http://informahealthcare.com/aut ISSN: 0891-6934 (print), 1607-842X (electronic) Autoimmunity, 2014; 47(3): 154–161 ! 2014 Informa UK Ltd. DOI: 10.3109/08916934.2014.883501

REVIEW ARTICLE

A review of the current literature and a guide to the early diagnosis of autoimmune disorders associated with neuromyelitis optica Anand Iyer1,2, Liene Elsone1, Richard Appleton2, and Anu Jacob1 The Walton Centre for Neurology and Neurosurgery, Liverpool, UK and 2Alder Hey Children’s Hospital, Liverpool, UK

Abstract

Keywords

Neuromyelitis optica (NMO) is an immune-mediated neurological disorder characterised by recurrent episodes of optic neuritis and longitudinally extensive transverse myelitis. A serum biomarker, aquaporin-4 IgG, the autoantibody against aquaporin-4 water channel, has been specifically associated with NMO and has assisted early recognition and prediction of relapses. Less commonly, a monophasic course, associated with antibodies to myelin oligodendrocyte glycoprotein has been reported. Specific diagnostic criteria have been defined; however, some cases that do not fulfil these criteria (but are nevertheless associated with aquaporin-4 IgG) are classified as NMO spectrum disorder and follow the same relapsing course. An ever-growing list of autoimmune disorders, both organ-specific and non-organ-specific, have been associated in up to 20–30% of patients with NMO. These disorders, which may become symptomatic before or after the development of NMO, are often diagnosed long after the diagnosis of NMO, as symptoms may be wrongly attributed to NMO, its residual effects or medication side effects. In addition, autoantibodies can be found in patients with NMO without coexisting disease (up to 40% in some series) and maybe suggestive of a heightened humoral immune response. We present a comprehensive review of the current literature on autoimmune disorders co-existing with NMO and identified 22 autoimmune conditions (myasthenia gravis, coeliac disease, ulcerative colitis, sclerosing cholangitis, systemic lupus erythematosus, rheumatoid arthritis, antiphospholipid antibody syndrome, Sjogren’s syndrome, autoimmune hypothyroidism, immune thrombocytopenic purpura, pernicious anaemia, narcolepsy, pemphigus foliaceus, alopecia areata, psoriasis, scleroderma, dermatitis herpetiformis, polymyositis, chronic inflammatory demyelinating polyneuropathy, paraneoplastic disorders, insulin dependent diabetes mellitus and autoimmune encephalitis).

Myasthenia gravis, optic neuritis, Sjogren’s syndrome, systemic lupus erythematosus, transverse myelitis

Introduction Neuromyelitis optica (NMO) is an immune mediated neurological disorder and typically presents with recurrent episodes of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM, defined as a lesion involving three or more contiguous vertebral segments on T2-weighted magnetic resonance images of the spine during an acute episode) and is distinct from multiple sclerosis [1] (Table 1). Brainstem symptoms, including intractable vomiting or hiccoughs, can be the presenting feature. The detection of an autoantibody against aquaporin 4 (AQP4-IgG), the predominant water channel protein in the central nervous system, is very specific for NMO and has led to advances in early diagnosis and treatment of NMO [2]. However, a small subset of patients have a monophasic course and may be associated with antibodies to myelin oligodendrocyte protein (MOG) [3,4]. AQP4-IgG is also detectable in patients with ON or myelitis Correspondence: Anu Jacob, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Liverpool L9 7LJ, UK. Tel: +441515295970. Fax: +441515295512. E-mail: anu.jacob@ thewaltoncentre.nhs.uk

History Received 29 August 2013 Revised 24 December 2013 Accepted 11 January 2014 Published online 10 February 2014

alone; its presence suggests future relapses [5]. Such cases that do not fit the diagnostic criteria are classified as NMO spectrum disorder (NMOSD) and usually follow a similar relapsing course. Patients with NMO have an increased predisposition to develop multiple autoimmune diseases, both organ specific and non-organ specific. The following vignette is a typical scenario where other autoimmune disorders coexisted with NMO, but was not recognised early. A 36-year-old Caucasian woman presented with severe ON with poor recovery despite steroids. Magnetic resonance imaging (MRI) brain was normal. Cerebrospinal fluid oligoclonal bands were negative. Twelve months later, she had a LETM treated with steroids and plasma exchange. NMO was diagnosed and AQP4-IgG was positive. She recovered incompletely with residual weakness in the legs and needed a cane to walk. She also had bladder and bowel problems. She was maintained on azathioprine and low-dose steroids and remained in remission. She reported troublesome fatigue attributed by the neurologist to the effort of walking with the weakness. She had weight gain attributed to steroids. She also had persistent diarrhoea, considered related to residual bowel dysmotility. Only 4 years after the diagnosis of

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1

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Table 1. Diagnostic criteria for NMO [1].

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2 absolute criteria plus at least two of three supportive criteria Absolute criteria

1. Optic neuritis (ON) 2. Acute myelitis

Supportive criteria

1. Negative MRI brain at disease onset (normal or not meeting radiological diagnostic criteria for MS). 2. Spinal cord MRI with T2 signal abnormality extending over three or more vertebral segments. 3. NMO-IgG (AQP4-IgG) seropositive status

NMO were alternate causes considered, and tests revealed autoimmune hypothyroidism and coeliac disease (CD), the management of both vastly improved her quality of life. A literature review immediately revealed the association of these with NMO. If thought of earlier and tested appropriately, this delay would have been avoided. While it would be impractical to do serological testing for all the autoimmune conditions known to be associated with NMO in every case, it is reasonable to look for the clinical features of these autoimmune disorders and then investigate as appropriate. This article reviews the current literature on the coexistence of autoimmune disorders with NMO and provides an aide memoir for the clinician, including a pragmatic screening checklist.

