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DEVELOPMENTAL MEDICINE & CHILD ORIGINAL ARTICLE

Clinical association of intrathecal and mirrored oligoclonal bands in paediatric neurology

ADRIANE J SINCLAIR1 | LOUISE WIENHOLT2 | ESTHER TANTSIS3 | FABIENNE BRILOT3 | RUSSELL C DALE3

1 Department of Child Neurology, Sydney Children's Hospital, Sydney; 2 Immunology laboratory, Royal Prince Alfred Hospital, Sydney; 3 Neuroimmunology Group, Institute for Neuroscience and Muscle Research, the Children's Hospital at Westmead, University of Sydney, Australia.

Correspondence to Professor Russell C Dale at Clinical School, the Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail: [email protected]

This article is commented on by Lim on pages 10–12 of this issue.

PUBLICATION DATA AIM Biomarkers such as autoantibodies, neopterin, and oligoclonal bands (OCBs) are increasingly Accepted for publication 21st July 2012. used for the diagnosis of treatable inflammatory central (CNS) disorders. We Published online 24th October 2012. investigated the correlation between the results of OCB testing and clinical diagnoses in a large contemporary cohort of children with a broad range of neurological conditions. ABBREVIATIONS METHOD Cerebrospinal fluid (CSF) and serum from 200 children (94 females, 106 males; age ADEM Acute disseminated encephalo- range 2mo–15y 10mo, mean age 6y 9mo, SD ±4.9) who underwent CSF investigation for their neu- myelitis rological condition were tested for OCBs using isoelectric focusing. CSF RESULTS The patients were divided into those with inflammatory (n=58) and non-inflammatory HSV Herpes simplex virus (n=142) CNS disorders. Intrathecal OCBs (OCBs restricted to the CSF) were found in 11 out of 58 NMDAR N-methyl-D-aspartate receptor (19%) of those with inflammatory CNS disorders compared with none of the 142 patients with OCB Oligoclonal band VGKC Voltage-gated potassium channel non-inflammatory CNS disorders (p<0.001). Diseases associated with intrathecal OCB were , Rasmussen , N-methyl-D-aspartate receptor (NMDAR) encephalitis, voltage-gated potassium channel (VGKC) , herpes (HSV) encephalitis, ‘other’ encephalitides, acute cerebellar , and aseptic . Mirrored OCBs (identical OCBs in the serum and CSF) were less specific but were still found in 14 out of 58 (24%) children with inflammatory CNS disorders compared with only 6 out of 142 (4%) children with non-inflamma- tory CNS disorders (p<0.001). Diseases associated with mirrored OCBs included acute dissemi- nated (ADEM), VGKC encephalopathy, West syndrome, NMDAR encephalitis, ‘other’ encephalitides, polio-like illness, Rasmussen encephalitis, cerebral vasculitis, metachro- matic leukodystrophy, and bacterial meningitis. Intrathecal OCBs and mirrored OCBs had a positive predictive value for inflammatory CNS disease of 1 (95% confidence interval [CI] 0.68–1) and 0.7 (95% CI 0.46–0.87) respectively. CONCLUSION Intrathecal OCBs were restricted to patients with inflammatory CNS disorders. They are a useful, but non-specific, biomarker of CNS inflammation of multiple causes. Mirrored OCBs are less specific, but still support a possible inflammatory CNS disorder. The presence of either intrathecal or mirrored OCBs should raise suspicion of an inflammatory CNS disorder.

There is increasing interest in biomarkers that diagnose useful in the identification of unusual variants of known potentially treatable inflammatory autoimmune encephalopathy.6 (CNS) disorders.1 Some serum and cerebrospinal fluid (CSF) OCBs are clones of immunoglobulin (typically IgG) that autoantibodies are specific biomarkers associated with auto- can be detected in the CSF and ⁄ or serum. The qualitative immune syndromes such as N-methyl-D-aspartate receptor method of isoelectric focusing on agarose gels followed by (NMDAR) encephalitis and voltage-gated potassium channel immunoblotting is the accepted standard method for OCB (VGKC) encephalopathy. Other biomarkers, including CSF detection. The IgG index (the ratio of CSF ⁄ serum IgG to neopterin and oligoclonal bands (OCBs), are less specific, CSF ⁄ serum albumin), a quantitative method of analysis, is a but they are still useful markers of immune activation or less sensitive test, and when elevated is suggestive of a CNS inflammation in the CNS.2 Before the discovery of the B-cell response. There are limited reports of use of the IgG NMDAR antibody biomarker, OCBs were used to support index in paediatric studies, but in adult studies the IgG index the hypothesis that and immune- has been found to be only rarely elevated in patients with mediated encephalopathy syndrome were autoim- multiple sclerosis who have negative OCBs.7–11 Alper et al.,7 mune diseases; these syndromes have subsequently been in a paediatric cohort, found that the IgG index was less fre- shown to be NMDAR encephalitis.3–5 OCBs have also been quently elevated in those with acute disseminated encephalo-

ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press DOI: 10.1111/j.1469-8749.2012.04443.x 71 7 myelitis (ADEM) than in those with multiple sclerosis. What this paper adds Interpretation of OCBs is dependent on the comparison of • Intrathecal OCBs have a strong positive predictive value of inflammatory CNS CSF and serum samples, with a number of patterns described disease in children. (Fig.1).8 • Although less specific, mirrored OCBs are also found more commonly in chil- WhenOCBsarepresentintheCSFandabsentfromthe dren with inflammatory CNS disease. serum, this is termed an ‘intrathecal pattern’ and is indicative associations and sensitivity ⁄ specificity of intrathecal and of local antibody production and hence a humoral immune mirrored OCB in a contemporary cohort of children with response within the CNS. When identical clones of IgG are neurological diseases. present in the CSF and serum, this is termed a ‘mirrored pat- tern’ and suggests that IgG has entered the CNS from the sys- METHOD temic circulation, such as occurs in blood–brain barrier We identified 205 paediatric neurology patients who had damage. OCB testing between January 2006 and February 2010. Dur- A combination of mirrored and intrathecal patterns can ing that time, OCB testing was routinely requested for all pae- occur, in which identical clones of IgG are present in the CSF diatric neurology patients at the Children’s Hospital at and serum; however, the CSF also contains additional OCBs. Westmead undergoing CSF analysis. This study was part of This is consistent with both CNS contamination and local ethically approved studies of inflammatory and autoimmune (intrathecal) IgG synthesis. Intrathecal OCBs are accepted to disorders of the CNS at the hospital. We excluded five be of greater clinical significance than mirrored OCBs in the patients in whom paired CSF and serum samples or clinical diagnosis of inflammatory CNS disorders.10 information was unavailable. Patients were aged 2 months Data pertaining to OCBs in paediatric patients are largely to 15 years 10 months, with a mean age of 6 years 9 months restricted to specific diseases, for example multiple sclerosis,12 SD ±4.9. There were 94 females and 106 males. All CSF and ADEM,13 and opsoclonus– syndrome.14 In 1986, sera specimens were analysed by isoelectric focusing at a single Kostulas et al.9 reported OCB findings in a paediatric cohort laboratory. In the case of those patients with acquired disor- with varying neurological diagnoses. They found OCBs most ders, analysis was performed on samples taken during the commonly in patients with inflammatory disorders; however, acute period of illness, and in the first episode if the disorder they also reported finding OCBs in children with presumed was relapsing. The study also included patients with chronic non-inflammatory disorders such as and . In illnesses who were undergoing CSF analysis in an ‘elective’ recent years, the ability to diagnose disorders of inflammatory manner. Patient case notes were reviewed and patients were aetiology has greatly improved. We studied the diagnostic categorized by (inflammatory vs non-inflam-

1. CSF No OCB

2. Serum

3. CSF Intrathecal 4. Serum

5. CSF Mirrored

6. Serum

7. CSF Mirrored and intrathecal

8. Serum

Figure 1: Isoelectric focusing on agarose gels followed by immunoblotting. Lanes 1 and 2: no oligoclonal bands (OCBs) detected in cerebrospinal fluid (CSF) or serum. Lanes 3 and 4: OCB detected in CSF but not in serum indicative of intrathecal immunoglobulin G (IgG) production. Lanes 5 and 6: identical OCB detected in both CSF and serum suggestive of an abnormal CSF-blood barrier (mirrored pattern). Lanes 7 and 8: combination of mirrored and intrathecal IgG production, a pattern not observed in this study but observed in subacute sclerosing panencephalitis.

