Antiphospholipid antibody syndrome Primary antiphospholipid syndrome is characterized by re current thrombosis and miscarriages in the setting of high titres of anti- bodies, either a nticardiolipin IgG or IgM, lupus anticoagulant, or anti-B2-glycoprotein 1 ( \200\230Sapporo criteria \200\231) (47). Chorea has been reported in 1.3% of patients (48). Th e clinical presentation resembles that of patients with SLE chorea. Imaging studies may be normal or m ay reveal non-specifi c changes that fail to explain the chorea. Th us, a functional, immun ologically mediated mechanism, rather than an ischaemic one, is suspected. Successful treat ment has occurred with corticosteroids, anticoagulants, aspirin, and dopamine antagonists. Hemidystonia, writer \200\231s cramp, and parkinsonism have also been reported in primary a ntiphospholipid syndrome. Sj gren \200\231s syndrome Sj gren \200\231s syndrome is associated with a wide range of neurologi- cal disorders, including rare movement disorders. Parkinsonism has been well described in association with Sj gren \200\231s syndrome. Clinically, patients have fea tures of atypical parkinsonism with very slow progression over time (49). A symmetric akine tic \200\223rigid syndrome, gait disorder, postural instability, and minimal tremor are typ ical (49). Lack of levodopa responsiveness is also typical (49). MRI may be normal or may r eveal multiple T 2 hyperintense lesions in periventricular, subcortical, and deep locations involving both gray and white matter (49). Pathophysiology is unclear, and response to imm unosuppressive therapy is unpredictable. Other movement disorders reported to occur in Sj gren \200\231s syndrome include cerebellar degeneration, chorea, and dystonia (50 \200 \22352). Hypothyroid states can lead to ataxia. Truncal ataxia is generally more prominent than appe ndicular ataxia (64). Th e ataxia improves as the patient becomes euthyroid. Parathyroid disease Hypoparathyroid states, both primary hypoparathyroidism and pseudo-hypo parathyroidism, are associated with move- ment disorders. Associated hypocalcaemia is respo nsible for the more common neurological complications such as tetany and neuromuscular irri tability, manifest as carpopedal spasm and Chvostek \200\231s sign (65). Calcifi cations oc cur in the basal gan- glia in most patients with primary hypoparathyroidism, but they do no t correlate well with the presence of movement disorders (66, 67). Chorea, paroxysmal dysto nias and choreoathetosis, and parkinsonism can all occur in hypoparathyroid states (67 \200 \22369). Th e pathophysiology is not well understood. In all the aforemen- tioned movement disorders, improvement occurs with treatment of the underlying hypoparathyroidism and assoc iated electrolyte abnormalities. Beh et \200\231s disease Beh et \200\231s disease can cause a variety of neurological symptoms including, rarely, movement disorders. Tremor, palatal myoclonus, chorea, oromand ibular dystonia, and parkinsonism have also been reported (53 \200\22356). CSF pleocytosis and elevated protein levels are common (56). MRI may be normal, or may reveal focal lesions throughout the brain (56). Pathologically, there may be scattered foci of necrosis, demyel ination, and scarring throughout the CNS (56). Response to immunosuppressive therapy is mix ed. Sarcoidosis Sarcoidosis is a systemic granulomatous disease that involves the CNS in approx imately 5% of cases (57). However, as many as Oxford Textbook of Movement Disorders 320 Diabetes mellitus Both hyperglycaemia and hypoglycaemia are rare causes of choreo- athetosi s (70, 71). When the cause is hypoglycaemia, the chorea usually resolves as blood sugar nor malizes; however, recurrent epi- sodes of hypoglycaemia have resulted in permanent bilatera l chorea (72). Th ere is a well-recognized syndrome of hemiballism \200\223hemi- chorea (HB \200\223HC) that occurs in diabetics with acute non-ketotic hyperosmolar hyperglycaemia in the range of 400 \200\2231000 mg/dl. Th is syndrome can sometimes be the presenting featur e of diabetes. Most reported cases have occurred in elderly women (73 \200\22376). Th e HB \200\223HC may resolve shortly aft er resolution of the hyperglycaemia, may improve slowly over months, or may be permanent (72 \200\22376). Brain MRI oft en reveals contralateral pu taminal hyperintensity on T 1 -weighted images (73). Th e pathophysiology of this disorder is uncertain, although