevailing complaints were headache (89 %) and transient visual obscurations (85 %) followed by tinnitus (59 %) and double vision (28 %). The majority of patients presented with grade 2 papilledema, followed by grade 1 and 3. Testing of the optic nerve functions revealed abnormal visual acuity in 17 % of the tested eyes. Abnormal color vision was found in 14 % of the eyes. An enlarged blind spot was the most frequently encountered finding on visual field testing (80 % of eyes), but nasal field defects and peripheral visual field constriction were also found in a significant proportion of patients (72 and 54 %, respectively). The mean visual field sensitivity (md = mean deviation) was depressed to -7.7 dB (normal range about -2 dB). Drug treatment consisted of acetazolamide, furosemid, topiramate and, in fulminant cases, corticosteroids. The average number of drugs used in one patient was 1.8 ± 0.9. In cases of drug treatment failure (22 % of patients), CSF diversion procedures and decompression of the optic nerve were performed. Six percent of patients underwent a ventriculo- or lumboperitoneal shunt and 7 % had optic nerve sheath fenestration. A further 7 % had both, shunt and optic nerve fenestration. Subtemporal decompression was performed in one patient. The mean follow-up was 61.3 ± 62.3 months, lasting from one to 27 years. Eight-four percent of the patients improved with respect to optic nerve appearance and visual field findings at the last follow up visit. Sixty-seven percent of the patients suffered a recurrence of IIH (on average 1.6 ± 1.7 recurrences per patient). Laboratory findings The results of the laboratory tests are summarized in Tables 2 and 3. Complete blood count
Ethical approval The study was approved by the local Ethical Committee of the Sheba Medical Center, Israel and was conducted
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About 14 % of the patients demonstrated significant iron deficiency anemia (Hb \ 10.5 g/dL). No dependence was found between the presence of anemia and the number of
Neurol Sci Table 1 Demographic data, presentation and outcome
Result Number of patients
%
Range
82
Women, no. of patients (%)
73
89
Men, no. of patients (%)
9
11
Mean age (years) ± SD
30.2 ± 12.9
Overweight (BMI [ 25 kg/m2), no. of patients (%)
67
11–68 82
Hypertension ([140/90 mmHg), no. of patients
36/64
56
Diabetes mellitus, no. of patients
5/82
6
Smoking, no. of patients
27/80
33
73
89
Presentation symptoms Headache, no. of patients (%) Transient visual obscurations
70
85
Tinnitus
49
59
23
28
Diplopia Papilledema according to Frise´, no. of eyes (%) Grade 0 Grade 1
19 (11) 40 (24)
Grade 2
56 (34)
Grade 3
39 (23)
Grade 4
10 (6)
Humphrey perimetry md (dB), mean ± SD
-7.7 ± 7.3
Visual field defects, no. of eyes (%) Enlarged blind spot
131 (80)
Nasal defect
119 (72)
Constriction
88 (54)
Abnormal visual acuity (LogMAR C 0.20), no. of eyes (%)
29 (17)
Abnormal color vision (\5/6 H.R.R.), no. of eyes (%)
23 (14)
Duration of follow up (months)
61.3 ± 62.3
Barosurgery, no. of patients (%)
5 (6)
Drug treatment, mean number of drugs ± SD
1.8 ± 0.95
Surgical treatment, no. of patients (%)
18 (22)
Ventriculo/lumboperitoneal shunt, no. of patients (%) Optic nerve sheath fenestration, no. of patients (%)
5 (6) 6 (7)
Shunt ? fenestration, no. of patients (%)
6 (7)
Subtemporal decompression, no. of patients (%)
1 (1)
Recurrence, no. of patients (%)
55 (67)
recurrences, visual outcome or treatment. However, in all patients, the anemia was treated promptly after establishing the diagnosis.
12–394 1–4
were found to be elevated in 22 % of patient, but did not seem to influence the clinical course and outcome. Serum protein levels
Liver enzyme tests Twenty percent of IIH patients had increased lactate dehydrogenase (LDH) levels. Those with elevated LDH demonstrated more improvement in visual acuity than patients with normal LDH levels (D VA 0.094 logmar scale as opposed to D VA 0.019 logmar scale, p = 0.032). The aspartate aminotransferase (AST), alanine aminotrasferase (ALT) and gamma glutamyltransferase (GGT)
Fourteen percent of patients had abnormal globulin serum levels, three of them had hyperglobulinemia and 11 hypoglobulinemia. There was a dependence between abnormal globulin levels and the number of recurrences (p = 0.04) as well as the need for multiple drug treatment (p = 0.004). The number of patients was too small to look for the influence of hyper- versus hypoglobulinemia on outcome parameters.
