Clinical manifestations

Presentation and course

Constantin von Economo delineated 3 main clinical presentations of encephalitis lethargica (248). The most common variety started with an influenza-like illness and was followed by increasing drowsiness and confusion, with progression to continuous sleep, stupor, and finally coma. External ophthalmoplegia, often with pupillary involvement and oculogyric crises, were early features of the disease, and some patients developed basal ganglia, cerebellar, or upper motor neuron signs. A second group of patients presented with severe acute parkinsonism, often combined with catalepsy and mutism, whereas a third hyperkinetic group mimicked acute catatonic schizophrenia with extreme motor restlessness, impulsions, visual hallucinations, and dyskinesias. The survivors of the pandemic left with postencephalitic parkinsonism presented with variable degrees of extrapyramidal disability, which hardly progressed over decades. The presence of oculogyric crises in many patients was another helpful distinguishing feature from idiopathic Parkinson disease. Patients with postencephalitic parkinsonism were extremely sensitive to small doses of L-dopa, improving within a few days but developing severe complications including dyskinesias, behavioral disturbances, and motor fluctuations. A study of patients with pathologically proven postencephalitic parkinsonism has confirmed that vertical supranuclear gaze palsy and eyelid apraxia were common findings in this condition (250). The following clinical features should be considered major criteria supporting the diagnosis of encephalitis lethargica. An acute or subacute encephalitic illness that as part of its clinical picture, displays at least 3 of the following criteria: (1) signs of basal ganglia involvement, (2) oculogyric crises, (3) ophthalmoplegia, (4) severe obsessive-compulsive behavior, (5) akinetic mutism, (6) central respiratory irregularities, and (7) somnolence or sleep inversion. In fact, a clinicopathologic study confirmed that onset before middle age, symptom duration lasting more than 10 years, and the presence of oculogyric crisis, as well as history of encephalitis lethargica, were good predictors of the diagnosis of postencephalitic parkinsonism (141). There are occasional reports of patients who develop parkinsonism following encephalitic illnesses. Aside from a few elderly patients who presented with a history of typical encephalitis lethargica, which occurred in the first years of the 20th century, a number of different viral encephalitides have been diagnosed in most subjects: Western equine encephalitis, Coxsackie B, measles, Epstein-Barr virus (105; 78; 194), chicken pox encephalitis, and Japanese encephalitis. The importance of the latter as cause of parkinsonism is shown by a study of 52 patients, of whom 5 developed pure parkinsonian syndrome poorly responsive to levodopa, ophthalmoparesis, opsoclonus, as well as isolated lesions of the substantia nigra on MRI (184). A review of a large database of patients who developed Parkinson disease or parkinsonism in the United Kingdom between 1994 and 2007 showed an association between seasonal influenza and development of parkinsonism (OR=3.03) but not Parkinson disease (239).

In the past few years many studies have raised the possibility of the pathogenesis of Parkinson disease being related to infections by different agents. One case-control study of a large population of Taiwanese patients has demonstrated that even after multiple corrections, infection by hepatitis C virus is associated with an increased (1.29) hazard ratio for the development of Parkinson disease (244). Interestingly, a study from mainland China suggests that this effect is probably nonspecific of a single infectious agent (28). In the report, there was increased risk of development of Parkinson disease in association with infection by cytomegalovirus, Epstein-Barr virus, herpes simplex type 1 virus, Borrelia burgdorferi (B burgdorferi), Chlamydophila pneumoniae (C pneumoniae), and Helicobacter pylori (H pylori). Nevertheless, studies from other areas of the world, such as South Korea, confirm that there is indeed a relationship between hepatitis C virus infection and increased risk of development of Parkinson disease (119). A review of a large cohort of Taiwanese patients with hepatitis C has shown that indeed this increases the risk of developing Parkinson disease by 30%. Interestingly, effective treatment with antiviral agents results in normalization of the odds ratio (222). The underlying mechanism of such an association remains to be determined. However, studies of large cohorts of patients infected with hepatitis C virus show that there is a wide spectrum of extra-hepatic manifestations. Neurologic conditions are found in as many as 50% of these individuals and include cognitive impairment, behavioral abnormalities, and sleep disorders that are unrelated to the severity of liver dysfunction. The underlying pathogenesis remains to be determined but might involve direct action of the virus, cytokines abnormalities, and iatrogenic factors (166). Other data indicate that the clinical phenotype of Parkinson disease can also be influenced by infections. For instance, patients who have H pylori infection in the stomach have worse motor performance (227). In the same vein, the existence of a relationship between gut microbiota and Parkinson disease has been demonstrated. Patients with a relative abundance of Enterobacteriaceae have greater severity of postural instability and gait difficulty (199). However, some data show that the relationship between gut microbiota and parkinsonism in general is fraught with multiple confounding factors (12). In contrast, and perhaps surprisingly, HIV infection does not change the clinical features and course of Parkinson disease (169). Although it is not within the scope of this article to discuss the pathogenesis of Parkinson disease, some have proposed that mutated alpha-synuclein has a prion-like behavior. This hypothesis would be fitting with the Braak staging: the protein undergoing mutation at the gut level migrates along the vagus nerve to the brainstem where it would induce more mutations and spread to other areas of the CNS (147; 175; 148). Interestingly, it is possible that changes in the bacterial population of the gut (microbiota) could be the triggering factor of mutation of alpha-synuclein of the Auerbach plexus (242).

Japanese encephalitis can cause severe, generalized dystonia refractory to treatment (114). A study demonstrated that patients with Japanese encephalitis and movement disorders often have imaging evidence of nigrostriatal dysfunction (139). A review of 1282 patients from India demonstrated that hyperkinesias, almost exclusively choreoathetosis, are found in 46% of subjects. The authors also found a significant proportion of individuals with opsoclonus-myoclonus (20%), but interestingly, there is no mention of parkinsonism (197). A study confirms that parkinsonism and dystonia are common features in Japanese encephalitis, with the former being equally present in both children and adults, whereas dystonia is more often seen in children (14). Since 1999, West Nile virus encephalitis has been increasingly diagnosed in North America. A prospective study of 16 patients with laboratory-confirmed diagnosis showed that tremor (94%), parkinsonism (69%), and myoclonus (31%) are common features of the acute phase of West Nile virus encephalitis (202). West Nile encephalitis involving the substantia nigra has been recognized as a cause of acute parkinsonism (19). When it affects other brainstem areas and the spinal cord, West Nile infection can present as acute poliomyelitis (02). A report from Canada confirms that tremor and myoclonus can occur in association with West Nile infection (237). Attention has also has been drawn to the finding that organ transplant recipients constitute a group particularly at risk of developing West Nile encephalitis in the United States. This particular group of patients also often develops parkinsonism (124). A follow-up study of 49 patients with this encephalitis in North Dakota reports the presence of tremor in 20% of subjects (52). A review of the literature of neuroinvasive West Nile virus infection confirms the notion that tremor, opsoclonus-myoclonus, parkinsonism, myoclonus, ataxia, and chorea are relatively common in these patients. Most of these movement disorders resolve spontaneously over the course of few weeks to months. Action tremor of the upper limbs is the most common phenomenology (136).

