CHAPTER 22 Non-Degenerative Choreas 237 since patients may present with a variable combination of neu- rological and hepatic manife stations. In most instances, there is a combination of diff erent movement disorders, but a few subjects may present with isolated chorea. MRI of the brain shows not only images comp atible with cavitations in the basal ganglia (hyper- intense signal on T 2 and hypointense on T 1 ) but also a hyperin- tense T 1 signal in the pallidum, putamen, and upper brainstem . Th e latter has been interpreted as being caused by deposition of manganese (112). that parkinsonism and myoclonus, rather than chorea, are the most common movement disorders associated with SLE (125). Diabetes mellitus is the most common risk factor for vascular chorea \200\223hemiballism, a condition almost invariably seen among the elderly (83). Diabetes mellitus type 2 induces unilateral or bilateral chorea in association with hypersignal in the basal ganglia mostly, for unknown reasons, in patients of Asian background. Although the issue remains contentio us, most studies suggest that these neu- roimaging fi ndings are related to microhaemorrhag es (113 \200\223116). More recently, there is growing interest in the association of cho- rea and non-ketotic hyp erglycaemia in type 2 diabetes mellitus, a condition particularly common among patients wit h an Asian ethnic background. Unlike the usual neurological manifestations of non-ketotic h yperglycaemia, patients do not have change in the level of consciousness but develop unilat eral or generalized chorea \200\223 ballism. Th e MRI fi ndings are characteristic, with a hyperintense signal in the pallidum on T 1 possibly refl ecting microhaemor- rhages, althou gh it has been suggested that infl ammation may also play a role in the pathogenesis (113, 114). Once glycaemic control is achieved, there is gradual remission of chorea (115, 116). At the onset of the AIDS epidemic, neurological complications were oft en diagnosed in HIV- positive patients. Physicians diagnosed chorea \200\223ballism related to toxoplasmosis in around 3% of patients (107). With the introduction of highly active antiretroviral therapy, there has been a decline in the incidence of neurological complica- tions among HIV-positi ve subjects (126). Th ere are no recent data specifi cally related to the epidemiology of m ovement disorders, including chorea, in this particular population. Nevertheless, judg- ing from clinical experience as well as the limited number of new publications related to the issue, one can assume that chorea and other extrapyramidal syndromes have become much rarer among HIV-positive patients. A few patients with hyperthyroidism may develop generalized chorea, or even ballism, relate d to this endocrine dysfunction. Th e lack of structural changes in the brain, the appearan ce with onset of thyrotoxicosis, and remission with endocrine control suggest that the basa l ganglia dysfunction is induced by hormonal infl uences (117, 118). Other possible metabol ic causes of chorea are even rarer and include hypoglycaemia, renal failure, and ketogenic diet (1). Future developments Despite the accumulating evidence pointing to the autoimmune nature of SC, it still remains to be proved beyond any reasonable doubt that circulating anti-basal g anglia antibodies are relevant to the pathogenesis of this condition. Th is is not a questi on with interest limited to the academic world. It is beyond the scope of this chapter to t ackle the concept of PANDAS (pediatric autoim- to streptococcus). mune neuropsychiatric dis orders related However, it is worth mentioning that some have suggested that streptococcus- induced antibodies are responsible for triggering conditions such as tics, obsessive \200 \223compulsive disorders, etc. (127). If such a hypothesis is proved to be true, the epidem iological rel- evance of streptococcus-related neurological complications will increase sub stantially. Currently, the majority of studies fail to sup- port such a causal relationship between streptococcus and clinical phenomena other than chorea (128). However, there is a need to address whether anti-basal ganglia antibodies are capable of induc- ing functional changes in vivo . Controlled studies to investigate treatments for movement disorders assoc iated with SLE as well as PAPS are limited because of their rarity. As they are ubiquitous conditions, it is quite likely that collaborative multicentre studies may lead to new devel opments in their management. In the fi eld of AIDS-related chorea, there has been a decline in its occurrence with the use of highly active antiretroviral agents. However, it is rath er disappointing that these drugs have not succeeded in com- pletely preventing the develop ment of CNS complications of HIV infection. Th is suggests that there is a need for more ac tive agents, or perhaps drugs that act via mechanisms distinct from those that are tackled by currently available medications. Miscellaneous Focal choreic limb movements or hemichorea can be a rare pre- senting symptom of primary or secondary brain neoplasms involv- ing the basal ganglia, subthalamic nucleus , or adjacent areas. Th is type of presentation has been described most oft en for primary CNS lymphoma, but may occur with any type of subcortical tumor or even nonneoplastic struct ural disease disrupting striato-pallido- thalamo-cortical motor circuitry (119, 120). Th er efore brain imag- ing is mandatory