Th e iron accumulation disorders are generally, though not invar- iably, distinguishable fr om HD and the other look-alike syndromes through the ability of MRI to detect deposited iro n in brain tissue. In the absence of a known family history, targeted genetic testing CHAPTER 21 Huntington \200\231s Disease Look-Alikes 227 (a) PKAN (b) Neuroferritinopathy Fig. 21.2 MRI in brain iron accumulation disorders: (a) axial T 2 -weighted brain MRI in PK AN demonstrating the \200\230eye of the tiger \200\231 sign due to globus pallidus hypoint ensity (arrow head) containing a high intensity focus (arrow). (Image reproduced from Harti g MB et al. Genotypic and phenotypic spectrum of PANK2 mutations in patients with neurodege neration with brain iron accumulation. Ann Neurol 2007; 59: 248 \200\22356, by permission o f Wiley Interscience) (b) T 2 * MRI scan in neuroferritinopathy, showing reduced signal in the basal ganglia (arrow) and thalamus (arrow head). (Image reproduced from Chinnery PF et al. Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation, Brain 2007; 130: 110 \200\22319, by permission of Oxford University Press) Th e other brain iron accumulation diseases, although heteroge- neous, are suffi ciently di ff erent from Huntington \200\231s disease that they need not be considered look-alikes. Ac eruloplasminaemia, caused by CP mutations resulting in systemic absence of ceruloplasmin, h as adult onset and can produce chorea, but is dominated by retinal degeneration and diabete s mellitus in addition to blepharospasm, facial and neck dystonia, tremor, and ataxia. PLA2 G6 -associated neurodegeneration (PLAN), of which the most common presenta- tion is infanti le neuroaxonal dystrophy (INAD), generally causes rapidly progressive psychomotor, corticos pinal, cerebellar, and dystonic features in the presence of high brain iron. Likewise, fatt y acid hydroxylase-associated neurodegeneration (FAHN), Woodhouse \200\223Sakati syndrome, and Kufor \200\223Rakeb syndrome are dominated by dystonia and neurological and systemic fe atures not seen in HD (28). Choreocanthocytosi s is an autosomal recessive condition caused by mutations in the CHAC ge ne, encoding the chorein protein, which may resemble HD clinically. It causes a range of mo ve- ment disorders including chorea, tics, and dystonia. Later, patients develop dementia a nd psychiatric features similar to those seen in HD. Age at onset is younger than HD, on av erage, but there is substantial overlap. Th e defi ning characteristic of choreoacan- thocy tosis is dominant orofacial dystonia, commonly with tongue protrusion, with biting of the t ongue and lips, resulting in per- manent damage in some cases. In addition, seizures are se en in around half of cases, and other features such as neuropathy, distal amyotrophy, and e levation of serum creatine kinase are not shared with HD (32). MacLeod syndrome is another neuroacanthocytosis that may mimic HD. Caused by mutations in t he XK gene encoding the Kell erythrocyte antigen, its inheritance is X-linked recessive; sy mp- toms are restricted to hemizygous males, while females with a single mutant allele are asymptomatic carriers. However, in small pedigrees, the inheritance may be ambiguous. MacLe od syndrome patients experience limb chorea, facial tics, subcortical dementia, and neurops ychiatric problems, with less dystonia than is seen in choreoacanthocytosis. However, it al so produces non-HD-like fea- tures including axonal neuropathy, hepatosplenomegaly, cardiom y- opathy, and haemolytic anemia (32). Neuroacanthocytosis Conditions in which neurological symptoms are seen in the pres- ence of acanthocytes (erythrocytes with thorn-like protrusions) in peripheral blood are collective ly referred to as neuroacanthocyto- sis syndromes. Th is classifi cation is awkward, as sev eral conditions meeting these criteria belong primarily to other disease families because a canthocytosis was not part of the initial description, or because acanthocytes are seen onl y rarely. Hyperkinetic movement disorders appear to be a feature of the \200\230core \200 \231 neuroacanthocytosis syndromes; in addition to choreoacanthocytosis and MacLeod syndrom e, acanthocytes may be seen in both NBIA and HDL2, described above. Demonstrating the presence of acanthocytes in peripheral blood may be instructive in the cl inical assessment of an HD-like patient, but is not necessarily straightforward. Acanthocyt es are seen in many common systemic conditions, including hypothyroidism Oxford Textbook of Movement Disorders 228 and chronic renal failure, and therefore may be an incidental find- ing, statistically spea king, as often they are of no neurological significance. In addition, even in cases of neur oacanthocyto- sis, several blood films may be required and sample handling has a bearing on yield. \200\230True \200\231 acanthocytosis may be missed in a significant proportion of cases because of the use of dry blood smears or EDTA blood tubes. Instead, it is recommende d that whole blood is mixed in a one-to-one ratio with a solution containing 10 units of he parin per milliliter of normal saline; after 30 minutes of agitation, phase-contrast micros copy of a wet preparation should be used to examine for spiculated cells (the normal value is less than 6.3%) (33). This approach offers diagnostic sensitivity approaching 100% but i s not universally available; thus biochemical techniques such as Western blot- ting for cho rein protein, and of course genetic testing, may be needed in suspected neuroacanthocytosis cases whether or not acanthocytes have been found. whom negative genetic testing for Huntington \200\231s disease preceded a positive test for Friedreich \200\231s ataxia (4). Th e situation is not common but should be borne in mind. Other causes We recently reinvestigated our cohort in the light of the discovery of an expa nded hexapeptide repeat in the fi rst intron of the C9orf72 gene in familial frontotemporal dementia and motor neuron dis- ease (39, 40). Of 514 subjects, ten (2%) had the expansion. In our cohort, this is therefore the commonest genetic cause of HD-like clinical presentat ions (unpublished data). We therefore tentatively propose screening for this expansion in t he diagnostic workup of HD-like patients. Mutations in mitochondrial DNA, and in nuclear genes encod- ing mitochondrial proteins, can produce a notoriously broad spec- trum of symptoms, which is ever increasing as more mutat ions are described. Myoclonus and dystonia are the most common move- ment disorders seen in mitochondrial disease , but chorea can occur and may be accompanied by cognitive decline o r psychiatric fea- tures (37). Wilson disease Wilson disease (hepatolenticular degeneration), which is described in detail in Chapter 23, is a genetic disorder of cop- per metabolism with autosomal recessive inher itance caused by mutations in ATP7B encoding a copper-transporting ATPase protein. It produ ces a wide range of clinical phenotypes con- sisting of hepatic dysfunction, neurological s ymptoms, and psychiatric disorder. The presence of all three is rare, and pure neurological or neuropsychiatric presentations are common. The neurological spectrum of Wilson disease includes chorea, choreoathetosis, and dystonia, while the psychiatric features include depr ession, anxiety, and psychosis; frontal and subcor- tical cognitive decline is also seen. T hus, with the right com- bination of features, Wilson \200\231s disease may mimic Huntingto n \200\231s disease, closely or otherwise. Benign hereditary chorea , an autosomal dominant disorder caused by mutations in TITF1 enco ding thyroid transcription fac- tor 1, is, as the name suggests, generally a slowly progres sive condi- tion of isolated chorea, albeit with relatively young onset. However, atypical cases have been described with dystonia and gait distur- bance. Intellectual impairment (as distinct from cognitive decline) may also be seen (38). Certain cases may resemble HD, at least transiently, and the condition should be borne in mind. Acquired causes of HD look-alike syndromes are seldom seen because of the chronic degenerat ive nature of HD and its mimics. Chorea and neuropsychiatric symptoms are seen in Sydenham \200\231s chorea and other syndromes associated with anti- basal ganglia antibodies, althou gh these are usually subacute and self-limiting, or at least non-progressive. Systemic lupu s erythematosus (SLE) with CNS involvement and thyrotoxico- sis can both produce chorea and psychiatric manifestations, but are likewise distinguishable from HD on the basis of tempo and associated systemic features. Rarely, chronic small vessel disease may produce a hyper kinetic movement disorder with cognitive involvement, but not without pyramidal signs and t ypical MRI changes (39). It is particularly crucial to seek a diagnosis of Wilson disease in any HD-like patient lac king an autosomal dominant family history because the condition can be eff ectively treated by copper chelating treatments and other approaches. Th e majority of patients with neu- r ological manifestations \200\224though not all, as is sometimes claimed \200\224 have patho gnomonic Kayser \200\223Fleischer rings caused by copper deposition in the cornea; these ar e best seen on slit-lamp examina- tion by an experienced ophthalmologist. Biochemical testi ng may reveal typical abnormalities of copper metabolism: low serum caeru- loplasmin, high urinary copper, and high hepatic copper are the most reliable tests, but are best used in c ombination. Molecular genetic testing may be targeted to specifi c mutations depending on e thnic- ity; sequence analysis of the entire