Infection by Chikungunya virus, also endemic in the Indian Subcontinent, was previously thought not to involve the central nervous system. However, a report describes 1 patient from India who developed ataxia and myoclonus in the context of meningoencephalitis by this virus (113). It is important to highlight that this virus has spread to the American continent where it has become epidemic. Levodopa-responsive dystonia has also been described in association with viral encephalitis (146). Opsoclonus-myoclonus ataxia is another movement disorder described in association with West Nile virus encephalitis (117; 05; 01). Dengue, an acute viral disease transmitted by Aedes mosquitoes, is highly endemic in many tropical and subtropical areas of the world. Although it is usually a benign, transient febrile illness, a small proportion of patients may develop neurologic complications, which can include opsoclonus-myoclonus or ocular flutter-myoclonus (247; 149; 49). Zika is another flavivirus transmitted by Aedes aegypti. The classical neurologic manifestation of Zika infection is microcephaly. A study of a cohort of Brazilian newborns with congenital Zika infection demonstrated that dyskinesias, presumably dystonia, is found in 40% of these patients (181). In adults immune-mediated problems, mainly opsoclonus-myoclonus, have also been reported. Other infections described in association with opsoclonus-myoclonus include cytomegalovirus, Epstein-Barr infection, herpes 6 virus, varicella-zoster, HIV (in the context of seroconversion as well as immune reconstitution inflammatory syndrome), Streptococcus, Lyme disease, Mycoplasma pneumoniae, Salmonella, and hepatitis C virus (158; 159; 246; 34; 36; 182; 56; 65; 216; 254; 256; 08; 87; 106; 115; 214; 174; 245). A review of a single-center cohort of adults concluded that infections accounted for 18 of 21 patients with opsoclonus-myoclonus (123). Although rarely, a few patients with Epstein-Barr virus infection may develop basal ganglia lesions, including hemorrhage, causing parkinsonism (82; 98; 109).

Nipah virus encephalitis is an emerging zoonosis, transmitted by bats, which has been described in Asia. The acute picture of the infection with this paramyxovirus is characterized by severe encephalitis with marked involvement of the brainstem, occasional presence of myoclonus and high mortality rate (95). Patients who survive the initial illness are often left with major neuropsychiatric sequelae, including cervical dystonia (203). There is a report of Holmes tremor related to pedunculitis caused by HSV-1 (193). A description of a series of patients from India described segmental myoclonus in 15% of subjects and a staggering mortality of 91% (177).

There are more reports of uncommon viral encephalitis causing movement disorders. Patients with brainstem encephalitis caused by enterovirus 71 (foot and mouth disease) commonly have tremor and myoclonus (257), as well as ataxia (134). During the outbreak that occurred in Australia between 2009 and 2011, tremor was also common in patients with Murray Valley encephalitis (219). Chorea was described in association with human herpes virus-6 encephalitis (186).

The classical description of varicella-related cerebellitis is in pediatric patients where the course is usually benign with full spontaneous recovery after weeks of disease (21). However, there are reports of this condition occurring in adults as well (207). A description of cases highlights that among subjects with postinfectious cerebellar ataxia there is a group of individuals with a more severe form characterized by ataxia and intracranial hypertension. The latter is a result of tonsillar herniation. The infectious agents are not identifiable in the majority of subjects but the outcome is relatively good in patients with early detection and treatment with steroids (255).

Movement disorders are not uncommon in patients with AIDS and have received much attention in the past (24; 38). At the height of the AIDS epidemic, they usually occurred in subjects already known to be HIV positive as a result of opportunistic infections, HIV encephalopathy, or side effects of drugs. In clinical practice, tremor was the most common movement disorder identified in HIV-positive patients (38). A literature review, however, suggested that hemichorea hemiballismus was the most frequently reported dyskinesia in HIV-positive subjects (183; 37). Characteristically, this hyperkinesia is an acute complication of patients with established AIDS, but in a few instances, hemichorea hemiballismus may be the presenting symptom of HIV infection (178; 40). Chorea as manifestation of HIV encephalopathy, in 1 case mimicking the clinical picture of Huntington disease, has been reported by some (179; 205). A French group described remission of chorea related to HIV encephalopathy after introduction of highly active antiretroviral therapy (243). Tremor was the second most commonly reported movement disorder in AIDS patients. It was often caused by Toxoplasma abscesses located in the mesencephalon or thalamus. Patients presented with tremor of subacute onset with rest, postural, and kinetic components, known as Holmes tremor (125; 161). “Wing beating” tremor, related to middle cerebellar peduncle lesions, mild postural tremor associated with HIV encephalopathy, and isolated rest tremor induced by dopamine receptor blockers or trimethoprim-sulfamethoxazole have also been reported (226; 208; 152; 37). Of note, trimethoprim-sulfamethoxazole can also induce tremor when used in high doses even in immunosuppressed, but HIV negative, patients (29). There are reports on the association of tremor with progressive multifocal leukoencephalopathy (190; 220). Less often, HIV-positive patients may develop other hyperkinesias, such as generalized or focal dystonia, Meige syndrome, myoclonus, painful legs and moving toes syndrome, akathisia, tics, stiff person syndrome, oculomasticatory myorhythmia associated with Whipple disease, and opsoclonus-myoclonus (111; 171; 238; 157; 133; 33; 85; 206; 251; 252; 245). One case report describes 1 patient with acute onset of myoclonus and other neurologic clinical features who was found to have West Nile virus infection in association with HIV (112). There is also 1 study describing the occurrence of paroxysmal hyperkinesia in 6 patients with advanced AIDS without underlying opportunistic infections (162). Parkinsonism as part of HIV encephalopathy and, less frequently, resulting from toxoplasmosis abscesses, parenchymatous tuberculosis granuloma, cryptococcal abscesses and other opportunistic infections has also been reported in patients with AIDS (51; 76; 163; 20). In 1 of these studies, the authors described 6 patients with parkinsonism and 10 others with “parkinsonian features.” In one half of the subjects, the akinetic rigid syndrome was related to exposure to neuroleptics, whereas no cause was identified in the remaining ones. These patients, who accounted for 5.2% of all subjects seen in a neuro-AIDS clinic, did not present with rest tremor, and the majority of them also had additional clinical features such as dementia, seizures, vacuolar myelopathy, and peripheral neuropathy. The CD4 values were consistently low (mean of 14 cells/mm3). There is also a description of parkinsonism in an HIV-positive patient secondary to interaction between ritonavir, an antiretroviral agent, and buspirone (63). The parkinsonian syndrome is usually nonresponsive to L-dopa. A Spanish group described an HIV-positive woman with probable progressive multifocal leukoencephalopathy involving 1 putamen who presented with contralateral eating-induced myoclonus and dystonia of the face (90). Probably as a result of the improvement of care of HIV infection, particularly, the advent of highly active antiretroviral therapy, there has been a decline of reports of movement disorders associated with this viral infection. Nevertheless, a report described the occurrence of PSP-like picture as an initial sign of HIV infection (110). There is also a study describing that the coexistence of HIV and Lyme neuroborreliosis may present with tremor (23). With the advent of highly active antiretroviral therapy, the clinical profile of movement disorders associated with HIV infection has changed. There are a growing number of descriptions of immune-mediated movement disorders such as opsoclonus-myoclonus and ataxia (180).

