Multiple Sclerosis and Related Disorders (2013) 2, 147–150
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Acute disseminated encephalomyelitis associated with positive voltage gated potassium channel complex antibody Marios Kaliakatsosa,1, Yael Hacohenb,1, Ata Siddiquic, Nomazulu Dlaminia, Angela Vincentb, Ming Lima,b,n a
Paediatric Neurosciences, Evelina Children’s Hospital at Guys and St Thomas’ NHS Foundation Trust, Kings Health Partners Academic Health Science Centre, London, UK b Nufﬁeld Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK c Department of Radiology, Evelina Children’s Hospital at Guys and St Thomas’ NHS Foundation Trust, Kings Health Partners Academic Health Science Centre, London, UK Received 5 July 2012; received in revised form 28 September 2012; accepted 28 September 2012
Voltage gated potassium channel (VGKC) complex antibodies are associated with encephalopathies both in adult and children. The incidence of antibodies in the central nervous system demyelinating disorders is increasingly reported although their direct pathogenic role remains to be evaluated, with the exception of Aquaporin 4 antibodies. Here we describe a case of a 28 month old boy presenting with acute disseminated encephalomyelitis, with positive VGKCcomplex antibodies and low sodium levels. He was treated with steroids and made a clinical and radiological recovery with normalisation of antibody levels. & 2012 Elsevier B.V. All rights reserved.
Voltage gated potassium channel (VGKC)-complex antibody associated central nervous system (CNS) disorders have n
been described both in adult and children (Vincent et al., 2011). In adults, the most commonly associated phenotype is limbic encephalitis; presenting with seizures, amnesia, limbic changes on imaging and frequently hyponatraemia
Corresponding author at: Paediatric Neurosciences, Evelina Children’s Hospital at Guys and St Thomas’ NHS Foundation Trust, Kings Health Partners Academic Health Science Centre, Lambeth Palace Road, London SE1 7EH, UK. E-mail address: [email protected] (M. Lim). 1 These authors contributed equally to the manuscript. 2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msard.2012.09.007
M. Kaliakatsos et al.
(Vincent et al., 2011). The paediatric presentation is more heterogeneous; patients have been reported with encephalopathies, seizure disorders, developmental regression, psychiatric features with neuroleptic malignant syndrome and a range of peripheral syndrome (Wong-Kisiel et al., 2012). A varied immunotherapy response have been shown in both groups (Wong-Kisiel et al., 2012; Vincent et al., 2011). The role of autoantigens in demyelinating disease is increasingly recognised primarily, comprising aquaporin 4 (AQP 4) or myelin oligodendrocyte glycoprotein (MOG). AQP 4 positive patients present with distinct CNS presentation, primarily neuromylitis optica (NMO) and this antibody can be used as a biomarker for diagnosis (Derfuss and Meinl, 2012). In contrast anti-MOG has been seen in a range of demyelinating diseases and at this point there is only modest experimental work into its pathogenic potential (Dale et al., 2012). Here we report a case of 28 month old boy presented with acute disseminated encephalomyelitis (ADEM) with lesions centred mostly around the lower brainstem and upper spinal cord, with concomitant hyponatremia and positivity for VGKC-complex antibody. To our knowledge this is the ﬁrst case of ADEM in association with VGKC-complex antibody positivity.
