Bank Robbing and Optic Neuropathy: Expanding the Differential Mark Mugavin MD, MPH March 31, 2017

Patient Presentation CC painless loss of vision right eye HPI 52 year old AAF presents to the resident PCC clinic for painless of vision in the right eye. Her interview is severely limited due to emotional outbursts and the inability to answer questions in a direct manner. She feels that her vision has progressively gotten worse for approximately 3 months. She is currently incarcerated at Louisville Metro Jail for unknown reason.

History (Hx) Past Ocular Hx: Refractive Error Past Medical Hx :Type 2 Diabetes, Generalized Depression Fam Hx: Non-contributory Meds: Lisinopril 10 mg, Escitalporam 20 mg Allergies: NKDA Social Hx: Incarcerated. Unable to formally interview. Denies utilizing illicit drugs. ROS: Unable to assess.

External Exam OD OS VA 20/100 20/25 Refraction unable Pupils 4→3mm 3+RAPD IOP 15 mmHg 14 mmHg EOM Grossly Full w/o pain or diplopia CVF Limited cooperation but w/o focal deficits Limited cooperation but grossly wnl

Anterior Segment Exam OD OS External/Lids WNL Conj/Sclera Cornea SLE OD OS External/Lids WNL Conj/Sclera Cornea Ant Chamber Deep and Quiet Iris Lens Trace Cortical

Posterior Segment Exam Fundus OD OS Optic Nerve Mild Temporal Pallor CDR .3 Macula WNL Vessels Periphery

Clinical Photos Fig. 1: Color Fundus photo of the right eye demonstrating mild temporal optic nerve pallor. Remainder of fundus exam appears wnl Fig. 2: Color Fundus photo of the left eye demonstrating healthy optic nerve with unremarkable posterior pole

Fig 4: High magnification of the Optic Nerve OD better demonstrating temporal pallor Fig. 5: High magnification of the Optic Nerve OS given for comparison sake

Assessment Initial Differential Diagnosis NeuroSyphilis NeuroSarcoidosis Lupus Cerebritis Atypical Giant Cell Arteritis Multiple Sclerosis Other??

Plan Obtain an MRI Orbits w/wo contrast Obtain basic labs for work up of Optic Neuropathy Inflammatory markers ESR, CBC, CRP Autoimmune and infectious panel: ACE, RPR, HIV, HSV 1, HSV 2, Lyme, ANA, TB quantitative interferon, Cryptococcus, NMO-IgG

Timeline Imaging and lab work ordered but not performed Call patients Primary Care Provider in town to coordinate follow up Patient has been “fired from the practice” for aggressive behavior towards staff, showing up late, causing disturbances, etc.

Follow Up Patient returns to clinic approximately 3 weeks later with responsible niece who reports patient has been ”dealing with a few issues” Recent diagnosis of paranoid schizophrenia over the last 3-4 months Clinical exam shows VA of 20/400 OD and 20/80 OS with persistent APD and Optic Nerve Pallor OD Fluorescein Angiogram is performed

Clinical Photos Fig. 6: Fluorescein Angiography serial images of the Right Eye demonstrating relatively normal perfusion of both the choroid and retina

The Plot Thickens

Plan Patient brought from KLEC to ER by niece to definitively obtain workup Labs: Platelets 434K (high), CRP 26.9 (high), and ESR 58 (high) MRI studies of the Brain and Orbits are obtained Admitted to Neurology Service for complete workup

Workup Fig. 7: Pre and Post Contrast MRI T1 Axial Cut demonstrating ”generalized leptomeningeal enhancement” of the brain with areas of hyperintensity in the frontotemporal lobes

Fig. 8: MRI Axial STIR sequence with contrast and fat suppression showing enhancement of the prechiasmatic and canalicular portions of the right optic nerve

Workup -Encephalitis workup begins based on imaging and clinical presentation -Infectious and Auto-immune panel performed: -HIV, RPR, HSV1, HSV2, Lyme, Tb Quantitative Interferon, are all negative -ACE, ANA, NMO-IgG are all negative -Lumbar Puncture is performed

Workup Lumbar Puncture yields: Clear Fluid RBC’s 26 Glucose 133 Total Protein 69 Lymphocytes 90 (elevated) Normal IgG Index Additional send out labs taken…..