dopamine hypersensitivity in postmenopausal women, co-existence of l acunar infarction in the contralateral basal ganglia, and increased blood fl ow in the cont ralateral striatum and thalamus have all been suggested as pathogenic factors (75, 76). If needed, treatment with dopamine receptor antagonists or tetrabenazine can be eff ective (73 , 77). Figure 29.2 and Video 29.4 feature a typical case. z Video 29.4 Th is 58-year-old man, who had not seen a physician in more than 30 years, was hospitalized for acute onset of right-sided hemichorea that began 4 weeks prior to admissi on. It started in the right arm but then disappeared for a week. Th e movement then recurre d and spread to involve both the right arm and leg. Upon admission, he was found to be in a hyperglycaemic non-ketotic state. Hospital work-up demonstrated a hemoglobin A1C of 14.8, with serum glucose as high as 401. CSF glucose was 113. An MRI scan showed hyperintensity o f the left striatum (Fig. 29.2). While in the hospital, he was started on treatment for his type 2 diabetes, and he was placed on risperidone for the involuntary movements. Movements diminished dramatically and the risperidone was eventually discontinued without recurrence . (Video courtesy of Dr Stewart Factor) Renal disease Multiple movement disorders, including tremor, ataxia, asterixis, myoclonus, and restless legs syndrome (RLS), can occur in the set- ting of renal failure and uraemic e ncephalopathy. Tremor usually manifests before asterixis and is coarse, irregular, absent a t rest, and most evident in the fi ngers of the outstretched hands. It may respond partiall y to beta-blockers (78). Multifocal myoclonus is common in uraemic encephalopathy, and both action myoclonus and stimulus-sensitive myoclonu s can occur (78 \200\22380). Myoclonus can oft en be treated eff ectively with benzodiazepi nes. Asterixis, or negative myoclonus, is a common sensitive early indication of urae- mic encephalopathy (81). RLS occurs in 15 \200\22320% of patients with chronic kidney disease ( 82). It can also occur in association with iron defi ciency, which is common in patients wi th renal disease. In addition to correcting the renal metabolic abnormality, dopamine agoni sts and levodopa are the fi rst-line treatments, followed by second-line agents such as ben zodiazepines, gabapentin, clonidine, and opioids. It may also be useful to utilize a lower- temperature dialysate, correct iron defi ciency, and treat anemia when present. RLS may imp rove dramatically aft er kidney transplantation (83, 84). Advances in transplant medicine have made kidney transplant a safer, more eff ective, and m ore widespread treatment option for patients with renal disease and therefore represent a k ey advance in the fi eld of renal disease. Liver disease Cirrhosis can lead to a variety of neurological complications, the most commo n being hepatic encephalopathy. Although movement disorders are uncommon in hepatic encepha lopathy, tremor, aster- ixis, and myoclonus can occur (85). More oft en, movement disor- de rs occur in patients with acquired hepatocerebral degeneration (AHD), which is a chronic pr ogressive neurological syndrome, characterized by parkinsonism, ataxia, and other movement disor- ders. AHD may occur in patients with advanced liver disease from any cause, especial ly those with portosystemic shunts. Rare cases have been reported in patients with portosys temic shunting in the absence of underlying hepatocellular disease, such as those with Fig. 29.2 T 1 axial MRI from a diabetic man presenting with right hemichorea in the context of acute non-ketotic hyperosmolar hyperglycaemia. Note the abnormal signal in the left str iatum. (Image courtesy of Dr Stewart Factor) CHAPTER 29 Systemic Disease and Movement Disorders 321 portal vein thrombosis (86). Portosystemic shunting may lead to AHD by allowing neurotoxins to bypass hepatic metabolism and enter the brain via the systemic circulation. While a pre cise neu- rotoxin has not been identifi ed, ammonia, aromatic amino acids, and manganese ar e candidates (87). Pathologically, there is patchy degeneration of neurons, with microcavit ation and pseudo-laminar necrosis in the deep cortical layers and basal ganglia (87, 88). I n contrast with hepatic encephalopathy, the movement disorders occurring in AHD are not ass ociated with a depressed level of con- sciousness (85). Th e exact prevalence of AHD is not