3. Comment Anti-NMDA-receptor encephalitis was initially described in 1997, in two separate reports of young women. These women presented with an ovarian teratoma and symptoms that included psychiatric manifestations and altered level of consciousness. In both patients, there was a gradual significant improvement in symptoms after tumor removal (Nokura et al., 1997, Okamura et al., 1997). In 2005, a series of four women with ovarian teratoma, psychiatric symptoms, altered level of consciousness and central hypoventilation was described. Authors hypothesized that the syndrome was a paraneoplastic process due to an antibody to an unknown antigen expressed in the hippocampus (Vitaliani et al., 2005). The associated antibody was discovered to be anti-NMDA-receptor in 2007 (Dalmau and Tüzün, 2007). In subsequent years, hundreds of cases have been reported in the neurology literature in both men and women, with approximately 80% of cases in females (Mann et al., 2014). The median age at onset of symptoms is 21 years old, although cases have been reported in patients ranging from 8 months to 85 years (Titulaer et al., 2013, Dalmau et al., 2011). Teratomas are found in large numbers of patients, most commonly in women between age 12 and 45 and in patients of Asian or African American descent (Titulaer et al., 2013, Dalmau et al., 2011). Most commonly, these are ovarian teratomas, though other germ-cell and rarely non-germ cell tumors have also been described in association with anti-NMDA-receptor encephalitis (Dalmau and Tüzün, 2007, Titulaer et al., 2013, Dalmau et al., 2011). Three cases have been described in pregnant women, all of whom recovered after removal of their ovarian teratoma and immunosuppression. Two of these women went on to have healthy infants, while one underwent termination of pregnancy (Kumar et al., 2010). The syndrome often begins with viral-like symptoms including headache, nausea, vomiting, fever, and fatigue (Dalmau et al., 2011). The non-specific nature of these symptoms generally precludes diagnosis at this stage and is recognized as a prodrome only after the illness progresses with a spectrum of neuropsychiatric symptoms. These symptoms have been divided into early and late stage symptoms. Early stage symptoms generally present with two weeks of prodromal symptoms and include confusion, memory loss, paranoia, hallucinations, mood disturbances, anxiety, self-harming behaviors, seizures and movement disorders such as facial twitching and choreoathetosis (Dalmau et al., 2011). As the psychiatric symptoms are often the most prominent, 77% of patients are initially seen by psychiatrists (Mann et al., 2014), and many patients are diagnosed with new-onset psychiatric disorders. However, these patients do not respond to anti-psychotics and progress to late stage symptoms, such as decreased responsiveness, hypoventilation, and autonomic instability including hypotension or hypertension, bradycardia or tachycardia, hyperthermia, and urinary incontinence (Mann et al., 2014). In patients with acute onset of psychiatric symptoms with any neurologic findings, or symptoms unresponsive to anti-psychotic medications, the diagnosis of encephalitis should be considered. In particular, serum and CSF studies for markers of viral and autoimmune causes of encephalitis, MRI, and electroencephalogram (EEG) may be useful in obtaining a diagnosis. Of note, while MRI may be normal in two-thirds of patients with anti-NMDA-receptor encephalitis, EEG abnormalities are seen in more than 90% of these patients (Titulaer et al., 2013). Definitive diagnosis is made when anti-NMDA-receptor antibodies are detected in the blood or CSF (Titulaer et al., 2013, Dalmau et al., 2011). Once definitive diagnosis has been obtained, imaging studies such as pelvic ultrasound, MRI, computed tomography, and positron emission tomography may be used to evaluate for an underlying teratoma. In rapidly-deteriorating patients in whom anti-NMDA-receptor encephalitis is highly suspected, but not yet confirmed, providers may consider imaging and removal of any detected neoplasms, as in this case. Delayed treatment may result in progression of the autoimmune process with associated clinical deterioration to autonomic instability, catatonia, status epilepticus, or coma. In one series of patients with anti-NMDA-receptor encephalitis, five out of six patients with an ovarian teratoma who did not undergo surgery died (Titulaer et al., 2013). In contrast, removal of the tumor may be curative. In approximately 80% of patients who undergo tumor removal and immunosuppressive treatment, substantial neurological