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Changes in prevalence, severity, and recov- ery in tardive d yskinesia with age. Arch Gen Psychiatry 1980; 37 : 1368 \200\2237 3 . 78. Gogtay N, Sporn A, Alfaro CL, et al. Clozapine-induce d akathisia in children with schi zophrenia. J Child Adolesc Psychopharmacol 2002; 12 : 347 \200\2239 . 54. Kane JM, Smith JM. Tardive dyskinesia: prevalence and risk factors, 1959 79. Braude WM, Barnes TRE. Late-onse t akathisia \200\224an incident of covert to 1979. Arch Gen Psychiatry 1982; 39 : 473 \200\2238 1 . dyskinesias: two case reports. Am J Psychiatry 1983; 140 : 611 \200\2231 2 . 55. Morgenstern H, Glazer WM. Identifying risk-factor s for tardive dyski- nesia among long -ter m outpatients maintained with neuroleptic medi- cations. Arch Gen Psychiatry 1993; 50 : 723 \200\2233 3 . 80. Burke RE, Kang UK, Jankovic J, et al. Tardive akathisia: an analysis of clinical featur es and response to open therapeutic trials. Mov Disord 1989; 4 : 157 \200\2237 5 . 56. 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A risk-benefi t assessment of vigabatrin in the 95. Hennings JM, B tzel KE, Wetter TC. Successful treatment of tar- dive lingual dystoni a with botulinum toxin: case report and review of the literature. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32 : 1167 \200\2237 1 . treatment of neurological disorders. Drug Saf 1994; 10 : 395 \200\22340 5 . 85. Pappa S, Tsouli S, Apostolou G, et al. Eff ects of amantadine on tardive dyskinesia: a randomized, double-blin d, placebo-controlled study. Clin Neuropharmacol 2010; 33 : 271 \200\2235 . 96. Gardos G, Cole JO, Tarsy D. Withdrawal syndromes associated with 86. Duncan E, Adler L, Angrist B, Rotrosen J. Nifedipine in the treatment of antipsychotic drugs. Am J Psychiatry 1978; 135 : 1321 \200\2234 . tardive dyskinesia. J Clin Pharmacol 1990; 10 : 414 \200\2231 6 . 97. Delay J, Pichot P, Lemperiere T, Elissalde B, Peigne F. [A non-phenothiazin e and non-r eserpin e major neuroleptic, haloperidol, in the treatment of psychoses.] Ann Med Psychol ( Paris) 1960; 118 : 145 \200\2235 2 . 87. Loonen AJ, Verwey HA, Roels PR, et al. Is diltiazem eff ective in treating the symptoms of (tardive) dyskinesia in chronic psychiatric inpatients? J Clin Psychopharmacol 1992; 12 : 39 \200\2234 2 . 88. Nishikawa T, Tanaka M, Tsuda A, et al. Clonidine therapy for tardive dys- kinesia and r elated syndromes. Clin Neuropharmacol 1984; 7 : 239 \200\2234 5 . 89. Aia PG, Revuelta GJ, Cloud LJ, et al. Tardive dyskinesia. Curr Treat 98. Naganuma H, Fujii I. Incidence and risk factors in neuroleptic malig- nant syndrome. Acta Psychiatr Scand 1994; 90 : 424 \200\2236 . 99. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Options Neurol 2011; 13 : 231 \200\2234 1 . Am 1993; 77 : 185 \200\22320 2 . 90. Adler LA, Rotrosen J, Edson R, et al. Vitamin E treatment for tardive dyskinesia. Veter ans Aff airs Cooperative Study #394 Study Group. Arch Gen Psychiatry 1999; 56 : 836 \200 \2234 1 . 100. Robottom BJ, Weiner WJ, Factor SA. Movement disorders emergencies. Part 1: Hypokinetic disorders. Arch Neurol 2011; 68 : 567 \200\2237 2 . 101. Pearlam CA. Neuroleptic malignant syndrome: a review of the litera- 91. Slotema CW, van Harten PN, Bruggeman R, et al. Botulinum toxin in the treatment of orof acial tardive dyskinesia: a single blind study. Prog Neuropsychopharmacol Biol Psychiatry 2 008; 32 : 507 \200\2239 . ture. J Clin Psychopharmacol 1986; 6 : 257 \200\2237 3 . 102. Neuhut R, Lindenmayer JP, Silva R. Neuroleptic malignant syndrome in children and adol escents on atypical antipsychotic medication: a review. J Child Adolesc Psychopharmacol 200 9; 19 : 415 \200\2232 2 . 92. Welter ML, Grabli D, Vidailhet M. Deep brain stimulation for hyperki- netics disorders: dystonia, tardive dyskinesia, and tics. Curr Opin Neurol 2010; 23 : 420 \200\2235 . 103. Strawn JR, Keck PE, Jr, Caroff SN. Neuroleptic-malignan t syndrome. Am J Psychiatry 2007; 164 : 870 \200\2236 . 93. Fahn S. Th e tardive syndromes: phenomenology, concepts on patho- physiology and treatm ent. A comprehensive review of movement disor- ders for the clinical practitioner. 