Methods We reviewed all the major clinical series on patients with NMO and extracted information on co-existing autoimmune conditions. A literature search was performed on the PubMed database from 1999–2013 to identify all English language publications using the keywords ‘‘neuromyelitis optica’’ AND ‘‘myasthenia gravis’’ OR ‘‘coeliac disease’’ OR ‘‘systemic lupus erythematosus’’, OR ‘‘Sjogren’s syndrome’’, separately and in combination with the following MeSH terms: ‘‘autoimmune disease’’, ‘‘paraneoplastic syndrome’’, ‘‘hypothyroidism’’, ‘‘autoimmune thyroiditis’’, ‘‘pernicious anaemia’’, ‘‘ulcerative colitis’’, ‘‘rheumatoid arthritis’’, ‘‘immune thrombocytopenic purpura’’ and ‘‘autoimmune encephalitis’’. This yielded a total of 58 citations, including large population-based reviews, which were then grouped together according to one specific co-existing autoimmune condition and relevance. Further sources were added from review of the bibliographies of these articles.

Results We identified 22 autoimmune conditions reported to be associated with NMO (Table 2) and will discuss the characteristics of the common ones. Myasthenia gravis Myasthenia gravis (MG) is caused by antibodies against the nicotinic acetylcholine receptor (AChR-Ab) at the neuromuscular junction [6]. Despite the rarity of MG and NMO, both these conditions coexist and are independently associated with other autoimmune diseases. Several cases or small series of patients with these co-existing conditions have been summarised in Table 3 [7–21]. In most cases, MG preceded

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the onset of NMO, and 70% of cases had previous thymectomy. Most patients reported had an early onset of myasthenia (550 years). It is now known that AQP4 is also expressed in the human thymus and that AQP4-IgG can sometimes be detected at the onset of MG and even several years before the diagnosis of NMO [9,22]. NMO without AQP4-IgG is also associated with MG [8,10,14]. The exact mechanisms linking the thymus with the NMO are poorly understood. Why only some patients develop NMO after thymectomy is also not known. In a long-term follow up study of patients with MG who underwent thymectomy, the occurrence of additional autoimmune conditions was 12.5% [23]. The majority of patients had generalised myasthenia, which followed a relatively benign course and was responsive to immune suppression with a high proportion of patients achieving remission. It is possible that the expression of both acetylcholine receptor and AQP4 in thymus gland may underlie the development of both conditions [2,9]. There are very few cases of patients developing MG after the onset of NMO. Etemadifar et al. [7] reported the case of a woman with recurrent ON and one episode of myelitis, who was initially diagnosed as multiple sclerosis based on neuroimaging. She then developed myasthenia and was detected to have positive AQP4-IgG as well, confirming the diagnosis of NMO. Similarly Leite et al. report two cases who developed MG 6 and 24 years after the first manifestations of NMOSD. These patients were not thymectomised [9]. Passive transfer of AChR-Ab across the placenta can cause transient neonatal myasthenia and Zifman et al. [24] reported such a case in a woman who had NMO but who was asymptomatic for MG. AChR-Ab was positive in the mother and neonate. The mother’s first baby also had transient hypotonia, which improved quickly and was probably due to similar mechanism. Not all patients with co-existing AChR-Ab develop clinical myasthenia. In a study from the Mayo Clinic, 177 patients with NMO were screened for co-existing autoantibodies in their sera [25]. 11% had AChR-Ab and only 2% had clinical myasthenia. AQP4-IgG can also be present before development of NMO, while the myasthenia is clinically manifest [9]. Implications for practice Patients with NMO may have co-existing myasthenia, which usually precedes the onset of NMO. Fatigue, weakness of limb or bulbar musculature can be common to both, and physicians should be wary of this possibility. AChR-Ab can often be present asymptomatically in NMO and does not necessarily predict future occurrence of clinical MG. The converse may also occur, but from current literature, most patients who have AQP4-IgG seem to develop clinical NMO after a varying period from 4 to 16 years [9]. Coeliac disease CD or gluten sensitivity is an autoimmune enteropathy triggered by the ingestion of wheat gliadin and related proteins in genetically susceptible (HLA DQ2.5 and DQ8) individuals. IgA anti-gliadin antibodies, IgA endomysial antibodies and tissue transglutaminase antibodies are

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Table 2. Reported autoimmune conditions coexisting with NMO. Co-existing autoimmune disorder Myasthenia gravis [5–19]

Fatiguable limb weakness, ptosis, diplopia

Coeliac disease [24–28] Ulcerative colitis [59,60] Sclerosing cholangitis [59,60]

Diarrhoea, weight loss, fatigue, nausea, vomiting, jaundice, abdominal pain

Systemic lupus erythematosus [40–51] Rheumatoid arthritis [59,60]

Arthritis, nephritis, rash Raynaud’s phenomenon Iridocyclitis Recurrent miscarriages, deep vein thrombosis

Antiphospholipid antibody syndrome [6,7,42,43,45,59] Sjogren’s syndrome [29–37] Autoimmune hypothyroidism [6,59,60] Autoimmunity Downloaded from informahealthcare.com by University of Laval on 06/01/14 For personal use only.

Common symptoms

Hypothalamic dysfunction [62–67]

Immune thrombocytopenic purpura [59,60] Pernicious anaemia [59,60] Narcolepsy [55,56]

Xerostomia Xerophthalmia Cold intolerance Constipation Mental slowing Hypersomnolence Hyperphagia Behavioural disturbances Diabetes insipidus Galactorrhea Amenorrhea Recurrent easy bruising Anaemia Neuropathy, fatigue Excessive day time sleepiness, cataplexy

Pemphigus foliaceus, alopecia areata, psoriasis, scleroderma, Dermatitis herpetiformis [6,32,59,70]

Recurrent skin rashes, bullous skin eruptions

Polymyositis HyperCKemia Chronic inflammatory demyelinating polyneuropathy [32,44,75] Cancer and paraneoplasia [64,65]

Muscle pain, tenderness Fatigue Numbness, weakness

Autoimmune encephalitis [7]

Hair loss

Investigations Acetylcholine receptor antibody Single fibre EMG, Tensilon test Tissue transglutaminase antibodies, anti-gliadin antibodies in coeliac disease Endoscopy, small bowel biopsy Ultrasound abdomen Liver function tests ANA, ds DNA Rheumatoid factor (RF) Full blood count Antiphospholipid antibody SS-A, SS-B Schirmer’s test Salivary or lip biopsy Thyroid function tests Antithyroid antibodies Endocrine consult Hypothalamic pituitary hormonal assays