improvement occurs (Dalmau et al., 2011). In the case above and in previously reported cases, symptoms of anti-NMDA-receptor encephalitis markedly improved within one month of tumor removal and immunosuppressive treatment, though recovery can continue for up to 24 months (Titulaer et al., 2013, Dalmau et al., 2011). Multiple regimens of immunosuppressive treatments have been described, including first line treatment with intravenous steroids and intravenous immunoglobulins (IVIG) or plasmapheresis and second line treatment with rituximab and cyclophosphamide (Titulaer et al., 2013, Dalmau et al., 2011). For the patient described above, a modified version of the BrainWorks protocol for severe antibody-mediated inflammatory brain disease was used (BrainWorks). This protocol consists of 1 g prednisone daily for three to seven days, followed by 60 mg daily for one month, followed by a six-month taper. Simultaneously, patients receive seven plasmapheresis treatments over 14 days, 70 g of IVIG every two weeks for five doses, rituximab 500 mg/m2 in two doses two weeks apart, and daily calcium and vitamin D supplementation. This protocol was developed by the BrainWorks Network based on experience from a web-based, international prospective cohort of pediatric patients with inflammatory brain diseases. It differs from previously described protocols (Titulaer et al., 2013, Dalmau et al., 2011) in that it is based solely on experience in the pediatric population, and includes rituximab in the initial treatment, rather than using it as a second line agent. In patients with no detectable underlying neoplasms, it has been hypothesized that the syndrome may be caused by microscopic germ cell tumors undetectable by imaging (Mann et al., 2014). This hypothesis is supported by the findings that recovery is more common and relapse less likely in patients with a detectable tumor (Dalmau et al., 2011). In addition, there have been reported cases of ovarian teratomas being detected years after presentation of anti-NMDA-receptor encephalitis symptoms (Mann et al., 2014). Therefore, for patients without detectable tumors, it is recommended to continue immunosuppression with azathioprine or mycophenolate for a minimum of 1 year after symptom relapse, and in female patients over age 12 without detectable tumors, to screen for ovarian teratomas with pelvic MRI or ultrasound every 6 months for 4 years (Mann et al., 2014, Titulaer et al., 2013, Dalmau et al., 2011). Following neurologic recovery, women of childbearing potential should receive counseling on contraception, particularly for those remaining on azathioprine and mycophenolate. These medications are both classified as Pregnancy Category D. These women should have a pregnancy test prior to treatment initiation and as indicated at follow up visits. For mycophenolate in particular, it is recommended to avoid pregnancy for an additional 6 weeks following discontinuation of treatment. Particular consideration should be given to use of long-acting reversible contraceptives in these patients given that many may have residual cognitive deficits including difficulties with memory and impulsivity that may make consistent contraceptive use more challenging. With appropriate diagnosis and rapid treatment, including resection of any underlying teratoma and immunosuppression, patients with anti-NMDA-receptor encephalitis have a high likelihood of a positive outcome. The gynecologist has an important role to play within the multidisciplinary team caring for these patients as early tumor detection and removal results in an improved prognosis, and those without tumors require frequent monitoring for tumor development.
Limbic encephalitis is characterized by rapid onset of working memory deficit, mood changes, and often seizures. The condition has a strong paraneoplastic association, but not all cases are invariably due to tumors.
Ion channels are complex transmembrane proteins that orchestrate the electrical signals necessary for normal function of excitable tissues, including the central nervous system, peripheral nerve, and both skeletal and cardiac muscle.