2003, 18 1 \200\22326 5 . This page intentionally left blank CHAPTER 29 Systemic Disease and Movement Disorders Leslie J. Cloud and Joseph Jankovic Summary Systemic illness is oft en complicated by the development of move- ment disorders, and the spectrum of movement disorders occur- ring in systemic diseases is as diverse as th e spectrum of diseases eliciting them. While movement disorders oft en develop in patients with a known systemic illness, they can sometimes be the present- ing feature of a systemic disease (1). Although pregnancy is not considered an \200\230illness \200\231, there are many movement disorders asso- ciated with this condition (2). Recognition and treatment of the underlying condition or a systemic disorder is essential for the opti- mal management o f associated abnormal movements. Th erefore, when evaluating patients with movement disorde rs, clinicians should carefully consider all medical historical details, associated symptom s and signs, and risk factors for systemic diseases, as these may provide important clues t o the underlying etiology of both the systemic and the associated movement disorders. Th e informa- tion presented in this chapter should serve as a guide not only to movement disord er clinicians but also to general and primary care physicians. Recognizing the movement dis order phenomenology is the fi rst step that eventually leads to the aetiological diagnosis. syndromes that cause movement disorders are cerebellar degen- eration, stiff person syndrom e (SPS), and opsoclonus \200\223myoclonus syndrome. Much less commonly, paraneoplastic chor ea, trem- ors, and parkinsonism can occur. Recently, antibodies to the N -methyl- d -aspart ate (NMDA) subtype of the glutamate receptor have been associated with a neuropsychiatric s yndrome, dystonia, and other dyskinesias, typically observed in young women with ovarian te ratomas. Paraneoplastic ataxia Paraneoplastic cerebellar degeneration presents subacutely with onset of cerebellar ataxia, asymmetric in many cases, over a few weeks or months. Th e ataxia ca n present as a pure cerebellar syn- drome or may be associated with signs and symptoms of a more widespread encephalomyelitis, limbic encephalitis, sensory neu- ropathy, or Lambert \200\223Eaton myasthenic syndrome (3). Patients may experience dizziness, oscillopsia, vert igo, diplopia, dysarthria, dys- phagia, gait dysfunction, and truncal and/or appendicular a taxia. A number of eye movement abnormalities can occur such as nystag- mus, ocular dysmetr ia, slow saccades, jerkiness of smooth pursuits, square-wave jerks, opsoclonus, and saccadi c oscillations (4). Aft er a subacute onset and progression, patients eventually stabilize at a severe level of disability. Th e diff erential diagnosis for subacute cer- ebellar ata xia is wide and is summarized in Table 29.1. Th e malig- nancies most commonly associated w ith paraneoplastic cerebellar degeneration are breast and ovarian cancer, small-cell lung c ancer, and Hodgkin \200\231s disease (5). Paraneoplastic cerebellar degeneration is associa ted with many diff erent antibodies (Table 29.2), and more than one antibody may be present in the same individual (5). In the early stages, brain imaging can be normal, though cereb ellar atrophy occurs as the disorder advances. Cerebrospinal fl uid (CSF) analysis may reve al mildly elevated protein or oligoclonal bands (6, 7). Histopathologically, diff use loss of Purkinje cells with infl am- matory infi ltrates in the cerebellar cortex, deep cerebell ar nuclei, and inferior olivary nuclei are seen (3). Prognosis depends on the antibody and cancer type. Earlier detection is associated with an improved prognosis. Figure 29.1 shows an MRI scan of a patient with paraneoplastic cerebellar degeneration with anti-Yo antibod- ies associated with her underlying breast cancer. Th is chapter reviews movement disorders occurring in conjunc- tion with several broad cate gories of systemic disease, including paraneoplastic, autoimmune, endocrine, metabolic, nut ritional, and infectious diseases. Paraneoplastic syndromes Paraneoplastic neurological syndromes are a heterogeneous group of disorders caused by an immune response to an underlying malig- nancy. Paraneoplastic antib odies simultaneously