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April2013 Vol.50 Issue:      2 Table of Contents
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Aquaporin-4 Antibodies in Egyptian Patients with Idiopathic Intracranial Hypertension

Noha T. Abo-Krysha1, Nirmeen A. Kishk1, Laila Rashed2

Departments of Neurology1, Biochemistry2; Cairo University; Egypt



ABSTRACT

Background: The etiology of idiopathic intracranial hypertension (IIH) is not clear. A dysfunction of the water channels could affect the cerebrospinal fluid (CSF) secretion or absorption and potentially contribute to its pathogenesis. Objective: Is to assess the possible role of Aquaporin (AQP)-4 antibodies in the pathogenesis of IIH. Methods: Eighteen symptomatic IIH patients who were diagnosed according to the updated modified Dandy criteria were selected from the Neurology Department of Kasr El-Aini hospital, Cairo University. Detection of anti-aquaporin antibodies in their CSF samples was measured by ELISA based Assay. Results: The CSF samples of IIH patients were positive for the Aquaporin (AQP)-4 antibody in 16(88.9%) of the patients. The CSF level of AQP-4 antibodies was 15.59±8.03 U/ml. Conclusions: There are two reports investigating the anti-AQP4 antibodies in IIH. Our study contradicted the results of these reports and indicated that AQP4 antibodies have a role in IIH pathogenesis and provided some support for the contribution of inflammatory mechanisms in IIH. [Egypt J Neurol Psychiat Neurosurg.  2013; 50(2): 109-112]

 Key Words: AQP4 antibodies, IIH.

Correspondence to Noha T Abo-Krysha, Department of Neurology, Cairo University, Cairo, Egypt.Tel.: +201010858127        e-mail: nhtaha@yahoo.com





INTRODUCTION

 

The pathogenesis of raised ICP in idiopathic intracranial hypertension (IIH) remains indistinguishable. There are many postulated hypotheses that have been put forward to elucidate its pathogenesis. A variety of factors including altered CSF dynamics abnormality have been suggested to play a role in the pathogenesis of this disorder.1,2

Aquaporin 4 (AQP4) is the main water channel membrane protein in the brain. It mediates osmotic water flow within the central nervous system (CNS) and has a significant role in the control of water content and volume homeostasis of the brain.3

AQP4 is copiously expressed in ependymal cells and astrocytes with a highly polarized distribution in glial membranes facing capillaries and pia mater. This pattern of distribution at the blood/brain and brain/cerebrospinal fluid (CSF) interface is further evocative of the participation of AQP4 in the water transport between different fluid compartments of CNS.4, 5

In healthy persons, CSF is generally formed in the choroid plexus with small contributions from extrachoroidal tissues, including ependymal surfaces of the brain and the capillary–astrocyte complex in the blood–brain barrier. It is reabsorbed into the dural venous sinuses through the arachnoid villi.6 Several theories have been suggested to explain the etiology of

raised CSF pressure in IIH, including increased CSF production, impaired CSF absorption, obstruction of dural venous sinuses and increased brain volume due to cerebral oedema.7

In recent times, the probable role of proinflammatory CSF profiles has been advocated in a number of studies.2,8 Bloch and colleagues9 suggested that AQP4 could facilitate CSF absorption in hydrocephalus. Recently, antibodies to AQP4 have been suggested to play a role in the pathogenesis of neuromyelitis optica (NMO) and AQP4 antibodies are identified in more than 75% of patients.10,11

It was hypothesized that a dysfunction of AQP-4 expression could affect CSF secretion or absorption and potentially contributes to the pathogenesis of IIH.

In this study, we utilized a recently described anti-AQP4 antibody assay12 to look for AQP4 antibodies in the CSF of patients with IIH.

 

MATERIALS AND METHODS

 

CSF samples from 18 female symptomatic IIH patients; with mean age 29.77±8.13 years, mean body mass index (BMI) 31.97±7.39 Kg/m2 diagnosed according to the updated modified Dandy criteria13; who were consecutively enrolled from January 2012 until October 2012 among the patients admitted to Neurology Department of Kasr El-Aini hospital, Cairo University were examined for anti-AQP4 antibodies. Detection of anti-aquaporin antibodies in CSF was measured by ELISA based Assay.12 Briefly the kit utilized colorimetric detection with peroxidase labeled streptavidin. ELISA was performed as outlined by manufacturer instruction. Absorbance of 450 nm was measured on Stat Fax 2100 Elisa reader (USA). The measuring range is 5–160 U/mL. Samples were considered to be positive for the antibody when levels were 6 U/mL or greater.12 

The study was approved by the ethical committee of the National Cancer Institute, Cairo University and all participants provided informed consent.

 

Statistical Analysis

Data were analyzed using SPSS version 8 (SPSS Inc., Chicago, IL, USA). Descriptive statistics such as percentage, mean, and standard deviation were used to describe study variables. Pearson’s correlation was used to estimate relations between quantitative variables. P values ≤ 0.05 were considered statistically significant.