Full blood count Ferritin, vitamin B12, folate Multiple sleep latency test CSF hypocretin Skin biopsy and dermatology consult Anti-desmoglein antibody in pemphigus foliaceus Coeliac antibody testing Creatine kinase Electromyography Nerve conduction studies

Previous history of malignancy. The cancers known to coexist with NMO are those involving thymus, prostate, breast, uterine cervix, lung and B cell lymphoma Psychosis, seizures, neuromyotonia

Oncology consult and antineuronal antibodies

Voltage-gated potassium channel (VGKC) antibodies

EMG ¼ electromyography, ANA ¼ antinuclear antibody, dsDNA ¼ double-stranded DNA, SS-A ¼ anti Ro antibody, SS-B ¼ anti La antibody and VGKC ¼ voltage-gated potassium channel antibody.

serological markers for autoimmunity in CD. The prevalence of neurological dysfunction, predominantly ataxia and peripheral neuropathy, among patients with established CD is approximately 10–22.5% [23]. Very few cases of myelopathy have been reported in cases with CD. In a cohort of 424 patients presenting to a gluten sensitivity clinic in Sheffield, UK, 18 (2%) had myelopathy [26]. The case reports about co-existing CD and NMOSD are summarised in Table 4 [27–31]. The median age at diagnosis of CD was 22 years and that at diagnosis of NMO was 36 years. AQP4-IgG was positive in four cases. It is important to note that gluten enteropathy can present as dermatitis herpetiformis, a cutaneous itchy rash [32]. Before the discovery of AQP4-IgG, ON and/or myelitis were considered to be within the spectrum of the neurological features of CD, and many were tried with dietary intervention and steroids. However, it has been increasingly recognised

that the two conditions can co-exist. Medications like Azathioprine, used in the treatment of NMO, can cause diarrhoea and symptoms suggestive of enteropathy further complicating the diagnosis. Aquaporin-4 is expressed in the gastric and colonic mucosa. Certain peptide sequences in AQP4 have homology to those in gut bacteria, e.g. Clostridium perfringens. It is known that T-cells from NMO patients proliferate to this homologous bacterial sequence, i.e. molecular mimicry [33]. Whether CD with its intestinal mucosal damage facilitates such an interaction is uncertain. Implications for practice Patients with CD presenting with symptoms of myelitis or ON should be screened for AQP4-IgG. The possibility of CD must be considered in patients with NMO who have gastrointestinal symptoms, particularly diarrhoea or weight loss.

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Table 3. Myasthenia gravis (MG) and NMOSD – summary of cases from literature.

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Authors

No. of Year patients

Age at NMO/NMOSD (years) AQP4-IgG ON LETM AChR-Ab Thymectomy

Age at MG (years)

O/G

42 NK

G NK

Y Y-11

N Y-9

G

Y - all

Y - 11/13

O-3, G-1 G G G G

Y Y Y Y Y

Y - all Y Y Y Y-1

G G G G G O G

Y Y Y Y N Y Y

Y Y N Y Y Y Y (6)

Etemadifar et al. [7] 2011 Vaknin-Dembinski 2011 et al. [8]

1 15

Leite et al. [9]

2012

16

Kister et al. [10] Uzawa et al. [11] Antoine et al. [12] Gotkine et al. [13] Furukawa et al. [14]

2006 2009 2004 2006 2006

4 2 1 1 2

27* 18, 20 49 10 23, 63

Nakamura et al. [15] Bichuetti et al. [16] Kay et al. [17] Isbister et al. [18] Ikeda et al. [19] Ogaki et al. [20] Jarius et al. [23]

2007 2007 2008 2003 2007 2012 2012

1 1 1 1 1 1 10

28 27 44 28 29 30 26*

26.5*

33 NK

Y Y-7

2 Y

3 Y

Y - all

1y

1y

38* 27, 41 49 26 48, 63

Y-2 Y NK NK N

4y 4y 1 0 1y

4y 3y 1 3 1y

38 31 49 36 53 43 43*

Y NK Y NK NK Y Y (10)

7 1 4 Y 2 2 1y

2 3 3 Y 2 3 2y

39.5*

Other autoimmune conditions/ antibodies No SLE, antiphospholipid syndrome, ITP, polymyositis, RA, pemphigus, psoriasis, UC, scleroderma, IDDM, alopecia areata, SS, TPO, ANA Autoimmune thyroiditis, SLE, VGKC limbic encephalitis and neuromyotonia, ANA, dsDNA, anticardiolipin GAD, ANA N N N Thyroiditis, SLE/ ANA, TPO, N ANA NK NK NK ANA IDDM, SS, SLE/ ANA, dsDNA, TPO, CD, GAD

Y ¼ yes, N ¼ no, NK ¼ not known, O ¼ ocular myasthenia, G ¼ generalised myasthenia, AChR antibody ¼ acetylcholine receptor antibody, ON ¼ number of optic neuritis episodes, LETM ¼ number of longitudinally extensive transverse myelitis episodes, SLE ¼ systemic lupus erythematosus, ITP ¼ immune thrombocytopenic purpura, RA ¼ rheumatoid arthritis, UC ¼ ulcerative colitis, IDDM ¼ insulin dependent diabetes mellitus, SS ¼ Sjogren’s syndrome, VGKC ¼ voltage-gated potassium channel, TPO ¼ thyroid peroxidase, dsDNA ¼ double-stranded DNA, ASMA ¼ anti smooth muscle antibody, CD ¼ coeliac disease, GAD ¼ glutamic acid decarboxylase and ANA ¼ antinuclear antibody. *Median age of patient in years. yMean number of relapses.

Table 4. Coeliac disease (CD) and NMOSD – summary of cases from literature.