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Neurol Sci Table 2 Results of routine laboratory examination in IIH patients Laboratory parameters
Reference values
Number of patients with abnormal values (%)
Number of patients:;
Hemoglobin Platelet count
[10.5 g/dL
11/80 (14)
;
130–450 9 103/mm3
7/77 (9)
White blood cells
5:, 2;
4–11 9 103/mm3
15/77 (19)
:
5/76 (6)
:
15/77 (19)
:
\45 mg/dL
3/77 (3)
:
\8.4 mg/dL
8/71 (11)
:
AST, ALT, GGT
AST \ 40, ALT \ 45, GGT \ 32 U/L
16/74 (22)
:
LDH
\260 U/L
15/74 (20)
:
Albumin
3.6–5.5 g/dL
10/67 (15)
;
Globulin Natrium
2.3–4.5 g/dL 135–148 mmol/L
14/67 (21) 0
3:, 11;
Kalium
3.5–5.2 mmol/L
9/75 (12)
2:, 7;
Calcium
8.5–10.5 mg/dL
7/72 (10)
1:, 6;
Chloride
98–110 mmol/L
2/65 (3)
:
Phosphorus
2–4 mg/dL
17/71 (2)
16:, 1;
Total cholesterol
\200 mg/dL
30/70 (43)
:
Glucose—diabetes mellitus [125 mg/dL Creatinine
Males \0.9, females \1.2 ng/ml
Urea Uric acid
HDL cholesterol
30–70 mg/dL
7/24 (29)
;
LDL cholesterol
40–160 mg/dL
7/31 (22.5)
:
Triglycerides
30–200 mg/dL
17/44 (39)
:
: increased, ; decreased AST Aspartate aminotransferase, ALT alanine aminotransferase, GGT Gamma glutamyltransferase, LDH lactate dehydrogenase
Table 3 Laboratory results of hormonal profile, inflammatory markers and hypercoaguability states Laboratory parameters
Reference values
Number of patients with abnormal values (%)
Number of patients:;
Thyroid-stimulating hormone
0.4-5 lU//mL
9/55 (16)
7:, 2;
Thyroxine, free (fT4)
10–25 ng/dL
2/36 (5.5)
;
Prolactin
\650
2/32 (6)
:
Cortisol
5–25 lg/dL
8/28 (28.5)
3:, 5;
Luteinizing hormone (LH)
According to the phase of menstruation cycle
4/28 (14)
1:, 3;
Follicle stimulating hormone (FSH)
According to the phase of menstruation cycle
3/28 (11)
;
Erythrocyte sedimentation rate C- reactive protein
Males \15, females \20 mm/h \0.6 mg/L
25/33 (47) 18/35 (51)
: :
Fibrinogen
\400 mg/dL
14/29 (48)
:
Complement 3
79–159 mg/dL
10/27 (37)
:
Complement 4
16–38 mg/dL
5/25 (20)
:
Partial thromboplastin time, activated
23–29 s
12/51 (23.5)
7:, 5;
Antiphosholipid antibodies
0–15 U
6/19 (31)
:
Antinuclear antibody
\1:40
3/51 (5)
:
Thrombofiliaa
Negative
12/77 (14)
Present
Homocysteinemia
5–15 lmol/L
3/46 (6)
:
: increased, ; decreased LH follicular phase 2–15 U/L, ovulatory phase 22–105 U/L, luteal phase 0.6–19 U/L, FSH follicular phase 3–20 mlU/mL, ovulatory phase 9–26 mlU/mL, luteal phase 18–153 mlU/mL a
thrombofilia—protein C or S deficiency, prothrombin, antithrombin III deficiency, Leiden factor, prothrombin G20210A
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Electrolytes Ten percent of IIH patients had abnormalities in calcium (Ca) serum level: six had hypocalcemia and 1 had hypercalcemia. A correlation was found between abnormal Ca metabolism and the number of recurrences (p = 0.002). However, the number of patients was too small to look for the influence of hyper- and hypocalcemia on the clinical course of the disease. Lipid profile Hypercholesterolemia (total cholesterol [200 mg/dL) was present in 44 % of IIH patients and hypertriglyceridemia in 41 %. No correlation was found between abnormal lipid metabolism and the recurrence rate, visual outcome or treatment modalities. Hormone levels Twenty-nine percent of the patients with IIH had increased cortisol blood levels. These patients suffered more recurrences than patients with normal cortisol blood levels (p = 0.022). Inflammatory markers Elevated C reactive protein (CRP) levels were revealed in 51 % of the patients with IIH. Patients with raised CRP had less improvement in visual field sensitivity (D md 0.867) than those with normal CRP (D 3.087), (p = 0.04). Other inflammatory markers such as fibrinogen, complement three and four levels and erythrocyte sedimentation rate did not influence the course of the disease. Hypercoagulability Thirty-one percent of the patients were found to have positive antiphospholipid antibodies (APLA), among them four were positive for lupus anticoagulant (LAC), two for anticardiolipin (ACA) and one for both, ACA and LAC. However, no difference in outcome was found between APLA positive and negative patients. A further 14 % of patients had markers associated with thrombophilia: protein C and S deficiency, antithrombin III deficiency, positive Leiden factor or the presence of prothrombin G20210A mutation. Patients with thrombophilia had a worse visual outcome as measured by visual field sensitivity (md = -2.04 ± 3.39) than patients without thrombophilia (md = -6.11 ± 7.15), (p = 0.005). Antinuclear antibodies and homocysteinemia were found in only 5 and 6 %, respectively, and did not influence the course of IIH.
There was no correlation between the magnitude of the abnormality and the course of IIH in all examined parameters. The presence of more than one laboratory abnormality (about 65 % of patients) did not seem to influence the outcome.