known, but movement disorders are estimated to occur in 20 \200\22390% of patients awaitin g liver transplantation (89). AHD arises subacutely, and its course is highly variably, oft en not paralleling other features of liver disease. Parkinsonism, ataxia, dystonia, chorea , and orobuccolin- gual stereotypy, mimicking tardive dyskinesia, can occur in AHD (89). In contrast with Parkinson \200\231s disease, the parkinsonism associ- ated with AHD tends to be symmetric, more rapidly progressive, and is more likely to be associated with cognitive impairment and postural instability early in the disease course (90). Also, action tremor is far more common than resting tremor in AHD (90). Response to levodopa is inconsistent (8 9, 91). Th e diff erential diag- nosis of AHD is broad and includes hepatic encephalopathy, cen- tral pontine myelinolysis, alcoholic cerebellar degeneration, Wilson disease, and Wer nicke \200\231s encephalopathy. Brain MRI reveals very characteristic changes, including in creased T 1 signal in the pallidal nuclei. T 2 and postcontrast images are usually normal ( 85, 89). In contrast with hepatic encephalopathy, movement disorders in AHD typically do no t respond to ammonia-lowering agents. Hyperkinetic movements such as chorea and orobuccolin gual stereotypies can be treated with dopamine receptor antagonists, although these agents carry the risk of inducing tardive dyskinesia (TD). Tetrabenazine, a dopamine-depleting age nt, can be used without the risk of TD (44). Levodopa and dopamine agonists may be useful i n some patients with parkinsonism. AHD and its characteristic movement disor- ders may impr ove dramatically during the months following liver transplantation (92). (94). Abrupt ethanol withdrawal in physically dependent individu- als is associated with a tremor that is promptly relieved by alcohol ingestion or benzodiazepines. Th is tremor is d istal, coarse, irregu- lar, rapid, and worse with movement. If left untreated, delirium tre - mens may ensue (95). Alcohol withdrawal has also been reported to cause transient parkins onism in older individuals. Th e parkin- sonism remits spontaneously in a few days or weeks (96). Transient orolingual dyskinesias, sometimes involving neck and arm muscles, have als o been reported in the setting of alcohol withdrawal (97). Tremor can also be found in alcoholics who are not actively drinking or withdrawing. Th is tremor is usually a mild asymmet- ric postural tremor with a higher frequency than essentia l tremor. Beta-blocking drugs can also be eff ective in suppressing this tremor. A 3 Hz tre mor of the legs that is slow and rhythmic, involving fl ex- ion and extension of the hip gi rdle muscles, can also be seen in alcoholics. Th is tremor may aff ect gait (97). Long-standing alcohol abuse can lead to alcohol liver disease, which can ultimately cause a cquired hepatic encephalopathy and/ or hepatocerebral degeneration, both of which are assoc iated with movement disorders discussed earlier. Cerebellar ataxia is a feature of acute alcohol intoxication, and chronic alcohol dependenc e can be associated with vermal degen- eration and a syndrome of truncal ataxia. Pathologic ally, there is degeneration of the anterior superior aspect of the vermis. In severe cases, there may be atrophy of the cerebellar hemispheres. Th ere is oft en a striking loss of Pu rkinje cells (98). Infectious diseases Viruses Movement disorders such as hemichorea \200\223hemiballismus, my o- clonus, dystonia, tremor, parkinsonism, and akathisia have been identifi ed in 5 \200 \22344% of HIV/AIDS patients in prospective studies (99). Several pathogenic mechanisms are possible. HIV can directly involve the basal ganglia, thereby causing signifi cant motor d ys- function (100). Immunocytochemistry studies have revealed high viral loads in the basal ganglia and substantia nigra, and SPECT and PET studies lend further support to this mecha nism by dem- onstrating abnormal metabolic activity of the basal ganglia in HIV patients (1 01, 102). Alternatively, movement disorders can result from the presence of opportunistic i nfections (e.g. toxplasmosis), primary CNS lymphoma, progressive multifocal leucoencephalop - athy, or AIDS dementia complex (ADC). Lastly, HIV patients are signifi cantly more suscep tible to the development of extrapyrami- dal reactions when exposed to neuroleptics (103). Autopsy studies reveal severe neuronal loss in the