AGA/TTG

Biopsy

AQP4-IgG

ON

LETM

Authors

Year

McNamara et al. [27] Jacob [28] Jacob [28] Bergamaschi et al. [29] Bergamaschi et al. [29] Matijaca et al. [30]

2010 2005 2005 2009 2009 2011

1 1 1 1 1 1

F F F F F F

NK 36 15 22 22 34

NK Y Y Y Y NK

NK Y Y Y Y NK

32 36 30 41 24 54

Y NK NK Y N Y

5 1 1 9 2 1

2 2 2 5 6 3

2011 In press

1 1

F F

8 30

NK NK

Y Y

8 53

Y Y

5 N

1 2

Meyts et al. [31] Iyer et al. [32]

M/F

Age at CD (years)

Age at NMO (years)

No. of patients

Autoimmune conditions/ antibodies NK N N NK NK ANA, dsDNA, SS-B Hypothyroidism N

M ¼ male, F ¼ female, AGA ¼ antigliadin antibody, TTG ¼ tissue transglutaminase antibody, Biopsy ¼ small bowel biopsy confirming CD, ON ¼ number of episodes of optic neuritis, LETM ¼ number of episodes of longitudinally extensive transverse myelitis, Y ¼ yes, N ¼ no, NK ¼ not known, ANA ¼ anti-nuclear antibody, dsDNA ¼ double stranded DNA and SS-B ¼ anti La antibody.

Sjogren’s syndrome Sjogren’s syndrome (SS) is an autoimmune condition characterised by mononuclear infiltration and destruction of the salivary and lacrimal glands [34]. Xerophthalmia and xerostomia are the usual presenting features; serological

markers like anti-SS-A/Ro and/or anti-SS-B/La antibodies, Schirmer’s test and salivary gland biopsy exhibiting focal lymphocytic sialadenitis support the diagnosis. Neurological involvement is thought to occur in 20% of SS. In those with neurological involvement, myelitis is reported in 34% [35,36].

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Table 5. Sjogren’s syndrome (SS) and NMOSD – summary of cases from literature.

Authors

Year

No. of patients

Koga et al. [37] Kahlenberg [38] Min et al. [34] Sofat et al. [39] Gokcay et al. [40] Barroso [41] Arabshahi et al. [42] Mochizuki et al. [43] Kim et al. [36]

2011 2011 2009 2008 2007 2006 2005 2000 2009

1 1 9 1 1 1 1 1 8

Age at SS (years)

Sicca symptoms

25 54 NK 78 20 48 11 Child 46*

N N N Y N N Y Y Y

SS-A

Salivary biopsy

Age at NMO

AQP4-IgG

ON

LETM

Autoimmune conditions/ antibodies

Y Y NK Y Y Y Y Y Y

N Y Y Y Y Y Y Y Y

31 54 NK 78 10 34 11 51 NK

N Y Y Y NK N NK NK 4

1 N Y Y 5 2 2 2 5y

1 2 Y Y 3 2 1 1 8

ANA ANA NK N N N ANA ANA ANA

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SS-A ¼ anti Ro antibody, ON ¼ number of optic neuritis episodes, LETM ¼ number of longitudinally extensive transverse myelitis episodes, N ¼ no, Y ¼ yes, NK ¼ not known and ANA ¼ antinuclear antibody. *Median age of patient in years. yTotal number of patients who had optic neuritis.

A list of studies on the association between NMOSD and SS is summarised in Table 5 [34,36–43]. AQP4-IgG is present in approximately 50% of patients with SS and myelitis [36,44]. NMO symptoms may precede SS by even a decade. The annualized relapse rate in NMO seems lower when associated with SS [3,4,36]. The high association of NMO in SS may be coincidental or may have as yet unproven explanations. Aquaporin 5 (AQP5) is expressed at high levels in the salivary gland and bears protein sequence identity with AQP4. It could be hypothesized that NMO patients may have a subset of auto reactive immune cells that recognise homologous portions of AQP5 and cause inflammation of salivary glands [5,38]. Implications for practice Patients with SS who develop LETM or ON often have NMO, and testing for AQP4-IgG is recommended. Patients with NMO may have coexisting SS. Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with protean manifestations. Neurological features are present in up to 60% of patients with SLE, mainly manifesting as psychosis, seizures, headaches and cerebrovascular disease [6,45]. The incidence of transverse myelitis occurring in SLE is reported to be 1–2% in some large case series and occurs as a monophasic illness in approximately 79% [7–21,45,46] with poor recovery. There are several case reports of recurrent episodes of LETM, some recurring as frequently as 30 times and ON in patients diagnosed with SLE. A summary of these cases is presented in Table 6 [9,22,47–58]. In most cases, SLE symptoms preceded the onset of NMOSD symptoms by a few years; however, it is not unusual for neurological symptoms to be the first presenting feature of SLE. Patients with SLE who have NMOSD usually present with LETM and less frequently ON. A cohort of 15 patients with SLE associated with transverse myelitis was compared with 39 patients with idiopathic transverse myelitis [23,46], and most patients in the SLE cohort had evidence of LETM on their MRI, in comparison with the idiopathic group. In the largest reported cohort of patients with SLE and myelitis, AQP4-IgG was seen in 57.1% patients [7,50].

Implications for practice Patients with SLE, who develop LETM or ON (often relapsing ON), often have NMO, and testing for AQP4-IgG is recommended. Patients with NMO may have coexisting SLE. Narcolepsy Narcolepsy can be an immune-mediated condition associated with loss of hypocretin secreting hypothalamic cells, characterised by excessive daytime sleepiness and cataplexy [24,59,60]. Since AQP4 is highly expressed in the hypothalamic periventricular regions, an immune attack on AQP4 may be involved. Hypersomnolence can be the initial presentation or signify a relapse in NMO and there are several cases in the literature of hypersomnolence associated with NMOSD [25,61]. Many of these cases have associated hypothalamic lesions identified on neuroimaging. Other endocrine dysfunction probably related to hypothalamic disturbance, i.e. syndrome of inappropriate diuretic hormone secretion, anhidrosis, diabetes insipidus, hyperphagia, galactorrhea, amenorrhoea, behavioural change and disorders of thermoregulation, have been reported [26,62–66]. Baba et al. [67] report a case with narcolepsy, who subsequently developed recurrent episodes of myelitis and ON and was AQP4-IgG positive. Kanbayashi et al. [33,68] discussed a cohort of four patients with NMOSD who developed narcolepsy, three of whom were positive for AQP4-IgG. Implications for practice Patients presenting with symptoms suggestive of narcolepsy, hypersomnolence or hypothalamic dysfunction and ON or myelitis need to be screened for AQP4-IgG. Similarly, patients with NMOSD presenting with hypersomnolence may be developing a relapse. Other autoimmune disorders Several case reports and large case series mention the coexistence of the following other autoimmune disorders with NMOSD – autoimmune thyroiditis, ulcerative colitis, pernicious anaemia, primary sclerosing cholangitis, idiopathic thrombocytopenic purpura, rheumatoid arthritis, insulin

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Table 6. Systemic lupus erythematosus (SLE) and NMOSD – summary of cases from literature.