ATP7B is also available (34). Diagnostic yield A number of studies have sought to identify large cohorts of patients with HD look-alike syndromes by applying diff erent panels of genetic tests to each subject in order to screen for previ- ously described and novel genetic causes of such syndromes. Th e se cohorts generally consist of patients where there was a suspicion of HD suffi cient to j ustify genetic testing for that disorder, but the test was negative. Friedreich \200\231s ataxia Friedreich \200\231s ataxia has autosomal recessive inheritance and is the most prevalent cause of inherited ataxia. Th e vast majority of cases do not re semble Huntington \200\231s disease at all, but it is now accepted that chorea may be a fea ture alongside ataxia (35), while, conversely, Huntington \200\231s disease may produce cer ebellar ataxia and atrophy (36). We reported a patient homozygous for abnormal GAA tract ex pansions in the FRDA gene, who developed generalized chorea, eye-movement restriction, and cognitive impairment, alongside the more typical features of ataxia and sensory neuropathy, and in Such studies cannot be taken as being representative of HD look-alikes as a whole because t hey usually exclude very rare disorders, like DRPLA, and conditions where clinical features or non-genetic approaches, such as metabolic testing and slit-lamp examination in Wilson d isease or blood fi lm examination in choreoacanthocytosis, may reveal a diagnosis before HD genetic testing is contemplated. Nonetheless, such studies off er insights CHAPTER 21 Huntington \200\231s Disease Look-Alikes 229 into the relative frequencies of those conditions where genetic test- ing is useful. Howeve r, the overwhelming impression they give is pessimistic. Combining the results of fi ve HD look-alike cohorts, tested for a variable number of conditions, with 285 patients of our ow n, tested for nine genetic conditions, produced a diagnostic yield of only 2% for genetic t esting (see Fig. 21.1). Th is contrasts dra- matically with the 99% probability that a susp icion of Huntington \200\231s disease will be confi rmed by genetic testing, and suggests t wo con- clusions: fi rst, the majority of HD look-alike cases are caused by as yet unknown genetic (or non-genetic) factors; secondly, the patient in whom HD genetic testing is unexp ectedly negative should be counseled to prepare for a long diagnostic process with a very l ow probability of success. diagnostic techniques does suggest a rational strategy for the assess- ment of HD look-alik e patients, combining clinical assessment with non-genetic and genetic tests. Th is approac h is summarized in Fig. 21.3. Above all, it should be borne in mind that positive and negat ive genetic test results may have widespread ramifi cations for patients and family members , so expert neurogenetic counseling is essential throughout the process of investigation. S uch counseling is just as important in the symptomatic patient as when performed for predic tive testing, and when performed for an HD-like condi- tion rather than for Huntington \200 \231s disease itself. Th e presence of associated clinical features may be suffi cient to prompt directed genetic testing \200\224for instance, Kayser \200\223Fleischer rings in Wilson disease, myoclonic epilepsy in DRPLA, or prominent orofacial dystonia in choreoacanthocytosis. Directed non-ge netic testing is oft en cheaper and quicker than genetic test- ing, and may also be more se nsitive; thus, peripheral blood fi lms, repeated several times or prepared as suggested ear lier in this chap- ter, should be considered in all HD look-alike patients, and MRI scannin g with T 2 * or SWI sequences may disclose a wide variety of abnormalities such as focal at rophy, signal change, or brain iron accumulation. Nonetheless, the 2% of patients in whom a diagnosis is ultimately found do give an idea of the relative frequencies of each genetic cause. In that handful of patients, the most commo n diagnosis was SCA17, accounting for 44% of diagnoses; HDL2 accounted for 32%; the single Friedreich \200\231s ataxia case represented 15% of diag- noses; and familial prion disease (including HDL1) was found in 10% (see Fig. 21.1) (5). Where genetic testing is carried out, it should be approached rationally according to the p atient \200\231s clinical presentation and the likelihood of a positive result. In turn, th is depends on the relative frequencies presented above and in Fig. 21.1, and factors such a s Diagnostic approach Although the yield from genetic testing is starkly low, combining these relative frequencies with the clinical features and available HD Negative C9orf72 SCA17 Negative Ataxia or peripheral neuropathy? African heritage? Abnormal blood \201lm? Myoclonus or dementia? Abnormal MRI? Seizures? Prion disease Mitochondrial