72 Developmental Medicine & Child Neurology 2013, 55: 71–75 matory CNS disease), disease group, and diagnosis (Table I). RESULTS Case note review and patient categorization were performed Intrathecal OCBs were detected in patients with inflammatory by a neurology registrar (AJS), with verification provided by a CNS disorders (11 ⁄ 58; 19%), but not in those with non- paediatric neurologist (RCD). Assigned diagnoses were based inflammatory CNS disorders (0 ⁄ 142; 0%; p<0.001; Table II). on those documented in the case notes by the treating paediat- Diagnoses associated with intrathecal OCBs were multiple ric neurologist. The inflammatory CNS group (n=58; 29%) sclerosis (n=3), Rasmussen encephalitides (n=2), NMDAR included patients with diagnoses with an established infec- encephalitis (n=1), VGKC encephalopathy (n=1), acute cere- tious, autoimmune, immune-mediated, or inflammatory cause. bellar ataxia (n=1), aseptic meningitis (n=1), herpes simplex The term ‘inflammatory CNS’ will be used to describe infec- virus (HSV) encephalitis (n=1), and ‘other’ encephalitis (n=1; tious, autoimmune, inflammatory, or immune-mediated CNS Table II). Mirrored OCBs were found more frequently in disorders. The non-inflammatory CNS group (n=142; 71%) those with inflammatory CNS disorders (14 ⁄ 58, 24%) than in included patients with diagnoses for which there was no estab- those with non-inflammatory CNS disorders (6 ⁄ 142; 4%; lished inflammatory pathophysiology and patients in whom p<0.001; Table II). Mirrored OCBs were detected in patients we were unable to assign a diagnosis. with ADEM (n=4), VGKC encephalopathy (n=1), NMDAR We subdivided the inflammatory CNS group into demye- encephalitis (n=2), basal ganglia encephalitis (n=1), ‘other’ linating diseases (n=26), infection-mediated diseases (n=11), encephalitides (n=1), polio-like illness (n=2), Rasmussen autoantibody-associated diseases (n=7), and ‘other’ immune- encephalitis (n=1), varicella zoster-associated cerebral vasculitis mediated diseases (n=14). Diagnoses within these subgroups (n=1), bacterial meningitis (n=1), West syndrome (n=2), and are presented in Table I. Within the infection-mediated metachromatic leukodystrophy (n=1), and in several patients group, six patients were categorized as having ‘other’ with unknown diagnoses (n=3). No patient showed a combina- encephalitides. These patients had evidence of encephalitis tion of mirrored and intrathecal patterns. (acute or chronic) fulfilling criteria for encephalitis but with- Intrathecal OCBs had a sensitivity of 0.19 (95% CI 0.10– out definite evidence of a specific infectious agent.15 The 0.32), a specificity of 1 (95% CI 0.97–1), a positive predictive non-inflammatory CNS group included patients with very value of 1 (95% CI 0.68–1), and a negative predictive value of diverse diagnoses (Table I) along with patients in whom the 0.75 (95% CI 0.68–0.81) for the presence of inflammatory diagnosis was unknown (n=15). The two-tailed Fisher’s exact CNS disease (Table II). Mirrored OCBs had a sensitivity of test was used to calculate p-values, and a p-value <0.05 was 0.24 (95% CI 0.14–0.37), a specificity of 0.96 (95% CI 0.91– considered significant; 95% confidence intervals (CI) are pre- 0.98), a positive predictive value of 0.7 (95% CI 0.46–0.87), sented for positive predictive value and negative predictive and a negative predictive value of 0.76 (95% CI 0.68–0.82; value. Table II).

Table I: Disease groups and diagnoses

Disease group (n) Diagnoses (n)

Non-inflammatory CNS (n=142) Epilepsy (n=58) Electroclinical syndromes: West syndrome (n=6), Dravet syndrome (n=1), febrile plus (n=1), epilepsy with myoclonic astatic ⁄ atonic seizures (n=2), juvenile absence epilepsy (n=1) Structural or metabolic: perinatal brain injury (n=1), traumatic brain injury (n=1), hypoglycaemia (n=1), malformation of cortical development (n=4), previous CNS infection (n=3) Genetic: PCDH19 (n=1), SCN1A (n=2) Other or unknown (n=34) Static encephalopathy (n=15) Cerebral palsy (n=3), developmental delay (n=4), chromosomal disorders (n=6), unknown (n=2) Progressive genetic or Metachromic leukodystrophy (n=1), Menkes disease (n=1), mitochondrial ⁄ probable mitochondrial metabolic (n=8) (n=2), hereditary spastic paraplegia (n=2), unknown (n=2) Other (n=61) Functional disorders (n=10), movement disorders (n=10), Guillain–Barre´ syndrome (n=5), disorders (n=4), (n=4), miscellaneousa (n=13), unknown (n=15) Inflammatory CNS (n=58) Demyelinating (n=26) MS (n=6), ADEM (n=11), clinically isolated syndrome (n=9): optic neuritis (n=3), transverse myelitis (n=3), other (n=3) Infection-mediated (n=11) Bacterial meningitis (n=1), aseptic meningitis (n=1), ‘other’ encephalitides (n=6), acute necrotizing encephalopathy (n=2), HSV encephalitis (n=1) Autoantibody-associated (n=7) NMDAR encephalitis (n=3), VGKC encephalopathy (n=3), basal ganglia encephalitis (n=1) Other immune-mediated (n=14) Rasmussen encephalitis (n=3), acute cerebellar ataxia (n=4), Polio-like illness (n=2), cerebral vasculitis (n=1), opsoclonus–myoclonus syndrome (n=2), Sydenham chorea (n=1), Aicardi–Goutie`res syndrome (n=1) aMiscellaneous: paroxysmal tonic upgaze of infancy, idiopathic intracranial hypertension, isolated cranial nerve palsy, acquired brain injury, pseudoparalysis secondary to vitamin C deficiency, posterior reversible encephalopathy syndrome, autism spectrum disorder with behavioural disturbance, with ventriculoperitoneal shunt dysfunction, myasthenia gravis, hereditary motor sensory neuropathy, urea cycle disorder, syncope, malformation of cortical development. CNS, central nervous system; MS, multiple sclerosis; ADEM, acute disseminated encephalomyelitis; HSV, herpes simplex virus; NMDAR, N-methyl-D aspartate receptor; VGKC, voltage-gated potassium channel.