Discussion The most frequent abnormal laboratory findings in this relatively large group of patients with IIH were elevated CRP (51 %), thrombofilia (31 %), increased cortisol levels (29 %) and elevated LDH (20 %). Patients with elevated CRP and patients with thrombophilia had a worse visual outcome than those with an absence of inflammatory or thrombophilic parameters. Increased cortisol levels and abnormal calcium metabolism correlated with a higher rate of recurrence. The visual outcome of patients with elevated LDH was better than of those with normal LDH. Abnormal serum protein levels correlated with the number of drugs used per patient and the recurrence rate. Chronic inflammation in obesity has been lately recognized and is attributed to the release of inflammatory cytokines from adipose tissue [6]. Obesity is considered as a proinflammatory state associated with increased levels of adipokines and cytokines such as leptin, ghrelin, interleukin-6 and macrophage chemotactic protein-1. Some of them have been found to be elevated in the serum and CSF of patients with IIH, but their role in the etiology of IIH has not been settled. The finding of increased levels of CRP in half of IIH patients and its negative influence on the outcome might be, therefore, in keeping with the hypothesis about the participation of inflammation in the pathophysiology of the disease. Over the past decades, thrombophilia has been repeatedly reported to be associated with IIH [7]. It was presumed that hypercoagulability causes a micro-thrombotic obstruction of the CSF outflow in the cerebral sinuses even in the absence of an overt sinus vein thrombosis on neuroimaging. Antithrombin and protein C and S deficiency were found in 4–5 % of IIH patients, but not in controls. Increased levels of other thrombophilic factors such as fibrinogen levels, D-dimer, factor VIII, IX and XI were reported [7]. The finding of 31 % IIH patients with thrombophilia in this study is impressive. Moreover, we found that patients with thrombophilia had a worse visual outcome than those without thrombophilic markers. Ischemia of the optic nerve develops during longstanding papilledema [4]. The presence of prothrombotic factors might further worsen the ischemia of the swollen optic nerve head. The mechanism by which antiphospholipid antibody syndrome (APLA) causes thrombotic vascular events has
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not been entirely clarified. Many targets such as endothelial cells, naturally occurring anticoagulants or apoprotein H have been implicated [10, 11]. Anticardiolipin antibodies have been reported to be present in 8–43 % of IIH, according to different studies [8–11]. The prevalence of IIH in systemic lupus erythematosus (SLE) patients was also found to be increased, being sometimes the presenting picture of the disease [11]. In our study, 31 % of the IIH patients were positive for APLA, among them one also had SLE. However, the presence of APLA did not seem to influence the course of the disease. The finding of increased cortisol levels in 29 % of IIH patients and the higher recurrence rate of the disease in this group of patients deserves mention. The association of IIH with relative glucocorticoid deficiency, as occurs during corticoid therapy withdrawal or after surgical resection of a pituitary adenoma in Cushing disease, is well recognized and was presumed to be the result of increased cerebral edema [12]. Glucocorticoids also affect the 11-betahydroxysteroid dehydrogenase, an enzyme involved in the production and absorption of the CSF in the choroid plexus. In addition, cortisol influences the aquaporin 1 receptor, which regulates water entry into the ventricles. While acute cortisol withdrawal can activate the enzymes participating in CSF production, we speculate that chronic exposure to increased levels of the hormone may upregulate the enzyme receptors and lead to inappropriate CSF production during spontaneous cortisol level oscillations. Abnormal calcium metabolism was classically associated with IIH, but this association, as many others, has been abandoned in view of insufficient evidence of a causative relationship [13, 14]. In this study, Ca serum level was abnormal in only 10 % of IIH patients, but a correlation was found between this anomaly and the recurrence rate of the condition. Abnormal protein levels, found in 14 % of IIH patients, were associated with a worse clinical course. Abnormal protein level is a non-specific finding and can be encountered in a wide range of diseases, including chronic inflammation. Further analysis of the protein spectrum in IIH patients would, thus, be justified. Since this study was retrospective and serum protein electroimmunophoresis was not routinely performed, this issue deserves further investigation. LDH reflects tissue breakdown and is elevated in hemolysis, cancer, meningitis, encephalitis, acute pancreatitis and other diseases. Elevated LDH in 20 % of our patients could reflect hepatic involvement in the form of fatty liver accompanying obesity [15]. We are not aware of the previous reports about increased LDH levels in IIH patients. However, if this turns out to be consistent, it deserves attention since patients with elevated LDH had a better visual outcome than others.
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Iron deficiency anemia has been repeatedly reported to be associated with IIH. Reactive thrombocytosis accompanying idiopathic iron deficiency anemia has been suggested as a causative factor, but IIH has also been in patients with anemia and normal thrombocytes as well as the absence of cerebral vein thrombosis. Anemia and tissue hypoxia leading to increased capillary permeability and intracranial pressure has been another proposed theory to explain the relationship between IIH and anemia. In seven out of eight patients with IIH and iron deficiency anemia, IIH resolved on correction of anemia alone [16]. In our study, 14 % of the patients had anemia that was treated simultaneously with initiation of diuretic therapy. The presence of anemia did not demonstrate any influence on the course or outcome of IIH. There are some limitations of this study. Firstly, the laboratory findings in the present study were compared to normal values of non-obese individuals. Abnormalities in calcium and cortisol metabolism in overweight patients as well as the link between inflammation and hypercoagulation and obesity have been reported [17–19]. A comparison to the values of obese persons might reveal fewer abnormalities, mainly in lipid profiles and hormone levels. However, since the purpose of this study was to investigate the influence of laboratory deviations on the clinical course in patients with a disease (IIH), a higher sensitivity for detecting laboratory abnormalities, as achieved by relating the findings to normal population, seems appropriate. Secondly, the patients’ sample was variable with respect to clinical findings, severity of the disease and the duration of follow-up, limiting thus the generalizability of the results. Finally, the findings of laboratory abnormalities were reported irrespective to their clinical interpretation, i.e., if they were just incidental findings without major clinical significance or if they were signaling another, previously undetected, disorder. The detection of an underlying disease could render a part of patients to a group with secondary intracranial hypertension, as opposed to idiopathic intracranial hypertension. In conclusion: It seems that certain metabolic, inflammatory and coagulation abnormalities may influence the course of IIH. An extensive laboratory workup in IIH patients might be helpful in predicting the prognosis of the disease. Further studies are necessary to confirm our findings. Conflict of interest The authors report no conflict of interest. This work received no funding.