Authors

Year

No. of patients

Birnbaum & Kerr [47] Birnbaum & Kerr [48] Birnbaum et al. [50]

2007 2008 2009

1 1 22

Ferreira [49]

2005

Gibbs et al. [51] Mehta et al. [52] Nasir et al. [53] Pellkofer et al. [54] Sergio et al. [55] Jacobi et al. [56] Polgar et al. [57] Karim & Majithia [58]

Age at SLE (years)

Age at NMO (years)

AQP4-IgG

ON

LETM

31 38 31*

Y Y Y - 5/15

2 2 6/22

6 3 9/22

NK

44

N

1

1

Y Y

N Y

48 47

N Y

2 0

1 2

Y NK Y Y Y Y

Y NK N Y Y N

Y Y Y NK Y Y

0 9 2

ANA

ds-DNA

21 25 21*

Y Y Y - all

Y Y Y - 16

1

42

Y

2002 2008

1 1

45 NK

2009 2010 2010 2006 2010 2009

1 1 1 1 2 1

37 Childhood 13 44 34, 42 22

40 44 13 37 48, 36 22

Y 1y Y

19 22 2 Y 3.5y Y

Autoimmune conditions/ antibodies N N SS-A, anticardiolipin antibody, antiphospholipid antibody Antiphospholipid antibody syndrome N Antiphospholipid antibody syndrome NK NK NK SS-A N NK

Y ¼ yes, N ¼ no, NK ¼ not known, ANA ¼ antinuclear antibody, ds-DNA ¼ double stranded DNA, SS-A ¼ anti Ro antibody, ON ¼ number of optic neuritis episodes and LETM ¼ number of longitudinally extensive transverse myelitis episodes. *Median age in years. yMean number of episodes of ON/LETM.

dependent diabetes mellitus, scleroderma, psoriasis, polymyositis, limbic encephalitis (voltage-gated potassium channel – VGKC), chronic inflammatory demyelinating neuropathy, alopecia areata and antiphospholipid antibody syndrome [34,44,49,50,52,69–72]. The correlation of NMOSD with autoimmune skin diseases is uncertain; it could be linked to the expression of some members of the aquaglyceroporins, i.e. AQP3 in the skin. Salazar et al. [35,36,73] reported a case of a 16-year-old girl who presented with a new-onset pruritic rash, which was diagnosed to be pemphigus foliaceus. She has positive antibodies to anti-desmoglein 1, which is implicated in the pathogenesis of this autoimmune dyskeratotic condition. A few weeks into the diagnosis, she presented with ON and relapsing LETM and was found to be AQP4-IgG positive, thereby diagnosing the co-existing NMO. Neuropathic pruritus can also be a manifestation of NMOSD and can occur during relapses [74]. Dermatitis herpetiformis, the cutaneous manifestation of CD, can co-exist in NMO [32].

(mean 4 months) [36,44,77,78]. Aquaporin-4 is expressed in the thymus gland, and there is a correlation between thymic carcinoma/thymoma with MG and NMO [22]. AQP4 is also expressed in the membranes of skeletal muscle, glandular epithelia (breast and salivary glands), lungs, kidneys, stomach and colon [77]. Tumour cells from these sites might express proteins and cancer-directed immune responses initiated by these proteins might target CNS antigens including aquaporin4. In patients with NMOSD presenting with atypical features like uveitis, limbic encephalitis, ataxia or peripheral neuropathy, clinicians should also screen for paraneoplastic antibodies. In another series, six cases with different malignancies and positive CV2/CRMP5 antibodies presented with NMOSD [21]. These antibodies target collapsin response mediator protein 5, and ON and myelitis can be present in 7% and 16% of patients with these antibodies. Testing for paraneoplastic conditions and these antibodies in seronegative cases of NMO is recommended. Co-existent autoantibodies without diseases

HyperCKemia and NMO HyperCKemia has rarely been associated with an attack of NMO [32,75]. AQP4 is expressed in the fast twitch skeletal muscle fibres, and it is postulated that leak of CK occurs due to AQP4-IgG-mediated damage of the plasmalemma [76]. However, myopathy with weakness has not been reported so far in NMO. In fact, the majority of patients with NMO do not have raised serum CK, and this may be because of the protective effect of complement regulatory proteins (CD46 or CD59) normally present on the plasmalemma. Perhaps, CK release occurs only if this mechanism is overwhelmed or is defective [76].

Approximately 40% of NMOSD have coexistent antibodies without an obvious autoimmune illness. Pittock et al. [44] have reported the association of non-organ-specific autoimmunity in a large cohort of 153 patients with NMOSD. The frequency of coexisting autoantibodies (percentages) in this cohort was as follows – antinuclear antibody (43%), extractable nuclear antigen (15%), SS-A (10%), SS-B (3%) and rheumatoid factor (5%). Apart from those mentioned in detail in the review, antibodies against MOG [4,79] have been reported to be associated with seronegative NMOSD. Antibodies to glutamic acid decarboxylase, VGKC and voltage-gated calcium channel have been detected in a few cases [25,80].