Herpes simplex virus 1 is the most common cause of sporadic encephalitis worldwide. Although this infection is not usually associated with movement disorders, chorea often occurs in children with relapse of herpes simplex encephalitis. Reports indicate that this hyperkinesia is related to anti-NMDA receptor or anti-D2 receptor antibodies (77; 127; 99; 165; 93). The myoclonus-dystonia syndrome can be causally related to herpes virus-6A infection (17). There is also a remarkable report, describing a patient with rabies after bat bite who survived, though having been left with major neurologic sequelae, including chorea (253). Rarely myoclonus can be found in patients with dengue virus infection that is a common condition in large areas of the globe such as Asia and Latin America (164). Finally, there is a report relating parvovirus B19 infection in association with chorea (88). A review of 39 patients from India with subacute sclerosing panencephalitis confirmed the traditional view of myoclonus as a common clinical feature of this condition (185).

In the year of 2010 there was a pandemic of H1N1 influenza. Despite the initial fear of a severe global public health threat, the infection came under control quite rapidly. This was partly related to the development of a vaccine. Despite thousands of cases worldwide, there were relatively few reports of neurologic complications of H1N1 infection. Among these subjects, few developed movement disorders, mostly tremor and parkinsonism (57; 96). In the same vein, the study of a large number of survivors of the last outbreak of Ebola virus in West Africa showed that they can be left with seizures, memory loss, headaches, cranial nerve abnormalities, and tremor (16).

Sydenham chorea is the most common movement disorder associated with bacterial infection. Typically, patients develop this disease 4 to 8 weeks after an episode of streptococcal pharyngitis. In most series, there is a female preponderance. The usual age at onset of Sydenham chorea is 8 to 9 years of age, although there are reports of patients developing chorea in the third decade of life (47). The chorea rapidly spreads, becoming generalized, but 20% of patients remain with hemichorea (172; 47).

The random and continuous flow of contractions typical of chorea produces motor impersistence, particularly noticeable during tongue protrusion and ocular fixation. The muscle tone is usually decreased and in severe and rare cases (8% of all patients) is so pronounced that the patient may become bedridden (chorea paralytica). Patients often display other neurologic and nonneurologic symptoms and signs. Although the distinction between chorea and motor tics may be difficult, the latter, as well as simple vocal tics, are frequently reported to occur in Sydenham chorea. One possible way of making a distinction of the 2 phenomena is by attempting to identify premonitory sensory experience, which is reported by more than 90% of patients with Tourette syndrome (131). However, if a description of 10 of 13 patients with Sydenham chorea mentioning premonitory symptoms in relation with chorea is confirmed, this feature is of no help in distinguishing the 2 hyperkinesias (192). In a cohort of 108 Sydenham chorea patients carefully followed up at our unit, we have identified vocalizations in just 8% of subjects. We have avoided the term “tic” because there was no premonitory sign or complex sound, and, conversely, the vocalizations were associated with severe cranial chorea. Taken together, these findings suggest that involuntary sounds present in a few patients with Sydenham chorea result from choreic contractions of the upper respiratory tract muscles rather than true tics (230). Dysarthria is common, and patients with more severe forms of this condition may present a remarkably decreased verbal output reminiscent of Huntington disease. There is evidence that many patients with active chorea have hypometric saccades, and a few also show oculogyric crisis. In the older literature, there are also references to papilledema, central retinal artery occlusion, and seizures in some patients with Sydenham chorea. Similarly to what has been reported in Tourette syndrome (132), migraine is more common in children with Sydenham chorea than in controls. In a cohort of 55 patients with this movement disorder, 21.8% were found to have migraine, whereas this type of headache was seen in no more than 8% of 110 matched controls (232). Attention has been drawn to behavioral abnormalities associated with this condition. We investigated the behavior of 56 patients with Sydenham chorea, 50 subjects with Rheumatic fever without chorea, and 50 healthy matched controls. Obsessive-compulsive disorder was diagnosed in 23% of the patients with chorea, whereas just 6% and 4% of the rheumatic fever group and healthy controls met criteria for this condition (151). Other studies have confirmed that obsessions and compulsions are commonly seen in patients with Sydenham chorea (07; 160; 104). In a careful investigation of psychiatric comorbidities in 50 patients with Sydenham chorea, it was found that the most frequent psychiatric disorders observed were: major depression (14%), generalized anxiety disorder (16%), social phobia (24%), and obsessive-compulsive disorder (24%). The frequency of psychiatric disorders did not differ between patients in remission in comparison with patients with persistent chorea, except for depressive disorders, which were more frequent in the latter (167). We saw 1 patient with paranoid psychosis with onset in parallel with Sydenham chorea (235). We also found that 1 of our patients with Sydenham chorea developed trichotillomania (128). These findings and the observation that hyperactivity, learning disorders, and other behavioral problems are common in patients with rheumatic fever and chorea contributed to establish the notion that Sydenham chorea is a model for childhood autoimmune neuropsychiatric disorders (223). A cognitive dysfunction present in patients with Sydenham chorea is a rather specific pattern of decreased phonic verbal fluency (68). One study not only showed that patients performed worse than healthy controls in tasks of phonemic and semantic verbal fluency but they also had a poorer performance on the Token test that assesses verbal comprehension. Interestingly, individuals with rheumatic fever without chorea also had a significantly worse verbal fluency (101). Our group has also reported that adult patients with present or past history of Sydenham chorea may present with a dysexecutive syndrome, suggesting disruption of the prefrontal striatal loops (44). We have failed, however, to identify evidence of peripheral nervous system involvement in a cohort of patients with Sydenham chorea (45). It must be kept in mind that Sydenham chorea is a major manifestation of rheumatic fever, although in approximately 20% of patients, chorea is the sole finding. Nevertheless, 60% to 80% of patients display cardiac involvement in Sydenham chorea, whereas the association with arthritis is less common, seen in 30% of subjects (47). The current diagnostic criteria of Sydenham chorea are a modification of the Jones criteria: chorea with acute or subacute onset and lack of clinical and laboratory evidence of alternative cause are mandatory findings, and the diagnosis is further supported by the presence of additional major or minor manifestations of rheumatic fever (06; 47; 48). The first validated scale to rate Sydenham chorea has been published. The UFMG Sydenham Chorea Rating Scale was designed to provide a detailed quantitative description of the performance of activities of daily living, behavioral abnormalities, and motor function of patients with Sydenham chorea. It comprises 27 items, and each 1 is scored from 0 (no symptom or sign) to 4 (severe disability or finding) (233).