TOLLE CAUSAM Tanya Lee, ND We are just beginning to understand the complex nature of the immune system and the cross-talk between the immune system and other systems in the body. The influence of sex hormones is not limited to reproductive tissues; they also exert effects on peripheral systems such as the immune system. In the context of autoimmune disease, there is a known female predominance of many autoimmune diseases. Some examples of female-to-male ratios of specific autoimmune diseases include 16:1 for primary biliary cirrhosis; 12:1 for antiphospholipid syndrome; 9-10:1 for systemic lupus erythematosus (SLE); and 2:1 for multiple sclerosis.1,2 Other autoimmune conditions with female predominance include Hashimoto’s thyroiditis, Graves’ disease, scleroderma, and Sjögren’s syndrome.2 The female predominance of autoimmune disease is highlighted by the fact that the onset of most female-dominant autoimmune diseases occurs following puberty. The ratio of female-to-male risk of SLE and thyroiditis before puberty is lower (3-4:1) than after puberty (9:1), and other autoimmune diseases, such as Sjögren’s syndrome and primary biliary cirrhosis, are extremely rare in pediatric populations.2 Autoimmune diseases whose onset typically occurs before puberty, eg, type 1 diabetes mellitus, appear to exhibit no female polarization.2 The role of female hormones in autoimmune disease is also observed in symptom severity fluctuations throughout the different phases of the menstrual cycle.3 Both genetic and environmental factors contribute to the risk of autoimmune disease: when genetic risk is high, environmental factors become less influential on the onset and severity of disease progression. Although hormone status may play a role in the risk of developing disease, research has thus far found that modulating hormones appears to impact disease activity far more than disease risk.2 While sexual dimorphism of autoimmune disease includes many hormonal factors, female prevalence of certain autoimmune diseases suggest that sex hormones such as estrogen and progesterone are key players in the development and activity of the female-prevalent autoimmune diseases. Pregnancy is an excellent example for viewing how sex hormones may influence the immune system. There is a dramatic change in hormones during pregnancy, with progesterone and estrogen levels increasing 5-10-fold within the maternal circulation, and then dropping suddenly drop postpartum, alongside significant immunological shifts both during and after pregnancy.2 During pregnancy, the immune system must achieve a unique state of equilibrium: being strong and active at the maternal-fetal interface, while also maintaining a state of immunosuppression within the maternal circulation so as to not react to the partially allogenic cells of the fetus. During pregnancy, the uterine lining (the decidua) is an immunologically intense area, tightly regulated in order to ensure the survival of the fetus. Specialized uterine natural killer cells and monocytes are inactivated when encountering the unique HLA-G expression of fetal trophoblastic cells, but are active at disabling any foreign pathogen threatening the fetus.4 Other known mechanisms of this pregnancy paradox include T-helper-2 (Th2) dominance, upregulation of anti-inflammatory cytokines and immunosuppressive proteins, downregulation of the classical complement pathway, and the blockage of fetal antigen exposure to the maternal immune system.2,5 The local protective effects of the maternal-fetal interface appear to be influenced by estrogen and progesterone. While estrogen as well as other steroids play a large role in the totality of the immunological paradox of pregnancy and the development and progression of autoimmune disease, this article will focus on the effects of progesterone on the immune system during pregnancy and in female-prevalent autoimmune disease. PROGESTERONE’S BROAD ACTIONS PROGESTERONE & THE IMMUNE SYSTEM Progesterone is a steroid hormone produced by the corpus luteum, uterus, adrenal glands, and the brain. Progesterone (P4) binds to many different receptors on both reproductive and non-reproductive tissues; these receptors include membrane-bound progesterone receptors, intracellular progesterone receptors, and glucocorticoid receptors, which are expressed on human immune cells including mast cells, natural killer (NK) cells, macrophages, dendritic cells, and both CD4+ and CD8+ type cells.2,3 P4 is generally considered an anti-inflammatory hormone. Some of its known anti-inflammatory mechanisms include the suppression of proinflammatory Th1 and Th17 differentiation, T-regulatory (T-reg) cell induction and expansion (immune modulating), as well as polarization towards Th2 differentiation and activity.6 PROGESTERONE IN PREGNANCY Progesterone is secreted by the corpus luteum in the early stages of pregnancy, and later by the placenta after week 8 of gestation. P4 levels rise 10-fold within the maternal circulation and 100-fold within the placenta.3 This high concentration of P4 is strong enough to signal through the glucocorticoid receptor, which is thought