 

RESULTS

 

The demographic, clinical and laboratory results are given in Tables (1) and (2). The age of the patients in the present study ranged from 15 to 45 years with a mean of 29.78±8.13 years. The disease duration ranged from 1 to 24 days with a mean of 7.11±6.93 days. The CSF level of AQP4 antibodies in the patients ranged from 2.80 to 34.50 U/mL with a mean of 15.59±8.03 U/mL. There was no significant correlation between CSF level of AQP4 antibodies, age, BMI, Lumbar puncture (LP) opening pressure and duration of illness (Table 3).


 

 

Table 1. Demographic, clinical data of IIH patients.

 

Age

29.78±8.13 (Range 15-45 years)

Body weight

83.06±15.96 (Range 65-110 Kg)

Height

161.81±4.62 (Range 155-169 cm)

BMI

31.97±7.39 (Range 22.76-44.63 kg/m2)

Duration of symptoms of IIH

7.11±6.93 (Range 1-24 days)

Treatment

 

Acetazolamide therapy

 

18 (100%)

Mannitol

1(5.56%)

LP (Lumbar puncture) opening pressure

402.22±25.958 (Range 250-800  mmH2O)

 

IIH idiopathic intracranial hypertension

 

Table 2. CSF level of AQP-4 antibodies of IIH patients.

 

AQP4 antibodies

Quantitative results

Qualitative results

range

Mean±SD

positive

negative

2.80-34.50

15.59±8.03 (U/mL)

n=16 (88.9%)

n=2 (11.1%)

 

IIH idiopathic intracranial hypertension

 

Table 3. Correlations between AQP4 antibodies and clinical data of IIH patients.

 

Clinical data of IIH patients

AQP4 antibodies

p-value

LP (Lumbar puncture) opening pressure        

0.7

Duration of symptoms of IIH

0.3

BMI

0.9

Age

0.4


DISCUSSION

 

Despite the fact that the exact etiology of IIH remains uncertain, the proof of an inflammatory pathogenesis is debatable.14

AQP4 autoimmunity-related water flux impairment was accompanied by vasogenic edema15 and previous studies have shown increased water content of the brain tissue in patients with IIH. If IIH is associated with AQP4 autoimmunity, the differences between the clinical manifestations of this condition and NMO could be related to the differences in the IgG subclass distribution between these two diseases.7

In this study, the CSF samples of IIH patients were positive for the AQP4 antibody in 16 (88.9%) of the patients. The CSF AQP4 antibodies level in the patients ranged from 2.80 to 34.50 U/ml with a mean of 15.59±8.03 U/ml.

Our results proposed that anti-AQP4 antibodies are likely to take part in the pathogenesis of IIH. To our knowledge, this is the first study to prove the role of AQP antibodies in IIH.

On the contrary, Ekizoglu and colleagues16 could not detect any anti-AQP-4 antibodies in their twenty-nine patients. However, they identified different serum IgG binding patterns in 11 IIH patients. Their study confirmed the results of Dhungana and colleagues17 and indicated that AQP4 antibodies did not have a primary role in IIH pathogenesis, but provided some support for the contribution of inflammatory mechanisms in IIH.

The differences between our results and their results may be attributed to the different methodology. Ekizoglu and colleagues16 investigated by immunofluorescence and a cell-based assay for anti-AQP-4 antibodies in their serum samples, but not in their CSF samples. In addition, Anti-AQP-4 antibody was measured by a quantitative fluorescence immunoprecipitation assay (FIPA) for each serum or CSF sample of 10 symptomatic IIH patients by Dhungana and colleagues.17

Our finding puts its inference on IIH management; plasmapheresis may have efficacy in lowering ICP in such patients whose IIH has an inflammatory etiology and could be part of temporizing measures in a subset of individuals with IIH who have a more malignant or fulminant course with rapid development of vision loss until surgery can be performed. Further study of this type of management in IIH is warranted.

There are some limitations of the current study. First, the lack of a control group, however no control groups in other studies measuring anti-AQP4 antibodies.18,19 As well, the research was performed on a small sample size, however the possibility of anti-AQP4 antibodies being responsible for a subset of patients with this condition cannot be excluded; in view of the fact that the previous reports showed negative association were also performed on a small sample size of IIH patients. Further investigation, in a large cohort of patients should be considered to fully understand the pathophysiology of raised intracranial pressure in this condition.

 

Conclusion

In conclusion, our result proposed that Idiopathic intracranial hypertension (IIH) point to unbalanced water flux across cellular membranes, which is served by the brain water channel aquaporin-4. IIH could be connected to malfunctioning intracerebral water homeostasis and (CSF) reabsorption based on functional alterations of AQP4. Our finding puts its inference on IIH management; plasmapheresis may have efficacy in lowering ICP in such patients. Correlation studies with large sample size are to perform to approve this etiopathogenic linkage.

 

[Disclosure: Authors report no conflict of interest]

 

REFERENCES

 

1.        Ball AK, Clarke CE. Idiopathic intracranial hypertension. Lancet Neurol. 2006; 5:433-42.

2.        Ball AK, Sinclair AJ, Curnow SJ, Tomlinson JW, Burdon MA, Walker EA,et al. Elevated cerebrospinal fluid (CSF) leptin in idiopathic intracranial hypertension (IIH): evidence for hypothalamic leptin resistance? Clin Endocrinol. 2009; 70: 863-9.