References 1. Bruce BB, Biousse V, Newman NJ (2011) Update on idiopathic intracranial hypertension. Am J Ophthalmol 152:163–169
Neurol Sci 2. Fraser C, Plant GT (2011) The syndrome of pseudotumor cerebri and idiopathic intracranial hypertension. Curr Opin Neurol 24:12–17 3. Biousse V, Bruce BB, Newman NJ (2012) Update on the pathophysiology and management of idiopathic cranial hypertension. J Neurol Neurosurg Psychiatry 83:488–494 4. Wall M (2010) Idiopathic intracranial hypertension. Neurol Clin 28:593–617 5. Friedman DI, Jacobson DM (2002) Diagnostic criteria for idiopathic intracranial hypertension. Neurology 59:1492–1495 6. Sinclair JA, Ball AK, Burdon MA, Clarke CE, Stewart PM, Curnow SJ et al (2008) Exploring the pathogenesis of IIH: An inflammatory perspective. J Neuroimmunology 201–202:212–220 7. Kesler A, Kliper E, Ben Assayag E, Zwang E, Deutsch V, Martinowith U et al (2010) Thrombophilic factors in idiopathic intracranial hypertension: a report of 51 patients and a metaanalysis. Blood Coagul Fibrinol 21:328–333 8. Kesler A, Ellis MH, Reshef T, Kott E, Gadoth N (2000) Idiopathic intracranial hypertension and anticardiolipin antibodies. J Neurol Neurosurg Psychiatry 68:379–380 9. Dhungana S, Sharrack B, Woodroofe N (2009) Cytokines and chemokines in idiopathic intracranial hypertension. Headache 49:282–285 10. Leker R, Steiner I (1998) Anticardiolipin antibodies are frequently present in patients with idiopathic intracranial hypertension. Arch Neurol 55:817–820
11. Hershko AY, Berkun Y, Mevorach D, Rubonow A, Naparstek Y (2008) Increased intracranial pressure related to systemic lupus erythematosus: a 26-year experience. Semin Arthritis Rheum 38:110–115 12. Zada G, Tirosh A, Kaiser UB, Laws ER, Woodmansee WW (2010) Cushing’s disease and idiopathic intracranial hypertension: case report and review of underlying pathophysiological mechanisms. J Clin Endocrinol Metab 95:4850–4854 13. Sheldon RS, Becker WJ, Hanley DA, Culver RK (1987) Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association. Can J Neurol Sci 14:622–625 14. Asplund J (1980) Pseudotumor cerebri in pseudohypoparathyroidism. Acta Med Scand 4:331–332 15. Ko MW, Chang SC, Ridha MA, Ney JJ, Ali TF, Friedman DI et al (2011) Weight gain and recurrence in idiopathic intracranial hypertension. A case-control study. Neurology 76:1564–1567 16. Mollan SP, Ball AK, Sinclair AJ, Madill SA, Clarke CE, Jacks AS et al (2009) Idiopathic intracranial hypertension associated with iron deficiency anaemia: a lesson for management. Eur Neurol 62:105–108 17. Hamoui N, Anthone G, Crookes PF (2004) Calcium metabolism in the morbidly obese. Obes Surg 14:9–12 18. Lumeng CN, Saltiel AR (2011) Inflammatory links between obesity and metabolic disease. J Clin Invest 121:2111–2117 19. Niewdorp M, Stroes ES, Meijers JC, Bu¨ller H (2005) Hypercoaguability in the metabolic syndrome. Curr Opin Pharmacol 5:155–159
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ORIGINAL ARTICLE
The laboratory profile in idiopathic intracranial hypertension Lea Pollak • Efrat Zohar • Yoseph Glovinsky Ruth Huna-Baron
•
Received: 15 September 2014 / Accepted: 9 January 2015 Ó Springer-Verlag Italia 2015
Abstract While overweight and female gender play an undisputable role in the pathogenesis of idiopathic intracranial hypertension (IIH), the contribution of other factors is still unclear. We have evaluated the laboratory findings of patients with IIH in an attempt to find the influence of abnormalities on the disease course. Included were 82 females after menarche and males older than 18 years who were followed up for at least 1 year. A wide range of laboratory parameters were examined at the time of presentation. The most frequent abnormal laboratory findings were elevated C reactive protein (CRP) (51 %), thrombophilia (31 %), increased plasma cortisol levels (29 %) and elevated lactate dehydrogenase (LDH) (20 %). Patients with elevated CRP and patients with thrombophilia had an unfavorable visual outcome. Increased cortisol levels and abnormal calcium correlated with a higher rate of recurrence. The visual outcome of patients with elevated LDH was better than those with normal LDH. It seems that certain metabolic, inflammatory and coagulation abnormalities may influence the course of IIH. If confirmed in further studies, these findings could contribute to elucidation of the etiology and prognosis of IIH.
