Neuroimmunology in Clinical Practice - part 10 pps

242 ANDREW J. CHURCH AND GAVIN GIOVANNONI Outbreaks of SC have recently been reported in developed countries even among communities with good access to healthcare, although this worldwide increase could be coincidental, it could also suggest the emergence of highly pathogenic or antibiotic- resistant strains (Ayoub, 1992). Poststreptococcal tic disorders and PANDAS Interest in SC was reignited in the 1980s after the recognition that sudden-onset tic disorders in children appeared to follow an outbreak of streptococcal infection. An outbreak of streptococcal tonsillitis in Rhode Island, USA was associated with a 10-fold increase in children presenting with a motor tic disorder, without evidence for RHF or SC (Kiessling et al., 1993). As the clinical phenotype was tics and neuropsychiatric features, SC was proposed as a model of these disorders, which were termed PAN- DAS (pediatric neuropsychiatric disorders associated with streptococcal infections) (Swedo et al., 1998). As GABHS is a prevalent infectious agent in the community, two or more exacerbations of the tic disorder following streptococcal infection were required to make a diagnosis (Swedo et al., 1998) (Table 21.1). The PANDAS classification is defined as the presence of OCD and/or a tic disorder which meets DSM- III-R or DSM-IV criteria with an acute, pediatric (prepubescent) onset occurring after three years of age, with a later episodic course of symptom exacerbations and recovery (Swedo et al., 1998). The association with streptococcal infection(s) was shown by a positive GABHS throat culture with initial raised streptococcal serology, which declined with clinical recovery (Swedo et al., 1998). Patients with RHF, SC, or other neurological disease were excluded from the study in order to meet the clinical diagnosis of PANDAS (Swedo et al., 1998). As a large number of patients are excluded by the narrow definition of the PANDAS classification, the phenotypic breadth of neuropsychiatric and motor disorder symptoms associated with streptococcal infections is currently unknown. However, PANDAS is phenotypically identical to Tourette’s syndrome. The hypothesis that Tourette’s may have an autoimmune eitology has proved to be exceedingly controversial. Recently two adult cases which conform to a wider definition of PANDAS have been described, expanding the proposed syndrome classification (Martinelli et al., 2002) to adult-onset tic disorders. Pathology of poststreptococcal disorders Due to the nonfatal course of SC, pathological studies of brain abnormalities have been rare, and those that exist may only reflect severe or complicated cases, or inadvertently include cases of encephalitis, metabolic or genetic syndromes. The reports all found abnormalities mostly localized in the basal ganglia, which included cellular infiltration and neuronal loss with relative sparing of other brain areas (Colony and Malamud, 1956; Marie and Tretiakoff, 1920), (Table 21.2). These focal changes have also been reported in the context of diffuse neuronal loss, which was the predominant feature, and an encephalitic pathogenesis was proposed (Greenfield and Wolfsohn, 1922) (Table 21.2). The consistent findings appeared to be specific abnormalities of the basal ganglia with conflicting evidence regarding disseminated brain involvement (Table 21.2). The clinical similarities of SC to HD may have influenced early reports of degenerative changes in the pathology of SC (Table 21.2). However, the similarities of SC to HD and the recognition of the basal ganglia as an area controlling movement, led to the hypothesis that the basal ganglia were also the central area of pathogenesis causing SC (Aron, 1965; Dale, 2003; Jummani and Okun, 2001). Neuroimaging Brain imaging studies have been reported as normal in most cases of SC and PANDAS, casting doubt as to Table 21.1 The diagnostic criteria for PANDAS devised by Swedo and colleagues (1998). Number Criterion 1 Tics (chorea would be an exclusion criteria) 2 Obsessive-compulsive disorder 3 Acute onset with an episodic course 4 Exacerbation following proven GABHS infection 5 GABHS infection diagnosed by throat culture and/or falling, rising streptococcal serology 6 Other neuropsychiatric manifestations and nonchoreic movement disorders NICP_C21 03/05/2007 10:50 AM Page 242 Poststreptococcal movement disorders 243 whether widespread neuronal loss is an important feature of the disease, although this does not rule out subtle alterations (Dale, 2003; Giedd et al., 1995; Swedo et al., 1993). Only rarely have suspected inflammatory changes seen on magnetic resonance imaging (MRI) been associated with SC, and these have been