Paraneoplastic disorders

Conclusion

In the eight cases where cancers were associated with NMO, the diagnosis of NMO was made after that of cancer in six (median 14 months) and preceded the diagnosis in two patients

This review reiterates the strong association of NMO with other systemic autoimmune disorders and identifies the 22 conditions reported so far to be associated with it. It seems

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A. Iyer et al.

20–30% of patients with NMO [57,69] have co-existing autoimmune conditions. Approximately 40% have co existent autoantibodies without disease. This supports the notion that NMO is a condition with a genetic predisposition to humoral autoimmunity. While we would not recommend testing all of these autoantibodies routinely in patients with NMO and vice versa, it is important for clinicians to be aware of these comorbidities, pursue relevant history, perform necessary clinical examinations and have a low threshold for testing in the right clinical context facilitating early diagnosis and treatment. This is likely to improve the quality of life of many patients with NMO, often already burdened with irreversible severe neurological disability.

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Declaration of interest A. I. and R. A. have no conflicts of interest, L. E. has received travel grants to attend scientific meetings from TEVA and Novartis and A. J. has received honoraria for speaking on NMO and for clinical trial advisory boards from Biogen, Chugai and Terumo BCT.

References 1. Wingerchuk, D. M., V. A. Lennon, S. J. Pittock, et al. 2006. Revised diagnostic criteria for neuromyelitis optica. Neurology. 66: 1485–1489. 2. Lennon, V. A. V., D. M. D. Wingerchuk, T. J. T. Kryzer, et al. 2004. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 364: 2106–2112. 3. Haase, C. G., and S. Schmidt. 2001. Detection of brain-specific autoantibodies to myelin oligodendrocyte glycoprotein, S100beta and myelin basic protein in patients with Devic’s neuromyelitis optica. Neurosci. Lett. 307: 131–133. 4. Kitley, J., M. Woodhall, P. Waters, et al. 2012. Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology. 79: 1273–1277. 5. Weinshenker, B. G. B., D. M. D. Wingerchuk, S. S. Vukusic, et al. 2006. Neuromyelitis optica IgG predicts relapse after longitudinally extensive transverse myelitis. Ann. Neurol. 59: 566–569. 6. Hoedemaekers, A. C. A., P. J. P. van Breda Vriesman, and M. H. M. De Baets. 1997. Myasthenia gravis as a prototype autoimmune receptor disease. Immunol. Res. 16: 341–354. 7. Etemadifar, M., S.-H. Abtahi, A. Dehghani, et al. 2011. Myasthenia gravis during the course of neuromyelitis optica. Case Rep. Neurol. 3: 268–273. 8. Vaknin-Dembinsky, A., O. Abramsky, P. Petrou, et al. 2011. Myasthenia gravis-associated neuromyelitis optica-like disease: an immunological link between the central nervous system and muscle? Arch. Neurol. 68: 1557–1561. 9. Leite, M. I., E. Coutinho, M. Lana-Peixoto, et al. 2012. Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients. Neurology. 78: 1601–1607. 10. Kister, I., S. Gulati, C. Boz, et al. 2006. Neuromyelitis optica in patients with myasthenia gravis who underwent thymectomy. Arch. Neurol. 63: 851–856. 11. Uzawa, A., M. Mori, Y. Iwai, et al. 2009. Association of antiaquaporin-4 antibody-positive neuromyelitis optica with myasthenia gravis. J. Neurol. Sci. 287: 105–107. 12. Antoine, J. C., J. P. Camdessanche, L. Absi, et al. 2004. Devic disease and thymoma with anti-central nervous system and antithymus antibodies. Neurology. 62: 978–980. 13. Gotkine, M., Y. Fellig, and O. Abramsky. 2006. Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Neurology. 67: 881–883. 14. Furukawa, Y., H. Yoshikawa, A. Yachie, and M. Yamada. 2006. Neuromyelitis optica associated with myasthenia gravis: characteristic phenotype in Japanese population. Eur. J. Neurol. 13: 655–658.