target antigens expressed by tumor cells and cellular components of th e central and/or peripheral nervous system(s), thereby producing neurologi- cal symptoms th at are not due to direct invasion of the aff ected tis- sue by the primary tumor or metasta sis. Th e underlying cancer is oft en occult and the paraneoplastic neurological syndrome m ay be the presenting complaint. Fortunately, paraneoplastic neurologi- cal syndromes are ra re, occurring in <1% of all cancer patients (3). A subset of paraneoplastic neurological sy ndromes presents with movement disorders. Th e classical paraneoplastic neurological Oxford Textbook of Movement Disorders 316 a paraneoplastic etiology should be considered when SPS only aff ects one or both upper ext remities, has a very rapid onset, responds poorly to benzodiazepines, occurs at an advanced age, or occurs as part of an encephalomyeloneuropathy (8). While the non-paraneoplastic fo rm is usually associated with glutamic acid decarboxylase (GAD) antibodies, the paraneoplas tic form is most frequently associated with amphiphysin antibodies, although anti-gephyrin antibodies have also been described (9). Adenocarcinoma of the breast is the most commonly associated malignancy, though SPS may also be associated with underlying thymoma, Hodgkin \200\231s lymphoma, renal cell carcinoma, myeloma, and lung cancer (10 \200\22312). Althoug h SPS is a clinical diagnosis sup- ported by the presence of appropriate autoantibodies, el ectromy- ography (EMG) can also be used to support the diagnosis. Surface EMG reveals an in itial burst of myoclonic activity followed by continuous muscle activity and prolonged toni c muscle contrac- tion in response to cutaneous stimulation. Th is pattern is virtu- ally d iagnostic of SPS. CSF analysis may demonstrate oligoclonal bands. MRI of the brain is usual ly normal. Pathologically, the dis- order involves inhibitory interneurons in the spinal co rd, vacuolar degeneration of anterior horn motor neurons, and infl ammatory infi ltrates (1 3). Benzodiazepines, drugs that enhance GABAergic inhibition (e.g. baclofen), and steroids may relieve spasms, but they do not usually infl uence the natural course. Table 29.1 Di \200 erential diagnosis of subacute cerebellar ataxia Hypothyroidism, Hashim oto \200\231s thyroiditis Endocrine Infectious Infections and postinfectious cerebellitis Alcohol-related cerebellar ataxia, vitamin B 12 or folate de \201 ciency, medications Toxic and nutritional Malignancy Posterior fossa tumors (primary and metastatic) Table 29.2 Antibodies associated with paraneoplastic cerebellar degeneration Antineuronal a ntibody Anti-Hu/ANNA-1 Clinical syndromes PCD Associated tumors SCLC Anti-Yo/PCA-1 PCD Breast, ovarian Anti-Ri/ANNA-2 PCD, OM Breast, gynecological, SCLC Anti-Tr PCD Hodgkin \200\231s lymphoma Anti-P/Q type VGCC PCD, LEMS SCLC Anti-Ma PCD Many Anti-Ta/Ma2 PCD, limbic encephalitis Testis Anti-CRMP5/CV2 PCD SCLC, thymoma, gynecological Anti-mGluR1 PCD Hodgkin \200\231s lymphoma Paraneoplastic opsoclonus \200\223myoclonus syndrome Paraneoplastic opsoclonus \200\223myoc lonus syndrome presents with chaotic but conjugate eye movements which consist of involunta ry arrhythmic high-amplitude saccades in all directions (opsoclonus), in conjunction with s udden jerky movements of the body (myo- clonus). It is clinically indistinguishable from no n-paraneoplastic forms of opsoclonus \200\223myoclonus (OM), listed in Table 29.3. In child ren, paraneoplastic OM accounts for roughly 50% of all OM cases and is most frequently asso ciated with underlying neurob- lastoma (14). Antibodies are rarely identifi ed in children with paraneoplastic OM (15). In adults, roughly 20% of cases of OM are paraneoplastic, with breast and lung cancer being the most com- monly associated malignancies (16). In patients with breast cancer, paraneoplastic OM may be associated with anti-Ri antibodies. CSF studi es and brain MRI are normal in most cases. Pathologically, there may be no abnormalities, a lthough cases with cerebellar atrophy and perivascular lymphocytic cuffi ng have been repor ted (17). Treatment of pediatric paraneoplastic OM involves treating the underlying tumor a long with administration