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A great proportion of recent clinical and paraclinical studies of NMO was reported by investigators at the Mayo Clinic (Lennon et al., 2003, 2004, 2005; Lucchinetti et al., 2002; Pittock et al., 2005, 2006a,b; Wingerchuck et al., 1999, 2003, 2005, 2006). Clinical phenotype Prior to the availability of a biomarker, the question persisted as to whether the distinct clinical, magnetic resonance imaging (MRI), and pathological features of the NMO phenotype reflect a separate entity or rather a subtype within the spectrum of multiple sclerosis (MS). Clinically, patients with NMO present with isolated or simultaneous symptoms of optic neuritis (ON) and myelitis. The index events at nadir are usually associated with severe visual loss and/or paraplegia, sensory impairment, and loss of bowel and bladder control. Patients, who only have one index event at onset, typically develop all index events (myelitis and bilateral ON) within a few days to a few years. Reviewing medical records and MRI data between 1950 and 1993, and adding personal observations of patients between 1993 and 1997 at the Mayo Clinic, Wingerchuck et al. (1999) summarized demographics and clinical, laboratory, and MRI characteristics of NMO. Seventy-one predominantly Caucasian patients were retained in the analyses based on strict criteria (bilateral ON and myelitis, occurring within two years of one another without signs of disease outside of optic nerves and spinal cord) or not meeting strict criteria (unilateral ON or development of a second index event in more than two years). In this series, NMO presented with monophasic and relapsing pheno- types in 23 and 48 patients, respectively. The female to male ratio was close to 1:1 in the monophasic and 5:1 in the relapsing group. The median onset age of 29 years in the monophasic cohort was 10 years earlier than that in the relapsing cohort. While there was no difference in the rate of preceding viral illnesses or immunizations, 30% of patients with the relapsing form of NMO also had another autoimmune disorder. In relapsing NMO, optic neuritis or myelitis alone was the index event in 48% and 42% of cases, respect- ively, while 31% of patients with monophasic NMO presented with simultaneous bilateral optic neuritis and myelitis (Wingerchuck et al., 1999). The clinical severity of index events tended to be more severe at presentation and at recovery in the monophasic as compared to the relapsing form of NMO, but patients with the relapsing form also accumulated severe disability over time. Respiratory failure caused by cervical myelitis was noted 19 times in 16 relapsing patients and twice in two monophasic patients, and contributed to a 93% mortality rate in the relapsing group. The survival rate at five years was 90% in the monophasic and 68% in the relaps- ing group (Wingerchuck et al., 1999). Predictors of relapsing course included longer interattack intervals between the first two clinical (index) events, older age at onset, female gender, and less severe motor impairment with the myelitis. Mortality due to relapsing NMO was related to the history of other autoimmune disease, higher attack rate in the first two years, and a better motor recovery after the index myelitis (Wingerchuck and Weinshenker, 2003). The original Wingerchuck et al. (1999) criteria proposed that only clinical symptoms and imaging signs of lesions affecting the optic nerves/chiasm and the spinal cord (but not the brain) are compatible with the diagnosis of NMO. These clinical criteria 4 Dévic’s disease Bernadette Kalman NICP_C04 03/05/2007 10:35 AM Page 83 84 BERNADETTE KALMAN agreed with the opticospinal restriction of pathology emphasized by Mandler et al. (1993). However, in a more recent study using newer MRI and laboratory methods, Wingerchuck et al. (2005) found that 20% of their 84 patients with NMO also had neuro- logical symptoms suggesting disease outside of the optic nerves and spinal cord. Variables with high discriminative power included the NMO-IgG (see below) and distinct T2-weighted MRI features of the spinal cord lesion (see below) (Wingerchuck et al., 2005). The possible involvement of the central ner- vous system (CNS) in addition to lesions in the optic nerves and spinal cord was re-emphasized in the new NMO diagnostic criteria that incorporate the highly disease-specific NMO-IgG biomarker status (Wingerchuck et al., 