The consistent findings appeared abnor-to be specific abnormalities of the basal ganglia withconflicting evidence regarding disseminated braininvolvement Table 21.2.. 1 Tics chorea would
Trang 1Outbreaks of SC have recently been reported indeveloped countries even among communities withgood access to healthcare, although this worldwideincrease could be coincidental, it could also suggestthe emergence of highly pathogenic or antibiotic-resistant strains (Ayoub, 1992).
Poststreptococcal tic disorders and PANDAS
Interest in SC was reignited in the 1980s after therecognition that sudden-onset tic disorders in chil-dren appeared to follow an outbreak of streptococcalinfection An outbreak of streptococcal tonsillitis
in Rhode Island, USA was associated with a 10-foldincrease 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 amodel of these disorders, which were termed PAN-DAS (pediatric neuropsychiatric disorders associatedwith streptococcal infections) (Swedo et al., 1998)
As GABHS is a prevalent infectious agent in the munity, two or more exacerbations of the tic disorderfollowing streptococcal infection were required tomake a diagnosis (Swedo et al., 1998) (Table 21.1)
com-The PANDAS classification is defined as the ence 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 ofage, with a later episodic course of symptom exacer-bations and recovery (Swedo et al., 1998) The asso-ciation with streptococcal infection(s) was shown by
pres-a positive GABHS thropres-at culture with initipres-al rpres-aisedstreptococcal serology, which declined with clinicalrecovery (Swedo et al., 1998) Patients with RHF,
SC, or other neurological disease were excluded fromthe study in order to meet the clinical diagnosis ofPANDAS (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 symptomsassociated with streptococcal infections is currentlyunknown
However, PANDAS is phenotypically identical toTourette’s syndrome The hypothesis that Tourette’smay have an autoimmune eitology has proved to beexceedingly controversial Recently two adult caseswhich conform to a wider definition of PANDAS havebeen described, expanding the proposed syndromeclassification (Martinelli et al., 2002) to adult-onsettic disorders
Pathology of poststreptococcal disorders
Due to the nonfatal course of SC, pathological studies
of brain abnormalities have been rare, and those thatexist may only reflect severe or complicated cases, orinadvertently include cases of encephalitis, metabolic
or genetic syndromes The reports all found malities mostly localized in the basal ganglia, whichincluded cellular infiltration and neuronal loss with relative sparing of other brain areas (Colonyand Malamud, 1956; Marie and Tretiakoff, 1920),(Table 21.2) These focal changes have also beenreported in the context of diffuse neuronal loss, whichwas the predominant feature, and an encephaliticpathogenesis was proposed (Greenfield and Wolfsohn,1922) (Table 21.2) The consistent findings appeared
abnor-to be specific abnormalities of the basal ganglia withconflicting evidence regarding disseminated braininvolvement (Table 21.2) The clinical similarities of
SC to HD may have influenced early reports of ative changes in the pathology of SC (Table 21.2).However, the similarities of SC to HD and the recog-nition of the basal ganglia as an area controllingmovement, led to the hypothesis that the basal gan-glia were also the central area of pathogenesis causing SC (Aron, 1965; Dale, 2003; Jummani andOkun, 2001)
degener-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).
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
Trang 2Poststreptococcal movement disorders 243
whether widespread neuronal loss is an importantfeature of the disease, although this does not rule out subtle alterations (Dale, 2003; Giedd et al., 1995;
Swedo et al., 1993) Only rarely have suspectedinflammatory changes seen on magnetic resonanceimaging (MRI) been associated with SC, and thesehave been predominantly localized to the basal gan-glia (Kienzle et al., 1991) The abnormalities in thesecases were reversible with disease remission, sug-gesting that temporary neuronal disruption ratherthan neuronal loss is one possible mechanism ofpathogenesis (Giedd et al., 1995) One study has alsofound an increased association between MRI andbasal ganglia abnormalities in SC patients who hadrepeated episodes of chorea during a one-year study(Faustino et al., 2003)
However, MRI lesions in some cases of SC may belinked 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 gangliafeatures For example, Dale et al (2001) described
10 cases of acute disseminated encephalomyelitis(ADEM) associated with GABHS infection The clin-ical phenotype was novel, with 50% having a dys-tonic extrapyramidal movement disorder, and 70%
a behavioral syndrome None of the patients hadRHF or SC MRI studies showed hyperintense basalganglia in 80% of patients with poststreptococcalADEM, compared to 18% of patients with non-streptococcal ADEM These findings may support anew subgroup of postinfectious autoimmune inflam-matory disorders associated with GABHS, abnormal
basal ganglia imaging, and extrapyramidal ment disorder
move-Volumetric imaging studies have also found basalganglia (caudate nucleus and putamen) involvement
in SC The basal ganglia have been reported to beenlarged during acute SC compared to controls, whichmay suggest inflammation (Giedd et al., 1995).Further evidence for basal ganglia involvement in SChas come from magnetic resonance spectroscopystudies, which have shown increased glucose turn-over and hypermetabolism, which could suggestthat alterations in local metabolism are important(Weindl et al., 1993) It has been shown that thesemetabolic changes can be reversible with diseaserecovery, which may be important in light of thereversible volumetric changes
Autoimmune hypothesis
Rheumatic fever is considered to be an matory or autoimmune disorder so SC and PANDAShave 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 RHFtheir role in SC has not been studied However, onestudy has reported a modest upregulation of cytokineproduction in acute SC as a third of patients withacute SC had elevated Th1 or Th2 serum cytokinescompared to controls In cerebrospinal fluid (CSF)both IL-4 and IL-10 (Th2 cytokines) were raisedwhile the Th1 cytokine, INF-γ, was undetectable inacute SC Additional evidence for the importance
inflam-of Th2 cytokines and perhaps antibody production
Table 21.2 Pathological reports in Sydenham’s chorea.
