Neuropsychiatric Syndromes: Autoimmune Encephalitis. Scott E. Hirsch, MD Assistant Professor NYU School of Medicine March 2016

Transcription

1 Neuropsychiatric Syndromes: Autoimmune Encephalitis Scott E. Hirsch, MD Assistant Professor NYU School of Medicine March 2016

2 Disclosures No Financial Disclosures There will be discussion of pharmaceutical products being used for non- FDA approved indications Neuropsychiatric Syndromes: Neuroinflammation 2

3 Systemic Inflammation and behavior 45% of non-depressed hepatitis C and cancer patients treated with INF-α develop depressive symptoms associated with increased serum IL-6 levels Patients with Lupus, a systemic autoimmune disease, exhibit higher rates of anxiety, mood symptoms, and psychosis. 90% of Lupus patients with psychosis have auto-antibodies in CSF Hypothesis: the blood-brain barrier has broken down, allowing auto-antibodies enter the brain somehow leading to symptoms Dantzer et al., Nature Reviews Neuroscience 2008 Haroon et al., Neuropsychopharmacology 2012 Postal et al., CNS Drugs 2011 Neuropsychiatric Syndromes: Neuroinflammation 3

4 Para-neoplastic neurological syndromes Associated with systemic cancer. Due to auto-antibodies that affect the nervous system: Subacute sensory neuropathy Chronic sensorimotor neuropathy Acute sensorimotor neuropathy Paraneoplastic autonomic neuropathy Lambert-Eaton myasthenic syndrome Dermatomyositis Paraneoplastic neuromyotonia Paraneoplastic encephalomyelitis Limbic encephalitis Dalmu et al, Brain Pathology 1999 Neuropsychiatric Syndromes: Neuroinflammation 4

5 Classical Neuroinflammation: Acute Limbic Encephalitis Depressed mental status Acute onset temporal lobe seizures, then refractory seizures Mood symptoms Psychotic symptoms Longstanding cognitive deficits Associated with occult cancer (e.g., Small Cell Lung, Breast, etc) Neuropsychiatric Syndromes: Neuroinflammation 5

6 Acute Limbic Encephalitis, Imaging Leypoldt et al Ann. N.Y. Acad. Sci Neuropsychiatric Syndromes: Neuroinflammation 6

7 Anti-neuronal auto-antibodies cause Limbic Encephalitis: anti-nmda receptor anti-hu anti-ma2 anti-crmp5 LGI1 antibodies anti- AMPAR receptor anti-gaba-a receptor anti-gaba-b receptor anti-caspr-2 anti-iglon5 Najjar et al., Journal of Neuroinflammation 2013 Neuropsychiatric Syndromes: Neuroinflammation 7

8 Autoimmune Limibic Encephalitis is not always para-neoplastic. No cancer is found in up to 15% percent of patients with para-neoplastic antibody associated autoimmune encephalitis. Some anti-neuronal auto-antibodies known to cause encephalitis are not associated with cancer: anti-gad (glutamic acid decarboxylase) anti-vgkc (voltage-gated potassium channel) Sillevis et al, J Neurology 2002 Neuropsychiatric Syndromes: Neuroinflammation 8

9 Voltage Gated Potassium Channel Antibody associated Limbic Encephalitis/Morvan s syndrome 31 year-old investment banker presented with hot flashes, sweating, severe insomnia over two weeks. He described worsening insomnia over two months, relating sleep difficulty new onset frequent visual and olfactory hallucinations. He also described persecutory delusional thinking. His speech was pressured. Mental status exam revealed poor immediate memory, recalled 0/3 words at 5 minutes. General physical exam significant for hypertension and tachycardia. The neurological physical examination was unremarkable. Neuropsychiatric Syndromes: Neuroinflammation 9

10 Voltage Gated Potassium Channel Antibody associated Limbic Encephalitis/Morvan s syndrome MRI brain showed left mesial temporal sclerosis. Neuropsychiatric Syndromes: Neuroinflammation 10