PANDAS remains a controversial concept, according to which infection with group A beta-hemolytic streptococci, may induce tics, obsessive compulsive behavior, and other neuropsychiatric disturbances. The following working diagnostic criteria for this condition have been proposed: (1) presence of obsessive compulsive disorder or a tic disorder, (2) prepubertal symptom onset, (3) episodic course of symptom severity, (4) association with group A beta-hemolytic streptococci infections, and (5) association with neurologic abnormalities. According to a description of 50 patients who met these criteria, the onset of tics and obsessive-compulsive disorder were at a mean age of 6.3 years and 7.4 years respectively. The same study also noted “significant psychiatric comorbidity”: emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, and oppositional behaviors (225). Some observations suggest that the spectrum of movement disorders associated with Streptococcus infections may be wider than previously thought; dementia, dystonia, encephalitis lethargica-like syndrome, motor stereotypies, myoclonus, opsoclonus, parkinsonism, paroxysmal dyskinesia, restless leg syndrome, and tremor, for instance, have been added to the list of phenomena associated with this infection (70; 69; 71; 73; 72; 81; 135; 156; 41; 204). There remain many doubts whether there is indeed a solid causal relationship between streptococcal infection and some of these clinical phenomena (129). The skepticism grows because of the lack of cardiac abnormalities in patients meeting criteria for PANDAS (218). One may argue that if the pathogenesis of Sydenham chorea and PANDAS is the same, there is no reason for only patients with the former have carditis. Moreover, there is growing evidence that nonspecific infections may be associated with tics. In a 1 study, a German group reported that markers of Mycoplasma pneumoniae are more commonly found in Tourette syndrome patients than in controls (170). A prospective study performed in the United States demonstrated that the clinical exacerbations of tics and behavioral symptoms in patients who meet criteria for PANDAS are not related to Streptococcus infections (130; 209). On the other hand, an Italian group demonstrated that a subset of patients with Tourette syndrome have increased titers of anti-streptococcal and anti-basal ganglia antibodies. Moreover, there has been the description of an antibody against pyruvate kinase in patients with Tourette syndrome. This antibody cross-reacts with streptococcal M proteins and its concentration increases when patients develop worsening of symptoms (116). The observation that patients with a diagnosis of poststreptococcal movement disorders often have concurrent psychogenic symptoms demonstrates the problems surrounding the concept of PANDAS (221). An epidemiological study failed to identify a strong relationship between streptococcal infection and neuropsychiatric syndromes (200), further weakening the hypothesis of PANDAS. Nevertheless, a group of investigators demonstrated that previous history of Streptococcus infections predicts future tic severity in a small subset of patients with Tourette syndrome (140). The PANDAS hypothesis has been further weakened by the finding that unlike Sydenham chorea, sera of patients who meet criteria of PANDAS do not bind to neuronal surface (25). Moreover, a new study again failed to find immunologic abnormalities that distinguish controls from patients with Tourette syndrome and who meet criteria for PANDAS (168). In the light of all these problems surrounding PANDAS, a group of investigators proposed that it is time to abandon this concept (210). These authors coined the term CANS (Childhood Acute Neuropsychiatric Symptoms) to encompass the heterogeneous situation of pediatric patients who have sudden onset of neuropsychiatric features. This is recognition of the nonspecific etiologic nature of this group of symptoms. Indeed, there is growing evidence that nonspecific infections may be associated with tics. Another newly described entity, termed Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) has been proposed to acknowledge that there is a subgroup of children presenting with an abrupt onset of obsessive-compulsive disorder and acute neuropsychiatric symptoms, accompanied by a variety of comparably severe and acute neuropsychiatric symptoms (224). In contrast to PANDAS, the diagnostic criteria for PANS no longer include tics. In contrast, a study provided evidence of elevated serum IgG antibodies against lysoganglioside, tubulin, and dopamine receptors (D1R and D2R) in children with tics and/or obsessive-compulsive disorder and a history of previous streptococcus infections. The authors compared the titers with data from healthy controls (64). The same group published a new study reinforcing the relationship between these antibodies and Sydenham chorea and PANDAS. Moreover, they report that these antibodies are capable of increasing the activity of calcium calmodulin dependent protein kinase II (54). The most recent piece of evidence in this controversial area comes from Denmark. Danish authors have done an epidemiological study of more than 1 million children over a 17-year follow up. They found that individuals with a streptococcal throat infection had elevated risks of mental disorders, particularly obsessive compulsive disorder and tic disorders. However, nonstreptococcal throat infection was also associated with increased risks, although less than streptococcal infections for obsessive compulsive disorder and any mental disorder. Their data support the notion that infections in general, and not exclusively by Streptococcus, have a nonspecific effect of inducing neuropsychiatric abnormalities in children (176). A published prospective, multicenter international study followed up children and adolescents with tics (154). The authors failed to identify significant association with exacerbation of tics and markers of streptococcal infection.

There are reports describing the association between other bacterial infections and movement disorders. Lyme disease, already mentioned as related to the development of opsoclonus-myoclonus, has been reported as causing tremor (216; 15). Kinetic tremor of the upper limbs has also been found in patients with Legionnaires’ disease, a common cause of pneumonia rarely related to central nervous system complications (108). Neurosyphilis was described as a cause of parkinsonism (50) and opisthotonus (55). Not surprisingly, there have been reports of listeria-associated rhombencephalitis causing palatal tremor (58).

In May 2011, there was an outbreak of Shiga toxin-producing enterohemorrhagic E coli O104:H4 in northern Germany that led to a high proportion of patients developing postenteritis hemolytic uremic syndrome and thrombotic microangiopathy. Despite a heated controversy, there is mounting evidence that neurologic complications, observed in 50% of patients, are caused by an autoimmune process. Stimulus-sensitive myoclonus is among the most common reported features (97).

There are descriptions of tuberculous meningitis in association with movement disorders than previously recognized (03; 04). Among 180 consecutive patients with this condition, 30 were found to develop movement disorders, mainly tremor and chorea. Interestingly, 1 patient with a cerebellar tuberculoma developed dystonia that came into full remission after specific treatment induced disappearance of the tuberculoma. The relationship of the latter to chorea has been confirmed by a case report (126). A study described the rare association between dystonia and autonomic instability with an interpeduncular tuberculoma (215). A review of a series of patients with cerebral malaria in Mali has shown that persistent dystonia can be detected in up to 2% of patients (173).

We reported an immune-competent patient who developed a parkinsonian syndrome in association with cryptococcomas (32). Brain abscess caused by Cladophialophora bantiana has also been described as cause of tremor (18).