to be one of the mechanisms for the immunosuppressive effect seen during pregnancy.7 The surge of P4 is credited for Th2 shift, for the expansion and production of the Th2-promoting cytokine, interleukin (IL)-4, the increased expression of uterine NK cells, the suppression of inflammatory cytokine, Th17, and the induction of the T-reg cells during pregnancy.2,3 A recent study by Shah et al observed that administration of progesterone to healthy, pregnant women suppressed the production of interferon-gamma (IFN-γ), a promoter of Th1-mediated immunity. The study also found that mifepristone, a progesterone receptor antagonist, induced IFN-γ expression.8 PROGESTERONE & AUTOIMMUNE DISEASE The transient modification of the immune system during pregnancy and the clear influence of pregnancy on the presentation of different autoimmune conditions serves as a gateway for our understanding of the role progesterone plays in autoimmune disease. While research specifically studying the effects of natural P4 is still lacking, a strong backbone of evidence suggests that therapeutic use of P4 in certain autoimmune diseases may be beneficial in modulating the activity of the disease. RHEUMATOID ARTHRITIS The hormonal influence in rheumatoid arthritis (RA) is illustrated by the symptomatic changes that occur with the fluctuations of the menstrual cycle, the remission of symptoms during pregnancy, and the increase in flares in the postpartum period.9,10 RA onset typically occurs after menopause (45-75 years) and nulliparity appears to increase the risk of developing RA, suggesting that estrogen and progesterone may play a protective role in the risk and disease activity of RA.11 The rapid withdrawal of progesterone postpartum may contribute to the increase in risk of RA in susceptible women after delivery.12 In RA, there is a marked increase in the inflammatory Th17; as discussed, progesterone has been found to induce T-reg cells, suppress Th17 and Th1 differentiation, and promote Th2 dominance, suggesting its protective role in RA. An earlier study by Valentino et al found that women with RA exhibited significantly lower progesterone levels during the luteal phase of the menstrual cycle as compared to healthy controls.13 However, there is very little in the way of evidence supporting the use of progesterone alone for managing the risk and activity of RA. In fact, many studies (both in vivo and human) fail to show consistent results regarding the influence of P4 in RA, with many showing no amelioration of symptoms of RA by hormone replacement therapy (HRT).11,14,15 MULTIPLE SCLEROSIS Multiple sclerosis (MS) is an autoimmune condition targeting the central nervous system, driven by myelin-specific CD4+ Th1 cells and inflammatory cytokines. Considering the Th2-promoting effect of progesterone, and its known neuroprotective, anti-inflammatory and pro-myelinating properties, this hormone has been a therapy of interest for modulating disease activity in MS.16 Similar to RA, the hormonal impact of progesterone on disease activity in MS is represented by the amelioration of symptoms during pregnancy and the increase in disease flares within the postpartum period.2 The immunomodulatory effect of progesterone can be observed in animal models of experimental autoimmune encephalitis (EAE) – the in-vivo representation of MS. These animal models have shown that, at the onset of EAE, progesterone can suppress inflammation by reducing proinflammatory IL-2, IL-17, and IL-23, and increasing B-cells and anti-inflammatory IL-10, thereby reducing the severity of disease progression.17 In another in-vivo model of demyelination, Ye et al found that treatment of progesterone at the onset of disease ameliorated demyelination and the resulting neurobehavioral deficits.18 An ongoing human clinical trial plans to determine the effects of high-dose progestin administration on postpartum MS flares at the onset of the postpartum period.19 SYSTEMIC LUPUS ERYTHEMATOSUS The typical onset of SLE, occurring between menarche and menopause, as well as the high female:male dominance (9:1) of this disease, suggest that hormones play a role in the development and activity of SLE.11 Early menarche is considered an independent risk factor for SLE, and initial SLE flares in women have been linked to low P4, indicating a pathogenic role of estrogen and a protective role of P4 in both the risk and activity of SLE.11 Symptoms of SLE have been found to be exacerbated by pregnancy, with SLE flare rates higher in pregnant patients compared to non-pregnant patients.20 SLE flares have been associated with Th2 dominance and increased