predominantly localized to the basal ganglia (Kienzle et al., 1991). The abnormalities in these cases were reversible with disease remission, suggesting that temporary neuronal disruption rather than neuronal loss is one possible mechanism of pathogenesis (Giedd et al., 1995). One study has also found an increased association between MRI and basal ganglia abnormalities in SC patients who had repeated episodes of chorea during a one-year study (Faustino et al., 2003). However, MRI lesions in some cases of SC may be linked to severe disease spectrum or a tendency of SC to recur or become persistent in some patients. Alternatively abnormal MRI may be associated with a diffuse inflammatory disease with basal ganglia features. For example, Dale et al. (2001) described 10 cases of acute disseminated encephalomyelitis (ADEM) associated with GABHS infection. The clinical phenotype was novel, with 50% having a dys- tonic extrapyramidal movement disorder, and 70% a behavioral syndrome. None of the patients had RHF or SC. MRI studies showed hyperintense basal ganglia in 80% of patients with poststreptococcal ADEM, compared to 18% of patients with non- streptococcal ADEM. These findings may support a new subgroup of postinfectious autoimmune inflammatory disorders associated with GABHS, abnormal basal ganglia imaging, and extrapyramidal movement disorder. Volumetric imaging studies have also found basal ganglia (caudate nucleus and putamen) involvement in SC. The basal ganglia have been reported to be enlarged during acute SC compared to controls, which may suggest inflammation (Giedd et al., 1995). Further evidence for basal ganglia involvement in SC has come from magnetic resonance spectroscopy studies, which have shown increased glucose turn- over and hypermetabolism, which could suggest that alterations in local metabolism are important (Weindl et al., 1993). It has been shown that these metabolic changes can be reversible with disease recovery, which may be important in light of the reversible volumetric changes. Autoimmune hypothesis Rheumatic fever is considered to be an inflammatory or autoimmune disorder so SC and PANDAS have been proposed to have a similar pathogenesis (Church et al., 2002; Dale, 2003; Swedo et al., 1998). While T cells have an important role in RHF their role in SC has not been studied. However, one study has reported a modest upregulation of cytokine production in acute SC as a third of patients with acute SC had elevated Th1 or Th2 serum cytokines compared to controls. In cerebrospinal fluid (CSF) both IL-4 and IL-10 (Th2 cytokines) were raised while the Th1 cytokine, INF-γ, was undetectable in acute SC. Additional evidence for the importance of Th2 cytokines and perhaps antibody production Table 21.2 Pathological reports in Sydenham’s chorea. Reference Pathology Conclusions Delcourt and Sand, 1908 Inflammatory Perivascular inflammation of basal ganglia and cortex Guizzetti and Camisa, 1911 Inflammatory and vascular Disseminated encephalitis Harvier and Levanditi, 1920 Inflammatory Perivascular inflammation of mesencephalon Marie and Treitiakoff 1920 Inflammatory Perivascular inflammation of basal ganglia Greenfield and Wolfsohn, Inflammatory Perivascular inflammation of basal ganglia 1922 and cortex Lewy et al., 1923 Inflammatory Widespread Ziegler, 1927 Degenerative Basal ganglia Lhermitte and Pagniez, 1930 Inflammatory/degenerative Basal ganglia Von Santha, 1932 Vascular Encephalitic Glaser, 1952 Vascular Inflammatory features Colony and Malamud, 1956 ?Degenerative Cortex and thalamic involvement NICP_C21 03/05/2007 10:50 AM Page 243 244 ANDREW J. CHURCH AND GAVIN GIOVANNONI came from the persistent SC results, as 50% of these cases had raised CSF IL-4 levels, whereas other serum and CSF cytokines were within normal ranges. Antibasal ganglia antibodies, ABGA However, the majority of research has focussed on the detection of antineuronal antibodies as an indic- ator of an autoimmune pathology in SC and PAN- DAS. Husby in 1976 first described IgG antineuronal antibodies against neurons within the basal ganglia using an indirect immunofluorescence method in 46% of patients with acute SC (n=30) and only 1.8–4% of controls (n=203); interestingly, a higher proportion, 14% (n=50) of patients with RHF without chorea, were also positive. The staining pattern was described as cytoplasmic binding to caudate and subthalamic neurons with weaker staining in the cortex. This antibody reactivity was removed by preincubating positive samples with extracts of streptococcus (Husby et al., 1976). This led to the hypothesis that “basal ganglia antibodies” could be produced as a conse- quence of molecular similarity (mimicry) between streptococcal proteins