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
Lhermitte and Pagniez, 1930 Inflammatory/degenerative Basal ganglia
Colony and Malamud, 1956 ?Degenerative Cortex and thalamic involvement
Trang 3came from the persistent SC results, as 50% of thesecases had raised CSF IL-4 levels, whereas other serumand CSF cytokines were within normal ranges.
Antibasal ganglia antibodies, ABGA
However, the majority of research has focussed onthe detection of antineuronal antibodies as an indic-ator of an autoimmune pathology in SC and PAN-DAS Husby in 1976 first described IgG antineuronalantibodies against neurons within the basal gangliausing 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, werealso positive The staining pattern was described
as cytoplasmic binding to caudate and subthalamicneurons with weaker staining in the cortex Thisantibody reactivity was removed by preincubatingpositive samples with extracts of streptococcus (Husby
et al., 1976) This led to the hypothesis that “basalganglia antibodies” could be produced as a conse-quence of molecular similarity (mimicry) betweenstreptococcal proteins and brain ones (Fig 21.3)
Later reports suggested that ABGA detected byindirect immunofluorescence (IF) were present in100% 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 blotting, a common methodology used in the iden-tification of paraneoplastic antibodies, has been used to detect basal ganglia antibodies Rather thanpolyspecific binding to basal ganglia proteins, react-ivity to discrete antigens of 40, 45, and 60 kDa hasbeen described (Church et al., 2002) (Fig 21.4)
immuno-A separate study using western immunoblottingwas less discriminating between SC and normal andneurological disease controls, but found increasedantibody activity using a soluble supernatant frac-tion from caudate nucleus (Morshed et al., 2001).However, the presence of the same antineuronalantibodies in PANDAS and particularly a small sub-group of patients with Tourette’s syndrome have led
to significant controversy regarding both their roleand presence (Kurlan, 1998; Singer et al., 2005a)
As naturally occurring autoantibodies are known
to exist secondary to local damage the ABGA responsesreported 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 timepoints in disease, may explain the differences in anti-body results (Martino et al., 2005) However, what
is clear is that the significance of these antineuronalantibodies must only be made in the context of theclinical 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.
Trang 4Poststreptococcal 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 wasbetween 2% and 4% (Douglass et al., 1995; Flament
et al., 1988; Valleni-Basile, 1994) We have shownthe 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 fromhuman basal ganglia The 45 and 98 kDa antigensare 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 react with α-enolase All the antigens are glycolyticenzymes and are involved in energy homeostasisand as expected are found in the cytosol These pro-teins are also located on the neuronal surface (Lim etal., 1983; Nakajima et al., 1994), where they appear
cross-to have “moonlighting” or alternative functions; e.g
enolase located on the surface of neurons acts as areceptor 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 trophicsupport to mesencephalic dopaminergic neurons(Nakajima et al., 1994) Membrane neuronal aldolaseprovides local membrane energy and is enzymatic-ally active (Bulliard et al., 1997) It also forms an oxidoreductase complex with enolase and other pro-teins on the neuronal membrane and is thought tomonitor oxidative stress and induce an appropriatecellular response (Bulliard et al., 1997) Aldolase bindstightly with ATPase protein pumps on the plasmamembrane allowing direct coupling of glycolysis tothe proton pump (Lu et al., 2001) The monomer ofpyruvate kinase acts as thyroid hormone (T3) bind-ing protein Binding of T3 to pyruvate kinase inhibitsenzymatic activity, suggesting that this process may
be centrally involved in the control of some cellularmetabolic effects induced by thyroid hormones (Kato et al., 1989) Interestingly, hyperthyroidism
is a well-described cause of chorea Membrane colysis provides a preferential source of ATP in order
gly-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 compartmentalizedATP 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 func-tions 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 ofthe bacterium and appears to function as an efficientplasmin(ogen) binding protein which influences tissue invasiveness and pathogenicity (Pancholi andFischetti, 1998) The streptococcal surface enolaseantibodies appear to recognize a shared epitope withneuronal surface and cytoplasmic enolase
An important question is whether or not ABGAare directly involved in the pathogenesis of these disorders or simply a diagnostic marker Two studiesinvestigating the effects of infusing serum immuno-globulin from patients with PANDAS into rat stria-tum found an increase in stereotypical movementscompared to control antibodies (Hallett et al., 2000;Taylor et al., 2002) However, another group usingthe same methods failed to reproduce the results(Loiselle et al., 2004) and a study to replicate theseresults was unsuccessful (Singer et al., 2005b) Acontrolled trial of treatment with either plasmaexchange or intravenous immunoglobulin (IVIg) inchildren with PANDAS demonstrated a significantimprovement in motor and psychiatric symptoms for both therapies compared to placebo (Perlmutter