In the past few years, there were studies suggesting that Helicobacter pylori gastric infection could play a role in the pathogenesis of levodopa-related fluctuations in Parkinson disease. The obvious implication of this hypothesis is to treat fluctuations by the eradication of H pylori. However, a Cochrane systemic review failed to demonstrate any benefit of this strategy as a treatment of levodopa-induced fluctuations (188).

As of the writing of this clinical article, the world continues to be under the grip of the SARS-CoV-2 pandemic, COVID-19 (138). The massive and global distribution of this infection is reminiscent only of the so-called Spanish flu in 1918, which is estimated to have caused 50 million fatal victims worldwide. One year after its beginning, it is clear that up to 30% of individuals with COVID-19 eventually develop neurologic manifestations (153). Among others, they include encephalopathy, stroke, Guillain-Barré syndrome, and movement disorders. The actual underlying mechanism remains to be elucidated. There are, however, data suggesting that direct invasion of the virus are rare. In most cases there is evidence of a virus-induced inflammatory response resulting in damage of the nervous system. In some patients a prothrombotic state causes ischemic disease. Finally, an autoimmune response causes movement disorders or other neurologic disorders in a small subset of COVID-19 patients. Although it is not possible yet to determine the actual frequency of movement disorders in COVID-19, they are clearly infrequent. The most common phenomena are myoclonus, cerebellar ataxia, and oculomotor abnormalities in 63%, 39% and 20%, respectively, which are found in literature reports of movement disorders in COVID-19 (22). Other described phenomena are parkinsonism, catatonia, chorea, and dystonia. During the acute phase of COVID-19, up to 80% of patients develop loss of smell, and there are speculations that they may be at risk of developing parkinsonism in the future (27). Strengthening this frightening hypothesis, we and others have described the occurrence of presynaptic, levodopa-responsive parkinsonism in COVID-19 patients (84). It will be necessary to carefully follow up survivors of the acute phase of the illness to determine the possibility of an outbreak of COVID-19-related parkinsonism. Yet the current evidence suggests that this does not seem to be a likely hypothesis since the anosmia is transient and related to loss of supporting cells and not neurons of the olfactory epithelium (31); direct damage of the CNS is uncommon in contrast to what happened in Von Economo encephalitis.

Prognosis and complications

Patients with parkinsonism following encephalitis lethargica have a rather stable course, remaining essentially unchanged for many years, even in the absence of treatment. In contrast, some cases of postencephalitic parkinsonism, especially those associated with Japanese as well West Nile virus encephalitis, display a tendency for spontaneous improvement (184; 191).

The recognition of movement disorders in AIDS, particularly if associated with HIV encephalopathy, carries an ominous prognosis because it is a marker of advanced disease. However, the introduction of highly active antiretroviral therapy seems to be changing this picture. In fact, some trials suggest that the use of these drugs is capable of improving motor performance and reducing the incidence of neurologic complications (195).

The older literature describes Sydenham chorea as a rather benign, self-limited condition that comes into remission after a few months (172). Careful prospective follow-up of patients in the last few years demonstrates, however, that in up to one half of those studies, chorea remains active 2 years after its onset. Moreover, despite regular use of secondary prophylaxis, recurrences of the movement disorders are observed in up to 50% of subjects (48). It has been proposed that at least part of these recurrences occur independently of new Streptococcus infection (100). The most fearful problem in patients with Sydenham chorea is the occurrence of valvulopathy and other cardiac problems. The importance of this complication is illustrated by the finding that in areas where rheumatic fever is endemic, 70% of cardiac surgeries are performed to treat its complications (37).

Clinical vignette

A 41-year-old woman presented with involuntary movements. At 36 years of age, she first noticed the gradual onset of “jerks” on the right side of the body. Two years later, those movements ceased for a period of 1 year. After this period of time, the involuntary movement recurred and remained unchanged until her visit to our service. Her past medical history was remarkable for the presence of “rheumatism” at 12 years of age, intestinal schistosomiasis mansoni during childhood, and treated pulmonary tuberculosis. On physical examination, the most important findings were bilateral carotid bruit, cardiac systolic murmur, semantic verbal fluency of 9 words in 1 minute (normal range is above 11), phonetic verbal fluency of 1 word in 1 minute (normal range is above 11), and right hemichorea. Diagnostic work up included the following tests, which were normal or negative: sedimentation rate, serum glucose, mucoproteins, protein electrophoresis, rheumatoid factor, antistreptolysin-O, antinuclear factor, antiphospholipid antibody, thyroid function, CT scan of the brain, and spinal fluid analysis. Echocardiogram disclosed aortic stenosis and insufficiency, with thickening and calcification of the leaflets. Antineuronal antibodies cross-reactive with streptococcal and cardiomyocytes antigens were detected by enzyme-linked immunosorbent assay and Western Blot. Infusion of the serum of the patient into the subthalamic nucleus of a rat, followed by infusion of apomorphine, induced circling of the animal. The final diagnosis was adult-onset Sydenham chorea. A 2 mg twice a day dosage of pimozide induced remission of the chorea, but every attempt to reduce the dosage brought a recurrence of the movement disorder. Twelve years after the diagnosis, the patient is still on this neuroleptic, together with prophylaxis and penicillin.

Biological basis

Etiology and pathogenesis

The etiology of epidemic encephalitis lethargica remains unknown, but it is believed to be due to a transmissible agent (142). The presumed agent was shown to pass through filters; the disease was transmissible to monkeys by injection of brain tissue from affected patients. Other viral encephalitides can also be followed by parkinsonism, for instance, Western equine encephalitis, Coxsackie B, measles, chicken pox encephalitis, West Nile virus, and Japanese B encephalitis. Other conditions reported as associated with encephalitis lethargica, or parkinsonism are Lyme disease and streptococcal infection (53; 72). A study lists evidence in support of an enterovirus as the cause of Von Economo encephalitis lethargica (79).

Postencephalitic parkinsonism results from direct viral lesion of the substantia nigra pars compacta and other basal ganglia structures. In encephalitis lethargica, the usual latency of several years between the acute disease and the onset of parkinsonism was presumably accounted for by aging effects in the central nervous system. Despite use of technology to investigate the causative agent of postencephalitic parkinsonism, its identity remains unknown to date (189; 142). Postmortem pathological findings include extensive neurofibrillary degeneration in many brainstem regions as well as in parts of the cerebral cortex. The substantia nigra pars compacta is almost completely obliterated in the majority of patients, even when the clinical symptoms of parkinsonism are mild. Using histopathological methods, postencephalitic parkinsonism is extremely difficult to distinguish from progressive supranuclear palsy (92). Despite this similarity, Buee-Scherrer and colleagues demonstrated, using immunoblots, that in progressive supranuclear palsy there is tau protein triplet similar to the one seen in Alzheimer disease (30). In neuroimaging studies of patients with parkinsonism and other movement disorders following Japanese or other encephalitis, there is evidence of selective lesion of substantia nigra in some patients (184; 114; 198).