11 Voltage Gated Potassium Channel Antibody associated Limbic Encephalitis/Morvan s syndrome VEEG showed left hemispheric slowing. Over four hospital admissions, one Generalized Tonic Clonic seizure and subclinical bi-temporal seizures were captured. Neuropsycholgocial testing was significant for poor immediate and short term recall, overall cognitive performance below expectations given his education and career. Workup was unrevealing until CSF VGKC antibody was found to be 1000 (normal is <115). Diagnosis: VGKC Antibody associated Limbic Encephalitis, with autonomic features of Morvan s syndrome. Neuropsychiatric Syndromes: Neuroinflammation 11

12 Treatedment: VGKC Antibody associated Limbic Encephalitis Treated with Keppra and four cycles of Plasmaphresis, IVIG, and Solumedrol. Now: No recurrent seizures for 10 years. Hallucinations resolved. Significant cognitive improvement, but still has some difficulty with short term memory. Insomnia and delusional thinking persists, but in good control with Melatonin and Risperdal. Continues on Prednisone once weekly and IVIG monthly Neuropsychiatric Syndromes: Neuroinflammation 12

13 Autoimmune encephalitis is not always acute The inflammatory response associated with some auto-antibodies is milder than other auto-antibodies, resulting in a less severe presentation and milder symptoms overall. This leads to presentation of symptoms over months (indolent) rather than days to week (acute to subacute). Gultekin ett al, Brain 2000 Neuropsychiatric Syndromes: Neuroinflammation 13

14 Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis In 2007, serum IgG autoantibodies to the NMDAR were found in patients with autoimmune encephalopathy. 66% of the patients with NMDAR encephalitis presented with psychiatric symptoms. Dalmau et al, 2007 Neuropsychiatric Syndromes: Neuroinflammation 14

15 Typical Time Course for NMDAR Encephalitis Kayser, Dalmau Schizophrenia Research 2014 Neuropsychiatric Syndromes: Neuroinflammation 15

16 Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis Originally, diagnosis required a presence of the antibody in serum and at least one of the following: Fever Seizure Focal neurologic findings CSF pleiocytosis EEG findings consistent with encephalitis Imaging findings consistent with encephalitis Gable et. al, Eur J Clin Microbiol Infect Dis 2009 Neuropsychiatric Syndromes: Neuroinflammation 16

17 Objective findings in NMDA Encephalitis Diagnosis is confirmed by detection of IgG antibodies to the NR1 subunit of NMDAR in serum or CSF. CSF: can be normal or show lymphocytic pleiocytosis and oligoclonal bands EEG: can be normal, or show generalized slowing and/or interictial epileptiform discharges. Brain MRI: normal or transient FLAIR or contrast enhancing abnormalities in the cortex or subcortex. Neuropsychiatric Syndromes: Neuroinflammation 17

18 NMDAR Antibodies in Serum vs. CSF In one study 23.2% of patients with evidence of serum-positive NMDAR antibodies did not have anti-nmdar encephalitis or autoimmune diseases. Another study demonstrated that 14% of patients with NMDAR encephalitis did not have serum NMDAR antibodies; all had antibodies in the CSF. It is agreed upon that having CSF NMDAR IgG Antibodies is most associated with NMDAR Encephalitis. Zandi et. al J Neurol Neurosurg Psychiatry 2015 Kayser, Dalmau Biol Psychiatry 2015 Leypoldt et al Ann. N.Y. Acad. Sci Neuropsychiatric Syndromes: Neuroinflammation 18

19 Treatment of NMDA Encephalitis: Dalmau et al IVIG 0.4g/kg daily for five days and methylprednisolone 1 g/day for five days. If not significantly improved after 10 days, start second line therapy: rituximab 375 mg/m 2 combined with cyclophosphamide 750 mg/m 2. Follow with monthly cycles of cyclophosphamide Treatment is continued until substantial recovery occurs, which can take up to 18 months. Series of 577 patients, 81% had a good outcome. Relapse occurs in 15-24%, so immunotherapies are often continued for at least one year. Dalmau et al, Lancet Nerorl Titulaer et al, Lancet Neurol Neuropsychiatric Syndromes: Neuroinflammation 19

20 Immunotherapy for patients with acute psychosis and serum NMDAR antibodies: A description of a treated case series 18 cases Patients had psychotic symptoms for at least 1 week No patients had seizures. Insomnia was common, 15/18 cases Mood disorder diagnosed in 13/18 cases Brain imaging abnormalities were uncommon and non-specific 3 patients had EEG abnormalities No evidence for neoplasms Zandi et. al Schizophrenia Research 2014 Neuropsychiatric Syndromes: Neuroinflammation 20