et al., 1999) These observations and insights fromthe proposed treatment effects of IVIg suggest thatthese autoantibodies may be pathogenic
Phenotypic spread
As discussed above basal ganglia dysfunction hasvarious 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 gangliausing clinical criteria alone Although a particularphenotype can be typically associated with “specific”
Trang 5disease entities, for example chorea or tics in SC and
TS, respectively, one would expect from applyingbasic principles that immune-mediated basal gan-glia dysfunction should result in the full spectrum ofmovement and emotional disorders that have beenattributed to basal ganglia pathology Huntington’sdisease and Wilson’s disease, well-defined geneticdisorders with a predilection for the basal ganglia,are similarly associated with a wide spectrum of bothhyper- and hypokinetic movement disorders There-fore using a biomarker, such as ABGA, in addition tospecific clinical features, may be appropriate in definingthis 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 thesedisorders, suggests that they may represent one disease entity For example, patients with PANDASusually have psychiatric features and frequentlyhave choreiform movements Patients with SC oftenhave tics and OCD and patients with OCD often havetics and other subtle movement disorders If PAN-DAS, TS and OCD are the same disease as SC, whydon’t patients with these disorders have associatedRHF? A detailed cardiac evaluation of 60 subjectswith PANDAS did not reveal evidence of rheumaticcarditis (Snider et al., 2004) Whether or not sub-jects with ABGA have subtle cardiac involvementhas yet to be investigated systematically One could
speculate that the current strains of Streptococci that
induce neuropsychiatric disease are different fromthose that are capable of inducing rheumatic car-ditis These issues will hopefully be resolved with further research
Treatment
The treatment of SC is well established and can bedivided in symptomatic or disease-modifying strat-egies Antibiotic prophylaxis in subjects who have hadRHF and/or SC is essential and standard clinical practice (http://www.doh.gov.za/docs/facts-f.html).Recent studies suggest that antibiotic prophylaxismay be effective in reducing symptomatic exacer-bations in children with PANDAS Once-weekly
500 mg of azithromycin was effective in reducingboth 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 orplasma exchange in SC In a small study of five sub-jects treated with plasma exchange and four withIVIg (Garvey et al., 1996), subjects in both treatmentarms improved although the plasma exchange groupimproved 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
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
Trang 6Poststreptococcal movement disorders 247
children relapsed within four months of completingtreatment Several small studies have examined theeffectiveness of corticosteroids in SC A retrospectivestudy of eight subjects with SC showed rapid improve-ments with corticosteroids (Green, 1978) In anotherstudy five subjects with SC, refractory to standardsymptomatic therapy (valproate and neuroleptics),were treated successfully with intravenous methyl-prednisolone and then oral prednisolone
The only placebo-controlled trial examining thebenefit of immunomodulation (plasma exchange andIVIg) in PANDAS demonstrated improvements inthe patients treated with active agents compared topatients 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 patientswho did not have PANDAS, suggesting that the benefit
of immune modulation is restricted to the PANDASsubgroup of neuropsychiatric disorders (Nicolson et al.,2000) Currently, it is our recommendation thatimmune treatments should not be given routinely to
SC or PANDAS patients until further controlled trialsconfirm their benefit Carbamazepine and sodiumvalproate have been proposed to be useful sympto-matic treatments of SC, and are preferable to neuro-leptics (haloperidol and tetrabenazine), which cancause unacceptable side effects (Pena et al., 2002)
Interestingly, in some countries antibiotic phylaxis for rheumatic fever, which by definitionincludes Sydenham’s chorea, has now extended
pro-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 mostparts of the world GABHS remains sensitive to peni-cillin, which is the antibiotic of choice In subjects who cannot tolerate penicillin, macrolides are recom-mended although there is a risk of development ofantibiotic resistance
Summary
The identification of putative antigens would help todefine the existence and role of antineuronal anti-bodies in Sydenham’s chorea, PANDAS, and the con-troversial finding in a small subgroup of Tourette’ssyndrome A recent report suggested that brain-specific glycolytic enzymes: neuron-specific enolase,pyruvate kinase M1, and aldolase C might be putat-ive 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 usingbrain tissue, these results have not been reproduced(Singer et al., 2005b) An antibody response againstlysoganglioside has also been reported in SC (Kirvan
et al., 2003) The heterogeneity of antibody responses
in these disorders might suggest that a classic immune disorder is not supported The antineuronalresponses might be related to GABHS infection, transitory, of no functional role but useful for dif-ferential diagnosis Until methodological concernsare addressed, an autoimmune hypothesis of putat-ive poststreptococcal, extrapyramidal movementdisorders must be treated cautiously at present
sequelae Am J Med, 38, 89 – 93.
