Complement Factor I Deficiency Associated with Recurrent Meningitis Coinciding with Menstruation

OBSERVATION Complement Factor I Deficiency Associated With Recurrent Meningitis Coinciding With Menstruation

Carolina Gonza´lez-Rubio, PhD; Antonio Ferreira-Cerda´n, MD, PhD; Isabel M. Ponce, BS; Javier Arpa, MD, PhD; Gumersindo Fonta´n, MD, PhD; Margarita Lo´pez-Trascasa, PhD

Background: Complement (C) factor I deficiency is a munosorbent assay. This total deficiency was also found rare immunodeficiency state frequently associated with in her sister. Her parents and brother had approxi- recurrent pyogenic infections in early infancy. This de- mately half of the normal levels. In addition, the patient ficiency causes a permanent uncontrolled activation of had very low levels of C3; factor B; and an important re- the alternative pathway resulting in massive consump- duction of factor H, properdin, C5, C7, and C8 comple- tion of C3. ment components. Additional studies in the patient’s sera evidenced high levels of immune complexes containing Patient: A 23-year-old woman with monthly recurrent C1q and immunoglobulin (Ig) G, as well as C3b/factor meningitis episodes, mostly in the perimenstrual period, H, C3b/properdin, C3b/IgG, and properdin/IgG com- since August 1999. Previously, at age 16 years, she had plexes. Treatment with prophylactic antibiotics, anti- meningococcal sepsis, also coinciding with menstruation. estrogen medication, plasma infusions, or intravenous immunoglobulin has been unsuccessful in avoiding con- Objectives: To study the patient and her family to secutive meningitis episodes. elucidate the molecular defects in the pedigree and to evaluate her clinical evolution. Conclusion: For the first time to our knowledge, these data present an unusual relationship between meningi- Results: We describe clinical, immunological, and tis episodes and menstruation in factor I immunodefi- treatment follow-up during this period. First, we char- ciency. acterized the existence of a total complement factor I deficiency defined by undetectable levels by enzyme im- Arch Neurol. 2001;58:1923-1928

EREDITARY deficiency of concentrations of factor I of about 50% of factor I is a rare autoso- the normal range. mal recessive condition. HumancomplementfactorIisaplasma To date, 33 homozygous serine proteinase that plays an essential individuals from 23 dif- role in the modulation of the comple- ferentH pedigrees have been described.1-4 The ment cascade. Factor I cleaves the ␣Ј chains molecular basis of the deficiency has been of C4b and C3b and thereby is involved resolved in only 3 pedigrees.5,6 The clinical in the regulation of both the classical and manifestations usually begin in early child- alternative C pathways. Factor I function hood and consist essentially of severe re- is dependent on various cofactors: the current pyogenic infections mainly caused cleavage of C4b requires C4-binding pro- by Neisseria meningitidis, Streptococcus pneu- tein (C4bp), and the cleavage of C3b is de- moniae, and Haemophilus influenzae, as well pendent on complement factor H.7,8 Cell- as an increased incidence of glomerulon- surface molecules such as complement ephritis and systemic lupus erythematosus– receptor 1 (CD35) and membrane cofac- From the Immunology Unit like illness. Homozygous patients have low tor protein (CD46) act as factor I cofac- (Drs Gonza´lez-Rubio, levels of complement (C) 3 and factor B, re- tors on host tissues. By its action on C3, Ferreira-Cerda´n, Fonta´n, and Lo´pez-Trascasa and Ms Ponce) duced levels of factor H and, to a lesser ex- factor I prevents formation of the alterna- and Neurology Service tent, of properdin (P) and the terminal tive pathway C3 convertase and thereby (Dr Arpa), Hospital complement components. Heterozygous in- regulates the amplification loop of the al- Universitario, La Paz, Madrid, dividuals are often asymptomatic and have ternative pathway. Factor I is an 88-kd Spain. normal C3 and factor B values, with plasma plasma glycoprotein composed of 2 disul-