L. Pollak E. Zohar Y. Glovinsky R. Huna-Baron Sackler School of Medicine Tel Aviv University, Tel Aviv, Israel L. Pollak (&) Kibutz Galuyot 4, 74012 Nes Ziona, Israel e-mail: [email protected] Y. Glovinsky R. Huna-Baron Goldschleger Eye Institute, Sheba Medical Center, Tel-Hashomer, Israel
Keywords Idiopathic intracranial hypertension Laboratory findings Prognosis
Background Idiopathic intracranial hypertension (IIH) is characterized by increased intracranial pressure in the absence of an identifiable pathology related to the rise in CSF pressure [1, 2]. Its prevalence is about 1–2/100,000 in the general population, but up to twenty times more among young obese women [1, 2]. The entity is one of the most commonly encountered diseases at neuroophthalmological clinics and may lead to blindness. While overweight and female gender play an undisputable role in the pathogenesis of IIH, the contribution of other clinical factors, previously considered to be strongly associated with this condition, is still unclear [3, 4]. Various medications have been presumed to cause or precipitate IIH, but only a few of them, such as tetracycline, have been shown to be of probable significance [1]. The theory of increased intracranial venous pressure due to increased abdominal pressure has also been abandoned. Similarly, oral contraceptives have been implicated in the pathogenesis of IIH, probably only due to their concomitant use by young women with IIH. Stenosis of the distal portion of the transverse cerebral sinuses leading to impaired venous drainage and resulting in decreased CSF absorption and increased intracranial pressure could offer a plausible explanation for the pathogenesis of IIH, but this is still controversial [3, 4]. Therefore, until the etiology of IIH is definitely established, reports about other common findings associated with IIH might be of value. We have comprehensively evaluated the laboratory findings of patients with IIH in an attempt to find the influence of distinct abnormalities on the disease outcome.
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Neurol Sci
Materials and methods The medical records of patients with IIH who were treated at the Neuro-Ophthalmology service center and were prospectively recruited during the years 1995–2008 were reviewed. Amongst them were patients who presented for the first time and patients who came to the clinic for follow-up. The diagnosis of IIH was established according to the Modified Dandy Criteria: (1) Symptoms and signs, if present, reflect only increased ICP; (2) Documented elevated ICP ([250 mm H2O) during lumbar puncture. Patients with a characteristic clinical picture (headache and papilledema) and with ICP [200 mm H2O were also included in this study [5]; (3) Normal cerebrospinal fluid composition; (4) Normal neuroimaging including the cerebral venous sinuses. Included were females after menarche and males older than 18 years who were followed up for at least 1 year. Blood tests were performed during the first visit. A wide range of laboratory parameters including complete blood count, biochemical profile, hormone levels, lipid profile, clotting functions, and inflammatory and immunological markers were examined by routine laboratory methods. The demographic, clinical and ophthalmological data of the patients were collected and analyzed in respect to the laboratory findings. The number of drugs or surgical interventions needed as well as the number of recurrences was registered. Improvement was judged according to the resolution of papilledema and improvement of the visual fields. Recurrence was defined as the return of papilledema, usually accompanied by recurrence of symptoms during tapering off or after discontinuation of treatment. No time frame was used to assess recurrences. Statistical methods We used the Chi square test for comparing categorical variables. The paired sample t test was applied to compare means between variables with normal distribution, while the Mann–Whitney test served for comparison of nonparametric variables. Pearson’s correlation coefficient was used to evaluate interrelations between quantitative values with normal distribution and Spearman’s rank correlation coefficient was applied for nonlinear distribution. A p value of \0.05 was considered statistically significant. SPSS version 18 (SPSS Inc. Chicago, Il, 2008) was used for the analyses.
according to the principles of the Helsinki Declaration. In view of the retrospective nature of the study, a signed consent was not required.