Asbahr, F.R., Ramos, R.T., Negrao, A.B and Gentil, V
1999 Case series: Increased vulnerability to compulsive symptoms with repeated episodes of
obsessive-Sydenham chorea J Am Acad Child Adolesc
Psychi-atry, 38, 1522– 5.
Ayoub, E.M 1992 Resurgence of rheumatic fever
in the United States: The changing picture of a
preventable illness Postgrad Med, 92, 133 –136,
139 – 42
Ayoub, E.M and Wannamaker, L.W 1966 Streptococcal
antibody titers in Sydenham’s chorea Pediatrics, 38,
946 – 56
Bhatia, K.P and Marsden, C.D 1994 The behaviouraland motor consequences of focal lesions in the basal
ganglia in man Brain, 117, 859 – 76.
Bouteile, E.M 1810 Traite de la Choree, ou Danse de
St Guy, Vincard, Paris.
Bronze, M.S and Dale, J.B 1993 Epitopes of coccal M protein that evoke antibodies that cross-
strepto-react with Human brain J Immunol, 151, 2820 – 8.
Brown, J., Bullock, D and Grossberg, S 1999 How the basal ganglia use parallel excitatory and inhib-itory learning pathways to selectively respond
to unexpected rewarding cues J Neurosci, 19,
aldolase C Biochem J, 324, 555 – 63.
Trang 7Cardoso, F 2002 Chorea gravidarum Arch Neurol, 59,
868 – 70
Cardoso, F., Vargas, A.P., Oliveira, L.D., Guerra, A.A
and Amaral, S.V 1997 Persistent Sydenham’s
chorea Mov Disord, 12, 701– 3.
Church, A.J., Cardoso, F., Dale, R.C., Lees, A.J.,Thompson, E.J and Giovannoni, G 2002 Anti-basal ganglia antibodies in acute and persistent
Sydenham’s chorea Neurology, 59, 227 – 31.
Church, A.J., Dale, R.C., Lees, A.J., Giovannoni, G andRobertson, M.M 2003 Tourette’s syndrome: A crosssectional study to examine the PANDAS hypothesis
J Neurol Neurosurg Psychiatry, 74, 602 – 7.
Colony, H.S and Malamud, N 1956 Sydenham’s
chorea A clinicopathologic study Neurology, 6,
672 – 6
Dale, R.C 2003 Autoimmunity and the basal ganglia:
New insights into old diseases Q J Med, 96, 183 – 91.
Dale, R.C., Candler, P.M., Church, A.J., Wait, R.,Pocock, J.M and Giovannoni, G 2006 Neuronalsurface glycolytic enzymes are autoantigen targets
in post-streptococcal autoimmune CNS disease J
Neuroimmunol, 172, 187– 97.
Dale, R.C., Church, A.J., Cardoso, F et al 2001
Poststreptococcal acute disseminated myelitis with basal ganglia involvement and auto-
encephalo-reactive antibasal ganglia antibodies Ann Neurol,
a birth cohort of 18-year-olds: prevalence and
pre-dictors J Am Acad Child Adolesc Psychiatry, 34,
1424 – 31
Dubinsky, W.P., Mayorga-Wark, O and Schultz, S.G
1998 Colocalization of glycolytic enzyme activityand KATP channels in basolateral membrane of
Necturus enterocytes Am J Physiol, 275, C1653 – 9.
Faustino, P.C., Terreri, M.T., da Rocha, A.J., Zappitelli, M.C., Lederman, H.M and Hilario, M.O
2003 Clinical, laboratory, psychiatric and magneticresonance findings in patients with Sydenham chorea
Neuroradiology, 45, 456 – 62.
Flament, M.F., Whitaker, A., Rapoport, J.L et al 1988
Obsessive compulsive disorder in adolescence: An
epidemiological study J Am Acad Child Adolesc
Psy-chiatry, 27, 764 – 71.