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 PATIENTS, MATERIALS, purified P, factor H, or factor I protein, or a C5 calibrated serum (Dade Behring), was included for standard calibra- AND METHODS tion curves. Appropriate serum dilutions from pooled normal human serum (NHS) and from each member of the fam- PATIENTS ily were included. After an hour incubation, murine monoclonal anti-P (1/2 K diluted) (Chemicon, Temecula, Serum samples were obtained from all 5 family members, Calif), anti–factor H (1/8 K diluted) (Quidel), anti–factor aliquoted, and immediately frozen at −80°C until use. In- I (1/20 diluted supernatant) (Serotec, Oxford, England), formed consent was obtained from the patient and the other or goat immunoglobulins anti-C5 (1/1 K diluted) (ATAB) family members. was used as the detecting antibody. Anti–factor I autoantibodies (IgG, IgM, or IgA) METHODS were also checked by ELISA by coating purified factor I (50 ng/well) (Quidel) to the plates. In each case, the reac- Complement Studies tions were visualized by the appropriate peroxidase- Ј conjugated antibodies, using ABTS/H2O2 (2,2 azino-di-[3- Serum concentrations of immunoglobulins, C3, C4, and fac- ethylbenzthiazolinesulfonate (6)] diammonium salt/ tor B were measured by nephelometry. Concentrations of hydrogen peroxide) as substrate. C1q (The Binding Site, Birmingham, England) and C1 in- To detect possible C3/factor H, C3/P, C3/IgG, and P/IgG hibitor (C1-INH) (Dade Behring, Marburg, Germany) were complexes in factor I–deficient serum, ELISA was per- determined by radial immunodiffusion. Circulating im- formed. Briefly, plates were coated with either monoclo- mune complexes (ICs) containing immunoglobulin (Ig) G nal anti-C3 antibody (from A. Toran˜ o, PhD, Instituto de and C1q were measured by commercial enzyme immuno- Salud Carlos III, Madrid, Spain) or goat purified immuno- sorbent assay (ELISA) (Scimedx Corp, Denville, NJ). Func- globulins anti-P (ATAB), saturated, and then incubated with tional activity of the classical (CH50) and the alternative (AP50) NHS or the patient’s deficient serum (1/1 K diluted). To pathway of complement was measured by hemolytic assays search the molecule eventually bound to the captured an- according to standard procedures.12 C3-nephritic factor tigen, several antibodies for testing the presence of each of (C3-NEF) activity was measured by hemolytic assay.13 Ac- these complexes in serum samples were added: polyclonal tivities of C7 and C8 were also measured by hemolytic anti–factor H, rabbit polyclonal anti-C3 (DAKO A/S, Glos- assays by using deficient sera from previously diagnosed pa- trup, Denmark) or peroxidase conjugated anti-human IgG tients as described.14 Initial screening for qualitative estima- (Nordic Immunology, Tilburg, the Netherlands). The re- tion of complement components was performed by double action was developed with an appropriate peroxidase sec- immunodiffusion (Ouchterlony analysis) with polyclonal an- ondary antibody where needed. tibodies against most of the C components. Western Blot Test Complement Components, Anti–Factor I Autoantibodies, and ICs Quantitation by ELISA The Western blot test was also performed to verify factor I deficiency. Briefly, serum samples (1 µL) from all family Further quantification of P, factor H, factor I, and C5 was members were run on 10% SDS-PAGE (sodium dodecyl- performed by sandwich ELISA, all developed in our labo- sulfate-polyacrylamide gel electrophoresis) under nonre- ratory. Briefly, plates were coated overnight with either ducing conditions. After running the samples, the gel was a purified IgG fraction from goat anti-P antibodies (1 transferred to a nitrocellulose sheet and the membrane µg per well) (ATAB; Atlantic Antibodies, Scarborough, Me), probed with an anti–factor I polyclonal antibody (1/500 purified IgG from either anti–factor H or anti–factor I goat diluted). The reaction was revealed with a phosphatase- antiserum samples (1 µg per well and 2 µg per well, re- labeled secondary antibody and NBT/BCIP (nitroblue tet- spectively) (Quidel, Mountain View, Calif), or mouse mono- razolium/5-bromo-4-chloro-3-indolylphosphate) as pre- clonal IgG anti-C5 (40 ng per well) (Quidel). In each case, cipitating substrate.