of adjunctive immunotherapy. Steroids, intravenous immunoglobulin (IVIG), plasmapheresis, rituximab, and adrenocorticotrophic hormone (ACTH) are commonly emp loyed as adjunctive treatments in the pediatric population. In adults, treatment is targete d against PCD, paraneoplastic cerebellar degeneration; OM, opsoclonus \200\223myoclonus; LEMS, Lamber t \200\223Eaton myasthenic syndrome; SCLC, small-cell lung cancer Fig. 29.1 Di \200 use cerebellar atrophy on T 1 sagittal MRI in a woman presenting with su bacute cerebellar ataxia. A paraneoplastic antibody panel revealed anti-Yo antibodies, whic h ultimately led to the diagnosis of previously occult breast cancer. (MRI courtesy of Dr G eorge Wilmot) Paraneoplastic sti \200 person syndrome Paraneoplastic SPS clinically resembles non-parane oplastic SPS, presenting with prominent axial muscle rigidity and intermit- tent painful sp asms. Th e condition fl uctuates, with spasms oft en being exacerbated by emotion, activity , or sensory stimulation. Only about 5% of all cases of SPS are associated with an underly- ing malignancy (3). Although there is no clinically reliable way to distinguish paraneopla stic from non-paraneoplastic forms, Table 29.3 Non-paraneoplastic causes of opsoclonus \200\223myoclonus Postinfectious (postst reptococcal and postviral) Drug-induced (lithium, amitriptyline overdose, cyclosporin toxicity) Midbrain or thalamic hemorrhage or neoplasm Diabetic hyperosmolar coma Connective tissue and in \202 ammatory disorders Idiopathic CHAPTER 29 Systemic Disease and Movement Disorders 317 the underlying malignancy without the use of adjunctive immuno- therapy. Eye movements and myoclonus can be symptomatically treated with benzodiazepines and baclofen. Recently, antibodies to the NMDA subtype of the glutamate receptor have been associated wit h encephalopathy in young women with ovarian teratomas. Patients may present with psychi- a tric symptoms, memory problems, seizures, and can ultimately develop dystonia, dyskinesias, opsoclonus \200\223myoclonus syndrome, autonomic instability, unresponsiveness, and hypove ntilation (2, 20, 21). Th e dyskinesia has a predilection for the orofacial-lingual region and may be initially misdiagnosed as tardive dyskinesia (Video 29.2) (22). Rarely, a simila r syndrome can occur in young men with testicular teratoma. NMDA receptor encephalitis may be slightly more common in black than in white women (21). Initially, CSF analysis reveals pleocytosis and may ultimately reveal oligoclonal bands (23). Brain MRI may be normal or ma y show abnormalities in the white matter and hippocampi (23). Principal pathological featur es include microgliosis and IgG deposits with rare infl ammatory infi ltrates in the hippoc ampus, forebrain, basal ganglia, and spinal cord (24). Once diagnosed with a teratoma, pati ents are treated with tumor resection and immunotherapy (steroids, IVIG, plasmapheresis), a nd symptoms improve as anti- body titres fall (25). Other paraneoplastic movement disorders Paraneoplastic chorea, hemiballismus, dyskinesia, d ystonia, tremor, and parkinsonism have all been reported, although they are thought to be e xceptionally rare (3, 18). Paraneoplastic chorea is the best characterized of these movemen t disorders (Video 29.1). Paraneoplastic chorea is most frequently associated with CV2/ CRM P-5 antibodies and small-cell lung cancer; however, it has also been reported to occur with thymoma, lymphoma, and renal and testicular cancer (3). In one series of 16 patients with paraneoplas- tic chorea, 11 had small-cell carcinoma; the others had renal cell carcinoma, lymphoma, and other cancers. All had CRMP-5-IgG; six also had ANNA-1 (anti-Hu), including o ne without evident cancer. Chorea was the initial and most prominent symptom in 11 patients and was asymmetric or unilateral in fi ve patients. MRI or autopsy provided evidence for p erivascular infl ammation and microglial activation in the basal ganglia. In some patients, chemo- therapy and intravenous methylprednisolone were associated with improvement in the chorea (19). When presenting with any of the aforementioned classic paraneo- plastic neurological syndro mes, patients should be evaluated for an