ASM 2016 Tox Mimics in the Critically Ill Patient Information on Diagnosis

ASM 2016 Tox Mimics in the Critically Ill Patient Information on Diagnosis and Take Home Points Case #1 Discussion and more about Anti-NMDA receptor Ab encephalitis: Background and epidemiology: Autoimmune encephalitis may be divided into several groups of diseases: those with antibodies to cell surface proteins, those with antibodies to intracellular synaptic proteins, T-cell diseases associated with antibodies to intracellular antigens, and those associated with other autoimmune disorders. Many forms of autoimmune encephalitis are paraneoplastic, often necessitating tumor screening. Anti-N-methyl-D-aspartate (Anti-NMDA) receptor encephalitis was first described by Dalmau and colleagues in 2007. There are now more than 500 cases reported in the medical literature. Epidemiological evidence suggests that it is the most common cause of autoimmune encephalitis after acute demyelinating encephalitis. The California Encephalitis Project (between Sept 2007- Feb 2011), reviewed in detail 761 patients presenting with encephalitis. The frequency of anti-NMDA receptor encephalitis surpassed that of any single viral cause of encephalitis. There is a gender-predilection favoring women, but reports of anti-NMDA receptor encephalitis include both men and women ranging from 2 to 84 years of age. Pathophysiology: The NMDA receptor is a heterotetrameric assembly of an NR1 subunit usually in combination with modulatory NR2 and/or NR3 subunits. To date 7 different subunits have been identified—NR1, NR2a-d, NR3a+b. NR1 is ubiquitously distributed in the brain and is an obligate subunit of functional NMDA receptors. Patients with anti-NMDA receptor autoimmune encephalitis have IgG antibodies to the NR1 subunit of the NMDA receptor. This results in antibody mediated capping, cross-linking and internalization of the receptor, causing a decrease in NMDA receptor surface density, synaptic localization, while overall cellular structure and synaptic density is largely unchanged. So it appears that anti-NMDA receptor antibodies reversibly alter the number and distribution of glutamate receptors, which results in decreased glutamatergic synaptic function. Lack of neuronal cell death may, in part, explain why patients frequently experience recovery in this disorder. For unclear reasons, the hippocampal region is preferentially affected. Numerous other immune mediated synaptic disorders (also known as (ASPES) Autoimmune Synaptic Protein Encephalopathy Syndrome) have been identified but due to time constraints cannot be further discussed in this forum. It is important for the clinician to recogniZe that analysis should include a search for additional antibodies including: Glu1/2 subunit of AMPA receptor, GABAB1 receptor, GABAA, GlyR, NR2A/NR2B subunits of NMDA receptor, mGluR5, mGluR1, DNER, GAD, DPPX, and LGI1 and Caspr2 (previously known as VGKC, Voltage-gated K+ channel). Clinical Presentation: There is a prodromal phase of non-specific symptoms—low-grade fever, headache, or viral-like syndrome (respiratory or GI symptoms) that often goes unnoticed and may not result in presentation to healthcare. This is followed in several days to weeks by the onset of psychiatric symptoms or behavioral changes (including anxiety, bizarre behaviors, disinhibition, hallucinations, paranoid thoughts, grandiose or hyperreligious delusions). Erratic sleep patterns and insomnia commonly develop, as well as cognitive dysfunction such as short-term memory loss and concentration difficulties. Progression to decreased level of consciousness, seiZures, dyskinesias (including orofacial dyskinesias— grimacing or lip-smacking), choreathetoid movements or unusual postures can occur. Autonomic instability can cause cardiac dysrhythmias and hypoventilation may necessitate intubation. Differences in adults vs. children with the disorder: adults are more likely to develop hypoventilation and autonomic instability and children experience more behavioral changes such as agitation, aggression, new-onset temper tantrums, changes in mood or personality. Speech involvement is more common in children and may include reduced speech, mutism, echolalia, or perseveration. The differential depends on the stage of disease but may include new onset psychosis, schiZophrenia, catatonia, viral encephalitis, lupus, multiple sclerosis, cerebral vasculitis, Creutzfeld-Jakob disease, seizure disorder or status epilepticus. The toxicologic differential may include acute drug intoxication (PCP, ketamine, 2C series, etc.), withdrawal, Wernicke encephalitis, neuroleptic malignant syndrome, or possibly serotonin syndrome. NMS is particularly difficult to sort out because patients may be treated with neuroleptics for their early psychiatric symptoms then develop autonomic instability, motor