Freeman, J.M., Aron, A.M., Collard, J.E and MacKay,M.C 1965 The emotional correlates of Sydenham’s
chorea, Pedratrics, 35, 42 – 9.
Garvey, M.A., Swedo, S.E., Shapiro, M.B et al 1996
Intravenous immunoglobulin and plasmapheresis as
effective treatments of Sydenham’s chorea Neurology,
46, A147.
Gerfen, C.R 1984 The neostriatal mosaic: mentalisation of corticostriatal input and striatoni-
Compart-gral output systems Nature, 311, 461– 4.
Gibb, W.R., Lees, A.J and Scadding, J.W 1985
Persist-ent rheumatic chorea Neurology, 35(1), 101– 2.
Glaser, G.H 1952 Lesions of the central nervous
system in disseminated lupus erythematosus Arch
Neurol Psych, 67, 745.
Green, L.N 1978 Corticosteroids in the treatment of
Syednham’s chorea Arch Neurol, 35(1), 53 – 4.
Greenfield, J.G and Wolfsohn, J.M 1922 The pathology
of Sydenham’s chorea Lancet, 2, 603 – 6.
Giedd, J.N., Rapaport, J.L., Kruesi, M.J et al 1995.Sydenham’s chorea: Magnetic resonance imaging
of the basal ganglia Neurology, 45, 2199 – 202.
Guizzetti and Camisa 1911 Riv Sper de Fernait E di
of ATP in fueling Ca2+ uptake in smooth muscle
plasma membrane vesicles J Gen Physiol, 99(1),
21– 40
Harvier and Levanditi 1920 Bull et Mem de la Soc Med
des Hosp de Paris, xliv, t.iii:583.
Hattori, T., Takei, N., Mizuno, Y., Kato, K andKohsaka, S 1995 Neurotrophic and neuroprotect-ive effects of neuron-specific enolase on cultured
neurons from embryonic rat brain Neurosci Res, 21,
191– 8
Hornse, H., Banerjee, S., Zeitlin, H and Robertson, M
2001 The prevalence of Tourette syndrome in
13 –14-year-olds in mainstream schools J Child
Psychol Psychiatry, 42, 1035 – 9.
Husby, G., van de Rijn, I., Zabriskie, J.B., Abdin, Z.H.and Williams, R.C Jr 1976 Antibodies reactingwith cytoplasm of subthalamic and caudate nuclei
neurons in chorea and acute rheumatic fever J Exp
Med, 144, 1094 –110.
Jones, T.D and Bland, E.F 1935 Clinical significance
of chorea as a manifestation of rheumatic fever: a
study in prognosis JAMA, 105, 571– 7.
Jummani, R and Okun, M 2001 Sydenham chorea
Arch Neurol, 58, 311–13.
Kato, H., Fukuda, T., Parkison, C., McPhie, P and Cheng, S.Y 1989 Cytosolic thyroid hormone- binding protein is a monomer of pyruvate kinase
Proc Natl Acad Sci USA, 86, 7861– 65.
Kienzle, G.D., Breger, R.K., Chun, R.W., Zupanc, M.L.and Sackett, J.F 1991 Sydenham chorea: MR
manifestations in two cases AJNR Am J Neuroradiol,
12, 73– 6.
Trang 8Poststreptococcal movement disorders 249
Kiessling, L.S., Marcotte, A.C and Culpepper, L 1993
Anti-neuronal antibodies in movement disorders
Pediatrics, 92, 39 – 43.
Kirvan, C.A., Swedo, S.E., Heuser, J.S andCunningham, M.W 2003 Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea
Nat Med, 9, 914 – 20.
Kotby, A.A., El Badawy, N., El Sokkary, S., Moawad, H
and El Shawarby, M 1998 Antineuronal antibodies
in rheumatic chorea Clin Diagn Lab Immunol, 5,
836 – 9
Kurlan, R 1998 Tourette’s syndrome and “PANDAS”:
Will the relationship bear out? Pediatric immune neuropsychiatric disorders associated with
auto-streptococcal infection Neurology, 50, 1530 – 4.
Laplane, D., Levasseur, M., Pillon, B et al 1989
Obsessive-compulsive and other behavioural changeswith bilateral basal ganglia lesions A neuropsycho-logical, magnetic imaging and positon tomography
study Brain, 112, 699 – 725.
Lewy, F.H 1923 Die histopathologie der
choreatis-chen Erkrankungen Ztschr Neurol.u.Pschiat, 85,
rat brain synaptic plasma membranes J Neurochem,
41, 1177– 82.
Loiselle, C.R., Lee, O., Moran, T.H and Singer, H.S
2004 Striatal microinfusion of Tourette syndromeand PANDAS sera: Failure to induce behavioural
changes Mov Disord, 19, 390 – 6.