underlying malignancy with a CT scan of the chest, abdomen, and pelvis. A paraneoplastic antibody panel should be performed and may point tow ards a specifi c underlying malignancy. If the afore- mentioned tests fail to identify mali gnancy, a whole-body fl uoro-2 -deoxy-glucose (FDG) positron emission tomography (PET) scan may be useful. One study of patients with paraneoplastic neuro- logical syndromes and posi tive paraneoplastic antibodies found the sensitivity of FDG-PET for detecting malignancy to be 90%, which was signifi cantly higher than the 30% sensitivity reported for CT ( p < 0.0 1) (26). Identifi cation and treatment of the malignancy may lead to improvement or even re mission of the paraneoplastic neu- rological syndrome. As discussed previously, immunosuppr essive treatments can be useful in some cases. Paraneoplastic choreiform movements are usually part of a more widespread neurological synd rome which may include peripheral neuropathy, autonomic neuropathy, ataxia, dementia, neuro muscular junction problems, cranial neuropathy, limbic encephalitis, and optic neuritis (3) . Most patients with paraneoplastic chorea have non-specifi c basal ganglia changes on MRI. CSF is normal or shows mild leucocyto- sis with elevated protein or possibly oligoclonal b ands (3). z Video 29.1 Th is 60-year-old right-handed man presented with generalized seizure 4 years earlier and was found to have hyponatraemia but no speci \201 c cause was identi \201 ed. Th ree years later he was admitted to the hospital for evaluation of recent weight loss an d acute confusion. He had marked hyponatraemia (Na = 116 mEq/L). While in the hospital he w as also noted to have involuntary movements, initially in the shoulders, but gradually prog ressing to involve his legs as well, and he began to stumble when walking. He has a 60-pack -year smoking history. On his initial examination at the Movement Disorders Clinic, his Mon treal Cognitive Assessment (MoCA) score was 20/30 and he was noted to have generalized chor ea which was temporarily suppressible. MRI showed hyperintensity in the striatum on T 2 -we ighted images. He was found to have positive titre (1:245 760) of collapsin response-mediat or protein-5 (CRMP-5) IGG (by immuno \202 uorescence). All other tests were negative. He w as found to have lung cancer and died within 3 months after evaluation. z Video 29.2 Th is 3 year old boy was initially admitted to the Children \200\231s Hospital after a 2 \200\2233 day history of progressive lethargy and emesis. While in the emergency room he was noted to have abnormal involuntary movements manifested by orofacial stereotyp ies and generalized chorea. MRI of the head was normal on two occasions, as was extensive i nfectious work-up. His chorea markedly improved within 1 \200\2232 days after starting tetr abenazine, but when later tetrabenazine was lowered and eventually discontinued his chorea worsened and dystonic posturing emerged. Further autoimmune and metabolic testing was norma l except for the presence of high titre of anti-NMDA receptor antibodies. Th e patient was started on monthly IVIG and mycophenolate and his mental and neurological status gradually improved. Th e tetrabenazine was eventually discontinued without recurrence of the involunt ary movements. Oxford Textbook of Movement Disorders 318 Systemic lupus erythematosus Neurological manifestations of systemic lupus erythematosus (S LE) are diverse and can include psychosis, seizures, encephalopathy, neuropathy, transverse myelitis, and movement disorders. While spasmodic torticollis, hemiballismus, tremor, park insonism, and stiff person syndrome have all been reported, chorea is the most common movem ent disorder in SLE, occurring in up to 4% of patients (36, 37) (Video 29.3). It is usually accompanied by other neurological manifestations of the disease, although it can be the pr esenting feature, sometimes occurring years before other mani- festations (38). Most patien ts who develop chorea are young women. Chorea is oft en unilateral or asymmetrical, but usu ally evolves into a generalized chorea that interferes with speech, balance, and activ- iti es of daily living. While it usually spontaneously resolves