Intrathecal and Mirrored OCBs in Paediatric Neurology Adriane Sinclair et al. 73 likely to be found in patients with inflammatory CNS disease Table II: Clinical correlation of intrathecal and mirrored oligoclonal bands than in those with non-inflammatory CNS disease (24% vs (OCBs) 4%; p<0.001) and therefore can also be of clinical utility.

OCB result Mirrored OCBs imply the presence of clonal IgG in both CSF and serum. Indeed, many of the autoantibody biomarkers Disease groups and diagnoses Intrathecal, n (%) Mirrored, n (%) that are useful in CNS inflammation, such as antibodies Total 11 ⁄ 200 (6) 20 ⁄ 200 (10) against neuromyelitis optica ⁄ aquaporin-4, VGKC, leucine- Non-inflammatory CNS 0 ⁄ 142 (0) 6 ⁄ 142 (4) rich glioma-inactivated 1, and glyco- Epilepsy 0 ⁄ 58 (0) 2 ⁄ 58 (3) protein are measured in the serum, rather than in the CSF. In Static encephalopathy 0 ⁄ 15 (0) 0 ⁄ 15 (0) Progressive genetic 0 ⁄ 8(0) 1⁄ 8(13) the case of many autoantibody-associated CNS disorders, the or metabolic production of autoantibody might be first triggered in the Other 0 ⁄ 61 (0) 3 ⁄ 61 (5) periphery, rather than in the CNS, and the importance of Inflammatory CNS 11 ⁄ 58 (19) 14 ⁄ 58 (24) Demyelinating 3 ⁄ 26 (12) 4 ⁄ 26 (15) serum versus CSF antibody production is a central emerging ADEM 0 ⁄ 11 (0) 4 ⁄ 11 (36) theme in neuroimmunology.16,17 For these reasons, we believe Clinically isolated syndrome 0 ⁄ 9(0) 0⁄ 9(0) that mirrored OCBs should not be ignored but may be an Multiple sclerosis 3 ⁄ 6(50) 0⁄ 6(0) Infection-mediated 3 ⁄ 11 (27) 2 ⁄ 11 (18) important biomarker in inflammatory CNS disorders. Many Bacterial meningitis 0 ⁄ 11⁄ 1 of the patients in this report with mirrored OCBs had autoan- Aseptic meningitis 1 ⁄ 10⁄ 1 tibody-associated disorders, such as NMDAR encephalitis and HSV encephalitis 1 ⁄ 10⁄ 1 ‘Other’ encephalitides 1 ⁄ 61⁄ 6 VGKC encephalopathy. Interestingly, we noted that the Acute necrotizing 0 ⁄ 20⁄ 2 patients with NMDAR encephalitis who initially had mirrored encephalopathy OCBs subsequently developed intrathecal OCBs, suggesting Autoantibody-associated 2 ⁄ 7(29) 4⁄ 7(57) NMDAR encephalitis 1 ⁄ 32⁄ 3 that patients initially have a systemic autoimmune response, VGKC encephalopathy 1 ⁄ 31⁄ 3 which subsequently becomes localized intrathecally. No Basal ganglia encephalitis 0 ⁄ 11⁄ 1 patient was found to have a combination of both a mirrored Other immune-mediated 3 ⁄ 14 (21) 4 ⁄ 14 (29) Rasmussen encephalitis 2 ⁄ 31⁄ 3 and intrathecal OCB pattern, suggesting that this may be an Acute cerebellar ataxia 1 ⁄ 40⁄ 4 uncommon finding in paediatric populations, or a pattern that Polio-like illness 0 ⁄ 22⁄ 2 develops in chronic disease, such as in subacute sclerosing Opsoclonus–myoclonus 0 ⁄ 20⁄ 2 syndrome panencephalitis. Varicella zoster vasculitis 0 ⁄ 11⁄ 1 Specific diseases associated with OCBs were generally con- Aicardi–Goutie`res syndrome 0 ⁄ 10⁄ 1 sistent with findings previously reported by others. Among Sydenham chorea 0 ⁄ 10⁄ 1 our patients with demyelinating disorders (n=26), intrathecal CNS, central nervous system; ADEM, acute disseminated OCBs were detected only in patients with multiple sclerosis, encephalomyelitis; HSV, herpes simplex virus; NMDAR, N-methyl-D and mirrored OCBs were found only in patients with ADEM. aspartate receptor; VGKC, voltage-gated potassium channel. Our numbers were small; however, studies specifically of pae- diatric patients with demyelinating diseases have also reported Those with autoantibody-associated disorders were likely to a higher frequency