2006). Cerebrospinal fluid characteristics In the acute cerebrospinal fluid (CSF), a moderate pleocytosis and increased proteins can usually be seen. The presence of oligoclonal bands (OCB) and elevated IgG index are less characteristic in NMO than in MS. In the survey by Wingerchuck et al. (1999), the median values of white blood cells were 12 and 28/mm 3 with 50% and 60% neutrophils in the monophasic and relapsing groups, respec- tively. Generally, >50 white blood cells/ml and >5 neutrophils/ml was proposed to support the diagnosis of NMO. The median CSF protein level was higher (84 mg/dl) in the relapsing as compared to the mono- phasic group (54 mg/dl). Elevated IgG index was detected in only 20% of each group, and OCBs were found in 43% and 33% of the monophasic and relaps- ing groups, respectively (Wingerchuck et al., 1999). MRI characteristics Imaging hallmarks of NMO are demonstrated in Fig. 4.1. Typically, a longitudinal cervical lesion (often affecting both the gray and white matter) extending across three or more vertebrae can be seen. Cord swelling and gadolinium enhancement occur in more than half of the patients. Cervical lesions may also extend into the medulla, the high thoracic region or even the entire cord, and eventually show signs of necrosis and cavitation. The diffuse enhance- ment of optic nerves and chiasm in acute stages is usually followed by atrophy in chronic stages of the disease (Wingerchuck et al., 1999). While the presence of cerebral lesions was previously considered incom- patible with the diagnosis of NMO (Wingerchuck et al., 1999), Pittock et al. (2005) found in a follow-up study of 60 patients that 50% of them also had positive brain MRI with nonspecific lesions in most, and with features suggestive of MS in 10%. A small subgroup (8%, mostly children) had atypical, conflu- ent cerebral hemispheral, brainstem or diencephalic (thalamic/hypothalamic) lesions, uncharacteristic of MS (Pittock et al., 2005). The revised diagnostic criteria reflect these observations (Wingerchuck et al., 2006). Magnetization transfer and diffusion tensor imaging techniques also revealed that micro- scopic pathology may be present in the normal appearing gray matter in the brain of patients with NMO (Rocca et al., 2004). Pathological characteristics A modern and comprehensive pathological evalua- tion of NMO was reported by Mandler et al. (1993) using hematoxylin-eosin, Luxol fast blue-hematoxylin, periodic acid-Schiff and Bodian’s silver staining. Five of the studied eight patients died between one and four years after the onset. The spinal cord was affected throughout most of its length. Microscopically, cavit- ation and necrosis were noted in both the gray and white matter. Necrotic lesions were associated with the presence of macrophages and prominent blood vessels. Vessel walls were thickened and hyalinized with scarce nuclei. The perivascular and parenchymal infiltrate included macrophages but no lymphocytes or plasma cells. The anterior optic pathway showed signs of demyelination, gliosis, and cavitation (Mandler et al., 1993). Using a panel of markers for immuno- histochemistry, Lucchinetti et al. (2002) characterized 82 lesions from nine autopsy cases of clinically definite NMO. All patients had extensive demyelination (a) (b) Fig. 4.1 MRI images of Dévic’s disease. The lesion extends across the entire cervical and upper thoracic cord with swelling of the cervical cord on the T2-weighted scan (a). The axial T1-weighted postgadolinium image (b) shows enhancement of the optic nerves. NICP_C04 03/05/2007 10:35 AM Page 84 Dévic’s disease 85 associated with cavitation, necrosis and acute axonal spheroids across multiple vertebral levels in both the gray and white matter. The depletion of oligodendrocytes was profound. In addition to macro- phages, large numbers of neutrophils and eosinophils were seen in acute parenchymal and meningeal infiltrates, with a rare appearance of CD3 and CD8 positive T cells. Striking deposition of immunoglobu- lins (mostly IgM) and complement C9 neoantigen was associated with vascular fibrosis and hyalinization in active and inactive lesions (Lucchinetti et al., 2002). The involvement of humoral immunity in the pathogenesis of NMO was further confirmed by demonstrating the increased numbers of myelin- oligodendrocyte glycoprotein (MOG)-specific B cells that produced increased amounts of IL-5, IL-6, IgG, and IgM in the CSF (Correale and Fiol, 2004). The number of IgM-secreting B cells was much higher than that of the IgG-producing cells. Chemokines chemoattractant for eosinophils were also increased in the CSF of patients with NMO. Genetics NMO presents as a sporadic disease and has been observed in both Caucasians and non-Caucasians. Nevertheless, its preferential occurrence in ethnic groups (i.e. Asians, Africans, Canadian Aboriginals, and French Afro-Caribbeans) with lower prevalence rates of typical MS was recognized (Cabre et al., 2001; Kuroiwa, 1985; Mirsattari et al., 2001; Misu et al., 2002; Osuntokun, 1981). While the relative risk for developing MS is 0.64 in African Americans (AA) compared to that in Caucasian Americans (CA), AAs are more likely to present with the opticospinal form or with transverse myelitis and have a more aggressive disease course than Caucasians (Cree et al., 2004). The DRB1*1501 and DRB5*0101 alleles associated with Western-type of MS are absent in patients with NMO or Asian-type of the disease in Japan (Kira et al., 1996). In contrast, these patients have an increased frequency of the HLA-DPB1*1501 allele (Yamasaki et al., 1999). Whole-genome admix- ture analyses using polymorphic markers in AA individuals aimed to differentiate chromosomal segments of African and European origin, and defined that 79% of the composite ancestry is African and 21% is European in origin. The association of MS with both the HLA-DRB1*1501 allele of Caucasian origin and the DRB1*1503 allele of African origin revealed that MS susceptibility was not simply related to the Northern-European gene influx into the AA population (Oksenberg et al., 2004). Genetic markers associated with the opticospinal disease in AA indi- viduals, however, remain to be identified. Full sequence analyses of mitochondrial DNA in three Caucasian NMO patients excluded the possibility that the necrotic nature of pathology was related to inherited point mutations or deletions in this extranuclear part of the genome (Kalman and Mandler, 2002). NMO-IgG, a biomarker for NMO In accordance with histological data, recent serolo- gical studies also add support to the involvement of a humoral mechanism by identifying a new immuno- globulin specific for NMO (Lennon et al., 2003). Sera from patients with NMO, MS, and other autoimmune disorders were used against mouse brain sections in an indirect immunofluorescence assay. A distinct IgG binding pattern associated with capillaries and the blood–brain barrier in the cerebellar cortex, midbrain, pia, and a subpial mesh (prominent in the midbrain) was noted in 54% of patients with NMO. This pattern of staining was also identified with sera from eight patients among several thousands screened in a blinded fashion at the Mayo Clinic. Breaking the code revealed that all these eight patients had definite or possible NMO. Follow-up studies using this assay confirmed a sensitivity of 83% and a specificity of 91% for NMO, and a sensitivity of 58% and specificity of 100% for the Asian form of opticospinal MS (Lennon et al., 2004). This study, thus, established that the NMO-IgG is a biological marker that distinguishes NMO from typical (or western-type of ) MS, and confirmed the immunolo- gical similarity between NMO and the Asian form of opticospinal MS. The NMO-IgG is positive in about 40% of longitudinally extensive transverse myelitis at the first event and predicts recurrence in 50% of patients in one year (Weinshenker et al., 2006). Lennon et al. (2005) recently identified the aquaporin-4 water channel as the antigenic target of NMO-IgG. Aquaporin-4 is a component of the dystroglycan protein complex located in the abluminal surface of blood vessels and the foot processes of astrocytes at the blood–brain barrier. Pittock et al. (2006a) observed in a subgroup of NMO patients that the dis- tribution of MRI abnormalities in the hypothalamic and periventricular areas corresponds to cereb- ral regions with high aquaporin-4 water channel expression. These findings raise the possibility that NMO may belong to a new class of autoimmune channelopathies and is biologically distinct from NICP_C04 03/05/2007 10:35 AM Page 85 [...]