basal ganglia, along with reactive glios is, and macrophage and multinucleated giant cell infi ltration, particularly in the putamen , caudate, and substantia nigra (102). Table 29.4 summarizes the common movement disorders reported in association with HIV/AIDs. Key advances in antiretroviral ther- apy have reduce d the frequency of ADC and severe opportunistic infections such as CNS toxoplasmosis, both of which are common causes of movement disorders in HIV/AIDS. Future developments are likel y to include improvements in the effi cacy and tolerability of antiretroviral therapy and t he development and widespread avail- ability of a vaccine to prevent HIV infection. Advances in transplant medicine have made liver transplant a safer, more eff ective, and mo re widespread treatment option for patients with liver failure and therefore represent a ke y advance in the fi eld. Toxic and nutritional de \201 ciencies Vitamin E malabsorption Any disease causing fat mal absorption (e.g. cystic fi brosis) can lead to tocopherol (vitamin E) defi ciency, which ma y produce neurolog- ical dysfunction aft er several years. A syndrome of spinocerebellar at axia and peripheral neuropathy is typical. Dysarthria, oculomo- tor abnormalities, ataxia, and loss of vibratory and position sense occur. Loss of myelinated nerve fi bres in the pos terior columns and CNS are seen pathologically (93). Oral or parenteral vitamin E sup- plem entation should be initiated to prevent ongoing neurological decline. Ethanol Although alcohol may have some benefi cial eff ects on movement disorders such as e ssential tremor and myoclonus \200\223dystonia syn- drome, when abused it can lead to a var iety of movement disorders Many other viruses can lead to movement disorders, but a detailed discussion of each one is beyond the scope of this chapter. Oxford Textbook of Movement Disorders 322 Table 29.4 Movement disorders occurring in association with HIV/AIDS Movement disorder Park insonism Etiology HIV infection, ADC, opportunistic infections (CNS toxoplasmosis or tuberculosis, W hipple \200\231s disease, PML), drug-induced (neuroleptics) Clinical features and comments Often atypical with symmetric signs, lack of rest tremor, an d early postural instability Tremor HIV infection, ADC, CNS tuberculosis, drug-induced (neuroleptics and TMP \200\223SMX) Usually mild bilateral postural tremor, though other types of tremor have been described Hemichorea \200\223ballism Opportunistic infections (CNS toxoplasmosis, cryptococcus, PML), ADC, HIV encephalitis Toxoplasma abscess in subthalamic nucleus is the most common cause; most common MD in HIV/A IDS Dystonia CNS toxoplasmosis, ADC, drug-induced (neuroleptics) Rare Myoclonus HIV infection, ADC, opportunistic infections (CNS toxoplasmosis, tuberculosis, herpes zoste r, PML) Rare reports of spinal, segmental, and generalized myoclonus Tic disorder CNS toxoplasmosis Single report of a dystonic tic involving ocular oral and cervical movements Paroxysmal dyskinesias ADC Rare reports of both kinesigenic and non-kinesigenic forms HIV, human immunode \201 ciency virus; ADC, AIDS dementia complex; CNS, central nervous sy stem; PML, progressive multifocal leucoencephalopthy, TMP \200\223SMX, trimethoprim \200 \223 sulfamethoxazole; MD, movement disorder. Adapted from Tse W, Cersosimo MG, Gracies JM, et al. Movement disorders and AIDS: a review. Parkinsonism Relat Disord 2004; 10: 323 \200\22334. Table 29.5 Viruses known to cause movement disorders Virus Japanese encephalitis by chorea, which is generalized in 80% of cases, but may also present as pure hemichorea in 20% of cases (104). Other features of SD can include ballism, facial grimacing, tics, dysa rthria, ocu- lomotor abnormalities, motor impersistence, gait abnormalities, seizures, hype ractivity, obsessions, compulsions, anxiety, and even psychosis (104). Movement disorder Parkinsonism, dystonia, chorea, tremor Encephalitis lethargica Parkinsonism, myoclonus, chorea, oculogyric crisis In \202 uenza Parkinsonism, chorea, dystonia, tremor High titres of antistreptolysin are typical but non-specifi c as group G is associated with similarly high titres. It is not yet clear whether identifi cation of the B-cell alloantig en D8/17, which indicates increased risk for rheumatic fever, may be useful as a diagnostic test (104). Imaging is usually normal, although some cases may show enlargement of the cau date, putamen, and glo- bus