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Movement Disorders in Autoimmune Diseases
Introduction
An autoimmune disorder indicates an acquired process targeting the nervous system involving either autoreactive lymphocytes (T or B cells) or autoantibodies. These disorders are complex, multifactorial entities with potential involvement of underlying genetic vulnerabilities, innate and acquired immune systems, and environmental factors. , In this chapter, autoimmune disorders occurring in children and presenting with associated movement disorders have been divided into five major categories (see Table 18.1 ). The Introduction provides a brief overview of immunology and reviews requirements regarding the pathophysiological confirmation of autoimmune disorders, especially those that are autoantibody mediated.
Table 18.1
Childhood Autoimmune Movement Disorders
|
Immunology Overview
The two major human immune systems include (1) the cell-mediated immune system consisting of cytotoxic T cells and macrophages; cells derived from T1 lymphocytes under the influence of specific cytokines (e.g., IL2, INFα and β); and (2) the humoral immune system consisting of antibodies produced by B lymphocytes; the latter derived from T2 lymphocytes under the influence of cytokines (e.g., IL4-6 and IL10).
In most central nervous system autoimmune disorders, the inciting factor (e.g., tumor, infection, other) is external to the brain itself, leading to an initial controversy of how immune cells gain entrance to this structure. While the precise answer is often unclear, possibilities include (a) the presence of activated lymphocytes which are capable of crossing the blood brain barrier (BBB) , ; (b) a compromised BBB that allows antibody entrance into brain parenchyma ; and (c) a BBB that is more actively involved in the transfer of molecules and proteins. ,
A second issue involves how an antibody derived from an ovarian teratoma (or other tumor, or infectious agent) targets a brain protein. The most common mechanism is the process of “molecular mimicry,” that is, the CNS epitope “looks like” the antigenic agent.
A third consideration is the actual location of the antibody binding site. Antibody binding to neuronal cell surface components such as neurotransmitter receptors or channel antigens (see Table 18.2 ) located within motor pathway circuitry is the typical underlying mechanism for movement abnormalities. In contrast, antibodies that bind to intracellular proteins (see Table 18.3 ), especially if measured using techniques with denatured intracellular antigens (e.g., homogenized tissue), may be valuable biomarkers, but are usually not pathogenic. ,
Table 18.2
Antibodies Targeting Extracellular Receptors or Other Cell Surface Proteins
| Antigen | Clinical symptoms | Tumor |
|---|---|---|
| NMDAR | Anti-NMDA encephalitis | |
| Children < 12 years : Seizures, behavioral changes, autonomic symptoms, variable abnormal movements, (orofacial and limb dyskinesia, chorea, dystonia, myorhythmia, opisthotonos, stereotypies, perseverations, ataxia, hyperkinetic movements) | Usually none | |
| Adults : Psychiatric symptoms, seizures, fever, altered consciousness, dyskinesias, catatonia, autonomic instability, hypoventilation, and coma | Ovarian teratoma testicular tumor | |
| LGI1 | Rare in childhood: Limbic encephalitis, faciobrachial dystonic seizures, myoclonus, chorea, parkinsonism, neuromyotonia, sleep disorders | <10% thymoma |
| Caspr2 | Adults: Morvan's syndrome (encephalitis and, neuromyotonia), myoclonus, tremors | Thymoma 20%–40% |
| GlyR | Children : PERM-like symptoms, stiff person, dyskinesias, ataxia | Infrequent, lung |
| Adults: Stiff person, PERM, limbic encephalitis, CB degen, optic neuritis | Lymphoma, thymoma | |
| D2R | Children : Basal ganglia encephalitis; movement disorders (dystonia, chorea, oculogyric crisis, parkinsonism, sleep disturbances, dysautonomia, and neuropsychiatric sequelae | None |
| AMPAR | Adults : Limbic encephalitis, atypical psychosis | 70%, small cell lung/breast cancer |
| GABAbR | Adults : Limbic encephalitis, prominent seizures, opsoclonus-myoclonus, ataxia | 50%; small cell lung |