The HIV-induced profound immunosuppression renders patients susceptible to opportunistic agents, which injure basal ganglia structures, causing movement disorders. This is particularly evident in toxoplasmosis where granulomas are preferentially located in the basal ganglia, diencephalon, and midbrain. Such clinicopathologic correlation is obvious in chorea-hemiballismus, the most common hyperkinesia in AIDS, resulting from subthalamic lesion caused by T gondii (183; 37). There is a report on hemichorea-hemiballism in the context of HIV infection but in association with histoplasmosis (83). Another important mechanism underlying movement disorders in AIDS, especially parkinsonism, is dopaminergic dysfunction associated with HIV encephalopathy. A growing body of evidence suggests that HIV encephalopathy is associated with damage to basal ganglia, resulting in decreased dopaminergic activity. Such dysfunction would also explain the susceptibility of these patients to develop parkinsonism and other side effects after exposure to neuroleptics (118; 196; 163; 145). After the introduction of highly active antiretroviral therapy, there is a surge of movement disorders related to underlying autoimmune mechanisms such as opsoclonus-myoclonus and ataxia.

Taranta and Stollerman established the casual relationship between infection with group A beta-hemolytic streptococci and occurrence of Sydenham chorea (228). Based on the assumption of the existence of molecular mimicry between streptococcal and central nervous system antigens, it has been proposed that the bacterial infection in genetically predisposed subjects leads to formation of cross-reactive antibodies, which disrupt the basal ganglia function. Several studies have demonstrated the presence of such circulating antibodies in 50% to 90% of patients with Sydenham chorea (107). In a study of patients seen at the Movement Disorders Clinic of the Federal University of Minas Gerais, we demonstrated that all patients with active Sydenham chorea have antibasal ganglia antibodies demonstrated by ELISA and Western Blot. In subjects with persistent Sydenham chorea (duration of disease greater than 2 years despite best medical treatment), the positivity was about 60% (59). The genetic marker for rheumatic fever and related conditions would be the B-cell alloantigen D8/17 (86). Attempts to replicate the latter findings, however, failed. Although it is believed that a subset of population is susceptible to developing rheumatic fever, the susceptibility factor remains to be determined (249). In fact, 1 study showed that certain polymorphisms of the promoter region of the tumor necrosis factor-alpha predict the development of aortic valve lesions but are not associated with onset of chorea (187). Studying sera and CSF of patients with Sydenham chorea from the Movement Disorders Clinic of the Federal University of Minas Gerais, Church and colleagues found evidence suggestive of a Th1 response (60). However, while investigating other serum markers of cell-based immune response in Sydenham chorea, we found evidence of a Th2 response, which is consistent with what is found in rheumatic carditis (231). Sydenham chorea monoclonal antibodies were found to induce activity of calcium/calmodulin-dependent protein kinase. This result led the authors to speculate that Sydenham chorea may be related to antibody-mediated neuronal cell signaling (121). We have also shown that there is a linear correlation between concentration of anti-basal ganglia antibodies and influx of calcium into neuroendocrine cells exposed to sera of Sydenham chorea patients (232). Taken together, these results suggest that the antibodies may play an important role in the pathogenesis of chorea in rheumatic fever. It has been suggested that the antibodies react with the surface of the neurons, signal the induction of calcium calmodulin dependent protein kinase II with enhancement of activity of tyrosine hydroxylase. This enzyme leads to increase in the concentration of dopamine, resulting in chorea (122). Expanding this finding, this same group identified that the circulating antibodies present in Sydenham chorea have tubulin as their target. Moreover, they have shown that they are capable of inducing release of dopamine (120). However, although using different methodology, others have failed to identify consistent differences between controls and patients with Sydenham chorea in terms of reactivity for antineuronal antibodies (212). Studies provide compelling evidence that Streptococcus-induced antibodies cross-react with central dopamine receptors inducing movement disorders and behavioral abnormalities (26; 66; 74; 80; 67). The underlying mechanism responsible for the persistence of Sydenham chorea in up to 50% of individuals remains to be understood. Imaging studies rule out the occurrence of structural changes. One study demonstrated there is no lymphocyte dysfunction in patients with persistent chorea (241). The article on Sydenham chorea contains further information of the pathogenesis of this condition. Besides cross-reactive antibodies, other immune mechanisms may generate the basal ganglia dysfunction in Sydenham chorea. Some authors have suggested that streptococcal infection induces vasculitis of medium-sized vessels, leading to neuronal dysfunction. Such vascular lesions could be produced by antiphospholipid antibodies. There is also the suggestion of participation of cellular immune mechanisms in the pathogenesis of Streptococcus-related movement disorders (231). Another investigation confirmed that cellular immune mechanisms may be relevant to the pathogenesis of Sydenham chorea because there is a dysfunction of monocytes (240). A study confirmed that sera of patients with Sydenham chorea contain antibodies that react with neuronal surface antigens (75).

PANDAS would result from a pathogenic mechanism similar to the one proposed in Sydenham chorea. The resulting phenomenology, however, is different because in this case the clinical picture is dominated by tics and obsessive-compulsive behavior (225; 223). There are, however, many problems with this hypothesis:

(1) Although there are circulating antineuronal antibodies in some patients with Tourette syndrome, they are not correlated, either with clinical findings or even with markers of streptococcal infection (211). However, another group identified positivity for anti-basal ganglia antibodies on ELISA and Western Blot in 20% of patients with Tourette syndrome (60a). But another study did not find differences between Tourette syndrome and controls in terms of antistreptococcal, neuronal, and nuclear antibodies (144). In fact, even when studying patients identified as having PANDAS by the introducer of the concept, there has been no consistent finding that differentiated these subjects from controls (213). The diagnostic value of antibasal ganglia antibodies is still unclear. Although some believe that they are helpful (61), others remain skeptical (129). One of the difficulties in interpreting the results of studies of these antibodies is the lack of standardization among the different labs performing the assays. Moreover, even in a given center, the sensitivity and specificity of the technique varies depending on the report (59; 61). More importantly, attempts to induce behavioral changes in experimental animals by infusion of sera of patients have yielded conflicting results (143).

(2) Because the pathogenesis of Sydenham chorea and PANDAS is the same, one would expect that patients with the latter developed manifestations of rheumatic fever, such as carditis and arthritis. However, this has never been described (217).

(3) Tourette syndrome and other tic disorders are not more common in geographic areas where rheumatic fever is endemic.

(4) An initial study by the group of researchers who introduced the concept of PANDAS failed to prove that use of antibiotics modifies the clinical course of patients who meet criteria for this condition (91). Another investigation of this group reports that use of penicillin and azithromycin significantly decreases the severity of clinical manifestations of patients with PANDAS. However, despite the prospective and blinded nature of the trial, there was no placebo control. The clinical score of the patients on treatment were compared with historical ratings of the same subjects. This raises the issues of history bias as well as placebo effect (217).