Autoimmunity, 2014; 47(3): 154–161

15. Nakamura, M., I. Nakashima, S. Sato, et al. 2007. Clinical and laboratory features of neuromyelitis optica with oligoclonal IgG bands. Mult. Scler. 13: 332–335. 16. Bichuetti, D. B., T. M. de Barros, E. M. L. Oliveira, et al. 2008. Demyelinating disease in patients with myasthenia gravis. Arq. Neuropsiquiatr. 66: 5–7. 17. Kay, C. S. K., R. H. Scola, P. J. Lorenzoni, et al. 2008. NMO-IgG positive neuromyelitis optica in a patient with myasthenia gravis but no thymectomy. J. Neurol. Sci. 275: 148–150. 18. Isbister, C. M. C., P. J. P. Mackenzie, D. D. Anderson, et al. 2003. Co-occurrence of multiple sclerosis and myasthenia gravis in British Columbia. Mult. Scler. 9: 550–553. 19. Ikeda, K., Y. Araki, and Y. Iwasaki. 2007. Occurrence of CNS demyelinating disease in patients with myasthenia gravis. Neurology. 68: 1326; author reply 1327. 20. Ogaki, K., T. Hirayama, K. Chijiiwa, et al. 2012. Anti-aquaporin-4 antibody-positive definite neuromyelitis optica in a patient with thymectomy for myasthenia gravis. Neurologist. 18: 76–79. 21. Jarius, S., K. P. Wandinger, K. Borowski, et al. 2012. Antibodies to CV2/CRMP5 in neuromyelitis optica-like disease: case report and review of the literature. Clin. Neurol. Neurosurg. 114: 331–335. 22. Chan, K. H., J. S. C. Kwan, P. W. L. Ho, et al. 2010. Aquaporin-4 water channel expression by thymoma of patients with and without myasthenia gravis. J. Neuroimmunol. 227: 178–184. 23. Jarius, S., F. Paul, D. Franciotta, et al. 2012. Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature. Mult. Scler. J. 18: 1135–1143. 24. Zifman, E., I. Litmanovitz, G. Segal, et al. 2010. Marked hypotonia in an infant of a mother with devic disease. J. Child Neurol. 25: 746–747. 25. McKeon, A., V. A. Lennon, A. Jacob, et al. 2009. Coexistence of myasthenia gravis and serological markers of neurological autoimmunity in neuromyelitis optica. Muscle Nerve. 39: 87–90. 26. Hadjivassiliou, M., D. S. Sanders, R. A. Gru¨newald, et al. 2010. Gluten sensitivity: from gut to brain. Lancet Neurol. 9: 318–330. 27. McNamara, P. H., L. Costelloe, Y. Langan, and J. Redmond. 2010. Aquaporin-4 seropositivity in a patient with coeliac disease but normal neurological examination and imaging. J. Neurol. 258: 702–703. 28. Jacob, S. 2005. Gluten sensitivity and neuromyelitis optica: two case reports. J. Neurol. Neurosurg. Psychiatry. 76: 1028–1030. 29. Bergamaschi, R., S. Jarius, M. Robotti, et al. 2009. Two cases of benign neuromyelitis optica in patients with celiac disease. J. Neurol. 256: 2097–2099. 30. Matijaca, M., S. Pavelin, D. M. Kaliterna, et al. 2011. Pathogenic role of aquaporin antibodies in the development of neuromyelitis optica in a woman with celiac disease. Isr. Med. Assoc. J. 13: 182–184. 31. Meyts, I., K. Jansen, M. Renard, et al. 2011. Neuromyelitis opticaIgG(+) optic neuritis associated with celiac disease and dysgammaglobulinemia: a role for tacrolimus? Eur. J. Paed. Neurol. 15: 265–267. 32. Iyer, A., D. Rathnasabapathi, L. Elsone, et al. 2013. Transverse myelitis associated with an itcy rash and hyperCKemia: neuromyelitis optica associated with dermatitis herpetiformis. JAMA Neurol. Accepted for publication. 33. Varrin-Doyer, M., C. M. Spencer, U. Schulze-Topphoff, et al. 2012. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann. Neurol. 72: 53–64. 34. Min, J., H. Kim, B. Kim, et al. 2009. Brain abnormalities in Sjogren syndrome with recurrent CNS manifestations: association with neuromyelitis optica. Mult. Scler. 15: 1069–1076. 35. Delalande, S. S., J. J. de Seze, A.-L. A. Fauchais, et al. 2004. Neurologic manifestations in primary Sjo¨gren syndrome: a study of 82 patients. Medicine (Abingdon). 83: 280–291. 36. Kim, S., P. Waters, A. Vincent, et al. 2009. Sjogren’s syndrome myelopathy: spinal cord involvement in Sjogren’s syndrome might be a manifestation of neuromyelitis optica. Mult. Scler. 15: 1062–1068. 37. Koga, S., K. Ikeda, D. Nakagomi, et al. 2011. A patient with neuromyelitis optica with positive anti-Ro (SS-A) antibody

DOI: 10.3109/08916934.2014.883501

38. 39. 40. 41. 42. 43. 44.

Autoimmunity Downloaded from informahealthcare.com by University of Laval on 06/01/14 For personal use only.

45.

46.

47.

48. 49. 50. 51. 52.

53. 54.

55.

56. 57. 58. 59.

presenting with intractable hiccup and nausea. Mod. Rheumatol. 21: 561–562. Kahlenberg, J. M. 2011. Neuromyelitis optica spectrum disorder as an initial presentation of primary Sjo¨gren’s syndrome. YSARH. 40: 343–348. Sofat, N. N., and P. J. P. Venables. 2008. Is Sjogren myelopathy Devic disease? Ann. Rheum. Dis. 67: 730–731. Go¨kc¸ay, F., N. C¸elebisoy, A. Go¨kc¸ay, et al. 2007. Primary Sjo¨gren’s syndrome presenting as neuromyelitis optica. Pediatr. Neurol. 36: 58–60. Barroso, B. 2007. Primary Sjo¨gren’s syndrome mimicking neuromyelitis optica. Eur. J. Intern. Med. 18: 507–508. Arabshahi, B., A. N. Pollock, D. D. Sherry, et al. 2006. Devic disease in a child with primary Sjogren syndrome. J. Child Neurol. 21: 285–286. Mochizuki, A., A. Hayashi, S. Hisahara, and S. Shoji. 2000. Steroid-responsive Devic’s variant in Sjogren’s syndrome. Neurology. 54: 1391–1392. Pittock, S. J., V. A. Lennon, J. de Seze, et al. 2007. Neuromyelitis optica and non organ-specific autoimmunity. Arch. Neurol. 65: 78–83. Kovacs, B., T. L. Lafferty, L. H. Brent, and R. J. DeHoratius. 2000. Transverse myelopathy in systemic lupus erythematosus: an analysis of 14 cases and review of the literature. Ann. Rheum. Dis. 59: 120–124. Schulz, S. W., M. Shenin, A. Mehta, et al. 2011. Initial presentation of acute transverse myelitis in systemic lupus erythematosus: demographics, diagnosis, management and comparison to idiopathic cases. Rheumatol. Int. 32: 2623–2627. Birnbaum, J., and D. Kerr. 2007. Devic’s syndrome in a woman with systemic lupus erythematosus: diagnostic and therapeutic implications of testing for the neuromyelitis optica IgG autoantibody. Arthritis. Rheum. 57: 347–351. Birnbaum, J., and D. Kerr. 2008. Optic neuritis and recurrent myelitis in a woman with systemic lupus erythematosus. Nat. Clin. Pract. Rheumatol. 4: 381–386. Ferreira, S. 2005. Devic’s syndrome in systemic lupus erythematosus and probable antiphospholipid syndrome. Rheumatology. 44: 693–695. Birnbaum, J., M. Petri, R. Thompson, et al. 2009. Distinct subtypes of myelitis in systemic lupus erythematosus. Arthritis Rheum. 60: 3378–3387. Gibbs, A. N., J. Moroney, D. Foley-Nolan, and P. G. O’Connell. 2002. Neuromyelitis optica (Devic’s syndrome) in systemic lupus erythematosus: a case report. Rheumatology (Oxford). 41: 470–471. Mehta, L. R., M. K. Samuelsson, A. K. Kleiner, et al. 2008. Neuromyelitis optica spectrum disorder in a patient with systemic lupus erythematosus and anti-phospholipid antibody syndrome. Multiple Sclerosis. 14: 425–427. Nasir, S., D. A. Kerr, and J. Birnbaum. 2009. Nineteen episodes of recurrent myelitis in a woman with neuromyelitis optica and systemic lupus erythematosus. Arch. Neurol. 66: 1160–1163. Pellkofer, H. L., R. Hohlfeld, and T. Kuempfel. 2010. Thirty-one episodes of myelitis and optic neuritis in a woman with neuromyelitis optica and systemic lupus erythematosus. Arch. Neurol. 67: 779–780; author reply 780. Sergio, P., B. Mariana, O. Alberto, et al. 2010. Association of neuromyelitis optic (NMO) with autoimmune disorders: report of two cases and review of the literature. Clin. Rheumatol. 29: 1335–1338. Jacobi, C., K. Stingele, R. Kretz, et al. 2006. Neuromyelitis optica (Devic’s syndrome) as first manifestation of systemic lupus erythematosus. Lupus. 15: 107–109. Polga´r, A., C. Ro´zsa, V. Mu¨ller, et al. 2011. Devic’s syndrome and SLE. Autoimmun. Rev. 10: 171–174. Karim, S., and V. Majithia. 2009. Devic’s syndrome as initial presentation of systemic lupus erythematosus. Am. J. Med. Sci. 338: 245–247. Mahlios, J., A. K. De la Herra´n-Arita, and E. Mignot. 2013. The autoimmune basis of narcolepsy. Curr. Opin. Neurobiol. 23: 767–773.