A previously well 28 month old boy of African Caribbean origin presented to his local hospital with generalised weakness and ﬂuctuating level of consciousness, two weeks after fully recovering from a viral prodrome. Three days
prior to his admission he started to have loose stools, vomiting and low grade pyrexia before becoming increasingly lethargic. On admission he was drowsy, refusing to stand, and was hypertensive (blood pressure ranging from 130 to 150 mmHg systolic and 91 to 103 diastolic) and bradycardic (labile heart rate ranging from 63 to 82 bpm) with ﬂuctuating respiratory rate requiring oxygen support. His sodium was 122 mmol/l with no clinical signs of dehydration and low urea (2.5 mmol/l). Of note, he did not receive any ﬂuid resuscitation prior to that. He was admitted to the paediatric intensive care unit (PICU) for respiratory support. On neurological examination he demonstrated antigravity movement in all 4 limbs. His deep tendon reﬂexes were brisk throughout and his gag reﬂex was present but weak. Brain neuroimaging demonstrated bilateral ill-deﬁned T2 high signal change in the medulla which extended into the cervical spine to the level of C5/C6 without any signiﬁcant cord swelling or gadolinium enhancement (Figure 1) suggesting a probable inﬂammatory process involving the brainstem and cervical cord. Cerebrospinal ﬂuid (CSF) was acellular with no organism and normal protein and glucose. A diagnosis of ADEM was made and he was treated with high dose methylprednisolone followed by a weaning regime of prednisolone. A thorough infectious work-up revealed entero/rhinovirus RNA in his nose swab, with no evidence of this or any other neurotrophic viruses in his CSF. His serum was positive for VGKC complex antibodies (initial titter 171 pmol), an investigation that was initiated in light of the hyponatreamia. Antibodies to the VGKC complex associated proteins (leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) and contactin-2), N-Methyl-D-Aspartic acid receptor (NMDAR), AQP4, MOG and
Figure 1 Sagittal T2-weighted image (A) at presentation demonstrating patchy subtle increased signal in the medulla and upper cervical spinal cord (black arrows), also seen on axial T2-weighted slices (white arrows) through the medulla (B), cervicomedullary junction (C) and upper cervical spinal cord (D).
Acute disseminated encephalomyelitis associated with positive voltage gated potassium channel complex antibody
Figure 2 Axial T2-weighted images pre-treatment (A) and post-treatment (B) showing signal change in the medulla (arrows) which has largely resolved on the follow up scan.
glycine receptor (GlyR) were not detected. CSF oligoclonal bands were not detected, but no further sample was available for detection of the aforementioned CNS direction autoantibodies. He made a dramatic neurological recovery and discharged home on day 10 with normal sodium levels. On review at 3 month there was no clinical concerns, his VGKC-complex antibodies were negative and his repeat MRI showed only minimal residual signal change (Figure 2).
ADEM is an immune-mediated demyelinating disorder of the central nervous system (CNS), typically transient and selflimiting. It is characterised by an acute or subacute encephalopathy with polyfocal neurological deﬁcits, and with MRI evidence of widespread demyelination that predominantly involves the white matter of the brain and spinal cord (Krupp et al., 2007). ADEM can represent a monophasic event or represent the beginning of a relapsing remitting disease such as multiple sclerosis (MS). As our patient presented with clinical signs and MRI changes involving the brain stem and cervical spinal cord a diagnosis of brainstem clinically isolated syndrome (CIS) should also be considered, albeit the ill-deﬁnition and longitudinal extent of the signal abnormality would be unusual for MS. Additionally, with the absence of supratentorial lesions on neuroimaging in our patient, is important to acknowledge that the diagnosis may indeed be of some variant of acute brain stem encephalitis or demyelination rather than ADEM. Antibodies against AQP4 have led to the recognition of NMO and NMO spectrum disorders in both adults (Derfuss and Meinl, 2012) and children (Dale et al., 2012) and can be used for diagnosis, predicting relapse and monitoring response to treatment in this very distinct demyelinating condition. Antibodies to MOG are detected in ADEM, CIS and MS (with persistent seropositivity) (Dale et al., 2012). It is possible that other autoantibodies might be involved in demyelinating conditions either as expanding phenotypes of already well characterised CNS antibodies mediated diseases or may include less commonly studied proteins like anti-myelin basic protein, anti-neurofascin and anti-
