Autoimmune movement disorders

Sydenham chorea

Sydenham chorea (SC) is a subacute, childhood-onset movement disorder that occurs as a result of infection with group A beta-hemolytic streptococcus (GABHS) typically in the setting of rheumatic fever (RF). RF, an autoimmune, multiorgan inflammatory disease, is associated with carditis (50%–78%), arthritis (35%–88%), chorea (2%–30%), erythema marginatum (less than 6%), and subcutaneous nodules (less than 1%–13%) ( ). Chorea is associated with RF in about 26% of cases, but in 20% of cases it may be the sole manifestation ( ). Chorea is usually asymmetrical, and it may manifest as pure hemichorea in about 20% of cases. Although usually not disabling, in about 8% of cases it may be associated with severe hypotonia resulting in the patient being bedridden (chorea paralytica). Other motor phenomena include motor impersistence (“milkmaid grip” and “darting tongue”), phonic or motor tics, altered ocular fixation and oculogyric crises, dysarthria, and impaired verbal fluency ( ). Chorea may also recur during pregnancy (chorea gravidarum). In one study, 15 of 20 (75%) SC patients developed chorea gravidarum, which also may be triggered by the use oral contraceptives ( ).

In SC the individual contractions are slightly longer (longer than 100 ms) compared with those in Huntington disease (50–100 ms), but both have reduced corticospinal excitability. Some have postulated that reduced excitability, as demonstrated by transcranial magnetic stimulation (TMS) studies, may be compensatory ( ; ).

In most cases of SC, various neuropsychiatric manifestations, such as obsessive-compulsive symptoms, attention deficit disorder, personality changes, emotional lability, anxiety, age-regressed behaviors, anorexia, and dysexecutive syndrome, follow the onset of or accompany chorea, and these behavioral problems may persist for years of decades after chorea resolves ( ). Typically, SC is a self-limited condition with a spontaneous remission after a course of 8 to 9 months, but up to 50% of patients may remain with chorea for years or decades. Despite regular use of secondary prophylaxis, recurrences are observed in up to 30% of patients (often without association with streptococcus infection or even anti–basal ganglia antibodies ( ).

A major concern in patients with SC is cardiac involvement, particularly mitral valve insufficiency, present in 60% to 80% of cases ( ). Because of the many neurologic, psychiatric, rheumatologic, cardiac, and other comorbidities the condition should be called Sydenham disease rather than Sydenham chorea (analogous to Huntington disease rather than Huntington chorea), but the term Sydenham chorea has been traditionally used in the medical literature.

The diagnosis of SC is supported by demonstration of a previous infection with GABHS using throat cultures, positive antistreptolysin O, or anti-DNAse antibodies. Magnetic resonance imaging (MRI) is usually normal, although an increase in basal ganglia volume has been reported using volumetric methods.

The pathogenic mechanism of SC is not well understood, but molecular mimicry and cross-reactivity between GABHS and certain components of the basal ganglia have been proposed. For example, rats immunized with GABHS developed antibodies against D1 and D2 receptors and clinically showed compulsive-like behaviors ( ). In addition, passively transferred serum obtained from GABHS-immunized mice caused behavioral disturbances ( ). Furthermore, anti–basal ganglia antibodies have been observed with a high sensitivity in patients with acute SC ( ; ). It has been postulated that some of these antibodies activate the CaMKII pathway of neurons leading to an increase in dopamine release, possibly explaining the chorea and some of the neuropsychiatric manifestations of SC. Some of the antibodies cross-react with various brain components besides the basal ganglia, and thus they should be referred to antineuronal, rather than anti–basal ganglia antibodies.

A full 10-day course of oral penicillin V therapy or an injection of benzathine penicillin G because penicillin prophylaxis is advisable in all patients for at least 10 years after RF or carditis. A brief course of prednisone, based on findings of beneficial effects in a double-blind, placebo-controlled study, has been also recommended ( ). Symptomatic treatment with a short course of fluphenaine or other dopamine receptor–blocking agent may improve chorea. Other drugs such as vesicular monoamine 2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine) ( ), valproic acid, and carbamazepine may also provide relief until the condition resolves spontaneously.