Neuromyelitis optica and autoimmunity

161

60. Wijnans, L., C. Lecomte, C. de Vries, et al. 2013. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine. 31: 1246–1254. 61. Suzuki, K., T. Nakamura, K. Hashimoto, et al. 2012. Hypothermia, hypotension, hypersomnia, and obesity associated with hypothalamic lesions in a patient positive for the antiaquaporin 4 antibody: a case report and literature review. Arch. Neurol. 69: 1355–1359. 62. Vernant, J. C., P. Cabre, D. Smadja, et al. 1997. Recurrent optic neuromyelitis with endocrinopathies: a new syndrome. Neurology. 48: 58–64. 63. Petravic´, D., M. Habek, S. Supe, and V. V. Brinar. 2006. Recurrent optic neuromyelitis with endocrinopathies: a new syndrome or just a coincidence? Mult. Scler. 12: 670–673. 64. Sekiguchi, T., S. Ishibashi, T. Kubodera, et al. 2011. Anhidrosis associated with hypothalamic lesions related to anti-aquaporin 4 autoantibody. J. Neurol. 258: 2293–2295. 65. Viegas, S., A. Weir, M. Esiri, et al. 2009. Symptomatic, radiological and pathological involvement of the hypothalamus in neuromyelitis optica. J. Neurol. Neurosurg. Psychiatry. 80: 679–682. 66. Nakajima, H., Y. Fujiki, T. Ito, et al. 2011. Anti-aquaporin-4 antibody-positive neuromyelitis optica presenting with syndrome of inappropriate antidiuretic hormone secretion as an initial manifestation. Case Rep. Neurol. 3: 263–267. 67. Baba, T., I. Nakashima, T. Kanbayashi, et al. 2009. Narcolepsy as an initial manifestation of neuromyelitis optica with antiaquaporin4 antibody. J. Neurol. 256: 287–288. 68. Kanbayashi, T., T. Shimohata, I. Nakashima, et al. 2009. Symptomatic narcolepsy in patients with neuromyelitis optica and multiple sclerosis: new neurochemical and immunological implications. Arch. Neurol. 66: 1563–1566. 69. Wingerchuk, D. M., W. F. Hogancamp, P. C. O’Brien, and B. G. Weinshenker. 1999. The clinical course of neuromyelitis optica (Devic’s syndrome). Neurology. 53: 1107–1114. 70. Wingerchuk, D. M., and B. G. Weinshenker. 2012. The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease. Mult. Scler. J. 18: 5–10. 71. Asgari, N., T. Owens, J. Frøkiaer, et al. 2010. Neuromyelitis optica (NMO) – an autoimmune disease of the central nervous system (CNS). Acta Neurologica Scandinavica. 123: 369–384. 72. Komolafe, M. A., E. O. Komolafe, T. A., Sunmonu, et al. 2008. New onset neuromyelitis optica in a young Nigerian woman with possible antiphospholipid syndrome: a case report. J. Med. Case. Rep. 2: 348. 73. Salazar, R., M. Cerghet, E. Farhat, and H. W. Lim. 2012. Neuromyelitis optica in a patient with pemphigus foliaceus. J. Neurol. Sci. 319: 152–155. 74. Elsone, L., T. Townsend, K. Mutch, et al. 2013. Neuropathic pruritus (itch) in neuromyelitis optica. Mult. Scler. J. 19: 475–479. 75. Suzuki, N., T. Takahashi, M. Aoki, et al. 2010. Neuromyelitis optica preceded by hyperCKemia episode. Neurology. 74: 1543–1545. 76. Saadoun, S., and M. C. Papadopoulos. 2013. Expression of AQP4 and complement regulators in human brain and peripheral organs: implications for NMO. Poster 733 ECTRIMS 2013, Copenhagen. 77. Pittock, S. J., and V. A. Lennon. 2008. Aquaporin-4 autoantibodies in a paraneoplastic context. Arch. Neurol. 65: 629–632. 78. Santis, G., L. Caniatti, A. Vito, et al. 2009. A possible paraneoplastic neuromyelitis optica associated with lung cancer. Neurol. Sci. 30: 397–400. 79. Mader, S., V. Gredler, K. Schanda, et al. 2011. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J. Neuroinflammation. 8: 184. 80. Honda, K., and T. Yuasa. 2008. A case of anti-aquaporin-4 and antiglutamate receptor antibodies positive myelitis presented with modest clinical signs. Magn. Reson. Med. Sci. 7: 55–58.