fide-linked polypeptide chains (␣,50kd;␤, 38 kd) that proximately 18 months (February 2001). Her family is circulates in an active form at a concentration of 30 to also described. 50 µg/mL.9 In the absence of factor I and/or factor H, there is an uncontrolled formation of C3 convertases, which results in marked production of C3b, sufficient to pro- RESULTS voke consumptive secondary immunodeficiency of component C3. Low levels of C3 may impair immune com- CLINICAL HISTORY AND TREATMENT plex metabolism10 and may reduce phagocytic activity, OF THE PATIENT opsonization, and antibody production induced by iC3b, C3dg, and C3 cleavage fragments produced after the ac- The proband was in good health until age 11 years when tion of factor I.11 she had an acute-onset abdominal pain and underwent We describe a Spanish factor I–deficient woman (age appendectomy. At age 16 years she had meningococcal 23 years) who has a history of recurrent meningitis epi- sepsis coincident with menstruation. Then she had re- sodes coinciding with the perimenstrual period for ap- current tonsillitis and underwent tonsillectomy 1 year

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 later. From age 22 years until February 2001, she has had monthly episodes of acute meningitis around the perimenstrual period (a total of 20 episodes). After the fourth con- I

secutive meningeal episode, she was studied for a possible 12 meningeal fistula with no conclusive results, but she underwent surgical intervention by bifrontal craniotomy to stop possible nasal cerebrospinal fluid (CSF) loss and to prevent meningitis; however, she had another meningeal episode. For 4 months the patient was treated with a daily II