dysfunction, and hypoventilation, making it much more difficult to discern NMS from anti-NMDA receptor encephalitis. Diagnostic Findings and Work-up: Obviously, it is crucial to rule out alternative diagnoses such as infectious etiologies, lupus, or multiple sclerosis. Patients are often empirically covered with antimicrobials pending completion of an infectious disease work-up. MRI of the brain is abnormal ~50-70% of the time. Cortical and subcortical T2-fluid-attenuated inversion recovery signal abnormalities and sometimes transient cortical-meningeal enhancement is seen. (In children MRI abnormalities were less common, seen in only 31% of kids in one series.) CSF analysis is abnormal in 80-94% of cases showing lymphocytic pleocytosis or increased protein synthesis or oligoclonal bands. (In patients with initially normal CSF--cell count, protein, glucose, and oligoclonal bands should be sought. Typically, if repeat LP is performed a few days later, pleocytosis will be present). EEG is abnormal in almost all patients. It usually shows diffuse slowing of the background in the delta- theta range. Although some patients may have focal slowing. There was a recent study that found that 30% of adults with anti-NMDA receptor encephalitis had a unique pattern on EEG called “extreme delta brush,” which is similar to a pattern seen in premature infants. Electrographic seiZures during continuous EEG monitoring occur in~60% of patients. There are several reports of patients with nonconvulsive status epilepticus which seems to underscore the importance of continuous EEG monitoring. Diagnosis is confirmed by demonstrating IgG Anti-NMDA receptor antibodies in serum or CSF. CSF being the more reliable and recommended specimen. A comparison of normaliZed IgG levels in serum and CSF indicates the presence of intrathecal synthesis of antibodies in virtually all patients. Whether levels of antibodies in the CSF or serum correlate with clinical signs and symptoms or with symptomatic improvement is controversial and actively debated. The most convincing evidence suggests interpretation of Ab titers and correlation with disease severity has several limitations and potential co- founders. Consequently, decisions regarding treatment are best made based on comprehensive clinical assessment and not Ab titers. Antibodies to cell surface or synaptic proteins are directed against conformational epitopes and reactivity is usually lost when the antigen is denatured so that these Abs cannot be detected by standard immmunoblot or ELISA. Detection of these Ab requires either an immunohistochemistry protocol adapted to cell surface antigens, live neurons cultures, or cell-based assays in which recombinant antigens are expressed in mammalian cells. Commercial and clinical laboratories use cell-based assays for determination of this type of Ab; while these assays are highly specific they are not without problems. Specificity and sensitivity of these assays vary among laboratories even when the same technique is used. Also the tests are read by visual assessment of fluorescence, making interpretation difficult if titers are low or if specimens have non-specific background reactivity. MRI of the abdomen and pelvis should be obtained to identify ovarian teratomas. Pelvic and transvaginal U/S can also be utiliZed. There are estimates that ~ 56% (range of 25-56%) of women > 18 years of age with anti-NMDA receptor encephalitis have unilateral or bilateral teratomas with tumors occurring in only 30% of women <18 years of age. Studies show positron emission tomography has variable evidence with some indicating cortical hypometabolism and others showing hypermetabolism. Currently the role of FDG-PET, 1H-MRS, SPECT, scanning in this disorder is in the experimental phase. One study showed frontal and temporal glucose hypermetabolism associated with occipital hypometabolism the authors suggest this gradient of brain glucose metabolism correlated with clinical disease severity and normaliZed when patients recovered. Treatment: Early diagnosis and institution of first-line immunotherapy is crucial. Although randomized controlled trials have not been done to establish the best treatment regimen, clinical experience (Dalmau et al) suggests high dose corticosteroids (methylprednisolone 1 g/daily X 5days) , intravenous immunoglobulin (IV Ig 0.4 g/kg daily X 5 days), and plasma exchange. Second line therapy is initiated for those patients not responding to first line therapy (within 10 days) and consists of rituximab (375 mg/m2 every week for 4 weeks) followed by monthly cycles of cyclophosphamide (750 mg/m2 can be given with first dose of rituximab). Prognosis and outcomes: With the regimen described above, up to 75-80% of patients exhibit total or near-total recovery while

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