3.        Bloch O, Manley GT. The role of aquaporin-4 in cerebral water transport and edema. Neurosurg Focus. 2007; 22:E3.

4.        Nielsen S, Nagelhus EA, Amiry-Moghaddan M, Nielsen S, Nagelhus EA, Amiry-Moghaddam M, et al. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997; 17:171-80.

5.        Rash JE, Yasumura T, Hudson CS, Agre P, Nielsen S. Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc Natl Acad Sci USA. 1998; 95:11981-6.

6.        Johanson CE, Duncan JA III, Klinge PM, Brinker T, Stopa EG, Silverberg GD.  Multiplicity of cerebrospinal fluid functions: New challenges in health and disease. Cerebrospinal Fluid Res. 2008; 5:10.

7.        Dhungana S, Sharrack B, Woodroofe NW. Idiopathic intracranial hypertension: a review. Acta Neurol Scand. 2010; 121(2):71-82.

8.        Dhungana S, Sharrack B, Woodroofe NW. Cytokines and chemokines in idiopathic intracranial hypertension. Headache. 2009; 49:282-5.

9.        Bloch O, Auguste KI, Manley GT, Verkman AS. Accelerated progression of kaolin-induced hydrocephalus in aquaporin-4-deficient mice. J Cereb Blood Flow Metab. 2007; 26:1527-37

10.     Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer TJ,et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology. 2007 69:2221-31.

11.     Waters P, Jarius S, Littleton E, Leite MI, Jacob S, Gray B ,et al. Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis. Arch Neurol. 2008; 65:913-9.

12.     Tokoro KM, Popov JM, Naides SJ. Detection of anti-aquaporin antibodies in human serum and CSF by ELISA based Assay. Clin Chem. 2011; 57: 10 Supplements.

13.     Friedman DI, Jacobson DM. Diagnostic criteria for idiopathic intracranial hypertension. Neurology. 2002; 59: 1492-5.

14.     Dhungana S, Sharrack B, Woodroofe NW. IL-1beta, TNF and IP-10 in the cerebrospinal fluid and serum are not altered in patients with idiopathic intracranial hypertension compared to controls. Clin Endocrinol. 2009; 71(6):896-7.

15.     Magana˜ SM, Matiello M, Pittock SJ, McKeon A, Lennon VA, Rabinstein AA, et al.  Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology. 2009; 72:712-7

16.     Ekizoglu E, Içoz S, Tuzun E, Birisik O, Kocasoy-Orhan E, Akman-Demir G, et al.  Aquaporin-4 antibodies are not present in patients with idiopathic intracranial hypertension. Cephalalgia. 2012; 32(3):198-202.

17.     Dhungana S, Waters P, Ismail A, Woodroofe, N., Vincent, A., Sharrack, B. Absence of aquaporin-4 antibodies in patients with idiopathic intracranial hypertension. J Neurol. 2010; 257(7):1229-30.

18.     Long Y, Lu Z, Hu X. Serum-positive and -negative AQP4 antibody NMO in Chinese patients. Can J Neurol Sci. 2012; 39(2):232-5.

19.     Siritho S, Nakashima I, Takahashi T, Fujihara K, Prayoonwiwat N. AQP4 antibody-positive Thai cases: clinical features and diagnostic problems. Neurology. 2011; 77(9): 827-34.


 

 

 

الملخص العربي


الأجسام المضادة لمسارات القنوات المائية في المرضى المصريين المصابين

بارتفاع الضغط السائل النخاعي الدماغي مجهول السبب

 

يمكن لخلل في مسارات قنوات المياه أن تؤثر على إفراز السائل النخاعي أو امتصاصه وتسهم في التسبب بارتفاع الضغط. هدفنا: هو تقييم الدور المحتمل للأجسام المضادة في التسبب في ارتفاع الضغط السائل النخاعي الدماغي مجهول السبب.

وقد تم اختيار ثمانية عشر مريضة بأعراض هذا المرض الذين تم تشخيصهن وفقا لمعايير داندي المحدثة. وقد تم قياس الأجسام المضادة لمسارات القنوات المائية في عينات السائل النخاعي. وقد أظهرت النتائج: إن عينات السائل النخاعي من المرضى كانت إيجابية للأجسام المضادة في 16 (88.9٪) من المرضى. كان مستوى الأجسام المضادة 15.59 +8.03 وحدة / مل. الاستنتاجات: هناك بحثان تناولا هذه الأجسام المضادة في ارتفاع الضغط السائل النخاعي الدماغي مجهول السبب لكن نتائجهما تتناقض مع نتائج دراستنا  التي تشير إلى أن هذه الأجسام المضادة قد يكون لها دور في التسبب بارتفاع الضغط السائل النخاعي الدماغي وهو ما ينبغي دراسته على مجموعة أكبر من المرضى.



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