dose of 500 mg of sodium cefuroxime as prophylactic. Af- 1 2 3 4 ter the fifth episode, she was referred to our hospital as she had low C3 levels. At each episode she was treated with Figure 1. Pedigree, age, and clinical manifestations of the family members sodium cefotaxime, 2 g every 4 hours for a minimum of 1 and patient (arrow). Father (I-1), aged 48 years, healthy. Mother (I-2), aged week. She had good evolution while receiving this treat- 42 years, healthy. Daughter 1 (II-1), aged 23 years, propositus). Son 1 (II-2), died (aged 7 years) from meningitis. Son 2 (II-3), aged 17 years, asthma. ment and recovered from cephalea and fever in a few days. Daughter 2 (II-4), aged 13 years, healthy. After 8 consecutive episodes, and because of the coinci- dence with menstruation, she was treated with triptoreline pamoate (3.5 mg, an antiestrogen drug, the effects of tected by polymerase chain reaction, but on 3 other which last for 3 months), but under this treatment, peri- samples, it was negative. Findings for herpes virus in CSF odical meningitis continued. Subsequently, she was also were also negative, and only once was cytomegalovirus treated with plasma infusions, 25 mL/kg of weight, every positive by polymerase chain reaction. 15 days, but she continued having meningeal episodes. Since all bacterial cultures of her CSF were sterile, Mollaret men- FAMILY HISTORY ingitis or an inflammatory situation was considered, and she was treated with daily corticoids (prednisone, 1.5- The patient has 1 sister and 1 brother who are 9 and 5 mg/kg body weight) owing to allergy to nonsteroidal anti- years younger, respectively. Both of them have no his- inflammatory agents. During this treatment, positive poly- tory of increased susceptibility to infections. Her par- merase chain reaction findings for N meningitidis type B DNA ents are both healthy, and there is no history of consan- was found in the CSF, and the patient was treated with peni- guinity although they come from the same village in the cillin G benzatine (1.2 million units), and later, after a new south of Spain. She had another brother who died of men- meningeal episode, she was treated with rifampicin, 300 ingitis when he was 7 years old (Figure 1). mg twice a day. Three months after triptoreline treatment, she had normal menstruation and meningitis peri- IMMUNOLOGICAL STUDIES odically continued without being as strictly related with the menstrual period. To discard allergic or toxic menin- Investigation of the patient revealed a normal complete gitis owing to medications, provocative tests were per- blood cell count and basic biochemical profile (including formed with the drugs she habitually received: amoxicil- hormones). Lymphocyte markers and function were nor- lin trihydrate, metamizol magnesic, and diclofenac sodium mal. The immunoglobulin concentrations were within the (Voltaren; Novartis Farmaceutica SA, Barcelona, Spain), all normal range, except for a polyclonal increase of IgM (IgM test results being negative, with the exception of diclof- Ϸ500 mg/dL, reference range: 40-260 mg/dL). The IgG sub- enac, which induced a rash reaction owing to her allergy class concentration gave no evidence of selective subclass to nonsteroidal anti-inflammatory agents, without her de- deficiency. Antinuclear antibodies (measured by veloping meningitis. After that, she continued under care indirect immunofluorescence on Hep-2 cells) and rheu- at the hospital and was treated with intravenous ␥-globu- matoid factor (measured by latex agglutination) were lin (Endobulin; Baxter SL, Valencia, Spain) infusions at the not detected. Other autoantibodies such as anti-myelo- immunomodulatory dose of 1.5 g/kg of weight every 10 peroxidase, anti-proteinase 3, anti-␤2 glycoprotein I, and days, but she has continued having meningitis except dur- C3-NEF were not detected. Tetanus and pneumococcal an- ing 1 menstrual period. At present, the dose of ␥-globulin tibody titers were within the normal range. has been reduced to 1 g/kg body weight every 15 days to Her complement system was investigated together avoid the possibility of hyperviscosity syndrome. The pa- with that of all 4 family members (Table). The results tient has recovered from all the episodes without any se- demonstrated the diagnosis of a total factor I deficiency quelae. in the patient and in her asymptomatic younger sister, since factor I was undetectable by Ouchterlony analy- ANALYSIS OF CSF FROM MENINGITIS EPISODES sis. This absence was confirmed by ELISA in both siblings as there was no detectable AP50 and CH50, and both Glucose was diminished and protein levels were highly had reduced levels of C3, C5, factor B, P, and factor H elevated, indicating an infectious situation. Leukocytes proteins. Activities of C7 and C8 were also reduced in were raised to 1550 per mm3 (85% were polymorpho- both siblings. Immune complexes were also elevated in nuclear cells and 15% monocytes). Beta-2-microglobu- both, although remarkably higher in the patient. Both par- lin was within the normal range. Bacteriological cul- ents and her brother had approximately half the normal tures of CSF were always sterile. In 2 independent samples concentration of circulating factor I, together with a slight of the CSF, DNA from N meningitidis group B was de- decrease in AP50 values. All these data indicated the in-

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Reference Variable† I 1 I 2 II 1 II 3 II 4 Values Classical pathway

CH50, U/mL 476 333 Ͻ50‡ 303 Ͻ50‡ 200-400 C3, mg/dL 97 101 24‡ 67‡ 22‡ 77-201 C4, mg/dL 18 20 14 14 20 14-47 C1q, µg/mL 152 176 140 116 116 100-300 C1-INH, mg/dL 33.8 26.3 25.2 19.5 18.5 14-35 Alternative pathway

AP50, % NHS 69‡ 44‡ . . . 68‡ . . . 70-130‡ Factor B, mg/dL 44.8 29.6 6.7‡ 19.9 7.3‡ 17-60 Factor H, µg/mL 316 134‡ 52‡ 373 65‡ 200-600 Factor I, % NHS 62‡ 46‡ . . . 52‡ 3‡ 100 P, µg/mL 45.3 41.4‡ 13.6‡ 25.7‡ 17‡ 43.8 Terminal pathway C5, µg/mL 67.5 120 27.5‡ 79 35‡ 43-115 C7, U/mL 1900 1100‡ Ͻ1000‡ 1900 Ͻ1000‡ 1600 C8, U/mL 7500 6900 5000‡ 6000 2200‡ 9000 ICs, µg/mL ...... Ͼ100‡ . . . 45‡ 0-35

*CH50 indicates total hemolytic complement; C3-C8, complement C3 to complement C8; C1-INH, complement C1 inhibitor; AP50, alternative complement pathway; NHS, normal human serum; ellipses, undetectable; P, properdin; and ICs, immune complexes. †Normal values of factor I, P, C7, and C8 were determined with a pool of NHS (n = 30). ‡Altered values.