21 Immunotherapy for patients with acute psychosis and serum NMDAR antibodies: A description of a treated case series All 18 patients treated with antipsychotics 9 treated with antipsychotic medications 5/9 responded to antipsychotic therapy 9 treated with immunotherapy, but treated with antipsychotics first: 4 without response to 1 antipsychotic 2 without response to 3 antipsychotics 1 without response to 3 antipsychotics, Clozapine, and ECT Immunotherapy: Corticosteriods Plasmaphersis IVIG Mycophenolate mofetil Rituximab Neuropsychiatric Syndromes: Neuroinflammation 21

22 Immunotherapy for patients with acute psychosis and serum NMDAR antibodies: A description of a treated case series Of the 9 treated with immunotherapy: 8 of 9 responded clinically 6 of 9 had subsequent significant relapse of symptoms Cases with longer history of treatment resistant illness did not have a long term response. Not randomized or blinded. However, the findings regarding time course and response to treatment is interesting. Neuropsychiatric Syndromes: Neuroinflammation 22

23 Psychiatric Symptoms and Antibodies Kayser et al reviewed 600 cases of NMDAR encephalitis in 2013 and noted that: while rare, some patients may demonstrate only psychiatric symptoms without any neurological involvement during the first disease episode or in a relapse episode. In 2012, Masedu et al reported screening 80 patients with new-onset psychosis who later met criteria for schizophrenia for NMDAR IgG antibodies. The IgG antibodies were not found in the patients or in controls. Other studies have shown patients with schizophrenia may have IgM or IgA NMDAR antibodies but those are all present in healthy controls and patients with a variety of other disorders. Neuropsychiatric Syndromes: Neuroinflammation 23

24 Why does Immunotherapy work? The improvement in symptoms is thought to be related to specific antibody removal. However, the improvement in symptoms could also be due to nonspecific changes induced in the underlying inflammatory mechanisms. We don t really know. There is some evidence that inflammation plays a role in primary psychiatric illness Neuropsychiatric Syndromes: Neuroinflammation 24

25 Brain Biopsy Findings Link Major Depressive Disorder to Neuroinflammation, Oxidative Stress, and Neurovascular Dysfunction: A Case Report 39 year-old man with onset of depressive mood symptoms at age 15 Baseline dysthymia persisted throughout teens and twenties Academic performance and personal achievement remained stellar Age 29, first major depressive episode, prominent hypersomnia and anergia and he was psychiatrically hospitalized Najjar, Pearlman, Hirsch, Friedman, Strange, Reidy, Khoukaz, Ferrell, Devinsky, Najjar, and Zagzag Biological Psychiatry 2013 Neuropsychiatric Syndromes: Neuroinflammation 25

26 Course Treated with a combination of psychotherapy and psychoactive medications, which continued going forward Only a partial response By age 35, the patient could not sustain work because of persistent mood symptoms and cognitive difficulties Over the next four years: Brain MRI was unremarkable Neuropsychological testing was remarkable only for high FSIQ EEG and sleep studies were unremarkable Neuropsychiatric Syndromes: Neuroinflammation 26

27 Treatment Age 38, diagnosed with neurological complications of Lyme disease. Treated with antibiotics, acupuncture, over-the-counter supplements, transcranial magnetic stimulation, and hyperbaric oxygen Psychoactive medications were optimized: fluoxetine bupropion quetiapine clonazepam dextroamphetamine No improvement noted Neuropsychiatric Syndromes: Neuroinflammation 27

28 My evaluation At age 39, after 10 years of psychotherapy, he terminated treatment and sought neuropsychiatric evaluation Comprehensive neurological physical examination was unremarkable. Mental status significant for depressed mood, psychomotor slowing, and suicidal ideation. Neuropsychiatric Syndromes: Neuroinflammation 28