Workup EEG obtained which demonstrates “mild generalized slowing of activity” Decision is made to perform frontal lobe biopsy with NES, pathology report: Mild chronic inflammation Increased gliosis based on GFAP staining No signs of cellular proliferation based on negative ki-67 markers

Timeline -Hospitalization complicated by 3 attempts to leave against medical advice, ICU admission following brain biopsy, Psychiatry consult for decisionality -Patient is started on high dose steroids methylprednisolone 250 mg IV QID -Vision OS improves to 20/60 however vision OD declines to No Light Perception -Emotional outbursts and subjective interview improve in a dramatic fashion

Timeline Patient is discharged home by Neurology Service although it’s unclear what caused her condition She is NOT maintained on a steroid taper She misses her scheduled outpatient follow up visit with Neurology

Timeline 6 weeks later she returns to the ED with NLP vision OD, and 20/200 vision OS A review of previously pending lab work returns: ELISA antibody testing of CSF is positive for NMDA Encephalitis (N-methyl-D-Aspartate) She is restarted on methylprednisolone 250 mg IV QID

Timeline CT scan of chest, abdomen, pelvis is performed to evaluate for mass that could contribute to a paraneoplastic process Nature of disease explained to her family and plan for reliable follow up established She is discharged on Prednisone 60 mg qday and receives three Rituximab 375 mg infusions over the next month

NMDA Encephalitis Epidemiology: -Largest published case series involved 577 cases -549 or (95%) younger than 45 with 4:1 female to male ratio -58% of women older than 18 had ovarian teratoma Clinical Presentation: a) Prodrome of headache, fever, viral-like illness b) Psychiatric symptoms including agitation, bizarre or disinhibited behavior, delusions, auditory/visual hallucinations c) Short-term memory loss d) Motor dysfunction including typical epileptic seizures, oral facial dyskinesias Source: #2 Armangue et. al

NMDA Encephalitis Pathophysiology -Autoantibodies against the NR1 or NR2 subunit of the NMDA Glutamate receptors of neurons found in the Thalamus and Frontal Cortex Diagnostics -MRI can be normal in up to 70% -EEG almost always shows ”non-specific slowing or slow continuous rhythmic activity” -CSF abnormal in more than 80% with lymphocytic pleocytosis -CSF autoantibodies considered the Gold Standard for diagnosis Fig. 9: Proposed mechanism of autoimmune attack of neurons in NMDA Encephalitis (Credit: Euro-Immun US http://euroimmun.us.org) Source: #3 Titulaear et. al.

NMDA Encephalitis Treatment -Includes identification and removal of secreting teratoma if present -Use of high dose corticosteroids, IVIG, Plasma Exchange -Second Line Agents include Rituximab and Cyclophosphamide Source: #4 Gastaldi et. al

Fig. 10: Case Report of 18 year old male presenting with seizures, hallucinations, and altered mental status. Diagnosed with NMDA Encephalitis 12 days post admission based on CSF antibodies. Frechette et al able to demonstrate a direct correlation between Anti-NMDA titers and clinical improvement in the setting of prolonged therapy (Frechette et. al #5)

NMDA Encephalitis Prognosis 7% all cause mortality at 24 months Favorable variables include: avoiding ICU admission, removal of identifiable tumor, prompt initiation of immunotherapy Relapse rate commonly cited between 12-25% Source #3 Titulauer et. al

Conclusions Always conduct a thorough Review of Systems in any patient presenting with a new onset Optic Neuropathy Never forget to maintain a steroid taper when treating for autoimmune optic neuropathies Be an advocate for your patients! Patient is now cleared of legal charges

Sources #1 Mugavin M, Mueller B, Desai M, Golnik K, “Optic Neuropathy as the Initial Presenting Sign of N-Methyl-D-Aspartate Encephalitis” Neuro-Ophthalmology Volume 41, 2017 Issue 2 #2 Armangue, T, Leypoldt F, Dalamau “Auto-immune encephalitis as differential diagnosis of infectious encephalitis” Current Opin Neurol. 2014 June; 27(3): 361-368 #3 Titulaer, MJ, et. al “Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observation cohort study” Lancet Neurol 2013;12:157-165 #4 Gastaldi M, Thouin A, Vincent A, “Antibody-Mediated Autoimmune Encepahlopthies and Immunotherapies” Neurotherapeutics (2016) 13:147-162 #5 Frechette, E et al “Prolonged follow up and CSF antibody titers in a patient with Anti-NMDA Receptor Encephalitis Neurology 2011;76;S64-S66