... and interleukins (IL) 10 and 6, each of which may be elevated 4 5 6 7 8 in cerebrospinal fluid (CSF), likely involved in pathogenesis IL-6 and TNF-α are likely proinflammatory and TNF-α may play a particular role in demyelination (Ichiyama et al., 2002) Disturbance of blood–brain barrier function is likely to be very important Lymphocytic perivenular in ammation is prominent Patchy perivenular demyelination... immunogenetically and clinically distinct disorders Ann Neurol, 40 , 569– 84 Kuroiwa, Y 1985 Neuromyelitis optica (Dévic’s disease, Dévic’s syndrome) In J.C Koetsier (ed.), Handbook of Clinical Neurology, Chapter 13 Elsevier, Amsterdam Lennon, V.A., Kryzer, T.J., Pittock, S.J., Verkman, A.S and Hinson, S.R 2005 IgG marker of optic-spinal multiple sclerosis binds to the aquaporin -4 water channel J Exp Med, 202, 48 3–8... radiographically including leukodystrophies, tumors, and infections CSF myelin basic protein concentration, usually positive in ADEM, may also be elevated in ONDs, including not only infections, but also tumors Rates of positivity of these tests as compared to clinically definite MS (CDMS), probable or possible MS (P/PMS), non-MS in ammatory illnesses (NMSI/I) or ONDs are shown in Table 5 .4 The EEG is abnormal... CDMS P/PMS ADEM NMSI/I OND CSF IgG/Albumin ratio CSF/Serum IgG index IgG synthetic rate Oligoclonal bands 60–80% 88– 94% 88–96% 83–100% 21– 24% 44 –55% 27–67% 24 89% 16–20% 15–20% 16–18% 10–12% 14 42 % 43 –57% 29% 27–72% 6–10% 3–18% 4 12% 2–29% NICP_C05 04/ 05/2007 12:26PM Page 95 Acute disseminated encephalomyelitis delta, or spikes may be found in the waking state during the early stages of as many as 2–7%... V.A., Lucchinetti, C.F and Weinshenker, B.G 2005 Neuromyelitis optica diagnostic criteria revisited: Validation and incorporation of NMO-IgG serum antibody Neurology, 64, A38 Wingerchuk, D.M and Weinshenker, B.G 2003 Neuromyelitis optica: Clinical predictors of a relapsing course and survival Neurology, 60, 848 –53 Yamasaki, K., Horiuchi, I., Minohara, M et al 1999 HLA-DPB1*0501-associated opticospinal multiple... experimental evidence (Levine and Wenk, 1965) However, changes of both AHLE and ADEM may develop in association with infectious encephalitis due to HSV, VZV, HHV6 and possibly other viruses Clinical settings in which AHLE has been found are listed in Box 5.13 Although cases do occur in adults, most postinfectious/post-vaccination cases of AHLE have occurred in young individuals (infancy to adolescence)... and in various laboratory results including cerebrospinal fluid (CSF) immune profile testing These CSF tests, shown in Box 5 .4, are of considerable importance in the evaluation of patients suspected of having MS, since approximately 95% of all individuals who have MS can be expected to show abnormalities of most or all of these tests upon their second clinical bout and thereafter Although CSF myelin basic... features that also distinguish ADEM from childhood-onset MS The absence of such abnormalities during the first bout of acute disseminated demyelinating illness in a child significantly increases the risk for ultimate MS diagnosis (Rust et al., 1989) EEG abnormalities are not found in adult ADEM (Hollinger et al., 2002) Imaging studies Focal low-density abnormalities are found in the brain computed tomography... found in deeper white matter, optic nerves, basal ganglia (30 40 %), thalamus (12 40 %), brainstem (45 –55%), cerebellum (30 40 %), and spinal cord Periventricular lesions (30 45 %) and corpus callosum lesions (10–15%) are much less common in childhood ADEM than in MS where they are so characteristic Various unusual lesions identified by MRI imaging in the nervous system of individuals with ADEM are listed in. .. helpful in distinguishing ADEM from alternative diagnoses (Hung et al., 2000; Takahashi et al., 1992) None of these approaches is likely to render a pathognomonic finding of ADEM or MS and diagnosis of ADEM should always rest on clinical grounds (Hollinger et al., 2002) Treatment Treatment of ADEM involves providing whatever support is indicated based upon the clinical circumstances In as many as 30 45 % . Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group. 2001. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: Clinical results 9, 647 – 64. Zivadinov, R., Cookfair, D., Locatelli, L. et al. 2006. Interferon-beta-1a slows down progression of brain atrophy in relapsing-remitting multiple sclerosis by reducing predominantly. multicenter, randomized, double-blind, placebo-controlled trial. Neurology, 43 (4) , 655–61. The International SNP Map Working Group. 2001. A map of human genome sequence variation con- taining 1 .42 million single nucleotide