disease SCA1-3 Neuro- acanthocytosis Neuroferritinopathy NBIA HDL2 DRPLA Friedreich \200\231s ataxia Fig. 21.3 Suggested approach to directed genetic testing in Huntington \200\231s disease lo ok-alike syndromes. (Modi \201 ed from Wild E, Tabrizi S. Huntington \200\231s disease phe nocopy syndromes. Curr Opin Neurol 2007; 20: 681 \200\2237, by permission of Wolters Kluwer Health/Lippincott \200\223Williams & Wilkins) Oxford Textbook of Movement Disorders 230 family history and ethnicity. SCA17 is the most frequent cause of HD look-alike syndromes a nd should form the fi rst line of genetic testing, especially in patients with ataxia. HDL2 , although relatively common, is essentially confi ned to people with African ances- try. T h e presence of myoclonus or early dementia should prompt genetic testing for familial prio n disease, through PRNP sequenc- ing rather than targeted mutation analysis. Genetic testin g for other disorders should be considered on the basis of the clinical features described earlier and in Fig. 21.3 (5). 16. Schneider SA, van de Warrenburg BPC, Hughes TD, et al. Phenotypic homogeneity of the Hu ntington disease-lik e presentation in a SCA17 family . Neurology 2006; 67 : 1701 \200\223 3 . 17. Loy CT, Sweeney MG, Davis MB, et al. Spinocerebellar ataxia type 17: extension of pheno type with putaminal rim hyperintensity on magnetic resonance imaging . Mov Disord 2005; 20 : 1521 \200\2233 . 18. Rolfs A, Koeppen AH, Bauer I, et al. Clinical features and neuropathol- ogy of autosoma l dominant spinocerebellar ataxia (SCA17) . Ann Neurol 2003; 54 : 367 \200\22375 . 19. Shah AG, Friedman MJ, Huang S, Roberts M, Li XJ, Li S. Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocer- ebellar ataxia type 17 . Hum Mol Genet 2009; 18 : 4141 \200\22352 . Management Th e management of HD look-alike patients depends on whether a specifi c diagnos is is found (in which case the patient ceases to be an HD look-alike) and, if so, whether ( as in the case of Wilson disease) the diagnosis suggests particular treatments. In practice , for the vast majority of patients, management consists of supportive multidisci- plinary care, combined with an ongoing series of directed investiga- tions and, where possible, sto rage of DNA for research use and future clinical testing as it becomes available. As noted above, such care is best delivered through the specialist neurogenetics clinic. 20. Counts SE, Mufson EJ. Th e role of nerve growth factor receptors in cholinergic basal f orebrain degeneration in prodromal Alzheimer dis- ease . J Neuropathol Exp Neurol 2005; 64 : 263 \200\22372 . 21. Rong J, McGuire JR, Fang ZH, et al. Regulation of intracellular traffi ck- ing of hunti ngtin-associate d protein- 1 is critical for TrkA protein levels and neurite outgrowth . J Neurosci 2006; 26 : 6019 \200\22330 . 22. Schols L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias : clinical features, genetics, and pathogenesis . Lancet Neurol 2004; 3 : 291 \200\223304 . 23. Smith JK, Gonda VE, Malamud N. Unusual form of cerebellar ataxia; combined dentato-rubr a l and pallido-luysian degeneration . Neurology 1958; 8 : 205 \200\2239 . References 1. Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of the Huntington \200\231s disease mutation: the sensitivity and specifi city of measur- ing CAG repeats . N Engl J Med 1994; 330 : 1401 \200\2236 . 24. Koide R, Ikeuchi T, Onodera O, et al. Unstable expansion of CAG repeat in hereditary de ntatorubral-pallidoluysia n atrophy (DRPLA) . Nat Genet 1994; 6 : 9 \200\2231 3 . 25. Yamada M. Dentatorubral-pallidoluysia n atrophy (DRPLA) . Neuro- pathology 2010; 30 : 453 \200\2237 . 2. Bates G, Harper PS, Jones L (eds) Huntington \200\231s disease (3rd edn). Oxford : 26. Zhang S, Xu L, Lee J, Xu T. Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes . Cell 2002; 108 : 45 \200\22356 . Oxford University Press , 2002. 3. Douglas I, Evans S, Rawlins MD, et al. Prevalence of adult Huntington \200\231s disease in the UK based on diagnoses recorded in general practice records. J Neurol Neurosurg Psych iatry 2013: doi:10.1136/jnnp-2012-304636 4. Wild EJ, Mudanohwo EE, Sweeney MG, et al. Hunti ngton \200\231s disease phe- nocopies are clinically and genetically heterogeneous . Mov Di sord 2008; 23 : 716 \200\22320 . 27. Burke JR, Wingfi eld MS, Lewis KE, et al. Th e Haw River syndrome: den- tatorubropallid oluysian atrophy (DRPLA) in an African \200\223America n fam- ily . Nat Genet 1994; 7 : 521 \200\2234 . 28. Gregory A, Hayfl ick SJ. Genetics of neurodegeneration with brain iron accumulation . Curr Neurol Neurosci Rep 2011; 11 : 254 \200\22361 . 5. Wild EJ, Tabrizi SJ. Huntington \200\231s disease phenocopy syndromes . Curr 29. Ching KH, Westaway SK, Gitschier J, Higgins JJ, Hayfl ick SJ. HARP syn- drome is alleli c with pantothenate kinase-associate d neurodegeneration . Neurology 2002; 58 : 1673 \200 \2234 . Opin Neurol 2007; 20 : 681 \200\2237 . 