1.0 kd Mks NHS I 1 I 2 II 4 II 1 II 3 NHS II 1 200 0.8

97.4 0.6 Factor I

OD 405 nm 0.4

69 0.2

0.0 C3/P C3/IgG C3/Factor H P/IgG Complexes in Serum

Figure 2. Factor I antigen detection by Western blot test on the patients’ Figure 3. Levels of complement C3/factor H, C3/properdin (P), serum samples. All 5 family members’ serum samples were included in C3/immunoglobulin (Ig)G, and P/IgG complexes in patient’s (II 1) and normal consecutive lanes. Mks indicates molecular weight markers; NHS, normal human serum (NHS). The mean±SD optical density is plotted; n=5. human serum. The arrow indicates purified factor I migration. denced the presence of C3b/factor H, C3b/P, and P/IgG complexes (Figure 3). Experimental conditions showed heritance of the trait throughout the family in an auto- that these complexes were present throughout the study. somal recessive manner (Figure 1). Western blot stud- These also were found in other patients with different dis- ies are concordant with the diagnosis and showed no other eases and the presence of immune complexes, but they were factor I anomalous species (Figure 2). always negative in the tested controls (n=10) and in a serum pool from 30 normal controls. COMPLEMENT AND IMMUNE COMPLEXES ANALYSIS COMMENT The different clinical treatments induced some changes; dur- This is the first description to our knowledge of a factor ing plasma infusions, instead of the lack of successful re- I–deficient family in Spain, with 23 other pedigrees pre- sults for preventing meningitis, C3 plasma values were raised viously being described.1-4 This pedigree presents 1 healthy nearly to normal levels, and AP and CH were normal- 50 50 homozygous sibling, while to our knowledge, only 2 ized. In addition, circulating immune complexes were low- healthy homozygous siblings have been previously de- ered with these infusions and more so when the patient re- scribed.15 Moreover, the homozygous patient presents a ceived corticoids and rifampicin (data not shown). very unusual and dangerous situation owing to the ex- Intravenous immunoglobulin also produced a great reduc- traordinary frequency of the meningeal attacks. Factor I tion of these immune complexes (to Ϸ30 µg/mL, refer- deficiency causes severe secondary C3 and factor B deple- ence value, Ͻ35 µg/mL). The ELISA experiments evi- tion; in addition, the C profile in this patient showed a