and brain ones (Fig. 21.3). Later reports suggested that ABGA detected by indirect immunofluorescence (IF) were present in 100% of acute SC but less prevalent in persistent or recovered cases (Church et al., 2002; Kotby et al., 1998). To expand upon this hypothesis western immunoblotting, a common methodology used in the identification of paraneoplastic antibodies, has been used to detect basal ganglia antibodies. Rather than polyspecific binding to basal ganglia proteins, reactivity to discrete antigens of 40, 45, and 60 kDa has been described (Church et al., 2002) (Fig. 21.4). A separate study using western immunoblotting was less discriminating between SC and normal and neurological disease controls, but found increased antibody activity using a soluble supernatant frac- tion from caudate nucleus (Morshed et al., 2001). However, the presence of the same antineuronal antibodies in PANDAS and particularly a small subgroup of patients with Tourette’s syndrome have led to significant controversy regarding both their role and presence (Kurlan, 1998; Singer et al., 2005a). As naturally occurring autoantibodies are known to exist secondary to local damage the ABGA responses reported in SC and PANDAS could be an epiphen- omenon secondary to other disease mechanisms. Alternatively different methodological approaches, particularly in western immunoblotting detection of antibody reactivity and sampling at different time points in disease, may explain the differences in antibody results (Martino et al., 2005). However, what is clear is that the significance of these antineuronal antibodies must only be made in the context of the clinical phenotype and the presence of documented or laboratory supported streptococcus infection. Without streptococcus evidence these antibodies are of no obvious significance. Fig. 21.3 Anti-neuronal antibodies against human basal ganglia in Sydenham’s chorea, PANDAS, and normal controls. (A) Second antibody diluted 1/30 and tested against human basal ganglia section. No specific staining. (B) Normal control sample diluted 1/50 and tested against human basal ganglia section. Lipofuschin granules. (C) PANDAS sample diluted 1/50 and tested against human basal ganglia tissue. Staining of neuronal-like cells (arrow). (D) SC sample diluted 1/50 and tested against human basal ganglia tissue. Strong staining of neuronal-like cells (arrow). Key: Bar = 5 µm. Reproduced with permission from Church et al. (2002), Neurology, published by Lippincott Williams & Wilkins. Fig. 21.4 Western immunoblotting of human basal ganglia showing IgG reactivity from SC patients. NICP_C21 03/05/2007 10:50 AM Page 244 Poststreptococcal movement disorders 245 Potential prevalence Focusing on TS and OCD only, the prevalence in children may be of the order of 1%. In a community- based study the prevalence of TS in children was 2% (Hornse et al., 2001) and the prevalence of OCD was between 2% and 4% (Douglass et al., 1995; Flament et al., 1988; Valleni-Basile, 1994). We have shown the ABGA positivity rate in children attending spe- cialist clinics with TS and OCD to be 25% and 42%, respectively (Church et al., 2003; Dale et al., 2005). Potential functional effects of ABGA ABGA recognize four main protein bands of 40, 45, 60, and 98 kDa in an antigen preparation from human basal ganglia. The 45 and 98 kDa antigens are the monomeric and dimeric forms of γ-enolase, the 40 kDa antigen is aldolase C (neuron specific) and the 60 kDa antigen is pyruvate kinase. γ-Enolase or neuron-specific enolase-reactive ABGA cross- react with α-enolase. All the antigens are glycolytic enzymes and are involved in energy homeostasis and as expected are found in the cytosol. These proteins are also located on the neuronal surface (Lim et al., 1983; Nakajima et al., 1994), where they appear to have “moonlighting” or alternative functions; e.g. enolase located on the surface of neurons acts as a receptor for plasmin/plasminogen (Pancholi, 2001) and has been shown to be a trophic factor for neurons (Hattori et al., 1995). Plasminogen binding to neuronal surface enolase also provides trophic support to mesencephalic dopaminergic neurons (Nakajima et al., 1994). Membrane neuronal aldolase provides local membrane energy and is enzymatic- ally active (Bulliard et al., 1997). It also forms an oxidoreductase complex with enolase and other proteins on the neuronal membrane and is thought to monitor oxidative stress and induce an appropriate cellular response (Bulliard et al., 1997). Aldolase binds tightly with ATPase protein pumps on the plasma membrane allowing direct coupling of glycolysis to the proton pump (Lu et al., 2001). The monomer of pyruvate kinase acts as thyroid hormone (T3) binding