6. Almqvist EW, Elterman DS, MacLeod PM, Hayden MR. High incidence rate and absent family h istories in one fourth of patients newly diag- nosed with Huntington disease in British Col umbia . Clin Genet 2001; 60 : 198 \200\223205 . 30. Hartig MB, H rtnagel K, Garavaglia B, et al. Genotypic and phenotypic spectrum of PA NK2 mutations in patients with neurodegeneration with brain iron accumulation . Ann Neurol 2006; 59 : 248 \200\22356 . 7. Moore RC, Xiang F, Monaghan J, et al. Huntington disease phenocopy is 31. Chinnery PF, Crompton DE, Birchall D, et al. Clinical features and natu- ral history of neuroferritinopathy caused by the FTL1 460InsA mutation . Brain 2007; 130 : 110 \200\223 19. a familial prion disease . Am J Hum Genet 2001; 69 : 1385 \200\2238 . 8. Mead S, Poulter M, Beck J, et al. Inherited prion disease with six octapep- tide repeat insertional mutation \200\224molecular analysis of phenotypic het- erogeneity . Brain 2006; 129 : 2297 \200\223317 . 32. Danek A, Walker RH. Neuroacanthocytosis . Curr Opin Neurol 2005; 18 : 386 \200\22392 . 9. Krause A, Hetem C, Holmes SE, Margolis RL. HDL2 mutations are an important cause of Hunt ington \200\231s disease in patients with African ances- try . J Neurol Neurosurg Psychiatr y 2005; 76 (Suppl 4): A16 \200\22326 . 33. Storch A, Kornhass M, Schwarz J. Testing for acanthocytosis. A prospec- tive reader-bli nde d study in movement disorder patients . J Neurol 2005; 252 : 84 \200\22390 . 10. Santos C, Wanderley H, Vedolin L, Pena SD, Jardim L, Sequeiros J. Huntington disease-li k e 2: the fi rst patient with apparent European ancestry . Clin Genet 2008; 73 : 480 \200 \2235 . 34. Ferenci P. Pathophysiology and clinical features of Wilson disease . Metab Brain Dis 2004; 19 : 229 \200\22339 . 35. Hanna MG, Davis MB, Sweeney MG, et al. Generalized chorea in two patients harboring the Friedreich \200\231s ataxia gene trinucleotide repeat expansion . Mov Disord 1998; 13 : 33 9 \200\22340 . 11. Walker RH, Jankovic J, O \200\231Hearn E, Margolis RL. Phenotypic features of Huntington \200\231s disease-lik e 2 . Mov Disord 2003; 18 : 1527 \200\22330 . 12. Rudnicki DD, Holmes SE, Lin MW, Th ornton CA, Ross CA, Margolis RL. Huntington \200\231 s disease-like 2 is associated with CUG repeat-containin g RNA foci . Ann Neurol 2007; 61 : 272 \200\22382 . 36. Rodda RA. Cerebellar atrophy in Huntington \200\231s disease . J Neurol Sci 1981; 50 : 147 \200\22357 . 37. Caer M, Viala K, Levy R, et al. Adult-onse t chorea and mitochondrial 13. Wilburn B, Rudnicki DD, Zhao J, et al. An antisense CAG repeat tran- script at JPH3 loc us mediates expanded polyglutamine protein toxicity in Huntington \200\231s disease-lik e 2 mice . Neuron 2011; 70 : 427 \200\22340 . cytopathy . Mov Disord 2005; 20 : 490 \200\2232 . 38. Kleiner-Fisman G, Rogaeva E, Halliday W, et al. Benign hereditary chorea: Clinical, genetic, and pathological fi ndings . Ann Neurol 2003; 54 : 244 \200\2237 . 14. Kambouris M, Bohlega S, Al-Tahan A, Meyer BF. Localization of the gene for a novel auto somal recessive neurodegenerative Huntington-lik e disorder to 4p15.3 . Am J Hum Genet 2000 ; 66 : 445 \200\22352 . 39. DeJesus-Hernandez, M, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011. 72(2): p. 245 \200\22356. 15. Stevanin G, Fujigasaki H, Lebre A-S, et al. Huntington \200\231s disease-lik e phenotyp e due to trinucleotide repeat expansions in the TBP and JPH3 genes . Brain 2003; 126 : 1599 \200\223603 . 40. Renton, AE, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromos ome 9p21-linked ALS-FTD. Neuron 2011. 72(2): p. 257 \200\22368. CHAPTER 22 Non-degenerative Choreas Francisco Cardoso Summary Non-genetic choreas can have myriad causes which fi t into the fol- lowing categori es: autoimmune, vascular, drug-induced, infectious, metabolic and toxic encephalopathy, and miscellaneous. Sydenham \200\231s chorea, an autoimmune condition related to streptococcal infec- tion, is the most common cause of chorea in children worldwide. In contrast, vascul ar disease, particularly in association with diabetes mellitus type 2, accounts for the maj ority of non-genetic choreas in adults. HIV infection, systemic lupus erythematosus, drugs, para- neoplastic syndromes, hyperthyroidism, brain neoplasms, etc. are also causes of chor ea. Th e aim of this chapter is to discuss the epi- demiology, clinical features, diagnosis , pathogenesis, and manage- ment of acquired causes of chorea. According to a recent study from Pennsylvania, Sydenham \200\231s cho- rea (SC) accounts fo r almost 100% of acute cases of chorea seen in children (2). Recent studies from Australia confi rm that it is a relatively common cause of acute chorea in children (3, 4). In con- t rast, the situation is quite distinct