pallidus (36). PET and SPECT studies may show reversible striat al hypermetabolism (104). Autopsy studies show widespread cell loss in the basal ganglia, f rontal cortex, and temporal cortex, along with vasculitis of small vessels (104). Antineuro nal anti- bodies (ANABs) cross-reacting with caudate and subthalamic nuclei neurons have be en found in the serum of 95% of acute SD patients (105). Animal models suggest that ANABs c ause auto- immune subthalamotomy, leading to disinhibition of the ventro- lateral thalamus and subsequent hyperexcitability of the motor cortex (104). Arbovirus Parkinsonism Enterovirus Parkinsonism, chorea Epstein \200\223Barr virus Chorea, opsoclonus \200\223myoclonus Varicella-zoster virus Parkinsonism, chorea, opsoclonus \200\223myoclonus Cytomegalovirus Chorea Paramyxovirus Chorea Rubella virus Chorea Measles virus Parkinsonism, chorea, myoclonus (subacute sclerosing panencephalitis) Herpes simplex virus Tics, chorea Adapted from Cardoso F. Infectious and transmissible movement disorders. In: Jankovic J, To losa E (eds) Parkinson \200\231s disease and movement disorders (3rd edn), pp. 945 \200\223 66. Baltimore, MD: Williams & Wilkins, 1998. . In order to prevent SD, accurate diagnosis and proper antibiotic treatment of the acute pha ryngitis is needed. Symptomatic treat- ment can be achieved with valproic acid or neurolept ics until the condition spontaneously resolves. Prednisone was also shown to be eff ective in a double-blind placebo-controlled study (106). Table 29.5 lists the movement disorders associated with other viral infections. Bacteria Bacterial infections can lead to movement disorders through both antibody-mediated and direct mechanisms. Classic examples of both mechanisms are discussed below. Th e acronym PANDAS (pediatric autoimmune neuropsychiat- ric disorders aft er streptococcal infections) was introduced in 1998. According to this theory, which was based on an initia l series of 50 patients, a subset of patients with Tourette \200\231s syndrome, obsessive \200\223 compulsive disorder (OCD), and other neuropsychiatric disorders may be attributabl e to streptococcal infections (107). Five diagnos- tic criteria for PANDAS have been propos ed: the presence of OCD or tic disorder, pre-pubertal onset, abrupt onset and dramatic exac - erbations, temporal association with GABHS infection, and associ- ated neurological abnor malities. Th ese criteria are vague and have yet to be validated. Th us the PANDAS hypothes is remains contro- versial, and it is unclear whether PANDAS is simply a variant of SD Antibody-mediated disorders Sydenham \200\231s disease (SD) is a consequence of infection w ith group A beta-haemolytic streptococcus (GABHS). Th ough once relatively common, SD is no w encountered relatively rarely in developed countries because of the widespread use of ant ibiotics, which rep- resents a key advance. SD is most common between the ages of 8 and 9, is more common in females than males, and usually appears 1 \200\2236 months aft er the acu te pharyngitis (104). SD is characterized CHAPTER 29 Systemic Disease and Movement Disorders 323 or a separate entity (108). Over the past decade several studies have provided compelling d ata against any pathogenic link between PANDAS and Tourette \200\231s syndrome (109, 110). Table 29.6 Agents causing bacterial meningitis and movement disorders Mycoplasma pneumoniae Salmonella Legionella pneumophila Borrelia burgdorferi Treponema pallidum Streptococcus vi ridans Haemophilus in \202 uenzae Streptococcus pneumoniae Neisseria meningitides Direct mechanisms CNS tuberculosis can cause tremor, chorea, ballism, dystonia, myo- clonus , and parkinsonism. Both tuberculous meningitis and intra- cranial tuberculomas can cause m ovement disorders. Movement disorders may occur in up to 16.6% of tuberculous meningitis ca ses (1). Neuroimaging may be normal or may show ischaemic or haemorrhagic infarcts in the b asal ganglia (1). Alternatively, dif- fuse lesions at the diencephalic \200\223mesencephali c level can occur (1). Hydrocephalus is common (1). Th irty per cent of intracranial tuber- culomas are associated with movement disorders (111). Chorea and dystonia are associated w ith deep tuberculomas, while tremor is associated with surface lesions (111). Tremor and my oclonus can occur in spinal tuberculosis (1). Diagnosis is usually made via cul- ture of My cobacterium tuberculosis from