of intrathecal OCBs in children with multi- have either intrathecal or mirrored OCBs (6 ⁄ 7; 86%). In both ple sclerosis than with ADEM or CIS.7,12,13,18 The presence patients with NMDAR encephalitis whose initial samples of mirrored OCBs in ADEM has also been reported in other showed mirrored OCBs, CSF samples taken 59 and 70 days studies.19,20 Intrathecal OCBs were also found in patients with after the first samples were found to contain intrathecal OCBs. Rasmussen encephalitis and acute cerebellar ataxia, as previ- Among those with demyelinating disorders, intrathecal OCBs ously reported.21,22 were detected only in patients with multiple sclerosis (3 ⁄ 6; Although OCBs can be useful, we failed to detect OCBs in 50%), whereas mirrored OCBs were detected only in those many patients with recognized inflammatory CNS diseases. patients with ADEM (4 ⁄ 11; 36%). All three patients with Ras- The absence of OCBs should not preclude consideration of an mussen encephalitis had either intrathecal or mirrored OCBs. inflammatory CNS process, or testing for specific autoanti- Patients with infection-mediated disorders (n=11) had either bodies. intrathecal (3 ⁄ 11; 27%) or mirrored OCBs (2 ⁄ 11; 18%). There is emerging evidence that autoantibodies against VGKC and NMDAR are specific in autoimmune encephalop- DISCUSSION athy and it could be argued that these specific biomarkers will We sought to investigate the utility of OCBs in a contempo- increasingly replace non-specific markers of inflammation or rary group of child neurology patients and make diagnostic immune activation, such as OCBs and CSF neopterin.1,2 associations. We found intrathecal OCBs only in patients with However, non-specific biomarkers are likely continue to be of evidence of inflammatory CNS disease; however, a variety of clinical utility as they can alert the clinician to atypical variants autoantibody-associated, demyelinating, infection-mediated, of autoimmune encephalopathy or to potential autoimmune and other immune-mediated diseases were associated with diseases yet to be fully defined.6 Additionally, specific autoan- intrathecal OCBs. Mirrored OCBs were less specific than tibody tests are less widely available than OCBs and may have intrathecal OCBs for CNS inflammation, but were still more a longer processing time; given that early diagnosis and treat-

74 Developmental Medicine & Child Neurology 2013, 55: 71–75 ment can improve outcomes, OCBs are likely to continue to for collection of all pertinent data (such as auxiliary evidence play a useful role. of inflammation) and would increase the level of accuracy for Assessing a diagnostic test such as OCBs ideally requires the ‘less precise’ diagnoses and would perhaps reduce the comparison with a criterion standard, but unfortunately there numbers of patients in whom the diagnosis is unknown. is no practical criterion standard test for CNS inflammation as brain biopsy is too invasive. The group with CNS inflamma- ACKNOWLEDGEMENTS tory disorders in this study is a heterogeneous group in which The authors have funding from the National Health Medical the precision of diagnosis and the certainty regarding the Research Council, the University of Sydney, Multiple Sclerosis inflammatory basis of the disease varies substantially. A pro- Research Australia, and the Star Scientific Foundation. spective study with an extended follow-up time would allow

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Intrathecal and Mirrored OCBs in Paediatric Neurology Adriane Sinclair et al. 75