in adult patients. Although no published data are ava ilable, it is likely that levodopa-induced cho- rea in Parkinson \200\231s disease (PD) pat ients is the most common cause of chorea seen by neurologists. One study of consecutive pat ients seen at a tertiary hospital found that stroke accounted for 50% of all cases, drug ab use was identifi ed in a third of patients, and the remaining patients had chorea related t o AIDS and other infections as well as metabolic problems (5). Autoimmune choreas Sydenham \200\231s chorea SC, the most common form of autoimmune chorea world- wide, is a major feature of acute rheumatic fever (ARF), a non-suppurative complicat ion of group A beta-haemolytic streptococcus infection. Despite the decline of ARF, it rema ins as the most common cause of acute chorea in children in the USA and a major public heal th problem in developing areas of the world. Clinically, it is characterized by a combinati on of cho- rea, other movement disorders, behavioral abnormalities, and cognitive changes ( 1, 2, 6). Essential background Chorea is a hyperkinetic syndrome characterized by brief, abrupt invol untary movements resulting from a continuous fl ow of ran- dom muscle contractions. Th e pa ttern of movement may sometimes appear playful, conveying a feeling of restlessness to the observer. When choreic movements are more severe, assuming a fl inging, sometimes violent, character, they are called ballism. Regardless of its etiology, overall chorea has the same motor features, although the muscle tone varies depending on the underlying etiology (1). As several basal ganglia circuits are oft en involved in conditions associated with chorea, non-motor features such as subcortical cognitive decline, obsessions, compulsions, attenti on defi cit, etc. are oft en present in choreic syndromes. Chorea has both genetic causes, described in other chapters of this book, and non-genetic causes (Table 22.1). Th e latter include vascular choreas, autoimmune choreas, metabolic and toxic choreas, and drug-induced choreas. Th e aim of this chapter is to provide an overview of the main causes of non-here ditary choreas, discussing their clinical features, aetiol- ogy, and pathogenesis, and mana gement. As they represent separate entities, each category will be discussed separately, al though always following the same outline: etiology, pathophysiology, clinical fea- tures, d iagnosis, and management. Etiology and pathogenesis Taranta and Stollerman (7) established the casual relationship be tween infection with group A beta-haemolytic streptococci and the occurrence of SC (7). Bas ed on the assumption of molecular mimicry between streptococcal and central nervous system anti- gens, it has been proposed that the bacterial infection in genetically predisposed su bjects leads to formation of cross-reactive antibod- ies that disrupt basal ganglia functio n. Several studies have dem- onstrated the presence of such circulating antibodies in 50 \200\22390% of patients with SC (8, 9). A specifi c epitope of streptococcal M proteins tha t cross-reacts with basal ganglia has been identifi ed (10). In one study it was demonstrat ed that all patients with active SC have antibasal ganglia antibodies demonstrated by ELISA and Western blot. In subjects with persistent SC (duration of disease greater than 2 years despite best medical treatment) the positiv- ity was about 60% (11). Recently it was deter mined that neuronal tubulin is the target of antineuronal antibodies (12). It must be Epidemiology Although there are very few community-based studies available regarding the pr evalence and incidence of choreas as a whole, there is information regarding the situation in tertiary care centers. Oxford Textbook of Movement Disorders 232 Table 22.1 Non-genetic causes of chorea Immunological emphasized that the biological value of the antibasal ganglia anti- bodies remains to be de termined. However, one study suggests that they may interfere with neuronal function. Kirva n and col- leagues demonstrated that the IgM of one patient with SC induced expression of c alcium-dependent calmodulin in a culture of neu- roblastoma cells (13). Our fi nding that t here is a linear correlation between the increase of intracellular calcium levels in PC12 c ells and antibasal ganglia antibody titre in the serum from SC patients further strengthens the hypothesis that these antibodies have a pathogenic role (14). \227\206 Sydenham \200\231s chorea and variants (chorea gravidarum and contraceptive-induc ed chorea) \227\206 Systemic lupus erythematosus \227\206 Antiphospholipid antibody syndr ome \227\206 Paraneoplastic syndromes \227\206 Acute disseminated encephalomyelopathy \227\206 Coeliac disease Drug-related \227\206 Amantadine \227\206 Amphetamine \227\206 Anticonvulsants (carbamazepine, phenyt