CSF, although CSF PCR may also be useful in diagnosis. Th era py includes anti-tuberculosis drugs for a minimum of 6 months. Movement disorders generally improve within a few weeks. Adapted from Janavs JL, Amino \200 MJ. Dystonia and chorea in acquired systemic disorders. J Neurol Neurosurg Psychiatry 1998; 65: 436 \200\22345. opsoclonus \200\223myoclonus syndrome has been reported to respond well to oral clonazepam (115). Neurocysticercosis (NCC) is caused by the encysted larvae of the Taenia solium tapeworm. Mo vement disorders occur in 3.5% of cases of NCC, with parkinsonism and tremor being the most common (1). Rarely, chorea, myoclonus, hemifacial spasm, and dystonia have been described (1). Th e presence of cysts in the basal ganglia and related structures is the presumed pat hogenic mechanism. Chorea and dystonia are associated with deep lesions, while tremor is as sociated with surface cysts (1). Parkinsonism is associated with hydrocephalus (1). Movemen t disorders improve aft er treatment with albendazole, praziquantel, or surgery (1). Whipple \200\231s disease (WD) is a rare multisystem illness caused by Tropheryma whipplei infection. Classic WD is characterized by malabsorption with steatorrhoea, arthralgia and a rthritis, lym- phadenopathy, and rarely neurological involvement. Neurological symptoms inc lude dementia, visual impairment, papilloedema, supranuclear ophthalmoplegia, seizures, myo clonus, ataxia, and a depressed level of consciousness. Oculomasticatory myo- rhythmia is a movement disorder unique to WD in which there are slow, repetitive synchronous rhythmic co ntractions in ocu- lar, facial, and masticatory muscles (112). Ocular myorhythmia presents with continuous, horizontal, pendular, small-amplitude, vergence oscillations of the eyes, occurring approximately every second. Movements of the face and jaw may be somewhat quicker and resemble rhythmic myoclonus. Th ese movements may persist in sleep. In the past, diagn osis of WD was made by jejunal biopsy, which reveals macrophages laden with periodic acid \200\223Schiff -positive granules and bacilli within macrophages (113). Recent molecular ch aracterization of T. whipplei , a key advance in the fi eld, has enabled development of pol ymerase chain reaction (PCR) techniques for detection in various samples (113). Current rec ommended treatment is with oral administra- tion of trimethprim \200\223sulfamethoxazole fo r 1 \200\2232 years, preceded by parenteral administration of streptomycin and penicillin G or ceft riaxone for 2 weeks (113). Conclusion Th e variety of systemic diseases associated with movement dis- orders and the d iverse mechanisms whereby these diseases elicit abnormal movements pose a formidable challe nge for clinicians. Th e authors hope that the information in this chapter will serve as a guide for movement disorder clinicians in this oft en challenging process. Top clinical tips Movement disorders may be the presenting feature of a systemic disease. \227\206 Th e mechanisms by which systemic diseases lead to movement disorders are diverse, even wit hin the context of individual diseases. \227\206 Movement disorders may occur in the course of bacterial men- ingitis caused by a variety of organisms (see Table 29.6). Th e patho- genesis of these movement disorders is poorly unde rstood, and a detailed discussion of each causative agent is beyond the scope of this chapt er. In all cases, identifi cation and treatment of the underlying sys- temic disease is essenti al, although symptomatic treatment of the associated movement disorders may also be require d. Chorea, which can occur in all categories of systemic disease, is the most common sympto matic movement disorder. \227\206 \227\206 Parasitic infections Infection with Falciparum malaria can be complicated by move- ment dis orders. Cerebellar involvement with opsoclonus and tremor can occur acutely or as part of a delayed neurological syn- drome (114). Opsoclonus \200\223myoclonus syndrome, chorea, dyst onia, and parkinsonism have also been described (115). Th e patho- physiological mechanisms are uncertain. CT and MRI images are usually normal. Antimalarial treatments are essential . Th e References 1. Alarcon F, Gimenez-Roldan S. Systemic diseases that cause movement disorders. Parkinsonism Relat Disord 2005; 11 : 1 \200\2231 8 . 2. Kranick SM, Mowry EM, Colcher A, et al. 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