Results Demographics, presentation and treatment Eighty-two patients with a mean age of 30.2 ± 12 years were included [73 (89 %) were women (Table 1)]. Eightytwo percent of the patients were overweight (BMI [ 25 kg/m2). The prevailing complaints were headache (89 %) and transient visual obscurations (85 %) followed by tinnitus (59 %) and double vision (28 %). The majority of patients presented with grade 2 papilledema, followed by grade 1 and 3. Testing of the optic nerve functions revealed abnormal visual acuity in 17 % of the tested eyes. Abnormal color vision was found in 14 % of the eyes. An enlarged blind spot was the most frequently encountered finding on visual field testing (80 % of eyes), but nasal field defects and peripheral visual field constriction were also found in a significant proportion of patients (72 and 54 %, respectively). The mean visual field sensitivity (md = mean deviation) was depressed to -7.7 dB (normal range about -2 dB). Drug treatment consisted of acetazolamide, furosemid, topiramate and, in fulminant cases, corticosteroids. The average number of drugs used in one patient was 1.8 ± 0.9. In cases of drug treatment failure (22 % of patients), CSF diversion procedures and decompression of the optic nerve were performed. Six percent of patients underwent a ventriculo- or lumboperitoneal shunt and 7 % had optic nerve sheath fenestration. A further 7 % had both, shunt and optic nerve fenestration. Subtemporal decompression was performed in one patient. The mean follow-up was 61.3 ± 62.3 months, lasting from one to 27 years. Eight-four percent of the patients improved with respect to optic nerve appearance and visual field findings at the last follow up visit. Sixty-seven percent of the patients suffered a recurrence of IIH (on average 1.6 ± 1.7 recurrences per patient). Laboratory findings The results of the laboratory tests are summarized in Tables 2 and 3. Complete blood count
Ethical approval The study was approved by the local Ethical Committee of the Sheba Medical Center, Israel and was conducted
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About 14 % of the patients demonstrated significant iron deficiency anemia (Hb \ 10.5 g/dL). No dependence was found between the presence of anemia and the number of
Neurol Sci Table 1 Demographic data, presentation and outcome
Result Number of patients
%
Range
82
Women, no. of patients (%)
73
89
Men, no. of patients (%)
9
11
Mean age (years) ± SD
30.2 ± 12.9
Overweight (BMI [ 25 kg/m2), no. of patients (%)
67
11–68 82
Hypertension ([140/90 mmHg), no. of patients
36/64
56
Diabetes mellitus, no. of patients
5/82
6
Smoking, no. of patients
27/80
33
73
89
Presentation symptoms Headache, no. of patients (%) Transient visual obscurations
70
85
Tinnitus
49
59
23
28
Diplopia Papilledema according to Frise´, no. of eyes (%) Grade 0 Grade 1
19 (11) 40 (24)
Grade 2
56 (34)
Grade 3
39 (23)
Grade 4
10 (6)
Humphrey perimetry md (dB), mean ± SD
-7.7 ± 7.3
Visual field defects, no. of eyes (%) Enlarged blind spot
131 (80)
Nasal defect
119 (72)
Constriction
88 (54)
Abnormal visual acuity (LogMAR C 0.20), no. of eyes (%)
29 (17)
Abnormal color vision (\5/6 H.R.R.), no. of eyes (%)
23 (14)
Duration of follow up (months)
61.3 ± 62.3
Barosurgery, no. of patients (%)
5 (6)
Drug treatment, mean number of drugs ± SD
1.8 ± 0.95
Surgical treatment, no. of patients (%)
18 (22)
Ventriculo/lumboperitoneal shunt, no. of patients (%) Optic nerve sheath fenestration, no. of patients (%)
5 (6) 6 (7)
Shunt ? fenestration, no. of patients (%)
6 (7)
Subtemporal decompression, no. of patients (%)
1 (1)
Recurrence, no. of patients (%)
55 (67)
recurrences, visual outcome or treatment. However, in all patients, the anemia was treated promptly after establishing the diagnosis.
12–394 1–4
were found to be elevated in 22 % of patient, but did not seem to influence the clinical course and outcome. Serum protein levels
Liver enzyme tests Twenty percent of IIH patients had increased lactate dehydrogenase (LDH) levels. Those with elevated LDH demonstrated more improvement in visual acuity than patients with normal LDH levels (D VA 0.094 logmar scale as opposed to D VA 0.019 logmar scale, p = 0.032). The aspartate aminotransferase (AST), alanine aminotrasferase (ALT) and gamma glutamyltransferase (GGT)
Fourteen percent of patients had abnormal globulin serum levels, three of them had hyperglobulinemia and 11 hypoglobulinemia. There was a dependence between abnormal globulin levels and the number of recurrences (p = 0.04) as well as the need for multiple drug treatment (p = 0.004). The number of patients was too small to look for the influence of hyper- versus hypoglobulinemia on outcome parameters.