protein. Binding of T3 to pyruvate kinase inhibits enzymatic activity, suggesting that this process may be centrally involved in the control of some cellular metabolic effects induced by thyroid hormones (Kato et al., 1989). Interestingly, hyperthyroidism is a well-described cause of chorea. Membrane glycolysis provides a preferential source of ATP in order to maintain myocyte K + channels (Weiss and Lamp, 1987), ATPase and calcium uptake (Hardin et al., 1992), and Na + K + pumps on intestinal cells (Dubinsky et al., 1998). The maintenance of these pumps may be directly linked to functionally compartmentalized ATP to ADP ratios on the cell membrane (Dubinsky et al., 1998). In summary therefore, membrane glycolytic enzymes are involved in the energy pro- vision and maintenance of ion channels on the neuronal membrane, trophic support, and other functions. Disrupting their activity may lead to neuronal dysfunction. Molecular mimicry All three of the major candidate autoantigens have protein homologs in Streptococci. Interestingly, streptococcal enolase is also found on the surface of the bacterium and appears to function as an efficient plasmin(ogen) binding protein which influences tissue invasiveness and pathogenicity (Pancholi and Fischetti, 1998). The streptococcal surface enolase antibodies appear to recognize a shared epitope with neuronal surface and cytoplasmic enolase. An important question is whether or not ABGA are directly involved in the pathogenesis of these disorders or simply a diagnostic marker. Two studies investigating the effects of infusing serum immunoglobulin from patients with PANDAS into rat striatum found an increase in stereotypical movements compared to control antibodies (Hallett et al., 2000; Taylor et al., 2002). However, another group using the same methods failed to reproduce the results (Loiselle et al., 2004) and a study to replicate these results was unsuccessful (Singer et al., 2005b). A controlled trial of treatment with either plasma exchange or intravenous immunoglobulin (IVIg) in children with PANDAS demonstrated a significant improvement in motor and psychiatric symptoms for both therapies compared to placebo (Perlmutter et al., 1999). These observations and insights from the proposed treatment effects of IVIg suggest that these autoantibodies may be pathogenic. Phenotypic spread As discussed above basal ganglia dysfunction has various manifestations, all of which fall into a relat- ively well-defined symptom complex or syndrome (Ring and Serra-Mestres, 2002). It is difficult to make an etiological diagnosis in disorders of basal ganglia using clinical criteria alone. Although a particular phenotype can be typically associated with “specific” NICP_C21 03/05/2007 10:50 AM Page 245 246 ANDREW J. CHURCH AND GAVIN GIOVANNONI disease entities, for example chorea or tics in SC and TS, respectively, one would expect from applying basic principles that immune-mediated basal ganglia dysfunction should result in the full spectrum of movement and emotional disorders that have been attributed to basal ganglia pathology. Huntington’s disease and Wilson’s disease, well-defined genetic disorders with a predilection for the basal ganglia, are similarly associated with a wide spectrum of both hyper- and hypokinetic movement disorders. There- fore using a biomarker, such as ABGA, in addition to specific clinical features, may be appropriate in defining this emerging group of disorders. The apparent over- lap between the clinical phenotype of SC, PANDAS, TS and OCD, and the finding of serological evidence of recent streptococcal infection and ABGA in these disorders, suggests that they may represent one disease entity. For example, patients with PANDAS usually have psychiatric features and frequently have choreiform movements. Patients with SC often have tics and OCD and patients with OCD often have tics and other subtle movement disorders. If PAN- DAS, TS and OCD are the same disease as SC, why don’t patients with these disorders have associated RHF? A detailed cardiac evaluation of 60 subjects with PANDAS did not reveal evidence of rheumatic carditis (Snider et al., 2004). Whether or not subjects with ABGA have subtle cardiac involvement has yet to be investigated systematically. One could speculate that the current strains of Streptococci that induce neuropsychiatric disease are different from those that are capable of inducing rheumatic carditis. These issues will hopefully be resolved with further research. Treatment The treatment of SC is well established and can be divided in symptomatic or disease-modifying strat- egies. Antibiotic prophylaxis in subjects who have had RHF and/or SC is essential and standard clinical