Lu, M., Holliday, L.S., Zhang, L., Dunn, W.A Jr andGluck, S.L 2001 Interaction between aldolase andvacuolar H+-ATPase: evidence for direct coupling
of glycolysis to the ATP-hydrolyzing proton pump
J Biol Chem, 276, 30407–13.
Marie, P and Tretiakoff, C 1920 Examen histologique
de centres nerveux dans un cas de choree aigue de
Sydenham Rev Neurol, 36, 603 – 6.
Martinelli, P., Ambrosetto, G., Minguzzi, E., Battaglia, S.,Rizzo, G and Scaglione, C 2002 Late-onset PANDAS
syndrome with abdominal muscle involvement Eur
Neurol, 48, 49 – 51.
Martino, D., Church, A.J., Dale, R.C and Giovannoni, G
2005 Antibasal ganglia antibodies and PANDAS
Mov Disord, 20, 116 –17.
Mercadante, M.T., Busatto, G.F., Lombroso, P.J et al
2000 The psychiatric symptoms of rheumatic fever
Am J Psychiatry, 157, 2036 – 8.
Moore, D.P 1996 Neuropsychiatric aspects of
Sydenham’s chorea: A comprehensive review J Clin
Psych, 57, 407–14.
Morshed, S.A., Parveen, S., Leckman, J.F et al 2001
Antibodies against neural, nuclear, cytoskeletal, andstreptococcal epitopes in children and adults with
Tourette’s syndrome, Sydenham’s chorea, and
auto-immune disorders Biol Psychiatry, 50, 566 – 77.
Nakajima, K, et al., 1994 Plasminogen binds fically to alpha-enolase on rat neuronal plasma
speci-membrane J Neurochem, 63, 2048 – 57.
Nakano, K 2000 Neural circuits and topographicorganisation of the basal ganglia and related regions
Brain Dev, 22(Suppl 1), S5 –S16.
Nausieda, P.A., Bieliauskas, L.A., Bacon, L.D., Hagerty, M., Koller, W.C and Glantz, R.N 1983 Chronicdopaminergic sensitivity after Sydenham’s chorea
Neurology, 33, 750 – 4.
Nicolson, R., Swedo, S.E., Lenane, M et al 2000 Anopen trial of plasma exchange in childhood-onsetobsessive-compulsive disorder without poststreptococ-
cal exacerbations J Am Acad Child Adolesc Psychiatry,
39, 1313 –15.
Pancholi, V 2001 Multifunctional alpha-enolase: Its
role in diseases Cell Mol Life Sci, 58, 902 – 20.
Pancholi, V and Fischetti, V.A 1998 Alpha-enolase, anovel strong plasmin(ogen) binding protein on the
surface of pathogenic streptococci J Biol Chem, 273,
14503 –15
Pena, J., Mora, E., Cardozo, J., Molina, O and Montiel, C
2002 Comparison of the efficacy of carbamazepine,haloperidol and valproic acid in the treatment of children with Sydenham’s chorea: Clinical follow-up
of 18 patients Arq Neuropsiquiatr, 60, 374 – 7.
Perlmutter, S.J., Leitman, S.F., Garvey, M.A et al 1999.Therapeutic plasma exchange and intravenousimmunoglobulin for obsessive-compulsive disorder
and tic disorders in childhood Lancet, 354, 1153 – 8.
Ring, H.A and Serra-Mestres, J 2002 Neuropsychiatry
of the basal ganglia J Neurol Neurosurg Psychiatry,
72, 12 – 21.
Rolls, E.T 1994 Neurophysiology and cognitive
functions of the striatum Rev Neurol (Paris), 150,
Neurology, 65, 1701– 7.
Singer, H.S., Mink, J.W., Loiselle, C.R et al 2005b.Microinfusion of antineuronal antibodies into rodentstriatum: failure to differentiate between elevated
and low titers J Neuroimmunol, 163, 8 –14.
Snider, L.A., Sachdev, V., MaCkaronis, J.E., St Peter, M.and Swedo, S.E 2004 Echocardiographic findings
in the PANDAS subgroup Pediatrics, 114, 748 – 51.
Snider, L.A., Lougee, L., Slattery, M., Grant, P andSwedo, S.E 2005 Antibiotic prophylaxis withazithromycin or penicillin for childhood-onset
neuropsychiatric disorders Biol Psychiatry, 57,
788 – 92
Special Writing Group of Committee of RheumaticFever, Endocarditis and Kawasaki Disease of the
Trang 9Council on Cardiovascular Disease of the Young ofthe American Heart Association 1992 Guidelines
for the diagnosis of rheumatic fever JAMA, 268,
2069 – 73
Swedo, S.E., Leonard, H.L., Garvey, M et al 1998
Pediatric autoimmune neuropsychiatric disordersassociated with streptococcal infections: clinical
description of the first 50 cases Am J Psychiatry, 155,
264 – 71 Erratum in: Am J Psychiatry, 155, 578.