| GABAaR | Refractory seizures, status epilepticus, epilepsy partialis continuans, stiff person, opsoclonus, dystonia, chorea, ataxia, orofacial dyskinesias, hemidystonia, opsoclonus-myoclonus | Infrequent Hodgkin's lymphoma |
| mGluR5 | Teens and adults : Ophelia syndrome—psychiatric symptoms, cognitive and memory impairments | Hodgkin's lymphoma |
| mGluR1 | Ataxia | Hodgkin's lymphoma |
| DPPX | Adults : Encephalitis, agitation, myoclonus, seizures, tremor, PERM-like symptoms, ataxia, hyperekplexia, nystagmus, myoclonus, seizures | B-cell lymphoma |
| IgLON5 | Adults: Sleep disorder with severe insomnia, NREM parasomnias, sleep disordered breathing, cognitive decline, severe gait instability, chorea, oculomotor dysfunction, dysautonomia, bulbar/laryngeal symptoms, | None |
Abbreviations: AMPAR , α-amino-3-hydroxy-5 methyl-4 isoxazolepropionic acid receptor; Caspr 2 , contactin-associated protein-related 2; CB , cerebellum; D2R , dopamine 2 receptor; DPPX , dipeptyl-peptidase-like protein-6; GABAaR and GABAbR , γ-aminobutyric acid receptors; GlyR , glycine receptor; IgLON5 , Immunoglobulin-like cell adhesion molecule 5; LGI1 , leucine-rich glioma inactivated 1; mGluR5 , metabotropic glutamate receptor 5; NMDAR , N-methyl- d -aspartate receptor; NREM , Non rapid eye movement; PERM , progressive encephalomyelitis with rigidity and myoclonus.
Table 18.3
Antibodies Targeting Intracellular Proteins
| Target | Clinical symptoms | Tumor |
|---|---|---|
| GAD 65 (glutamic acid decarboxylase) | Stiff person syndrome, autoimmune encephalitis | |
| Amphiphysin | Stiff person syndrome | |
| Ma 2 | Dystonia | |
| Hu | Opsoclonus myoclonus ataxia syndrome, obsessive-compulsive disorder | Neuroblastoma Small-cell lung cancer |
| TPO (thyroid peroxidase) | Ataxia, tremor, myoclonus, dystonia, seizures | |
| TrPC (canonical transient receptor potential channels) | Cerebellar degeneration (ataxia, nystagmus) | |
| CRMP5 (collapsin-response-mediator-protein 5) | Ataxia, peripheral neuropathy | Lung |
| Yo (anti-Purkinje cell antibody type 1) | Paraneoplastic cerebellar degeneration (PCD) | Gynecological cancers, Hodgkins lymphoma |
| Ri (antineuronal nuclear antibody 2) | PCD, opsoclonus | Gynecological cancers |
Lastly, the mechanism of antibody action can vary. For example, some autoantibodies alter receptor function (i.e., anti-N-methyl- d -aspartate receptor [NMDAR] causes internalization of the receptor), whereas other antibodies may trigger additional T-cell mechanisms with resultant cytotoxicity and cell death. ,
Confirmatory evidence required to support a proposed antibody being pathogenic includes proof that it: (a) binds to the target antigen in its native conformation and shape (i.e., proven using assays that express the suspected antigen at the cell surface of live eukaryotic cells); (b) binds to a specific antigen subunit (e.g., in anti-NMDAR encephalitis, to the GluN1 not GluN2/3 subunits); (c) belong to the immunoglobulin IgG class (not IgA or IgM); (d) be present at the pathological site; (e) be clinically responsive to immunomodulatory therapy; and (f) be able to be passively transferred to animal models. It is also noteworthy that in some disorders, the presence of the antibody in cerebrospinal fluid (CSF) can have a major role in the diagnostic criteria.
Diseases and Disorders
Autoimmune Encephalitis
Autoimmune encephalitis tends to have a subacute onset and to be manifested by cognitive/behavioral symptoms (developmental regression, temper tantrums, inattention), movement disorders, seizures (focal/generalized), and/or autonomic dysfunction. Its etiology can be parainfectious, paraneoplastic, or idiopathic. Movement disorders are common (up to 90%) in affected children, often occur early in the course of the disease, and tend to persist. The phenomenology may include hyperkinetic (ataxia, athetosis, chorea, dystonia, hemiballismus, myoclonus, myorhythmia, oculogyric crises, opisthotonis, orofacial lingual dyskinesias, stereotypies, tics, tremor) and hypokinetic (catatonia, parkinsonism, perseverations) movements. To date, a variety of antibodies have been associated with autoimmune encephalitis, including anti-NMDAR, AMPA, mGluR5, GABAa, GABAb, dopamine, contactin-associated protein-like 2(Caspr2), and leucine-rich glioma inactivated 1(LGI1).