29 Quantitative Measures MOCA score 30/30 Montgomery-Asberg Depression Scale (MADRS) score 25 Beck Depression Inventory (BDI-II) score 27 Beck Anxiety Inventory (BAI) score 22 Neuropsychological testing results revealed cognitive strengths beyond expectations given his complaints about cognition: FS-IQ 127 (96 th percentile) V-IQ 141 (99.7 th percentile) P-IQ 119 (90 th percentile) Processing speed average Neuropsychiatric Syndromes: Neuroinflammation 29

30 Workup Comprehensive serological and cerebrospinal fluid assays for infectious agents, systemic autoimmune diseases, and anti-neuronal antibodies were all unremarkable 72 hour ambulatory electroencephalogram was normal Brain MRI: scattered white matter foci of increased signal Single photon emission computed tomography (SPECT): moderate to severe frontal hypo-perfusion Neuropsychiatric Syndromes: Neuroinflammation 30

31 Diagnosis and Treatment Plan Diagnosis: Major Depressive Disorder. Referred to NYU Langone Treatment Resistant Depression Program Dr. Norman Sussman: added memantine, glutamatergic effects could improve cognitive and mood symptoms recommended ECT Patient refused ECT due to concerns about cognitive effects No improvement Neuropsychiatric Syndromes: Neuroinflammation 31

32 Brain biopsy???? Risk of complications with brain biopsy <1% Risk of complications with Refractory Major Depression with suicidal ideation >1% Given worsening symptoms, the abnormal but nonspecific brain MRI and SPECT imaging findings, the patient agreed to a brain biopsy to determine whether there was any evidence of neuro-inflammation. Neuropsychiatric Syndromes: Neuroinflammation 32

33 Microscopy: activated microglia CD68 x400 Neuropsychiatric Syndromes: Neuroinflammation 33

34 Microscopy: mild, focal, and perivascular histiocytic infiltration CD63 x400 Neuropsychiatric Syndromes: Neuroinflammation 34

35 Microscopy: mild to moderate subcortical white matter astrogliosis glial fibrillary acidic protein x400 Neuropsychiatric Syndromes: Neuroinflammation 35

36 Ultrastructural analysis: lipofuscin granule accumulation within the neurovascular unit low magnification high magnification E: endothelial cell P: pericyte L: Lumen of capillary Neuropsychiatric Syndromes: Neuroinflammation 36

37 What do the brain biopsy results mean? The typical brain does not have evidence of : activated microglia perivascular histiocytic infiltration astrogliosis lipofuscin granule accumulation While the medical literature had previously documented increased central nervous system oxidative stress in MDD, this was the first demonstrated evidence of oxidative injury of the neurovascular endothelium. These findings taken together are evidence of inflammation and cellular-level dysfunction of the brain: Encephalitis. Neuropsychiatric Syndromes: Neuroinflammation 37

38 The Treatment After confirming presence of inflammation in the brain, immunomodulatory treatment was started: 0.5 g/kg IVIG pulse therapy twice weekly for nine months Three months later, intravenous minocycline 100 mg twice daily for six months: Psychotropic regimen remained constant Neuropsychiatric Syndromes: Neuroinflammation 38

39 Result: 10 months after treatment, repeat SPECT scan showed normalization of frontal hypo-perfusion Before After Neuropsychiatric Syndromes: Neuroinflammation 39

40 Clinical Result 13 months after treatment, the patient and family reported mood, anxiety, and cognitive symptoms improved significantly: MADRS score decreased from 25 to 15 BDI-II score decreased from 27 to 15 BAI score decreased from 22 to 3 18 months after treatment, the patient and family reported the bestsustained improvement in mood symptoms since age 15: MADRS score was 8. Patient s wife: I can't tell you how much I appreciate your efforts and those of Dr. Najjar's over the past few years, and I hate to think where he'd be if we hadn't found you. Neuropsychiatric Syndromes: Neuroinflammation 40

41 Summation There are indolent presentations of autoimmune encephalitis that can present as primary psychiatric disorders with chronic, mild inflammation. It remains unclear whether the improvement in symptoms is related to specific antibody removal or nonspecific effects of anti-inflammatory treatment. Without CSF antibodies confirming the diagnosis, tissue diagnosis should be strongly considered. Aggressive immunotherapy and brain biopsy both carry risk. Neuropsychiatric Syndromes: Neuroinflammation 41