Swedo, S.E., Leonard, H.L., Schapiro, M.B et al
1993 Sydenham’s chorea: Physical and
psycho-logical symptoms of St Vitus dance Pediatrics, 91,
706 –13
Sydenham, T 1848 The Entire Works of Thomas
Sydenham Vols 1 and 2, Sydenham Society, London;
Reprinted by ALA Classics in Medicine Society,Birmingham, 1979
Taranta, A and Stollerman, G.H 1956 The ship of Sydenham’s chorea to infection with Group A
relation-Streptococci Am J Med, 20, 170.
Taylor, J.R., Morshed, S.A., Parveen, S et al 2002 An
animal model of Tourette’s syndrome Am J Psychiatry,
159, 657– 60.
Valleni-Basile, L.A., Garrison, C.Z., Jackson, K.L et al
1994 Frequency of obsessive-compulsive disorder in
a community sample of young adolescents J Am Acad
Child Adolesc Psychiatry, 33, 782 – 91 Erratum in:
J Am Acad Child Adolesc Psychiatry, 1995, 34, 128 – 9.
Von Santha, K 1932 Ueber Gefassveranderungen
im Zentralnervensystem bei Chorea Rheumatica
Arch Path Anat, 287, 405.
Weindl, A., Kuwert, T., Leenders, K.L et al 1993.Increased striatal glucose consumption in Sydenham’s
chorea Mov Disord, 8, 437– 44.
Weiss, J.N and Lamp, S.T 1987 Glycolysis tially inhibits ATP-sensitive K+ channels in isolated
preferen-guinea pig cardiac myocytes Science, 238, 67– 9.
Yamashiro, K., Tomiyama, N., Ishida, A et al 1997.Characteristics of neurons with high frequency discharge in the central nervous system and theirrelationship to chronic pain Experimental and
clinical investigations Stereotact Funct Neurosurg,
68, 149 – 54.
Ziegler, Z.H 1927 The neuropathology findings in
case of Sydenham’s chorea J Nerv and Ment Dis, 65,
273
Trang 10Celiac disease (CD) was first described by Aretaeusthe Cappadocian, one of the most distinguishedancient Greek doctors of the first century AD In achapter entitled “on the celiac diathesis” from hisbook on chronic diseases he named this diseaseentity 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 Geegave a lecture entitled “On the celiac affection” at the Hospital for Sick Children, Great Ormond Street,London In it he acknowledged Areteaus’ contributionand went on to give an accurate description of CD inchildren based on his own clinical observations
With clinical manifestations primarily confined
to the gastrointestinal tract or attributable to sorption, it was logical to assume that the targetorgan and hence the key to the pathogenesis of thisdisease was the gut The first report of neurologicalmanifestations associated with CD was by Carnegie
malab-Brown in 1908 In his book entitled Sprue and its Treatment he mentioned two of his patients who
developed “peripheral neuritis” Elders reported theassociation between “sprue” and ataxia in 1925 Thevalidity of these and other such reports prior to 1960remains doubtful given that a precise diagnosis of CDwas not possible prior to the introduction of small-bowel biopsies
The treatment of CD remained empirical until theDutch pediatrician Willem Dicke noted the deleteri-ous effect of wheat flour on children with CD (Dicke
et al., 1953) Removal of dietary products containingwheat was shown to result in complete resolution
of the gastrointestinal symptoms and a resumption
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 stration of antibodies to the protein concerned.” Hewent on to demonstrate the presence of circulatingantibodies against gliadin, the protein responsiblefor CD (Taylor et al., 1961) These antibodies becameknown as antigliadin antibodies This provided furtherevidence that CD is immunologically mediated and thatthe immune response is not confined to the mucosa
demon-of the small bowel Antigliadin antibodies became auseful screening tool for the diagnosis of CD
In 1966, Marks and her colleagues demonstrated
an enteropathy in nine of 12 patients with dermatitisherpetiformis, an itchy vesicular skin rash mainlyoccurring over the extensor aspect of elbows andknees The enteropathy had a striking similarity tothat seen in CD (Marks et al., 1966) It was latershown that the enteropathy and the skin rash weregluten dependent but skin involvement could occureven without histological evidence of gut involve-ment This was the first evidence that the gut maynot be the sole protagonist in this disease
During the same year a landmark paper on 16patients with neurological disorders associated withadult CD was published (Cooke et al., 1966) Thiswas the first systematic review of the subject follow-ing 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 inflammatorychanges affecting both central and peripheral nervoussystems A striking feature was the loss of Purkinjecells with atrophy and gliosis of the cerebellum All
16 patients had evidence of severe malabsorption asevident by anemia and vitamin deficiencies as well asprofound weight loss
22
Neurological manifestations of gluten sensitivity
Marios Hadjivassiliou
Trang 11A number of case reports followed primarily based