practice (http://www.doh.gov.za/docs/facts-f.html). Recent studies suggest that antibiotic prophylaxis may be effective in reducing symptomatic exacerbations in children with PANDAS. Once-weekly 500 mg of azithromycin was effective in reducing both symptomatic streptococcal infections and exacerbation of symptoms in patients with PANDAS (Table 21.3) (Snider et al., 2005). Disease-modifying therapies There have been no well-controlled studies of IVIg or plasma exchange in SC. In a small study of five subjects treated with plasma exchange and four with IVIg (Garvey et al., 1996), subjects in both treatment arms improved although the plasma exchange group improved more rapidly. Three of the four IVIg-treated Table 21.3 Secondary continuous prophylaxis for recurrent rheumatic fever or rheumatic heart disease (from 3 years to either 21 or 35 years of age). Antibiotic Benzathine penicillin Or Phenoxymethyl penicillin Notes: Intramuscular penicillin should be encouraged in all patients. It is more effective than oral penicillin and results in better compliance. Adherence is very important. Continue up to 21 years of age or with cases of confirmed rheumatic heart disease up to 35 years of age. If a subject has a history of penicillin allergy, give erythromycin (same dosage as oral penicillin). Give one to two aspirins for migratory ployarthritis in acute rheumatic fever. Bedrest determined by doctor. Fluids and nourishment are very important in the recuperation period. Source: Adapted from http://www.doh.gov.za/docs/facts-f.html. Mode of administration Intramuscular (keep child under close observation for 30 minutes after the injection) Oral Dose Given every four weeks 1.2 MU for subjects weighing more than 30 kg 600,000–900,000 U for subjects weighing less than 30 kg 250 mg twice daily 125 mg twice daily for subjects less than 30 kg NICP_C21 03/05/2007 10:50 AM Page 246 Poststreptococcal movement disorders 247 children relapsed within four months of completing treatment. Several small studies have examined the effectiveness of corticosteroids in SC. A retrospective study of eight subjects with SC showed rapid improvements with corticosteroids (Green, 1978). In another study five subjects with SC, refractory to standard symptomatic therapy (valproate and neuroleptics), were treated successfully with intravenous methyl- prednisolone and then oral prednisolone. The only placebo-controlled trial examining the benefit of immunomodulation (plasma exchange and IVIg) in PANDAS demonstrated improvements in the patients treated with active agents compared to patients treated with sham (saline) infusions. Import- antly, the treatment improvements were maintained at one year (Perlmutter et al., 1999). Interestingly, the same finding was not reproduced in OCD patients who did not have PANDAS, suggesting that the benefit of immune modulation is restricted to the PANDAS subgroup of neuropsychiatric disorders (Nicolson et al., 2000). Currently, it is our recommendation that immune treatments should not be given routinely to SC or PANDAS patients until further controlled trials confirm their benefit. Carbamazepine and sodium valproate have been proposed to be useful symptomatic treatments of SC, and are preferable to neuroleptics (haloperidol and tetrabenazine), which can cause unacceptable side effects (Pena et al., 2002). Interestingly, in some countries antibiotic prophylaxis for rheumatic fever, which by definition includes Sydenham’s chorea, has now extended to the age of 35 (South African recommendations, http://www.doh.gov.za/docs/facts-f.html), because of the observation of delayed exacerbations. In most parts of the world GABHS remains sensitive to penicillin, which is the antibiotic of choice. In subjects who cannot tolerate penicillin, macrolides are recom- mended although there is a risk of development of antibiotic resistance. Summary The identification of putative antigens would help to define the existence and role of antineuronal antibodies in Sydenham’s chorea, PANDAS, and the controversial finding in a small subgroup of Tourette’s syndrome. A recent report suggested that brain- specific glycolytic enzymes: neuron-specific enolase, pyruvate kinase M1, and aldolase C might be putative autoantigens. These same enzymes are known to be present in Streptococcus and neurons and might support molecular mimicry (Dale et al., 2006). However, in common with earlier reports using brain tissue, these results have not been reproduced (Singer et al., 2005b). An antibody response against lysoganglioside has also been reported in SC (Kirvan et al., 2003). The heterogeneity of antibody responses in these disorders might suggest that a classic autoimmune disorder is not supported. The antineuronal responses might be related to GABHS infection, transitory, of no functional role but useful for differential diagnosis. Until methodological concerns are addressed, an autoimmune hypothesis of putative poststreptococcal, extrapyramidal movement disorders must be treated cautiously at present. References Alexander, G.E., DeLong, M.R. and Strick, P.L. 1986. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci, 9, 357–81. 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NICP_C21 03/05/2007 10:50 AM Page 250 Celiac disease (CD) was first described by Aretaeus the Cappadocian, one of the most distinguished ancient Greek doctors of the first century AD. In a chapter entitled “on the celiac diathesis” from his book on chronic diseases he named this disease entity κοιλιακη, the Greek word for abdominal. Aretaeus’ books were first published in Latin in 1500 and the new Latin word coeliac was used to trans- late κοιλιακη. CD remained obscure until 1887 when Samuel Gee gave a lecture entitled “On the celiac affection” at the Hospital for Sick Children, Great Ormond Street, London. In it he acknowledged Areteaus’ contribution and went on to give an accurate description of CD in children based on his own clinical observations. With clinical manifestations primarily confined to the gastrointestinal tract or attributable to malabsorption, it was logical to assume that the target organ and hence the key to the pathogenesis of this disease was the gut. The first report of neurological manifestations associated with CD was by Carnegie Brown in 1908. In his book entitled Sprue and its Treatment he mentioned two of his patients who developed “peripheral neuritis”. Elders reported the association between “sprue” and ataxia in 1925. The validity of these and other such reports prior to 1960 remains doubtful given that a precise diagnosis of CD was not possible prior to the introduction of small- bowel biopsies. The treatment of CD remained empirical until the Dutch pediatrician Willem Dicke noted the deleteri- ous effect of wheat flour on children with CD (Dicke et al., 1953). Removal of dietary products containing wheat was shown to result in complete resolution of the gastrointestinal symptoms and a resumption of normal health. The introduction of the small-bowel biopsy by Paulley in 1954 confirmed the gut as a target organ. The characteristic features of villus atrophy, crypt hyperplasia, and increase in intraepithelial lym- phocytes with subsequent improvement while on a gluten-free diet became the mainstays of the diagnosis of CD. In 1961 Taylor published an immunological study of CD. In his paper he commented that “. . . an obstacle to the acceptance of the immunological theory of causation has been the lack of satisfactory demon- stration of antibodies to the protein concerned.” He went on to demonstrate the presence of circulating antibodies against gliadin, the protein responsible for CD (Taylor et al., 1961). These antibodies became known as antigliadin antibodies. This provided further evidence that CD is immunologically mediated and that the immune response is not confined to the mucosa of the small bowel. Antigliadin antibodies became a useful screening tool for the diagnosis of CD. In 1966, Marks and her colleagues demonstrated an enteropathy in nine of 12 patients with dermatitis herpetiformis, an itchy vesicular skin rash mainly occurring over the extensor aspect of elbows and knees. The enteropathy had a striking similarity to that seen in CD (Marks et al., 1966). It was later shown that the enteropathy and the skin rash were gluten dependent but skin involvement could occur even without histological evidence of gut involvement. This was the first evidence that the gut may not be the sole protagonist in this disease. During the same year a landmark paper on 16 patients with neurological disorders associated with adult CD was published (Cooke et al., 1966). This was the first systematic review of the subject following the introduction of diagnostic criteria for CD. Ten of these patients had severe progressive neuropathy. All patients had gait ataxia and some had limb ataxia. Neuropathological data from postmortem examina- tions showed extensive perivascular inflammatory changes affecting both central and peripheral nervous systems. A striking feature was the loss of Purkinje cells with atrophy and gliosis of the cerebellum. All 16 patients had evidence of severe malabsorption as evident by anemia and vitamin deficiencies as well as profound weight loss. 22 Neurological manifestations of gluten sensitivity Marios Hadjivassiliou NICP_C22 04/05/2007 12:25PM Page 251 [...]... 