proteolipid protein (Derfuss and Meinl, 2012; Dale et al., 2012). As this is a new clinical phenotype associated with VGKCcomplex antibody, it is imperative that we do not immediately ascribe pathogenicity to this observation. Although the VGKC level in our patient is relatively low level, less is known about the precise correlation with clinical condition and/or severity with absolute antibody levels. VGKC are clustered at a variety of functionally important sites on the juxtaparanodes of myelinated axons (Rasband, 2010), and perturbations of VGKC function here by antibodies may potentially contribute to demyelination. VGKC-complex antibodies have also been described in patients with brain stem encephalitis and clinical features of peripheral nervous system demyelination (T¨ uz¨ un et al., 2010). Taken together with our case report, these observations highlight that VGKC may have a potential role in demyelination and requires further evaluation. Moreover, the potassium channel KIR4.1 has recently been identiﬁed as immune target in multiple sclerosis (Srivastava et al., 2012). The KIR4.1 is not part of the shaker family of VGKC and would not be diagnosed using the radioimmunoassay currently available. The link between VGKC-complex limbic encephalitis and hyponatremia (as observed in out patient) is well recognised but poorly understood. It is thought to be speciﬁc to the CNS spectrum diseases (which are also positive for LGI1) and is not found in patients with neuromyotonia (Vincent et al., 2011). Interestingly patients with dystonic seizures and LGI1 antibodies have normal sodium levels. A number of mechanisms have been suggested; inappropriate secretion of antidiuretic hormone (SIADH) and the role of LGI1 in hypothalamic ADH secretion. It has recently been recognised that the antibodies do not bind the channel directly but to the associated proteins LGI1, CASPR2 and contactin 2; LGI1 commonly associated with limbic encephalitis whereas CASPR2 more frequently (but not exclusively) described in the peripheral syndromes (Vincent et al., 2011). Our patient was negative for the associated proteins but as there are no reports of seropositive paediatric patients (Wong-Kisiel et al., 2012) this is not surprising and might represent a yet undiscovered antigen, associated with the VGKC complex, in this population.
M. Kaliakatsos et al.
VGKC-complex antibodies can be associated with CNS demyelination, although its incidence in a range of demyelinating conditions remains to be evaluated, as is its pathogenic role.
Conﬂict of interest statement MK, YH, ND and AS have no conﬂicts of interest to declare. AV has served on scientiﬁc advisory boards for the Patrick Berthoud Trust and the Myasthenia Gravis Foundation of America; has received funding for travel and a speaker honorarium from Baxter International Inc.; serves as an Associate Editor for Brain; receives royalties from the publication of Clinical Neuroimmunology (Blackwell Publishing, 2005); receives research support from the European Union, NIHR Biomedical Research Centre Oxford, and Sir Halley Stewart Trust; and has received Musk antibody royalties and consulting fees from Athena Diagnostics, Inc., and Musk antibody royalties from RSR Ltd., Cardiff, UK. The University of Oxford, where A.V. is based, receives royalties and payments for antibody assays in neurologic diseases. ML has received travel grants from Merck Serono, and educational grants to organise meetings from Novartis, Biogen Idec, Merck Serono and Bayer.
References Dale RC, Banwell B, Boa-Or A, Brilot F. Autoantibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein in paediatric CNS demyelination: Recent developments and future directions. Multiple Sclerosis and Related Disorders 2012;1(3):116–22. Derfuss T, Meinl E. Identifying autoantigens in demyelinating diseases: valuable clues to diagnosis and treatment? Curr Opin Neurol 2012;25(3):231–8. Krupp LB, Banwell B, Tenembaum S, International Pediatric MS Study Group. Consensus deﬁnitions proposed for pediatric multiple sclerosis and related disorders. Neurology 2007;68(16 Suppl 2):S7–12. T¨ uz¨ un E, K¨ urt¨ unc¨ u M, Lang B, et al. Bickerstaff’s encephalitis and Miller Fisher syndrome associated with voltage-gated potassium channel and novel anti-neuronal antibodies. Eur J Neurol 2010;17(10):1304–7. Rasband MN. Clustered K+ channel complexes in axons. Neurosci Lett 2010;486(2):101–6. Srivastava R, Aslam M, Kalluri SR, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 2012;367(2):115–23. Jul 12. Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol 2011;10(8):759–72. Wong-Kisiel LC, McKeon A, Wirrell EC. Autoimmune encephalopathies and epilepsies in children and teenagers. Can J Neurol Sci 2012;39(2):134–44.
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