We will discuss the clinical context of autoimmune neuropsychiatric disorders:
1) Should PANDAS/ CANS be considered separate entity?
2) Sydenham's chorea: What is new in this old disorder?
3) What is the long term impact of early autoimmune injury in opsoclonus myoclonus syndrome?
4) What is the pathophysiologic role of anti-NMDA, anti-VGKC and anti-dopamine receptor autoantibodies in autoimmune encephalitis?
Finally we will present therapeutic updates for these disorders in light of the
1. Educational: increasing awareness to what we know and what we don't know.
2. Invitation to research collaboration or related initiatives
3. Proposal to set up prospective multi-center clinical trial for immunemodulatory treatments
Should PANDAS/ CANS be considered separate entity?
Hilla Ben-Pazi, MD
Since the 17th entity was attributed to streptococcal infections until recently. PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection) was first described by Swedo et al (1998). Criteria include prepubertal sudden onset of obsessive compulsive disorder (OCD) and/or tics with neuropsychiatic symptoms (hyperactivity, emotional lability, anxiety, or choreiform movements) temporally associated with streptococcal infection. Whereas the association between SC and streptococcal infections is robust, casual and temporal association between tics/OCD and streptococcal infection in PANDAS remains challenging since these are common in school-aged children.
CANS (childhood acute neuropsychiatric symptoms), another entity defined by Singer et al (2011), includes dramatic onset of symptoms. This classification of a group of disorders with multiple causal factors has little practical implication. While active search for specific causes cannot be overemphasized, extensive lists of etiologies adds little to regular clinical practice. PANDAS-CANS debate demonstrates different psychiatric
(PANDAS)/ neurologic (CANS) approaches. Recent studies demonstrated that PANDAS with "choreiform" movements have a similar autoimmune profile to SC; thus these cases perhaps should be regarded as SC. Non-motor manifestations such as emotional lability and OCD are common in SC and fall within the PANDAS spectrum.
Regardless of ongoing terminology debate there are 2 main messages: 1) Acute onset of neuropsychiatric disorders cannot be regarded as PANDAS without further etiological evaluation excluding treatable causes. 2) Children with chorea after streptococcal infections, including those with "PANDAS with choreiform movements", should be regarded and treated as SC requiring prophylactic penicillin treatment.
Sydenham's chorea: What in new in this old disorder?
Francisco E.C. Cardoso
Thomas Sydenham originally described Sydenham’s chorea (SC) in England in 1686. In the original description the motor features of the illness were well described. The aim of this presentation is to provide an overview of features that have been recognized in the last years. There has been a decline of SC but it remains as the most common cause of acute chorea in children worldwide. Bouts of SC have been identified not just in deprived populations but also in groups with better socio-economic conditions. All frontal-basal ganglia loops are affected in SC: in addition to chorea, other motor changes are seen although tics are rare; behavioral abnormalities (mostly obsessions, compulsions, hyperactivity and attention deficit disorder) are common in subjects with SC; cognitive changes are also increasingly recognized in SC: reduced verbal fluency and dysexecutive function; hypometric saccades have also been described in patients with rheumatic chorea. There is also an association of SC with migraine-type headache. Longitudinal follow up studies show that 25-50% of patients with SC develop a persistent form of chorea where there are also non-motor findings. Finally, although the pathogenesis of SC remains to be fully elucidated, there is growing evidence of the involvement of Streptococcus-induced antibodies that cross-react with dopaminergic structures in the basal ganglia.
What is the long term impact of early autoimmune injury in opsoclonus myoclonus encephalopathy?
Michael R Pranzatelli, MD, PHD
OMS is a rare, prototypic, paraneoplastic, myoclonic disorder with significant neuropsychiatric repercussions. Though diagnostic autoantibodies are found in some autoimmune neurological disorders, none specific for OMS has been identified. However, considerable recent progress has been made in investigating biomarkers of disease activity (some cellular, others inflammatory mediators, such as chemokines) and linking them to OMS severity and duration. This approach employs modern immunological techniques to "stage" neuroinflammation to differentiate active from inactive disease, inform risk/benefit treatment decisions, and report on the capacity of immunotherapy to be disease- modifying. The B cell/humoral hypothesis of OMS causation is supported in cerebrospinal fluid (CSF) by B cell expansion, IgG oligoclonal bands, and hyper-production of B cell activating and sustaining factors. In contrast, some of the cytokine/protein abnormalities detected in multiple sclerosis, neurolupus, or neuromyelitis optica are not present in OMS. Data also demonstrate an immunological justification for the use of combination therapies. Biomarker-driven hypotheses must shed light on the immunological differentiation of the clinical subtypes (motor/behavior predominant) and evolution of symptomatology (monophasic, multiphasic-remitting, and none-remitting/progressive); the baffling cases in which neuroblastoma is not found; as well as lead to new treatment strategies and future randomized clinical trials. Relapse, a hallmark feature of most pediatric neuroimmunological disorders, remains a fundamental problem in OMS, and may involve other immunological mechanisms, perhaps memory T cells. Such a systematic approach is necessary to achieve the standard of care for OMS (and hope of every parent): to affect a rapid, durable, neurological remission and prevent or reverse relapse.
What is the pathophysiologic role of anti-NMDA, anti-VGKC and anti-dopamine receptor autoantibodies in autoimmune encephalitis?
Autoimmune disorders of the CNS are an important group of disorders to diagnose, as treatment can improve outcomes. The recently accepted paradigm in the field is that pathogenic autoantibodies bind to cell surface antigens such as receptors or synaptic proteins. Assays to measure these antibodies must express the cell surface antigen in its conformational state at the cell surface, known as ‘cell-based assays’. Antibodies against NMDA receptor define well-recognized encephalitis with psychosis, agitation, dyskinesias, aphasia and encephalopathy. Antibodies against Voltage Gated Potassium channel- complex have been found in children with limbic encephalitis and other immune mediated epilepsy- developmental syndromes. The antibodies do not bind to the actual potassium channel, and in children bind to an as yet unidentified protein in the complex. Antibodies against dopamine-2 receptor are found in some patients with autoimmune basal ganglia disorders presenting with Parkinsonism-dystonia or chorea. Although there is some evidence to support the pathogenic mechanism of these antibodies, the ‘functional effects’ of antibodies is relatively uninvestigated and unproven. There is now emerging evidence to show that immune therapy improves outcomes in autoimmune encephalitis, particularly NMDAR encephalitis, and early therapy is probably better than late treatment. The use of second line therapies (rituximab, cyclophosphamide) in patients who do not respond to first line therapy (steroid, plasma exchange, IVIG) will be discussed, as will other therapeutic decision making considerations.