230–1 innate immunity 3 interferon-gamma 5 internodal proteins 13–17 CD9 13 myelin-associated glycoprotein 13–14 myelin-associated oligodendrocyte basic protein 14–15 myelin basic protein 14 myelin oligodendrocyte glycoprotein 15 myelin protein zero 15 Nogo 15–16 NICP_D01 03/05/2007 10: 54 AM Page 261 Index oligodendrocyte-myelin glycoprotein 16 peripheral myelin protein (PMP22) 16 proteolipid protein... myelin genes 19–20 myelin-associated glycoprotein 13–14 myelin-associated oligodendrocyte basic protein 14–15 myelin basic protein 14 myelin lipids 19 myelin oligodendrocyte glycoprotein 15 myelin protein zero 15 myelin sheath 11, 12 myelin and T-lymphocyte protein (MAL) 17 myelitis 47–8 acute transverse 105 –7 myelopathy 47–8 NICP_D01 03/05/2007 10: 54 AM Page 262 262 natalizumab adverse effects 67–8 in. .. 03/05/2007 10: 54 AM Page 260 260 CIDP see chronic in ammatory demyelinating polyradiculoneuropathy claudin 11 17–18 claudin 19 18 Cogan’s syndrome 200–2 clinical characteristics 200 diagnostic criteria 200–1 paraclinical findings 201 therapy 201 collagen vascular diseases 225–8 concentric sclerosis, Balò type 103 –4 connective tissue diseases 147– 8 contactin 18 contactin-associated protein 18 corticosteroids... (GAD) is the rate-limiting enzyme in the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) GAD is found in both the central and peripheral nervous systems (including the enteric nervous system) as well as in the pancreatic beta cells (Kerr et al., 1995) Antibodies against pancreatic islet cell proteins were first detected in children with newly diagnosed insulin-dependent diabetes... autonomic neuropathy 143–5 acute cholinergic neuropathy 144 acute cholinergic pandysautonomia 140 acute disseminated encephalomyelitis 88 100 in childhood 93 clinical aspects 91–4 clinical subtypes 94 comparison with MS 88 CSF immune profile tests 90 diagnostic groupings 109 10 differential diagnosis 90 first disease bout 93 hyper-recurrent 99 100 imaging studies 95–6 infections associated with 91 laboratory... antibodies It has already been shown that there is cross-reactivity between antigliadin antibodies and Purkinje cell antigens (Hadjivassiliou et al., 2002b) Intraventricular injection of serum from a patient with gluten ataxia in mice induces ataxia This is accompanied by intense staining of the Purkinje cells following examination of the mice brain Treatment The neurological manifestations of gluten... of 108 prognosis 97–8 recurrent 98–9, 99 related complications 108 10 risk modification 99 syndromes 89 treatment 96–7 without prodrome 100 acute hemorrhagic leukoencephalitis 102 –3 acute in ammatory demyelinating polyradiculoneuropathy see Guillain–Barré syndrome acute motor axonal neuropathy 117–18 acute necrotic encephalitis 107 – 8 acute transverse myelitis 105 –7 causes 106 ADEM see acute disseminated... stiff-man syndrome, epilepsy, and type 1 diabetes melitus N Engl J Med, 318, 101 2– 20 Solimena, M., Piccolo, G and Martino, G 1988a Autoantibodies directed against gabaminergic nerve terminals in a patient with idiopathic late-onset cerebellar ataxia and type 1 diabetes mellitus Clin Neuropathol, 7, 211 NICP_D01 03/05/2007 10: 54 AM Page 259 Index Page numbers in italics represent figures, those in bold... proteins 17–19 claudin 11 17–18 claudin 19 18 contactin 18 contactin-associated protein 18 neurofascin 18–19 INDEX peripheral autonomic neuropathies 142 peripheral myelin protein (PMP22) 16 plasmapheresis Guillain–Barré syndrome 120, 143 multiple sclerosis 63–4 myasthenia gravis 160 polyarteritis nodosa 218–19, 220 polymyositis/dermatomyositis 169–78 association with malignancy 174 autoantibodies 173 clinical. .. diffusion imaging 62 disease-modifying agents multiple sclerosis 64–8 beta interferon 64–5 glatiramer acetate 64–5 mitoxantrone 66–7 natalizumab 67–8 poststreptococcal movement disorders 246–7 drug-related vasculitis 221 dysautonomia 148–9 ELISA 4 ELISPOT 4 encephalitis acute necrotic 107 – 8 herpes-related 92 idiopathic limbic 207–9, 208 meningoencephalitic 108 10 INDEX Miller–Fisher/Bickerstaff 107 periaxialis . vasculopathy 230–1 innate immunity 3 interferon-gamma 5 internodal proteins 13–17 CD9 13 myelin-associated glycoprotein 13–14 myelin-associated oligodendrocyte basic protein 14–15 myelin basic protein 14 myelin. oligodendrocyte basic protein 14–15 myelin basic protein 14 myelin lipids 19 myelin oligodendrocyte glycoprotein 15 myelin protein zero 15 myelin sheath 11, 12 myelin and T-lymphocyte protein (MAL) 17 myelitis. There- fore using a biomarker, such as ABGA, in addition to specific clinical features, may be appropriate in defining this emerging group of disorders. The apparent over- lap between the clinical

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