The terms PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus) and PANS (pediatric acute-onset neuropsychiatric syndrome) have been proposed to explain disorders triggered by GABHS infections and are manifested by young-onset obsessive-compulsive behavior, followed by tics and choreiform movements of fingers and toes that may be associated with poor handwriting skills (in PANDAS) ( ; ). These patients share a set of antibodies similar to those with SC. Although the concept of PANDAS is controversial and its existence has been questioned because of the lack of consistent link with GABHS infections, other microorganisms such as Mycoplasma or influenza viruses, and Lyme disease have been proposed to be associated with a similar disorder, which has led to coin the term PANS. Despite the separate terminology, the existence of PANDAS and PANS as nosologically distinct disorders is doubtful.

Anti–N-methyl-D-aspartate receptor encephalitis

Anti–N-methyl-D-aspartate receptor encephalitis (anti-NMDAR) encephalitis is considered the most common autoimmune encephalitis in childhood, but it also can occur in adults ( ; ). It affects predominantly young individuals with a mean age at onset of 23 years; women are affected four times more frequently than men, but female predominance is less prominent in individuals younger than 12 years and older than 45 years ( ). A substantial proportion of young females with NMDAR encephalitis have underlying ovarian teratomas, but testicular tumors and various carcinomas have been reported, especially in adults. The diagnosis is usually suspected by subacute manifestation of behavioral and neurologic (encephalopathic) symptoms and is supported by an abnormal electroencephalogram (EEG) and CSF with pleocytosis and oligoclonal bands. Definite diagnosis is based on the detection of immunoglobulin G (IgG) against the NR1 subunit of the NMDA receptor, particularly in the CSF ( ). In contrast to IgG NMDAR antibodies, which are highly specific for anti-NMDAR encephalitis ( ), IgA or IgM antibodies occur infrequently and nonspecifically ( ). The higher the antibodies in the serum and CSF, the worse is the prognosis. CXCL13, a B-cell–attracting chemokine, is a relatively sensitive and specific biomarker for anti-NMDAR encephalitis, as high concentrations in the CSF have been associated with relatively poor treatment response and poor outcome ( ).

Anti-NMDAR encephalitis is characterized by the onset of neuropsychiatric manifestations, followed by dysarthria, memory deficits, dysautonomia, insomnia followed by somnolence that can lead to altered consciousness, seizures, and a broad variety of movement disorders ( ; ; ). The following movement disorders have been described in patients with anti-NMDAR encephalitis: chorea, stereotypies, dystonia, catatonia, myoclonus, tremor, opsoclonus-myoclonus, and cerebellar ataxia ( ; ; ; ). Orofacial dyskinesia is typically manifested by dystonia, stereotypy, or myorhythmia ( ; ) ( Video 23.1 ).

The pathological abnormalities in the brains of patients with NMDAR encephalitis have not been well describes but the presence of concurrent anti-glial antibodies including antibodies directed against oligodendrocytes, causing a decrease of expression of GLUT1, may related to white matter alterations reported in patients with NMDAR encephalitis ( ; ). The latter is characterized by slow (1–4 Hz), repetitive, rhythmical movements affecting cranial or limb muscles ( ). The hyperkinetic movement disorders, particularly stereotypies, associated with anti-NMDAR encephalitis usually respond to dopamine-depleting drugs, such as tetrabenazine, deutetrabenazine, and valbenazine ( ; ). Although the movement disorders usually resolve after appropriate treatment, many patients have persistent behavioral abnormalities such as impaired attention and cognition, and fatigue ( ).

Video 23.1 Anti-NMDAR encephalitis. This 3-year-old boy with subacute onset of myalgias, frontal headaches, malaise, and vomiting; followed by confusional state, insomnia, hallucinations, dysarthria, and motor aphasia. He was admitted with diagnosis of viral encephalitis. During the hospitalization he developed generalized seizures, dysautonomia, repetitive orofacial stereotypies, dystonic contractions of the left side of his face, blepharospasm, dystonic flexion of the right hand and generalized chorea. He improved markedly with tetrabenazine.

Postherpes simplex encephalitis

A relapsing form of herpes simplex encephalitis, occurring in about 20% of patients after the initial illness, has been shown to be associated with the presence of anti-NMDA receptor antibodies in the serum or, more likely, in the CSF ( ; ; ). Antibody synthesis of several isotypes (IgG, IgA, or IgM) usually starts 1 to 4 weeks after the initial viral infection and may precede the onset of neurologic symptoms associated with the relapse. The most common manifestation is subacute, childhood-onset choreoathetosis, with or without orofacial and lingual stereotypies ( ). Most patients with this form of anti-NMDAR encephalitis, triggered by prior herpes simplex encephalitis, improve with immunotherapy.