oin, lamotrigine, valproic acid) \227\206 Carbon monoxide \227\206 Calcium-channel blocke rs (cinnarizine, \202 unarizine) \227\206 CNS stimulants (methylphenidate, pemoline, cyp roheptadine) \227\206 Cocaine \227\206 Dopamine agonists \227\206 Dopamine receptor bloc kers \227\206 Ethanol \227\206 Levodopa \227\206 Levo \202 oxacin \227\206 Lithium \227\206 Sympathomimetics \227\206 Th eophylline \227\206 Tricyclic antidepressants Although some investigations suggest that susceptibility to rheu- matic chorea is linked to human leucocyte antigen-linked antigen expression (15), others fail to identify any relati onship between SC and human leucocyte antigen class I and II alleles (16). However, an inve stigation has shown that there is an association between HLA-DRB1*07 and recurrent streptoc occal pharyngitis and rheu- matic heart disease (17). Th e genetic marker for ARF and relat ed conditions was the B-cell alloantigen D8/17 (18). Despite reports claiming high specifi city and sensitivity from the group which developed the assay (19, 20), the fi ndings of ot her authors suggest that the D8/17 marker lacks both specifi city and sensitivity (1). Anot her suggested genetic risk factor for the development of ARF, but not SC, is polymorphisms within the promoter region of the tumor necrosis factor-alpha gene (21). Because of diffi culties in accounting for the pathogenesis of SC with the molecular mimicr y hypothesis, studies have addressed the role of immune cellular mechanisms in this conditi on. In an investigation of sera and cerebrospinal fl uid (CSF) samples from patients of the Movement Disorders Clinic, Federal University of Minas Gerais, Brazil, Church and colleagu es (22) found elevation of cytokines that take part in the Th 2 (antibody-mediated) respons e, interleukins 4 (IL-4) and 10 (IL-10), in the serum of acute SC com- pared with persisten t SC (22). Th ey also described raised IL-4 and Il-10 in 31% of the CSF of patients with ac ute SC, whereas only IL-4 was raised in the CSF of patients with persistent SC. Th e author s concluded that SC is characterized by a Th 2 response. However, as they found an elevatio n of IL-12 in acute SC and, more recently, an increased concentration of chemokines CXCL9 a nd CXCL10 in the serum of patients with acute SC (23), it can be concluded that Th 1 (cell- mediated) mechanisms may also be involved in the pathogen- esis of this disorder. A recent investigation confi rmed that cellular immune mechanisms might be relevant to the pathogene sis of SC because there is a monocyte dysfunction (24). Infections \227\206 AIDS related (toxoplasmosis, progressive multifocal leucoencephalopathy, HIV encephalitis) \227\206 Bacteria Diphtheria \200 Scarlet fever \200 Whooping cough \227\206 Encephalitis B19 parvovirus \200 Japanese encephalitis \200 Measles \200 Mumps \200 West Nile Ri ver encephalitis \200 Others \227\206 Parasites Neurocysticercosis \227\206 Protozoan \200 Malaria \200 Syphilis Endocrine-metabolic dysfunction \227\206 Adrenal insu \203 ciency \227\206 Hyper/hypocalcaemia \227\206 Hyper/hypoglyca emia \227\206 Hypomagnesaemia \227\206 Hypernatraemia \227\206 Liver failure Currently, the weight of evidence suggests that the patho- genesis of SC is related to circ ulating cross-reactive antibodies. Streptococcus-induced antibodies can be associated with a form of acute disseminated encephalomyelitis characterized by a high frequency of dystoni a and other movement disorders as well as basal ganglia lesions on neuroimaging (25). Antin eural and anti- nuclear antibodies have also been found in patients with Tourette \200\231s syndrome, but their relationship with prior streptococcus infection remains equivocal (26) . Vascular \227\206 Post-pump chorea (cardiac surgery) \227\206 Stroke \227\206 Subdural haematoma It remains unclear why up to 50% of patients with SC develop a persistent course of the ill ness. In this subset of individuals, the titres of antibasal ganglia antibodies are low. Ta king into account this fi nding as well as our observation that serum brain-derived neurotr ophic factor (BDNF) levels are high in this group of patients, it can be hypothesized that the acute immune process causes struc- tural brain lesions, resulting in permanent dysfunct ion of the basal ganglia (27). Miscellaneous \227\206 Anoxic encephalopathy \227\206 Cerebral palsy \227\206 Kernicterus \227\206 Mu ltiple sclerosis \227\206 Normal maturation (<12 months old) \227\206 Nutritional (e.g. B 12 de \201 ciency) \227\206 Posttraumatic (brain injury) CHAPTER 22 Non-Degenerative Choreas 233 Clinical features Th e usual age of onset of SC is 8 \200\2239 years, but there are reports of patients who developed chorea during the third decade of life. In most series, there is a female preponderance (28). Typically, patients develop this disease 4 \200\2238 