Historically, prior to 2005, the only cell-surface antibodies associated with limbic encephalitis were believed to be the Kv1.1 and Kv1.2 subunits of the voltage-gated potassium channels (VGKC). Subsequently, these disease-causing antibodies were shown to be associated with the LGI and Caspr 2. The next major advance came in 2007 with the identification of antibodies to the NMDAR associated with subacute onset encephalitis that responded to immunotherapy and removal of an associated ovarian teratoma. After the latter discovery, the field dramatically expanded and the list of antibodies targeting cell surface receptors or synaptic proteins involved with synaptic neurotransmission and plasticity continues to expand.
Anti-N-methyl- d -aspartate Receptor Encephalitis
Anti-N-methyl- d -aspartate (NMDA) receptor encephalitis is now considered one of the most common immune mediated encephalitides. Anti-NMDAR antibodies target the NR1 subunit of the receptor, primarily the N-terminus. Antibody binding causes receptor internalization and diminished synaptic NMDAR-mediated currents. , Ovarian teratomas can express neuronal tissues thereby inducing immunologic cross reactivity. In cases following a viral infection, such as herpes encephalitis, antibody synthesis may occur via molecular mimicry, with expansion of the process in the CNS. No identifiable trigger is identified in more than one-half of cases.
Initially characterized in young women with ovarian teratomas, anti-NMDAR encephalitis has been shown to occur in all age groups and to be associated with infection in younger children. The typical presentation in children less than 12 years includes a mixture of seizures, abnormal movements, insomnia, and irritability. In contrast, in individuals greater than 18 years, psychosis is predominant. Movements, which occurred in 84% of children, include a combination of chorea, dystonia, myorhythmia (slow rest and postural movements), orolingual stereotypy, and other stereotypies (cycling, picking, self-injurious behaviors), some occurring unilaterally or asymmetrically. , The presence of stereotypies and perseverations were the main factors that distinguished NMDAR encephalitis from Sydenham chorea and basal ganglia encephalitis (BGE). Children also have movements ranging from catatonia to a stormy generalized hyperkinetic movement disorder with agitation, muscle rigidity, rhythmic abdominal contractions, kicking movements, hemiballismus, and intermittent dystonic or opisthotonic posturing. , The complex phenomenology of movement disorders in NMDAR encephalitis has been well documented. In adults, movements tend to involve the face and body; orobuccolingual movements including jaw opening and closing, facial grimacing, tongue protrusion, kissing, pouting, eyebrow elevation, and frowning being present in about 80% of cases. , , Another important feature of NMDAR encephalitis (and anti-IgLON5 encephalitis , ) is a prominent sleep disorder, manifested by insomnia followed by hypersomnia.
The most common alteration on brain MRI, occurring in only about one-half of patients, is a mild T2/FLAIR signal hyperintensity in medial temporal and frontal regions and leptomeningeal contrast enhancement. Cerebral FDG-PET has demonstrated extensive symmetric cortical hypometabolism in posterior regions and asymmetric anterior and basal ganglia metabolism. EEGs are abnormal in up to 90% of cases and usually show slow and disorganized backgrounds with generalized rhythmic delta (“extreme delta brush”). , The CSF may show pleocytosis, elevated protein levels, and, in some, positive oligoclonal bands. Individuals should be screened for the presence of tumors: ovarian teratomas are common in adult women, present in about one-third of teenage girls, and infrequent in those younger than age 14. Testicular tumors have been reported in adult males but are infrequent in boys. Screening for anti-NMDAR antibodies should include CSF since serum cell-based assays may be falsely negative. Several studies have reported the presence of anti-NMDAR antibodies in patients who developed movement disorders weeks after the diagnosis of herpes simplex encephalitis. These findings confirm the hypothesis that certain viral infections can trigger brain autoimmunity.
Treatment of anti-NMDAR encephalitis consists of tumor removal, if present, and immunotherapy (corticosteroids, IVIG, or plasmapheresis). Individuals refractory to these treatments have responded to rituximab or cyclophosphamide. Movement disorders have been treated with symptomatic therapies based on phenomenology (levodopa, trihexyphenidyl, clonidine, beta blocker, antiepileptics, dopamine receptor blockers, dopamine depleters), although many are refractory to these medications. , Benzodiazepines are the treatment of choice for catatonia, with electroconvulsive therapy as backup.