aft er several days or weeks, r arely it can be permanent. Some cases have occurred in association with hormonal shift s, s uch as during preg- nancy, in the postpartum period, or aft er starting or stopping oral co ntraceptives (39 \200\22341). Although the pathology is inconsistent, widespread microinfar cts are the classic hallmark of neurolupus. Antiphospholipid antibodies, which predispose p atients to recur- rent thrombotic events, are strongly associated with chorea in SLE; howev er, the mechanism whereby these antiphospholipid antibod- ies cause chorea and other featur es of the antiphospholipid syn- drome (see below) is unclear. Neuroimaging in patients with SLE and chorea is usually normal, although ischaemic lesions in the basal ganglia may be f ound (42). Th e chorea of SLE may respond to low doses of haloperidol or to tetrabenazine ( 43, 44) (Video 29.3). IVIG and plasma exchange have also been used to successfully treat re fractory chorea in SLE (45). Th e widespread commercial availability of gender-specifi c para- neoplastic antibody panel s represents a key advance in the manage- ment of paraneoplastic disease, and future develo pments are likely to include the identifi cation and characterization of additional paraneo plastic antibodies. Th e increasing availability of PET scans represents another key advanc e in the diagnosis and management of both paraneoplastic and neoplastic disease, and future develop- ments will almost certainly include improved imaging modalities for the early det ection of occult malignancy. Autoimmune diseases Autoimmune diseases, which arise from an overactive immune response aga inst normal body tissues, are frequently the cause of movement disorders (27). Autoimmune d isease can be restricted to certain organs or tissue types, or can occur in a more widespre ad distribution, making this a very heterogeneous group of diseases. Key advances in the fi eld of autoimmune disease include the devel- opment of newer immunosuppressant drugs. Th e se newer agents can be used in combination with steroids, thereby enabling the use of lower doses of both agents and reducing the potential for serious medication-related side eff ec ts. For example, a recent report sug- gested that adalimumab may be associated with parkins onism and dystonia (28). Th is section highlights the autoimmune diseases that are most oft en associated with movement disorders. Autoimmune thyroid disease In Hashimoto \200\231s thyroiditis, also referred to as steroid- responsive encephalopathy associated with autoimmune thyroiditis (SREAT) or Hashimoto \200 \231s encephalopathy, anti-thyroperoxidase and anti- thyroglobulin antibodies disrupt thyro id function, resulting in encephalopathy that is oft en accompanied by involuntary movement s and ataxia. All of this can occur despite a biochemically euthyroid state. Chorea, tremor , multifocal myoclonus, and ataxia are the most common movement disorders occurring in Hash imoto \200\231s thyroidi- tis; however, opsoclonus, akinetic \200\223rigid syndromes, palat al tremor, and myorhythmias have also been reported (1). Brain MRI is usu- ally normal (1). Prominent EEG changes (slowing and epileptiform activity) are common (1). Elevated CSF pro tein is common, and both mild pleo cytosis and oligoclonal clonal bands can also occur (29) . High-dose intravenous steroids usually lead to prompt resolution (1). Coeliac disease Ataxia is a common neurological manifestation of gluten enter- opathy (30, 31). Anti-gliadin antibodies are thought to be respon- sible for the ataxia, via direct cer ebellar toxicity (32). Cerebellar involvement may also occur in individuals with coeliac di sease and resultant low vitamin E levels, a condition discussed in detail later in this cha pter (33). Symptoms can include eye-movement abnor- malities, dysarthria, limb ataxia, and gait disturbance. Occasionally, biopsy-confi rmed coeliac disease is found; however, there is oft en no evidence of intestinal disease (32). MRI usually reveals cerebel- lar atrophy. Co-morbid sensorimotor axonal neuropathy is com- mon (32). Pathologically, there is periva scular cuffi ng with both CD4 and CD8 cells in the white matter of the cerebellum and