Case 1. Case 1 Summary: Case 1 Summary: Case 1 MRI 2/18/2011

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1 Case 1 Summary: Case 1 RAIN 2011 Difficult Diagnosis Susannah Brock Cornes, MD Assistant Professor of Clinical Neurology UCSF Epilepsy Center 58 year-old previously healthy woman with: Subacute onset of fluctuating confusion and psychiatric symptoms. Seizures occurring 3/hr despite divalproex and levetiracetam. Outside Labs: Hyponatremia Nl CSF; neg HSV PCR; neg anti- yo, ri, hu, Gad-65 Outside Studies: MRI s/f right mesial temporal swelling and FLAIR abnormality. EEG confirmed bilateral temporal lobe seizures. Case 1 Summary: Case 1 MRI PE: Normal except disorientation to year, decreased digit span (4 forward, 3 reverse), 0/4 recall, flat affect and slow response time CSF: WBC 13 (89%L), RBC 1, P 25, G 65 IgG 0.9, no OCB VPA 61 Normal TFTs, Thyroglobulin Ab negative 1

2 Which clinical syndrome best fits this presentation: A. Morvan s Syndrome B. Limbic Encephalitis C. TLE with Hippocampal Sclerosis D. Hashimoto s Encephalopathy 66% 25% 3% 6% A. B. C. D. Limbic Encephalitis The work-up for limbic encephalitis should include: Inflammatory CNS disorder with subacute onset (days or weeks) Fluctuating confusional state with memory impairment, personality changes, hallucinations Limbic involvement often manifest as temporal lobe seizures (bilateral) and mesial temporal imaging abnormalities (hippocampal) A. Exclusion of other, particularly treatable, causes of cognitive decline B. Evaluation for cancer C. Autoantibody testing (paraneoplastic and idiopathic) D. All of the above 91% Paraneoplastic or idiopathic 2% 5% 3% A. B. C. D. 2

3 Treatable Causes of Cognitive Impairment Neural-Specific Autoantibodies Autoimmune encephalopathies (paraneoplastic, idiopathic) Other inflammatory CNS disorders (MS, neurosarcoidosis, ADEM) Vasculopathies (Vasculitis, posterior reversible leukoencephalopathy) Neoplasm (Primary CNS lymphoma) Seizure disorders (NCSE) Toxic, Nutritional, or Iatrogenic (Alcohol, B12, Thiamine, Folate, Neuropsych meds) Infectious (HIV, HSV, whipples, neurosyphilis, HHV6, cryptococcus, mycobacterial) Metabolic (Organ dysfunction, OSA, mitochondrial diseases) VGKC NMDA receptor GAD65 x AMPA receptor GABA-B receptor ANNA-1 (Anti-Hu) x ANNA-2 (Anti-Ri) x LGI 1 CASPR2 ANNA-3 AGNA (SOX-1) PCA-2 CRMP-5 (Anti-CV2) Amphiphysin Ma/Ta Proteins NMO-IgG nnsa s Endocrine (Pituitary, thyroid, or adrenal dysfunction) Adapted from McKeon, A et al. Continuum.2010;16(2) Which antibody target is MOST likely associated with this patient s LE: Syndromes associated with VGKC antibodies A. LGI 1 B. VGKC C. ADAM22 D. CASPR2 55% Neuromyotonia or Isaac s Syndrome: Muscle cramps and stiffness associated with nerve hyperexcitability Morvan s Syndrome: Neuromyotonia with autonomic and CNS dysfunction with insomnia 15% 13% 17% Limbic Encephalitis: Amnesia, confusion, seizures, personality changes or psychosis, and hippocampal abnormalities on MRI A. B. C. D. 3

4 Age Clinical Spectrum of VGKC LE Buckley N=2 (2001) Thieben N=7 (2004) 44-73yo Vincent N=10 (2004) 44-79yo Graus N=13 (2008) 51-73yo Seizures 86% 9 75% 58% Mesial temporal MRI abnormality Hyponatremia Hypersalivation Neuromyotonia 10 Malignancy 5 Thymoma Spontaneous Full or marked Mild residua Disabled (92% bilateral) 57% 14% 14% Metastatic PCA (other abs in 4) 14% 71% 14% 8-1 Tan N=72 (2008) 9-85yo, median 66 42% (25% bilateral) 83% 36% 33% ANS sx s 17% 15% SCLC, BrCA (SOX1 or amphyphysin) % 23% 38% 47% SCLC, thymic carcinoma, PCA, hematologic, BrCa, colon, squamaous ca (25% had Hu, PCA-2, apmphiphysin, CRMP-5 ) 5 39% not marked Buckley et al. Ann Neurol 2001;50:73; Thieben et al. Neurology 2004;62:1177; Vincent et al. Brain 2004;127:701; Graus et al. Neurology 2008;71:930; Tan et al. Neurology 2008;70:1883 LGI 1 is the auto-antigen in previously named VGKC-mediated LE LGI 1: 1998: Isolated from glioblastoma cell line 2002: Linked to ADLTE 2009: Regulates excitatory transmission, dendritic spine density and seizure threshold Lai et al. Lancet Neurol 2010;9:776-85; Irani et al. Brain 2010:133; Lai N=57 (2010) Irani N=55 (2010) Seizures 82% 89% Mesial temporal MRI abnormality Associated: Hyponatremia ANS dysfunction Neuromyotonia 75% 56% % 15% 4% Malignancy 11% Recovery: Full or marked Disabled 78% 16% LGI1 Function: WT and ADLTE Which factor predicts a favorable treatment response for this patient: 1. Seizures 2. Elevated IgG index 3. VGKC Antibody 4. Psychiatric symptoms 33% 48% 14% 5% Zhou et al. Nat Med 2009;15: ; Matteo, C. Nat Med 2009;15:

5 Predictors of Response to Therapy in Suspected Autoimmune Dementia PREDICTIVE NOT PREDICTIVE Subacute onset (1-6w) Headache (p=0.06) Fluctuating course IgG index and OCB Tremor Co-existent or FH of CSF protein >100 autoimmune disease CSF WBC >5 TPO antibodies Cation channel complex Seizures autoantibody (VGKC) Anxiety, depression, or Shorter delay to psychosis treatment (~1y v 2y) FH of dementia Hospital Course January Hospitalization: Solumedrol 1g IV x 5d Malignancy work-up negative February Hospitalization: VGKC Abs 906 pmol IVIG x 4d, Solumedrol repeated, PLEX x 5cycles NCSE Long-term cognitive outcome: MMSE 18/30 in June on oral steroids MMSE 24/30 by November on weaning steroids Independent on IADLs except driving Flanagan et al. Mayo Clin Proc Oct;85(10): Epilepsy Directions Features of LE overlap with features of mesial temporal lobe epilepsy CASE 2 24% of adult onset TLE with HS could be classified retrospectively as having LE 11% of a select cohort of patients with epilepsy, many with autoimmune disease, were positive for VGKC antibodies Bien et al. Neurology 2007;69:1236; McNight et al. Neurology 2005;65:

6 Case 2 Summary: 63 year-old otherwise healthy woman presents for characterization of spells: Onset age 32; currently 2x/month 30 seconds of staring, fumbling Sudden fall with injuries Medications: LTG 150mg BID Carbamazepine 400mg/200mg/400mg PE and MRI were normal. 6

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8 The clinical correlate to this seizure would be most likely to include: 1. Left sided clonic activity 2. Sudden fall 3. Pseudosecondary generalization 4. B and D 48% 39% 11% 3% Ictal Asystole Video Frequency: 0.27% - 0.4% of patients at recorded epilepsy centers No known risk factors Semiology: 20 sec after clinical onset Duration 4-60 sec (mean=13 sec) Sudden atonia if > 8 sec Myoclonic jerks or other movements Pseudo-secondary generalization Delayed loss of tone during a focal dyscognitive seizure is a red flag for IA: Half of TLE pts with IA had a history of unexplained drop attacks Schuele et al. Neurology 2007;69(5):434-41; Rocamora et al. Epilepsia 2003;44(2): ; Winesett et al. Epilepsy Behav. 2009;14(1):258-60; Ruboli et al. Neurology 2008;70: ; Rugg-gunn et al. Lancet 2004;364: Ruboli et al. Neurology 2008;70:

9 Patients with Ictal Asystole are MOST likely to have: Cardiac Rhythm Changes in Epilepsy 1. Benefit from pacemaker placement 2. Seizures with ictal tachycardia 3. Seizures lateralized to the left 4. Increased risk of SUDEP 38% 56% Ambulatory EEG-EKG recordings have demonstrated ictal tachycardia: >100 in 92% >120 in 67% >140 in 3 >160 in 12% Original work characterized IA from left insular stimulation, but lateralization has not held up. 5% Blumhardt et al. Lancet 1986;1: ; Keilson et al. Arch Neurol 1989;46: Preventing SUDEP? What is the risk of SUDEP? Prospective data from patients with IA receiving DDD pacemakers: No event triggers in 5 years after DDD placement Other case reports of reduced falls RCT of DDD for neurocardiogenic syncope reveals no benefit Probably reasonable to consider, but not proven Retrospective data from patients with SUDEP: More extreme ictal tachycardia (149bpm v 126bpm) Lengthening of QTc with epileptiform discharges Post-mortem data show cardiac injury Incidence: /1000 patient-years for those with epilepsy /1000 patient-years at surgical centers Risk SUDEP 24x baseline risk sudden death Pediatric cohort had 3x mortality rate overall with a 7% cumulative risk of SUDEP over 40 years Risk factors: Tonic-Clonic Seizures Treatment with >2 AEDs Full-scale IQ <70 Nei et al. Epilepsia 2004;45: ; Tavernor et al. Seizure 1996;5:79-83; Natelson et al. Arch Neurol 1998;55: ; Schuele et al. Epilepsia (1): ; Strzelczyk et al. Epileptic Disord 2008;10(1):39-44; Connolly et al. JAMA 2003;289: Waczak et al. Neurology 2001;56: ; Ficker et al. Neurology 1998;51: ; Sillanpaa et al. NEJM 2010;368:

10 Hospital Course Transferred to cardiology for DDD pacemaker placement. Thank you! Subsequently lost to follow-up... 10