humoral activity, a state that is favorable for other autoimmune conditions, such as RA and MS.3 However, there is also evidence that pregnancy itself does not influence the risk of SLE flares and that the biggest risk factor for SLE flares during pregnancy is the severity of disease activity 6 months prior to conception, as well as the discontinuation of medication at the onset of pregnancy.21 Therefore, high circulating levels of hormones may not actually influence disease activity in SLE, as compared with autoimmune conditions such as RA and MS. A link has been observed between estrogen-containing HRT and oral contraceptive (OCP) use, as well as a dose-dependent relationship between the level of estrogen in HRT/OCPs and the risk for SLE flares in those with active disease.22,23 SLE patients often experience P4 deficiency during the luteal phase of the menstrual cycle, suggesting that P4 may have a protective role against SLE; however, it is unknown if this is a consequence of the disease or a risk factor.2 Progestin-only forms of OCPs and HRT do not appear to increase risk and can even reduce flares of SLE.24 High circulating levels of type 1 IFN-α and IFN-ß are a hallmark of SLE.3 A recent study found that progestogens (natural progesterone and synthetic medroxyprogesterone acetate) appear to suppress plasmacytoid dendritic cell production of IFN-α, as well as the activation of the IFN-inducing transcription factor IRF-5.25 This indicates that modifying P4 levels may be an effective target for modulating disease risk and activity of SLE. While there is some evidence to suggest that there is no conferred difference in the risk of SLE flares between combined and progestin-only OCPs and copper IUDs, other studies suggest that estrogen is an aggravating factor in terms of a link between SLE flares and HRT.2 However, especially considering the high risk for thrombosis in SLE patients (specifically those with high anti-phospholipid antibodies), progesterone-only OCPs should be considered for SLE patients seeking oral forms of contraception.2 CLINICAL CONSIDERATIONS While many experimental animal models indicate that progesterone may have a large impact on immunological function and disease activity of autoimmune conditions, human clinical trials are greatly lacking. Existing observational studies on the impact of HRT and OCPs on autoimmune disease typically used synthetic progestins to represent P4 activity rather than bioidentical P4, which would typically be the treatment of choice by naturopathic doctors. Considering the influence of physiological P4 on immune function observed in pregnancy when P4 levels are peaked, it may be safe to assume that bioidentical P4 represents a viable treatment option to mimic these effects. Another consideration are the inconsistent results from using HRT in autoimmune disease. Many of these studies fail to provide treatments that mimic the physiological levels of pregnancy; the activity of progesterone on progesterone- and glucocorticoid receptors (GRs) is dose-dependent, with the latter requiring extremely high levels of P4 (pregnancy levels) for activation.2 GR activation has been proposed as the main mechanism of immune modulation by P4, given that these receptors are highly expressed on immune cells and that steroids that bind to the GRs (ie, corticosteroids) are the standard treatment for inflammatory flares in autoimmune disease.26 Perhaps dosing bioidentical progesterone at levels mimicking pregnancy can produce more consistently positive results. Considering the currently available research, bioidentical progesterone may be a viable option in modifying disease activity in female-dominant autoimmune diseases. Clinicians should base this treatment on the patient’s individual requirements – the category of autoimmune disease (ie, whether it is a female-dominant type) and outcomes of progesterone testing. A detailed history of menstrual cycle activity and fertility should be used to help determine whether progesterone might be a treatment of value for an autoimmune patient. Autoimmune diseases still remain as complex, multifactorial conditions that are influenced by genetic, stochastic, and environmental triggers. It would be silly to consider hormones to be a sole contributing factor when managing female-dominant autoimmune disease. However, insights into how hormones impact risk and disease activity in autoimmune disease provide clinicians a valuable tool to consider when treating autoimmune patients. References: Borchers AT, Naguwa SM, Keen CL, Gershwin ME. The implications of autoimmunity and pregnancy. J Autoimmun. 