in any new-onset focal or hemichoreic syndrome. Uncommon causes of chorea recently reported include giant tume- factive perivascular spaces (121), intracranial sewing needles (122), and psychiatric diseases (123). Finally, although there is a decline in the frequency of cerebral palsy, a multicentre study demonstrated that pall idal deep brain stimulation is an eff ective treatment for chorea and dystonia related to t his condition (124). Despite the fact that the results of this study are preliminary, it is an important investigation considering the current limited treatment options for chorea an d dystonia associated with cerebral palsy. Key advances SC has been considered to be an autoimmune form of chorea related to rheumatic fever since the 1970s. In the last few years growing evidence supporting such a theory has been reported. Th e use of contemporary immunological methods has demonstrated that the ma jority of patients with the acute form of SC have high titres of circulating antibodies, wh ich recognize antigens of streptococcus as well as the basal ganglia (11). Th ere is also s ome evidence indicat- ing that these anti-basal ganglia antibodies are capable of inducing functional changes in neural cells (13, 14). Recent studies indicate Conclusions SC remains as the most common cause of chorea in children worldwide. In additio n to chorea, patients with SC oft en have behavioral disorders, such as obsessions and hype ractivity. In most patients there is spontaneous remission aft er a few months. Oxford Textbook of Movement Disorders 238 However, in 25% of subjects the condition remains persistent. Treatment is based on use of antichoreic drugs as well as prophy- laxis of new streptococcus infections with penicillin. SLE and related conditions cause chorea and other movement disorders in less than 5% of pa tients. Despite the lack of controlled studies, these patients are treated with immunosuppr essive agents com- bined with anticoagulants when there are circulating antiphos- pholipid antibodies. Vascular disease is the most common cause of acute non-hereditary chorea among adults. Most patients are eld- erly with diabetes mellitus type 2 who present with sudden-o nset hemichorea \200\223hemiballism. Although spontaneous recovery is the rule, severe hype rkinesia requires treatment with antidopaminer- gic agents. Levodopa and dopamine agonists are the most com- mon agents leading to chorea in clinical practice, although the list of a gents implicated in the causation of this phenomenon is quite long. HIV remains as the most frequent infectious cause of chorea, despite the decline of neurological complications in AIDS with the introduction of highly active antiretroviral therapy. Finally, there are othe r less common causes of acquired chorea such as para- neoplastic syndromes, moyamoya diseas e, hyperthyroidism, liver failure, subdural haematoma, and brain neoplasms. 9. Cardoso F. Chorea gravidarum . Arch Neurol 2002; 59 : 868 \200\22370 . 10. Bronze MS, Da le JB. Epitopes of streptococcal M proteins that evoke antibodies that cross-reac t with hu man brain . J Immunol 1993; 151 : 2820 \200\2238 . 11. Church AJ, Cardoso F, Dale RC, et al. Anti-basa l ganglia antibodies in acute and persi stent Sydenham \200\231s chorea . Neurology 2002; 59 : 227 \200\22331 . 12. Kirvan CA, Cox CJ, Swedo SE, Cunningham MW. Tubulin is a neuro- nal target of autoantibodies in Sydenham \200\231s chorea . J Immunol 2007; 178 : 7412 \200\22321 . 13. Kirvan CA, Swedo SE, Heuser JS, Cunningham MW. 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Th e causative gene en codes a copper-transporting P-type ATPase named ATP7B on chromosome 13q14.3 (7 \200\2239). In non-isolated populations, disease-causing ATP7B mutations are scattered across the entir e coding region and the adjacent splice sites, but there may be particular \200\230mutatio n hot spots \200\231. Th e distribution and frequency of the individual mutations varies be tween populations, with H1069Q being the most common mutation in European patients of Cauca sian origin (10). Mutations in the promoter region and large-scale ATP7B rearrangements hav e been reported, but are extremely rare (11, 12). Th e illness is named aft er S.A. Kinnier Wilson (1878 \200\2231937) who was born in the US A, but studied Medicine in Edinburgh and trained under Joseph Babinski in Paris. In 1905, w hilst working at the National Hospital for Nervous Diseases, London, he saw a female patien t who had developed severe dysarthria, a fi xed smile, and a coarse tremor of her hands and feet. She died at the age of 29 years. Wilson performed the autopsy himself and described a cir- rhotic liver and bilateral symmetrical destruction of the lenticular nucleus. He sub sequently extended his study to other patients with similar presentations (1). In the past, the use of inaccurate genetic screening techniques, which are now outdated, an d occasional over-generous inclusion of patients with clinically unconfi rmed WD suggested that a substan- tial proportion of WD patients only had one or indeed no detectable ATP7B m utation. However, a recently undertaken service evalua- tion of the UK WD/ ATP7B diagnostic genetic service confi rmed the detection of two mutations in >95% of all patients, but onl y if the entire coding region is sequenced (Ann Dalton, personal communi- cation). In our v iew, it is much more likely that the very few remain- ing patients with clinically confi rm ed WD but