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Neurol Sci Table 2 Results of routine laboratory examination in IIH patients Laboratory parameters
Reference values
Number of patients with abnormal values (%)
Number of patients:;
Hemoglobin Platelet count
[10.5 g/dL
11/80 (14)
;
130–450 9 103/mm3
7/77 (9)
White blood cells
5:, 2;
4–11 9 103/mm3
15/77 (19)
:
5/76 (6)
:
15/77 (19)
:
\45 mg/dL
3/77 (3)
:
\8.4 mg/dL
8/71 (11)
:
AST, ALT, GGT
AST \ 40, ALT \ 45, GGT \ 32 U/L
16/74 (22)
:
LDH
\260 U/L
15/74 (20)
:
Albumin
3.6–5.5 g/dL
10/67 (15)
;
Globulin Natrium
2.3–4.5 g/dL 135–148 mmol/L
14/67 (21) 0
3:, 11;
Kalium
3.5–5.2 mmol/L
9/75 (12)
2:, 7;
Calcium
8.5–10.5 mg/dL
7/72 (10)
1:, 6;
Chloride
98–110 mmol/L
2/65 (3)
:
Phosphorus
2–4 mg/dL
17/71 (2)
16:, 1;
Total cholesterol
\200 mg/dL
30/70 (43)
:
Glucose—diabetes mellitus [125 mg/dL Creatinine
Males \0.9, females \1.2 ng/ml
Urea Uric acid
HDL cholesterol
30–70 mg/dL
7/24 (29)
;
LDL cholesterol
40–160 mg/dL
7/31 (22.5)
:
Triglycerides
30–200 mg/dL
17/44 (39)
:
: increased, ; decreased AST Aspartate aminotransferase, ALT alanine aminotransferase, GGT Gamma glutamyltransferase, LDH lactate dehydrogenase
Table 3 Laboratory results of hormonal profile, inflammatory markers and hypercoaguability states Laboratory parameters
Reference values
Number of patients with abnormal values (%)
Number of patients:;
Thyroid-stimulating hormone
0.4-5 lU//mL
9/55 (16)
7:, 2;
Thyroxine, free (fT4)
10–25 ng/dL
2/36 (5.5)
;
Prolactin
\650
2/32 (6)
:
Cortisol
5–25 lg/dL
8/28 (28.5)
3:, 5;
Luteinizing hormone (LH)
According to the phase of menstruation cycle
4/28 (14)
1:, 3;
Follicle stimulating hormone (FSH)
According to the phase of menstruation cycle
3/28 (11)
;
Erythrocyte sedimentation rate C- reactive protein
Males \15, females \20 mm/h \0.6 mg/L
25/33 (47) 18/35 (51)
: :
Fibrinogen
\400 mg/dL
14/29 (48)
:
Complement 3
79–159 mg/dL
10/27 (37)
:
Complement 4
16–38 mg/dL
5/25 (20)
:
Partial thromboplastin time, activated
23–29 s
12/51 (23.5)
7:, 5;
Antiphosholipid antibodies
0–15 U
6/19 (31)
:
Antinuclear antibody
\1:40
3/51 (5)
:
Thrombofiliaa
Negative
12/77 (14)
Present
Homocysteinemia
5–15 lmol/L
3/46 (6)
:
: increased, ; decreased LH follicular phase 2–15 U/L, ovulatory phase 22–105 U/L, luteal phase 0.6–19 U/L, FSH follicular phase 3–20 mlU/mL, ovulatory phase 9–26 mlU/mL, luteal phase 18–153 mlU/mL a
thrombofilia—protein C or S deficiency, prothrombin, antithrombin III deficiency, Leiden factor, prothrombin G20210A
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Neurol Sci
Electrolytes Ten percent of IIH patients had abnormalities in calcium (Ca) serum level: six had hypocalcemia and 1 had hypercalcemia. A correlation was found between abnormal Ca metabolism and the number of recurrences (p = 0.002). However, the number of patients was too small to look for the influence of hyper- and hypocalcemia on the clinical course of the disease. Lipid profile Hypercholesterolemia (total cholesterol [200 mg/dL) was present in 44 % of IIH patients and hypertriglyceridemia in 41 %. No correlation was found between abnormal lipid metabolism and the recurrence rate, visual outcome or treatment modalities. Hormone levels Twenty-nine percent of the patients with IIH had increased cortisol blood levels. These patients suffered more recurrences than patients with normal cortisol blood levels (p = 0.022). Inflammatory markers Elevated C reactive protein (CRP) levels were revealed in 51 % of the patients with IIH. Patients with raised CRP had less improvement in visual field sensitivity (D md 0.867) than those with normal CRP (D 3.087), (p = 0.04). Other inflammatory markers such as fibrinogen, complement three and four levels and erythrocyte sedimentation rate did not influence the course of the disease. Hypercoagulability Thirty-one percent of the patients were found to have positive antiphospholipid antibodies (APLA), among them four were positive for lupus anticoagulant (LAC), two for anticardiolipin (ACA) and one for both, ACA and LAC. However, no difference in outcome was found between APLA positive and negative patients. A further 14 % of patients had markers associated with thrombophilia: protein C and S deficiency, antithrombin III deficiency, positive Leiden factor or the presence of prothrombin G20210A mutation. Patients with thrombophilia had a worse visual outcome as measured by visual field sensitivity (md = -2.04 ± 3.39) than patients without thrombophilia (md = -6.11 ± 7.15), (p = 0.005). Antinuclear antibodies and homocysteinemia were found in only 5 and 6 %, respectively, and did not influence the course of IIH.
There was no correlation between the magnitude of the abnormality and the course of IIH in all examined parameters. The presence of more than one laboratory abnormality (about 65 % of patients) did not seem to influence the outcome.