2010;34(3):J287-J299. Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev. 2012;11(6-7):A502-A514. Tan IJ, Peeva E, Zandman-Goddard G. Hormonal modulation of the immune system – A spotlight on the role of progestogens. Autoimmun Rev. 2015;14(6):536-542. Pazmany L, Mandelboim O, Vales-Gomez M, et al. Protection from natural killer cell-mediated lysis by HLA-G expression on target cells. Science. 1996;274(5288):792-795. Poole JA, Claman HN. Immunology of pregnancy. Implications for the mother. Clin Rev Allergy Immunol. 2004;26(3):161-170. Hughes GC, Clark EA, Wong AH. The intracellular progesterone receptor regulates CD4+ T cells and T cell-dependent antibody responses. J Leukoc Biol. 2013;93(3):369-375. Ugor E, Prenek L, Pap R, et al. Glucocorticoid hormone treatment enhances the cytokine production of regulatory T cells by upregulation of Foxp3 expression. Immunobiology. 2018;223(4-5):422-431. Shah NM, Imami N, Johnson MR. Progesterone Modulation of Pregnancy-Related Immune Responses. Front Immunol. 2018;9:1293. Latman NS. Relation of menstrual cycle phase to symptoms of rheumatoid arthritis. Am J Med. 1983;74(6):957-960. de Man YA, Dolhain RJ, Hazes JM. Disease activity or remission of rheumatoid arthritis before, during and following pregnancy. Curr Opin Rheumatol. 2014;26(3):329-333. Hughes GC, Choubey D. Modulation of autoimmune rheumatic diseases by oestrogen and progesterone. Nat Rev Rheumatol. 2014;10(12):740-751. Alpizar-Rodriguez D, Pluchino N, Canny G, et al. The role of female hormonal factors in the development of rheumatoid arthritis. Rheumatology (Oxford). 2017;56(8):1254-1263. Valentino R, Savastano S, Tommaselli AP, et al. Hormonal pattern in women affected by rheumatoid arthritis. J Endocrinol Invest. 1993;16(8):619-624. Ganesan K, Balachandran C, Manohar BM, Puvanakrishnan R. Comparative studies on the interplay of testosterone, estrogen and progesterone in collagen induced arthritis in rats. Bone. 2008;43(4):758-765. Holroyd CR, Edwards CJ. The effects of hormone replacement therapy on autoimmune disease: rheumatoid arthritis and systemic lupus erythematosus. Climacteric. 2009;12(5):378-386. De Nicola AF, Gonzalez Deniselle MC, Garay L, et al. Progesterone protective effects in neurodegeneration and neuroinflammation. J Neuroendocrinol. 2013;25(11):1095-1103. Yates MA, Li Y, Chlebeck P, et al. Progesterone treatment reduces disease severity and increases IL-10 in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2010;220(1-2):136-139. Ye JN, Chen XS, Su L, et al. Progesterone alleviates neural behavioral deficits and demyelination with reduced degeneration of oligodendroglial cells in cuprizone-induced mice. PLoS One. 2013;8(1):e54590. Vukusic S, Ionescu I, El-Etr M, et al. The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART’MUS) trial: rationale, objectives and state of advancement. J Neurol Sci. 2009;286(1-2):114-118. Ruiz-Irastorza G, Lima F, Alves J, et al. Increased rate of lupus flare during pregnancy and the puerperium: a prospective study of 78 pregnancies. Br J Rheumatol. 1996;35(2):133-138. Barbhaiya M, Bermas BL. Evaluation and management of systemic lupus erythematosus and rheumatoid arthritis during pregnancy. Clin Immunol. 2013;149(2):225-235. Costenbader KH, Feskanich D, Stampfer MJ, Karlson EW. Reproductive and menopausal factors and risk of systemic lupus erythematosus in women. Arthritis Rheum. 2007;56(4):1251-1262. Bernier MO, Mikaeloff Y, Hudson M, Suissa S. Combined oral contraceptive use and the risk of systemic lupus erythematosus. Arthritis Rheum. 2009;61(4):476-481. Chabbert-Buffet N, Amoura Z, Scarabin PY, et al. Pregnane progestin contraception in systemic lupus erythematosus: a longitudinal study of 187 patients. Contraception. 2011;83(3):229-237. Hughes GC, Thomas S, Li C, et al. Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol. 2008;180(4):2029-2033. Flammer JR, Rogatsky I. Minireview: Glucocorticoids in autoimmunity: unexpected targets and mechanisms. Mol Endocrinol. 2011;25(7):1075-1086. Tanya Lee, ND, received her Bachelor of Science degree (Honours) in Biochemistry and Biomedical Sciences from McMaster University, and was trained as a naturopathic doctor at the Canadian College of Naturopathic Medicine. Dr Lee practices full-time between 2 clinics, located in Toronto and Milton, Ontario. Although her primary-care practice focuses on family medicine, Dr Lee treats a wide variety of conditions, including endocrine disorders, infertility, digestive problems, cardiovascular disease, diabetes, insomnia, and fatigue. She has a special interest in the treatment of autoimmune diseases, as well as pediatric health.