oft e n signifi cant Purkinje cell loss (34). Th e ataxia, for the most part, is not responsive t o treatment. Some reports suggest that IVIG and gluten-restricted diets may be of benefi t (35). z Video 29.3 Th is 19-year-old college student was diagnosed with SLE meningoencephalitis a t age 10 years. She subsequently had intermittent paroxysmal abdominal complaints, myalgias , and arthralgias, and at age 18 years had an episode of pericarditis. All these SLE-relate d conditions generally responded to brief courses of prednisone. About 10 days before her i nitial evaluation at the Movement Disorders Clinic she noted rapidly progressive di \203 c ulties with \201 ne dexterity, progressing to generalized uncontrolled movements, slurred speech, and gait and balance problems. Th e video shows marked generalized chorea. She was initially treated with prednisone and subsequently switched to mycophenylate. Her chorea m arkedly improved within a few days after starting tetrabenazine. CHAPTER 29 Systemic Disease and Movement Disorders 319 Although parkinsonism has been described, it is a rare mani- festation of SLE. Antiphosphol ipid antibodies are not consist- ently reported in SLE parkinsonism as they are with SLE ch orea. MRI scanning may show hyperintensities in the thalamus or basal ganglia on T 2 -weigh ted images (46). CSF may reveal mild pleocytosis and protein elevation. Successful treatmen t has been reported with corticosteroids, other immunosuppressants, and levodopa, although the clinical response to treatment varies considerably. 15% of autopsy cases may have evidence of neurosarcoidosis (57). While basilar meningitis i s the most common neurological pres- entation of neurosarcoidosis, parenchymal lesions can also occur, producing a variety of neurological symptoms (58). Parkinsonism, hemidystonia, chorea, and hemiballismus have all been described when the granulomatous process infi ltrat es the basal ganglia (58). Th ese movement disorders oft en improve or resolve with admin- istration of corticosteroids or other immunosuppressants (59, 60). Th e diagnosis of neuros arcoidosis can be challenging because no test, apart from biopsy, is completely reliable. P arenchymal lesions oft en show gadolinium enhancement on MRI. CSF protein is usually elevat ed, and pleocytosis and oligoclonal bands may be present (59). Additional tests such as CSF ACE levels are of little added value. Cerebellar syndromes with an abrupt or subacute onset have been noted in less than 2% of pa tients with SLE. Truncal and appendic- ular ataxia, dysarthria, and nystagmus have been not ed. Isolated cases of tremor, hemiballismus, spasmodic torticollis, blepharos- pasm, and st iff person syndrome have been reported. Endocrine and metabolic disorders Th yroid disease Hyperkinetic movement disorders occur wi th hyperthyroid states, and the movement disorder usually presents and remits in parallel w ith other symptoms of hyperthyroidism. Enhanced physiologi- cal tremor is by far the most c ommonly seen movement disorder in hyperthyroidism, occurring in as many as 97% of hyperthyr oid patients (61). Changes in peripheral beta-adrenergic receptor tone may be the pathophys iological basis, a theory supported by the fact that beta-blockers eff ectively suppress th e tremor. Chorea is a much less common manifestation of hyperthyroid states, occurring in l ess than 2% of patients with thyrotoxicosis (61). Th e distal extremi- ties are most aff ec ted, although the neck and tongue may also be involved. Movements are usually continuous, a lthough paroxysmal choreoathetosis has been reported (62). Th e pathophysiology is not well understood, and no cerebral lesions have been identifi ed via MRI or post-mortem pathologi cal studies (36). Th e chorea is reversible with treatment of the underlying hyperthyroidis m. It also responds to dopamine receptor blocking agents which, in conjunc- tion with the f act that there are decreased concentrations of the dopamine metabolite homovanillic acid in the CSF of hyperthy- roid patients, seems to suggest that altered dopamine turnover or inc reased dopamine receptor sensitivity may be responsible (63). 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.