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©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 reduction in many other C components such as P, fac- laret recurrent meningitis was also found in another factor H, C5, C7, and C8. This situation was coincident with tor I–deficient woman.21 other factor I–deficient patients described earlier.1 Ap- Cerebral endometriosis has been described as being parently, this patient has all the C components altered associated with intermittent focal headaches,22 causing with the exception of the initial classical C components. catamenial epilepsy23 and subarachnoid hemorrhage,24 but This profile is compatible with the excess activation on in this patient, meningeal hemorrhage has never been the fluid phase of the alternative C pathway. Further- found as the absence of red cells in the CSF has proven. more, factor I deficiency interferes with the formation of Moreover, meningeal episodes have continued in the ab- C3 fragments, which are required for efficient phagocy- sence of menstruation as happened with triptoreline treat- tosis and B-cell memory (iC3b and C3dg, respectively). ment. The eventual relationship of meningitis with men- The lack of both types of fragments may also explain the struation is unknown. In a different situation, as hereditary predisposition for pyogenic infections.1-4 angioedema caused by C1-INH deficiency, hormonal fac- The patient also presents highly elevated levels of tors can regulate the episodes of this disease; for ex- ICs, without any consumption of the classical C com- ample, menstruation could be a triggering factor for epi- ponents (C1q or C4). This feature is uncommon, al- sodes, and pregnancy is also a condition that can improve though the presence of ICs has also been seen in other or worsen the course of this disease. Furthermore, an- factor I–deficient patients.10,16,17 In our case, the pres- drogens such as danazol are used for treating this angio- ence of C3b/factor H complexes could also be causing edema.25,26 Taking this into account, we can hypoth- the negative regulation of C3 convertase and producing esize that an unknown factor or mechanism related to an increase in C consumption. Binding of C3b to factor hormonal regulation in this complement deficiency, and H might act as a mechanism for the inactivation of some meningitis could be an underlying factor. Some authors of the biological effects of excess fluid-phase C3b. Fac- have shown that several components of the comple- tor H- and C3-altered mobility in agarose electrophore- ment system exist in the human endometrium in a hor- sis gels has been reported in other factor I–deficient pa- mone-dependent manner and may play a role in the nor- tients.4,18 Factor H in the proband’s serum migrates toward mal reproductive function.27 Recently, Nowicki et al28 have the anode with higher mobility than factor H from the shown that there is a higher susceptibility to gonococ- normal control (data not shown). This abnormal migra- cal infection by Neisseria gonorrhoeae during the men- tion could possibly be owing to the formation of these strual cycle, and changes in antibacterial activity are cor- C3b/factor H complexes, since in the absence of factor I, related with serum complement activity. These authors C3b persists in high levels and may increase its binding suggest that similar cyclic changes could be involved in to factor H. Furthermore, taking into account the pre- the pathogenesis of other infectious diseases in women. dicted existence of C3b/IgG complexes in normal se- Treatment with triptoreline has not abolished the men- rum,19,20 we have shown the presence of these com- ingeal episodes in this case, but other hormonal factors plexes by ELISA experiments. Results show that C3/P, could be involved. P/IgG, or C3b/IgG complexes are present in the serum In conclusion, we describe a factor I–deficient pa- of this patient at a higher concentration than in NHS. tient with an unusually high number of meningeal epi- Moreover, these C components could be involved in a sodes with resistance to several treatments, including large molecular complex (C3b/P/IgG) as predicted by Lutz plasma infusion, anti-inflammatory drugs, and prophy- et al,19 and in agreement with the proposed mechanism, laxis with antibiotics, the latter being previously sug- complexes could preserve this excess of C3b as de- gested in this3 and other C deficiencies.29 The molecular scribed by Jelezarova and Lutz.20 basis of this deficiency is being studied to characterize The main causes of recurrent meningitis were taken this patient’s genetic defect. into account, and most of them were discarded. A para- meningeal focus could never be evidenced; moreover, cryp- Accepted for publication July 12, 2001. tococcal cultures were always sterile as were Borrelia cul- This work was partly supported by grant FIS tures, and the patient never had Behçet disease. The clinical 00/0216 (Fondo de Investigacioń Sanitaria, Instituto de Salud situation was not like familial Mediterranean fever since Carlos III, Madrid) and Comunidad Autońoma de Madrid, her episodes were benign and clinical symptoms such as Madrid, grant 08.6/0028/2000. Dr Gonza´lez-Rubio is the cephalea and fever remitted in 2 to 3 days. The cause of recipient of a grant from Comunidad Autońoma de Madrid. these meningitides (infectious or Mollaret) is unclear. The Corresponding author and reprints: Margarita Lo´pez- possibility that they were all infectious is scarcely sup- Trascasa, PhD, Immunology Unit, Hospital Universitario ported since standard microbiological cultures for CSF were La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain always sterile. Moreover, polymerase chain reaction was (e-mail: [email protected]). positive twice for N meningitidis type B DNA and negative 2 more times in 4 different CSF samples. Further- more, we could not rule out that some of these were sep- REFERENCES tic and others aseptic as both types were possible. At each episode, antibiotics were administered, and the patient’s 1. Vyse TJ, Spa¨th PJ, Davies KA, et al. Hereditary complement factor I deficiency. clinical symptoms diminished with this treatment. We did Q J Med. 1994;87:385-401. 2. Kirschfink M, Binder R. 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