weeks af t er an episode of group A beta-haemolytic streptococcal pharyngitis. It does not occur aft er streptococcal infection of the skin. Th e chorea spreads rapidly and becomes generalize d, but 20% of patients remain hemichoreic (28, 29). Patients display motor impersistence, p articularly noticeable during tongue protrusion and ocular fi xation. Th e muscle tone is u sually decreased; in severe and rare cases (8% of all patients seen at the Movement Disorde rs Clinic of the Federal University of Minas Gerais, Brazil), this is so pronounced that th e patient may become bedridden (chorea paralytica). results were generally replicated by a more recent study which found that patients with ARF without chorea had more obses- sions and compulsions than healthy controls (44). Th is stu dy also tackled the issue of hyperactivity and attention defi cit disorder in SC and found that 45% of 22 patients met criteria for this con- dition. Maia and colleagues (45) investi gated behavioral abnor- malities in 50 healthy subjects, 50 patients with rheumatic fever w ithout chorea, and 56 patients with SC (45). Th e authors found that obsessive \200\223comp ulsive behavior, obsessive \200\223compulsive dis- order, and attention defi cit and hypera ctivity disorder were more frequent in the SC group (19%, 23.2%, and 30.4%, respectively) t han in the healthy controls (11%, 4%, and 8%, respectively) and in the patients with ARF wi thout chorea (14%, 6%, and 8%, respectively). In this study, the authors demonstrated that obses- sive \200\223compulsive behavior displays little degree of interference in the perfo rmance of the activities of daily living. Another study compared the phenomenology of obses sions and compulsions of patients with SC with subjects diagnosed with tic disorders. Th e authors showed that the symptoms observed among the SC patients were diff erent from those reported by patients with tic dis- orders, but were similar to those previously noted among samples of pediatric patients with primary obsessive \200\223compulsive disor- der (46). A nother investigation comparing healthy controls with patients with rheumatic fever showed t hat obsessive \200\223compulsive behavior is more commonly seen in patients with SC with re la- tives who also have obsessions and compulsions (47). Th is study makes clear that there is interplay between genetic factors and environment in the development of behavioral prob lems in SC. We recently reported that SC may rarely induce psychosis or tri- chotillomania during the acute phase of the illness (48, 49). Patients oft en display other neurological and non-neurological symptoms and signs. Th ere are reports of common occurrence of tics in SC. However, it is virtually impossible to dist inguish simple tics from fragments of chorea. Even vocal tics, found in 70% or more of pati ents with SC in one study, are not a simple diagnosis in patients with hyperkinesias (30). In a cohort of 108 SC patients carefully followed up at our unit, we have identifi ed vocal izations in just 8% of subjects. We have avoided the term \200\230tic \200\231 because the re was no premonitory sign or complex sound and, conversely, the vocalizations were associa ted with severe cranial chorea. Taken together, these fi ndings suggest that the involuntar y sounds present in a few patients with SC result from choreic contractions of the upper re spiratory tract muscles rather than true tics (31, 32). Th ere is evidence that many patien ts with active chorea have hypometric saccades, and a few of them also show oculogyric cris is. Dysarthria is common and there is also impairment of verbal fl uency. In fact, a case \200\223control study of patients described a pattern of decreased verbal fl uency which re fl ected reduced phonetic, but not semantic, output (33). Th is result is consistent with d ysfunction of the dorsolateral prefron- tal \200\223basal ganglia circuit. In a recent stud y of adults with SC, we have extended this fi nding, showing that many functions that depen d on the prefrontal area are impaired in these patients. Th e conclusion of this study is t hat SC should be included among the causes of dysexecutive syndrome (34, 35). Prosody is al so aff ected in SC. One investigation of 20 patients with SC has shown decreased vocal tess itura and increased duration of the speech (36 \200\22338). Interestingly, these fi ndings are similar to those observed in PD (39). In a survey of 100 patients with rheu- matic feve r, half of whom had chorea, we found that migraine is more frequent in SC (21.8%) than in n ormal controls (8.1%, p = 0.02) (40). Th is is similar to what has been described in Touret te \200\231s syndrome (41). In the older literature, there are also references to papilloed ema, central retinal artery occlusion, and seizures in a few patients with SC.