on patients with established CD often with persistingtroublesome gastrointestinal symptoms who thendeveloped neurological dysfunction A review of allsuch reports (with biopsy-proven CD) from 1964 todate reveals that ataxia and peripheral neuropathyare the commonest neurological manifestationsseen in patients with established CD (Hadjivassiliou
et al., 2002a) Less common manifestations includedmyopathy, myoclonic ataxia, and myelopathy Anumber of patients with epilepsy associated withoccipital calcifications on CT and CD have also beendescribed (Gobbi et al., 1992), mainly in Italy Thevast majority of these cases present with epilepsy inchildhood Based on data from patients with estab-lished CD followed up in a gastrointestinal clinic ithas been estimated that neurological dysfunctioncomplicates 6% of cases (Holmes, 1997)
The immunology of celiac disease has been sued with renewed interest in the last 20 years or so,thanks to the work of a number of visionaries whowere prepared to abandon dogma and suggest thatthe definition of gluten sensitivity based solely onbowel involvement was outmoded This is what led
pur-to the modern definition of gluten sensitivity as “astate of heightened immunological responsiveness
in genetically susceptible individuals,” a definitionthat does not imply gut involvement is a prerequisitefor the diagnosis (Marsh, 1995) By altering thegluten load Marsh demonstrated a range of bowelmucosal abnormalities in patients with gluten sens-itivity, ranging from histologically normal to the flatdestructive lesion This observation suggests thatsome patients with gluten sensitivity can have a his-tologically normal mucosa with the only marker ofthe disease being the presence of circulating anti-bodies against the etiological agent or based on morerecent work the presence of IgA deposits against tissue transglutaminases in the small-bowel biopsies(Hadjivassiliou et al., 2006) The term celiac disease
is best reserved for those patients with evidence ofenteropathy on small-bowel biopsy
The realization that gluten sensitivity, as defined
by the presence of antibodies against the etiologicalagent (antigliadin antibodies), is a systemic diseasewith diverse manifestations of which enteropathy(celiac disease) and dermatopathy (dermatitis her-petiformis) are examples, together with the fact thatprevalence studies suggested that for every onepatient with CD presenting with gastrointestinalsymptoms there are eight patients without suchsymptoms (silent CD), led to the identification of
neurological dysfunction as another tion belonging to the spectrum of gluten sensitivity(Hadjivassiliou et al., 1996) Such neurologicalmanifestations can occur with or without the pres-ence of enteropathy (Hadjivassiliou et al., 1998;Hadjivassiliou et al., 2002a)
manifesta-Clinical phenotypes/prevalence/diagnosis
The commonest neurological manifestations of glutensensitivity perhaps have been shown to be ataxia(gluten ataxia) and peripheral neuropathy (glutenneuropathy) Additional manifestations are listed inTable 22.1 and include myopathies (Hadjivassiliou
et al., 1997), headache with white-matter malities on magnetic resonance imaging (MRI)(Hadjivassiliou et al., 2001), myelopathies andchorea (Pereira et al., 2004) The interesting rela-tionship of gluten sensitivity with stiff-person syn-drome will be discussed further in Chapter 23 Thedata in Table 22.1 are based on probably the largestseries of 300 patients who have been diagnosed withgluten sensitivity as a result of their neurologicalpresentation and have been seen and followed up
abnor-in a specialist gluten sensitivity/neurology clabnor-inic atThe Royal Hallamshire Hospital, Sheffield, UK overthe last 12 years
Prevalence studies suggest that gluten ataxiaaccounts for a substantial number of cases of idio-pathic sporadic ataxias ranging from 11 to 41%(Bürk, 2001; Hadjivassiliou et al., 2003b) Variation
in these figures may relate to the antigliadin assaysused, the prevalence of these antibodies in the healthypopulation, and the number of patients screened (anumber of studies have looked at very small numbers
of patients and controls making meaningful sions impossible) As antigliadin antibodies can also
conclu-be found in the healthy population (5 –12%) it is sible that in a proportion of patients with ataxia andpositive antigliadin antibodies these antibodies arecoincidental rather than being etiologically linked
pos-to the ataxia At present there is no marker that is100% specific to the neurological manifestations
of gluten sensitivity Antigliadin antibodies, ever (particularly of the IgG class), remain the mostsensitive marker of the whole spectrum of glutensensitivity Antiendomysium antibodies are specific
how-to the presence of enteropathy Anti-tissue glutaminase antibodies are also said to be specific forthe presence of enteropathy but in our extensiveexperience they are found to be positive in more than50% of patients with gluten ataxia at various titers