Discussion The most frequent abnormal laboratory findings in this relatively large group of patients with IIH were elevated CRP (51 %), thrombofilia (31 %), increased cortisol levels (29 %) and elevated LDH (20 %). Patients with elevated CRP and patients with thrombophilia had a worse visual outcome than those with an absence of inflammatory or thrombophilic parameters. Increased cortisol levels and abnormal calcium metabolism correlated with a higher rate of recurrence. The visual outcome of patients with elevated LDH was better than of those with normal LDH. Abnormal serum protein levels correlated with the number of drugs used per patient and the recurrence rate. Chronic inflammation in obesity has been lately recognized and is attributed to the release of inflammatory cytokines from adipose tissue [6]. Obesity is considered as a proinflammatory state associated with increased levels of adipokines and cytokines such as leptin, ghrelin, interleukin-6 and macrophage chemotactic protein-1. Some of them have been found to be elevated in the serum and CSF of patients with IIH, but their role in the etiology of IIH has not been settled. The finding of increased levels of CRP in half of IIH patients and its negative influence on the outcome might be, therefore, in keeping with the hypothesis about the participation of inflammation in the pathophysiology of the disease. Over the past decades, thrombophilia has been repeatedly reported to be associated with IIH [7]. It was presumed that hypercoagulability causes a micro-thrombotic obstruction of the CSF outflow in the cerebral sinuses even in the absence of an overt sinus vein thrombosis on neuroimaging. Antithrombin and protein C and S deficiency were found in 4–5 % of IIH patients, but not in controls. Increased levels of other thrombophilic factors such as fibrinogen levels, D-dimer, factor VIII, IX and XI were reported [7]. The finding of 31 % IIH patients with thrombophilia in this study is impressive. Moreover, we found that patients with thrombophilia had a worse visual outcome than those without thrombophilic markers. Ischemia of the optic nerve develops during longstanding papilledema [4]. The presence of prothrombotic factors might further worsen the ischemia of the swollen optic nerve head. The mechanism by which antiphospholipid antibody syndrome (APLA) causes thrombotic vascular events has
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not been entirely clarified. Many targets such as endothelial cells, naturally occurring anticoagulants or apoprotein H have been implicated [10, 11]. Anticardiolipin antibodies have been reported to be present in 8–43 % of IIH, according to different studies [8–11]. The prevalence of IIH in systemic lupus erythematosus (SLE) patients was also found to be increased, being sometimes the presenting picture of the disease [11]. In our study, 31 % of the IIH patients were positive for APLA, among them one also had SLE. However, the presence of APLA did not seem to influence the course of the disease. The finding of increased cortisol levels in 29 % of IIH patients and the higher recurrence rate of the disease in this group of patients deserves mention. The association of IIH with relative glucocorticoid deficiency, as occurs during corticoid therapy withdrawal or after surgical resection of a pituitary adenoma in Cushing disease, is well recognized and was presumed to be the result of increased cerebral edema [12]. Glucocorticoids also affect the 11-betahydroxysteroid dehydrogenase, an enzyme involved in the production and absorption of the CSF in the choroid plexus. In addition, cortisol influences the aquaporin 1 receptor, which regulates water entry into the ventricles. While acute cortisol withdrawal can activate the enzymes participating in CSF production, we speculate that chronic exposure to increased levels of the hormone may upregulate the enzyme receptors and lead to inappropriate CSF production during spontaneous cortisol level oscillations. Abnormal calcium metabolism was classically associated with IIH, but this association, as many others, has been abandoned in view of insufficient evidence of a causative relationship [13, 14]. In this study, Ca serum level was abnormal in only 10 % of IIH patients, but a correlation was found between this anomaly and the recurrence rate of the condition. Abnormal protein levels, found in 14 % of IIH patients, were associated with a worse clinical course. Abnormal protein level is a non-specific finding and can be encountered in a wide range of diseases, including chronic inflammation. Further analysis of the protein spectrum in IIH patients would, thus, be justified. Since this study was retrospective and serum protein electroimmunophoresis was not routinely performed, this issue deserves further investigation. LDH reflects tissue breakdown and is elevated in hemolysis, cancer, meningitis, encephalitis, acute pancreatitis and other diseases. Elevated LDH in 20 % of our patients could reflect hepatic involvement in the form of fatty liver accompanying obesity [15]. We are not aware of the previous reports about increased LDH levels in IIH patients. However, if this turns out to be consistent, it deserves attention since patients with elevated LDH had a better visual outcome than others.
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Iron deficiency anemia has been repeatedly reported to be associated with IIH. Reactive thrombocytosis accompanying idiopathic iron deficiency anemia has been suggested as a causative factor, but IIH has also been in patients with anemia and normal thrombocytes as well as the absence of cerebral vein thrombosis. Anemia and tissue hypoxia leading to increased capillary permeability and intracranial pressure has been another proposed theory to explain the relationship between IIH and anemia. In seven out of eight patients with IIH and iron deficiency anemia, IIH resolved on correction of anemia alone [16]. In our study, 14 % of the patients had anemia that was treated simultaneously with initiation of diuretic therapy. The presence of anemia did not demonstrate any influence on the course or outcome of IIH. There are some limitations of this study. Firstly, the laboratory findings in the present study were compared to normal values of non-obese individuals. Abnormalities in calcium and cortisol metabolism in overweight patients as well as the link between inflammation and hypercoagulation and obesity have been reported [17–19]. A comparison to the values of obese persons might reveal fewer abnormalities, mainly in lipid profiles and hormone levels. However, since the purpose of this study was to investigate the influence of laboratory deviations on the clinical course in patients with a disease (IIH), a higher sensitivity for detecting laboratory abnormalities, as achieved by relating the findings to normal population, seems appropriate. Secondly, the patients’ sample was variable with respect to clinical findings, severity of the disease and the duration of follow-up, limiting thus the generalizability of the results. Finally, the findings of laboratory abnormalities were reported irrespective to their clinical interpretation, i.e., if they were just incidental findings without major clinical significance or if they were signaling another, previously undetected, disorder. The detection of an underlying disease could render a part of patients to a group with secondary intracranial hypertension, as opposed to idiopathic intracranial hypertension. In conclusion: It seems that certain metabolic, inflammatory and coagulation abnormalities may influence the course of IIH. An extensive laboratory workup in IIH patients might be helpful in predicting the prognosis of the disease. Further studies are necessary to confirm our findings. Conflict of interest The authors report no conflict of interest. This work received no funding.
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