Most patients with anti-NMDAR encephalitis have a full or substantial neurological recovery. Prognostic factors for a good outcome include early initiation of therapy, low disease severity within 4 weeks of onset, the absence of an intensive care unit admission, low antibody titer, absence of cerebellar atrophy, and CSF levels of the biomarkers C-X-C motif chemokine 13 (CXCL13) and cell-free mitochondrial (mt)DNA. , , Symptoms may relapse in up to one-quarter of patients, especially in those without a tumor or in those who received suboptimal treatment.
Encephalitis Associated With Antibodies Against Other Glutamate Receptors
- (a)
Metabotropic glutamate (mGluR5) receptors. The combination of memory loss, psychosis, hallucinations, and Hodgkin's lymphoma is known as Ophelia syndrome. Originally reported by a physician describing his 15-year-old daughter, the syndrome is named in memory of William Shakespeare's character in the play Tragedy of Hamlet, Prince of Denmark. Additional cases, with similar symptoms and Hodgkin's lymphoma, were shown to have pariatal-occipital hyperintensities on MRI and CSF anti-mGluR5 antibodies. Brain mGluR5 receptors are highly expressed within the hippocampus. Symptoms improved with treatment of the lymphoma. A case of an adult with Ophelia syndrome and myoclonus has been reported. In addition, a six-year-old, non–lymphoma-associated case with mGluR5 antibodies, presented with flu-like symptoms, status epilepticus, aphasia, memory loss, dystonia, oculogyric crises, ataxia, and psychomotor slowing.
- (b)
Metabotropic glutamate (mGluR1) receptors: Antibodies to metabotropic glutamate receptor type 1 have been described in patients with a subacute cerebellar syndrome with other behavioral/cognitive changes. Most cases occur in adults, but it can occur in children, with the additional phenomenology of chorea in the face and limbs. mGluR1 receptors are highly homologous to mGluR5 but are predominantly expressed in the cerebellum.
- (c)
AMPA ( α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors: A small number of cases of autoimmune encephalitis with anti-AMPA receptor antibodies have been reported. Case reports have included two children with seizures, status epilepticus, memory issues, and behavioral changes, but no movement abnormalities.
Encephalitis Associated With Antibodies to GABA (γ-aminobutyric Acid) Receptors
- (a)
GABAa: The GABAa receptor (GABAaR) is a ligand-gated ion channel that modulates fast inhibitory synaptic transmission in the brain. High serum and CSF titers of antibodies against the GABAaR (α1, β3, γ2 subunits) have been identified, more commonly in adults than children. About one-third had an associated neoplasm; thymoma being most common. In a small number of pediatric cases, symptoms have included focal and generalized seizures, status epilepticus, cognitive impairment, altered behaviors, and decreased levels of consciousness. A case of FIRES, febrile infection-related epilepsy syndrome, has been described in association with anti-GABA antibodies. Movement disorders occur more frequently in pediatric cases and have included oral facial dyskinesias, dystonic postures, choreoathetosis, dysmetria, and stiff person syndrome (SPS). , , One case report includes an eight-year-old, without seizures, but with an encephalopathy and catatonia. MRIs show multifocal cortical and subcortical lesions in most cases. Therapeutically, immunotherapy is commonly utilized, and anticonvulsants are often required for ongoing seizures. Although the number of cases is limited, outcome may not be as good as seen with NMDAR encephalitis.
- (b)
GABAb: The GABAb receptor (GABAbR) is a G-protein coupled receptor. In two series of more than 35 adult patients with GABAbR antibodies, the most common symptoms were limbic encephalitis, seizures, ataxia, and opsoclonus myoclonus. , About one-half of the cases were paraneoplastic in origin, with small cell lung cancer being the most identified neoplasm. In a single case report, a three-year-old previously healthy child, presented with a one-day history of confusion and lethargy. His initial examination showed opsoclonus, dystonic movements of the tongue, ataxia, and chorea of the limbs and trunk. Within 24 h, he developed frequent partial seizures, lymphocytic pleocytosis in CSF, and, ultimately, T2 hyperintensities in the basal ganglia on MRI. There was little response to treatment with high-dose corticosteroids/IVIG and the patient died 4 weeks after initial presentation.
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