(5) Antibodies present in patients who meet criteria for PANDAS are not identical to antibodies found in individuals with Sydenham chorea (122).

(6) Lack of relationship between exacerbations of tics and behavioral symptoms and Streptococcus infections in patients meeting criteria for PANDAS (130).

(7) Antibodies extracted from sera of patients who meet criteria for PANDAS do not recognize the antigens to which antibodies from Sydenham chorea patients bind (25).

(8) Antibasal ganglia antibodies lack specificity (43).

(9) Large, prospective, epidemiological studies failed to establish a relationship between tic exacerbations and streptococcal infections (154).

Epidemiology

Postencephalitic parkinsonism, once epidemic, is currently rare, although no population-based data are available. Encephalitis lethargica has disappeared, but occasionally there are reports on conditions mimicking its clinical features; it remains unclear, however, whether these patients have the same condition as the one described by von Economo. Japanese encephalitis, on the other hand, is a major public health problem in Asia, where there are 300,000 new cases each year. Many of these patients eventually develop movement disorders (184; 114).

There are also no community-based studies on the prevalence of movement disorders in HIV infection. However, in a series of patients seen at tertiary referral centers, approximately 2% to 3% of subjects with AIDS develop these complications. In 1 study, parkinsonian signs were identified in about 5% of patients (163; 37). The introduction of highly active antiretroviral therapy has led to a decrease in the frequency of HIV encephalopathy as well as of opportunistic neurologic complications in AIDS patients (155). Although movement disorders have not been specifically studied in these investigations, based on the decline of reports on this issue as well as the reduced number of HIV-positive patients seen in movement disorders clinics, one may speculate that their incidence has also decreased.

Sydenham chorea is the most common cause of acute chorea in children; however, its prevalence has decreased in conjunction with the reduction of rheumatic fever in North America and Western Europe. For instance, in Fairfax County, Virginia, the annual age-adjusted incidence rate of initial attacks of rheumatic fever per 100,000 children declined from 3.0 in 1970 to 0.5 in 1980 (201). Furthermore, Nausieda and colleagues demonstrated that Sydenham chorea accounted for 0.9% of children admitted to hospitals in Chicago before 1940, whereas this number dropped to 0.2% between 1950 and 1980 (172). However, at least 8 outbreaks of rheumatic fever with occurrence of chorea have been identified in the United States (09). Even in areas where there has been a decline in the incidence of rheumatic fever, such as Pennsylvania in the United States, this illness account for almost all cases of acute chorea among children (258). Rheumatic fever has remained a significant public health problem in developing areas, particularly within the low income population. In the top end of the Northern Territory in Australia, an area predominantly inhabited by Aborigine people, the prevalence of rheumatic fever was 9.6 per 1000 people aged 5 to 14 years in 1995 (35). Sydenham chorea occurs in about 26% of patients with rheumatic fever (47). Clinical observation in our unit suggests that there is a decline of the frequency of Sydenham chorea in Brazil, an area where rheumatic fever used to be endemic. The article on Sydenham chorea provides additional information on this topic.

Prevention

Once the diagnosis of Sydenham chorea is established, the patient must receive secondary prophylaxis with penicillin or, in patients with allergy, sulpha drugs. This has been shown to effectively decrease the risk of development of new episodes. The recommendation of the World Health Organization is to maintain the secondary prophylaxis up to 21 years of age. The policy is less clear in instances when Sydenham chorea diagnosis is made after this age.

Differential diagnosis

Postencephalitic parkinsonism is distinguished from other causes by history of encephalitis lethargica, onset before middle age, symptom duration lasting more than 10 years without substantial progression, or the presence of oculogyric crisis (141). As most subjects with postencephalitic parkinsonism display supranuclear ophthalmoplegia and lid apraxia, an important differential diagnosis is progressive supranuclear palsy. However, patients with the latter do not display a good response to levodopa and the clinical course is much more aggressive, with an average survival time of 6 years.

Movement disorders in HIV-positive patients rarely represent a significant clinical problem because the vast majority of subjects are already known to have advanced-stage AIDS. One exception to this rule is the rare patient whose presenting symptom of HIV infection is hemichorea hemiballismus. For this reason, it is advisable to order anti-HIV serology in all patients with this hyperkinesia.

Several conditions may present with clinical manifestations similar to Sydenham chorea. The most important differential diagnosis is systemic lupus erythematosus, wherein up to 2% of patients may develop chorea. From a clinical point of view, the majority of subjects with this condition will have other nonneurologic manifestations such as arthritis, pericarditis, and other serositis, as well as skin abnormalities. Moreover, even the neurologic picture proves to be more complex and includes psychosis, seizures, other movement disorders, and mental status and consciousness level changes. Only in rare instances will chorea be an isolated manifestation of lupus. The difficulty to distinguish the 2 conditions is increased by the finding that up to 50% of patients with Sydenham chorea display recurrence of the movement disorder. However, patients with lupus will eventually develop other features, meeting diagnostic criteria for this condition (10). Primary antiphospholipid antibody syndrome is differentiated from Sydenham chorea by the absence of other clinical and laboratory features of rheumatic fever and the usual association with repeated abortions, venous thrombosis, and other vascular events, as well as the presence of typical laboratory abnormalities. Encephalitides, either as a result of direct viral invasion, or by means of an immune-mediated postinfectious process, cause chorea. This usually happens, however, in younger children; the clinical picture is more diversified and includes seizures, pyramidal signs, and impairment of psychomotor development. There are laboratory abnormalities suggestive of the underlying condition. Drug-induced choreas are readily distinguished by careful history demonstrating temporal relationship between onset of the movement disorder and exposure to the agent (40).

Diagnostic workup

Diagnosis of postencephalitic parkinsonism is only confirmed at postmortem examination. MRI displaying lesion of the substantia nigra in a patient with a history of previous encephalitis helps to confirm the diagnosis. In the case of Japanese encephalitis, lesions are found not only in the substantia nigra, but also in other areas of the midbrain, thalamus, and basal ganglia.

The workup of AIDS patients with movement disorders includes neuroimaging studies and a search for opportunistic infections. On CT scan and MRI, toxoplasmosis typically produces multifocal lesions with necrotic center, peripheral contrast-enhancement, and severe mass effect located in the basal ganglia and upper brainstem. HIV encephalopathy, another important cause of movement disorders in AIDS, does not cause significant abnormalities on CT, but hyperintensity on T2 in the deep white matter and basal ganglia can be seen on MRI. Biopsy of brain lesions is reserved for patients who fail to respond to 15 days of treatment for toxoplasmosis. Spinal fluid analysis may be helpful to investigate opportunistic infections but must not be performed if the patient shows signs of increased intracranial pressure. Advanced stage HIV-positive patients with movement disorders usually have low CD4 cells level and, conversely, high viral load (163; 37).