only one (currently) detectable ATP7B mutation have an additional unusual mutatio n within ATP7B , such as sequence changes in as yet unidentifi ed regulatory regions within its introns, rather than suggesting genetic heterogeneity (i.e. the presence of a second W D gene). A role for copper as a possible pathogenic agent was fi rst sug- gested by Rumpel in 1913 w ho described increased copper content in the liver. Cummings then demonstrated that excess copper is present in both liver and brain of WD patients (2). Essential background Epidemiology Th e prevalence of WD is estimated to be 1:30 000 with a (heterozy- gote) ATP7B mutation carrier frequency in the general population of 1:90 (3). Ou r own genetic studies confi rm that the genetic preva- lence of ATP7B mutations in newborns is at least as high as this (unpublished data). One can then extrapolate these data to pre dict approximately 2000 cases of WD in the UK, or 10 000 cases in the USA. However, the num ber of clinically diagnosed cases of WD is substantially lower. Why? Reduced penetrance is well recognized in other autosomal recessively inherited metabolic disorders, and case repo rts suggest that it may also occur in individuals with two ATP7B mutations (4, 5). Alternat ively, unusual presentations of WD, perhaps mimicking late-onset neurodegenerative or psych iat- ric disorders, may be more common than previously thought. Th e most worrying, but pur ely speculative, explanation would be that a substantial proportion of WD patients die undi agnosed in infancy or childhood. In our view, reduced penetrance is the most likely Pathophysiology Copper is required for a wide range of crucial biochemical mecha- nisms suc h as cellular respiration, iron oxidation, neurotransmit- ter synthesis, antioxidant defens e and connective tissue formation (13). Th e average diet provides about 2 \200\2235 mg of copper per day, but only about 1 mg/day is needed (14). Copper is mostly absorbed in the du odenum and proximal small intestine. Bound to albumin and the amino acid histidine, it is t hen transported to the liver in the portal circulation. Excess copper is excreted into the bile, and it is this excretion which is impaired in WD. Th e protein encoded by the WD gene , the ATP7B protein, is a copper-transporting P-type ATPase. ATP7B protein is mainly expres sed in hepatocytes Oxford Textbook of Movement Disorders 242 and functions in the transmembrane transportation of copper within hepatocytes. Th e copper translocation cycle occurs in several stages, during which ATP hydrolysis drives the trans location of the copper: (1) binding of target ion; (2) binding of ATP to the nucleotide-bin ding (N) domain; (3) ATP hydrolysis and phosphor- ylation of the phosphorylation (P) domain ; (4) translocation of the target ion; (5) dephosphorylation of the P-domain by the actuato r (A) domain (15). neurological problems will manifest with a combination of these features. Th e frequency of the respective neurological features var- ies widely from one case series to the next and is summarized in Table 23.1. Terms such as \200\230fl apping tremor \200\231 or \200\230wing-beating tremor \200\231 a re frequently described as pathognomonic features for WD in the lit- erature, but any other , more common, type of tremor such as rest, action, and intention tremor can occur as well. Th e most common form of tremor may be an irregular, jerky, and somewhat asym- metrical dy stonic tremor combined with dystonic posturing and (action-induced) dystonia in the hands s uch as writer \200\231s cramp with abnormal fi ne fi nger movements on formal testing. Inde ed, WD can result in any form or distribution of dystonia, including gen- eralized, segment al, and multifocal dystonia (22). Common sub- types of focal dystonia, such as blepharospas m or torticollis, can be part of the dystonic presentation but isolated cervical dystonia i s unlikely to be due to WD (23). ATP7B mutations lead to impaired function of the ATP7B protein with reduced excretion of co pper into the bile, leading to increased copper levels in the liver and other organs, in pa rticular the brain. Excess copper leads to increased oxidative stress, mitochondrial dysfun ction, and cell death. Clinical presentation WD typically presents in the second or third decade of life. Patients with hepatic problems tend to present earlier than those with neu- ropsychiatric symptoms, the mean age of onset being 11 years for patients with hepatic problems compared with a me an age of 17 years for those with neurological symptoms in a large case series (16). A rece nt multinational study comprising 1223 patients con- fi rmed that about 90% of all patients become symptomatic below the age of 30 years (17). However, statistics and mean ages of on set help little if you are confronted with a patient in your own clinic who may or may not have WD. WD can start very early, the young- est case probably being a two-year-old child w ho presented with impaired liver function (18). More worryingly for adult neurolo- gists, a fi rst presentation of WD has also been reported in septua- genarians (19). Presentation a s late as this is likely to be very rare indeed but \200\230late-onset \200\231 WD, arbitr arily defi ned as patients only becoming symptomatic at age >40 years, is now well recogniz ed and, with 46/1223 (3.8%) of all WD patients included in the multi- national study mentio ned above, more common than perhaps pre- viously thought (17).