There is no specific biological marker of Sydenham chorea. The test of antineuronal antibodies is not commercially available, being performed exclusively for research purposes. Tests of acute phase reactions, such as erythrocyte sedimentation rate, C-reactive protein, and leukocytosis; other blood tests like rheumatoid factor, mucoproteins, and protein electrophoresis; and supporting evidence of preceding streptococcal infection (increased antistreptolysin-O, anti-DNase-B, or other antistreptococcal antibodies as well as positive throat culture for group A Streptococcus and recent scarlet fever), are much less helpful in Sydenham chorea than in other forms of rheumatic fever due to the usual long latency between the infection and the onset of the movement disorder. Serologic studies for systemic lupus erythematosus and primary antiphospholipid antibody syndrome must be ordered to rule out test conditions. Cardiac evaluation, including Doppler echocardiography, are mandatory because the association of Sydenham chorea with carditis is common. Spinal fluid analysis is usually normal, but it may show a slight increased lymphocyte count. CT scan of the brain invariably fails to display abnormalities. Similarly, head MRI is often normal, although there are case reports of reversible hyperintensity in the basal ganglia area. In 1 study, Giedd and colleagues showed increased signal in just 2 of 24 patients although morphometric techniques revealed mean values for the size of the striatum and pallidum larger than controls (94). Unfortunately, these findings are of little help on an individual basis because there was an extensive overlap between controls and patients. PET and SPECT investigations done on Sydenham chorea patients have shown reversible striatal hypermetabolism (103; 13; 37).

Management

Levodopa is the mainstay of the management of postencephalitic parkinsonism. Physicians must be aware that patients with forms related to encephalitis lethargica are highly sensitive to this medication; even low doses of levodopa may induce severe motor complications, such as fluctuations and dyskinesias, as well as psychiatric side effects like psychosis. In contrast, the reports on other forms of postencephalitic parkinsonism indicate that some of these patients are, in fact, resistant to levodopa. A reasonable initial dosage regimen is 62.5 mg of levodopa and 6.25 mg of carbidopa twice a day, which can later be increased to 125 mg of levodopa and 12.5 mg of carbidopa 3 times a day.

The symptomatic management of chorea-hemiballismus in AIDS patients can be done with the use of dopamine receptor blockers. In most patients, control of the hyperkinesia can be achieved with 2 mg of pimozide twice a day. As these patients have a dopaminergic deficit induced by the HIV, they are susceptible to development of tremor and parkinsonism when exposed to dopamine receptor blockers. It is not uncommon, for instance, that the hemiballism becomes controlled on 1 side of the body at the expense of parkinsonism on the other side. Fortunately, hemiballism hemichorea has a tendency for spontaneous improvement after a few weeks, when it becomes possible to discontinue the neuroleptics. Parkinsonism associated with HIV encephalopathy is rarely a clinical problem important enough to deserve symptomatic treatment. Unfortunately, in the rare instances when it is clinically problematic, patients do not respond to levodopa, although a few reports suggest that children do improve on this medication (163; 37). Because of the potential of medications to induce motor side effects in HIV-positive patients, it is extremely important to attempt to discontinue offending drugs, such as neuroleptics. One study suggests that low doses of clozapine (6.25 to 25 mg per day) can be a useful treatment of psychosis in AIDS patients. The limitation of this agent, however, is its potential to induce agranulocytosis, particularly in HIV-positive patients (137). In case there is a recognized associated opportunistic infection, patients must also receive specific therapy. Finally, although its role in the treatment and prevention of motor complications is not clearly established, initial evidence suggests that highly active antiretroviral therapy has a positive impact on these problems (155; 195; 24; 102; 38).

There are no controlled studies of symptomatic treatment of Sydenham chorea (42). Valproic acid, at the daily dosage of 15 mg/kg up to 1500 mg, is our first choice of treatment of chorea in this condition. Although having a longer onset of action, this drug is as effective as neuroleptics are and is usually better tolerated. Dopamine receptor blockers are reserved for patients with chorea paralytica when valproic acid fails to improve the movement disorder. Caution is warranted in the use of neuroleptics in Sydenham chorea. In a case-control study, we demonstrated that there is an increased risk of development of drug-induced parkinsonism in Sydenham chorea in comparison with Tourette syndrome (229). Risperidone, a relatively potent dopamine D2 receptor blocker, is usually effective in controlling the chorea. The usual initial regimen is 1 mg twice a day. If, 2 weeks later, the chorea is still troublesome, the dosage can be increased to 2 mg twice a day. Haloperidol and pimozide are also occasionally used in the management of chorea in Sydenham chorea. However, they are less well tolerated than risperidone. We published results of treatment with steroids of Sydenham chorea refractory to valproic acid and neuroleptics. Methyl-prednisolone, 20 mg/kg (up to 1 g/day intravenously) for 5 days (234), followed by oral prednisone (1 mg/kg per day) gradually tapered down according to clinical status was affective and well-tolerated (46). We have extended our experience with use of corticosteroids in selected patients with Sydenham chorea (236). Our experience has been confirmed by others (11). There are no published guidelines on when to discontinue antichoreic agents. Finally, the most important measure in the treatment of patients with Sydenham chorea is secondary prophylaxis with penicillin or, if there is allergy, sulpha drugs up to 21 years of age. In case the onset is after this, the recommendation is to maintain prophylaxis indefinitely (37). The introduction of the concept of PANDAS led to the proposal of the use of antibiotics or immunosuppressive measures such as intravenous immunoglobulins and even plasmapheresis. Because of the potential risks and lack of good quality studies, it is not recommended to treat patients with tics, obsessive-compulsive behavior, or both. A study shows, however, that despite the controversies surrounding the concept of PANDAS, antibiotics and immunosuppressive measures have been liberally used in the United States to treat patients with tics and related behavioral problems (89).

Management of patients with Escherichia coli O104:H4-associated hemolytic uremic syndrome remains controversial. Some authors propose using modulation of immune response, arguing that to use antibiotics may in fact worsen the clinical picture (97). Not all authors, however, accept this conclusion.

Special considerations

Pregnancy

Patients with previous history of Sydenham chorea may develop chorea gravidarum as a result of recurrence of the movement disorder during pregnancy. The onset of chorea is usually in the first trimester, with spontaneous improvement or even remission in the third trimester. If the movement disorder is not severe enough, no treatment is advisable. However, if necessary, low doses of neuroleptics are safe to the mother and child. There is no risk of teratogenesis, but 19th century literature describes fetal loss related to severe chorea. It is important to emphasize that there are also other causes of chorea gravidarum such as systemic lupus erythematosus (39). In 1 study, it was found that 75% of women with Sydenham chorea in remission who became pregnant developed chorea gravidarum (150). A worrying finding of this study was an abortion ratio of 13% among patients with chorea during pregnancy.

No information is available on the relationship between pregnancy and postencephalitic parkinsonism and AIDS-related movement disorders.