1. Clinical Pathology Conference October 16, 2015 Kara Wyant, MD Neurology Resident PGY-4 Department of Neurology, UPMC Julia Kofler, MD Assistant Professor of Pathology Division of Neuropathology, UPMC

2. Case Review GM is a 89 yo woman with PMHx Lewy Body Dementia, CAD s/p stent, HTN, recurrent UTIs, and recurrent aspiration c/b PNA who has been admitted to the hospital numerous times over the last several years for recurrent infections. In 2009 her daughter reported that the patient was having problems with gait instability, orthostasis, a tremor and mild cognitive impairment. A SPECT scan was ordered, and she was referred to one of our movement specialists for further evaluation.

3. SPECT 12/23/2009

4. Comparison of brain perfusion SPECT images for moderate AD and moderate DLB. DLB showed lower perfusion in occipital cortex than AD (arrows). Hiroshi Matsuda J Nucl Med 2007;48:1289-1300 (c) Copyright 2014 SNMMI; all rights reserved

5. Case Review Her initial evaluation by the movement disorder faculty in late 2009 was notable for a resting tremor and subtle bradykinesia on the right side, gait instability and mild cognitive impairment. Because of the report of orthostasis and parkinsonism on exam there was concern for MSA, so a QSART was ordered for further evaluation. Unfortunately, because of her failing health and repeat admissions to the hospital this testing was never obtained. Their interpretation of the SPECT scan at that time was non-diagnostic of a neurodegenerative process.

6. Case Review She was then evaluated by Dr. Lopez in early 2010 for her mild cognitive impairment. During that evaluation her daughter reported language problems for ~1 years time that were more significant than her cognitive issues. In addition to her other symptoms already mentioned, she also endorsed night time confusion, and vivid dreams which were sometimes difficulty to differential from reality.

7. Case Review There was no clear diagnosis established at that time, but given the results of her SPECT scan and report of vivid dreams, cognitive impairment, and parkinsonism the concern for LBD was raised. It addition, he noted that the language greater than memory deficits indicated a compromise of the frontal-temporal cortical function, which can be seen in subjects with tauopathies (FTD, PSP, CBD, MSA).

8. Case Review On repeat evaluation she endorsed having formed visual hallucinations described as seeing people coming into her room and a man urinating in the bathroom. She initially was able to differentiate the hallucinations from reality, but this slowly changed and she developed other delusions. Given the progression of her hallucinations, the diagnosis of LBD was favored.

9. MRI FLAIR 12/16/2010

11. Case Review PAST MEDICAL HISTORY: CAD s/p stent Paroxysmal atrial fibrillation. Peripheral vascular disease. Hypertension Hypothyroidism. Non-arteritic ischemic optic neuritis. Cervical disk disease s/p laminectomy Possible transient ischemic attacks. Depression with anxiety. Migraine headaches. Lumbar spinal stenosis s/p laminectomy. Rupture of a tendon in his right leg. GERD Urolithiasis. Recurrent UTIs Recurrent aspiration PNA Urinary incontinence. Anemia. Bilateral hearing loss. s/p tonsillectomy. s/p appendectomy. s/p hysterectomy. s/p thyroidectomy.

12. Case Review FAMILY HISTORY: Her father and mother were first cousins, and her father died of ischemic heart disease at age 48, and her mother died of a brain tumor at age 32. She has 3 siblings and only 1 is alive, who has Alzheimer disease. She has 1 sister who died of early-onset Alzheimer disease (in her 50s) and another sister who had a tumor in one of her eyes and suffered a "severe neurodegenerative disorder" after radiation treatment. SOCIAL HISTORY: No h/o tobacco, EtOH or drug use

13. Case Review She was admitted to Shadyside hospital at the end of February 2015 for respiratory distress attributed to bronchitis. The admission was complicated by recurrent PNA, persistent hyperactive delirium, and a. fib with RVR. During that stay she had an abnormal EEG with bilateral frontotemporal SW and generalized RDA so she was started on Keppra. Unfortunately, after her discharge to Select Specialty at the beginning of April she developed respiratory failure secondary MRSA PNA and was readmitted to PUH.

14. Case Review During that admission she required tracheostomy for recurrent respiratory failure. She was eventually discharged back to Select in June, but again bounced back later that month. In the middle of August she had worsening respiratory status and was diagnosed with MDR pseudomonas VAP and sent back to PUH for the final time. She deteriorated over the next month with MOD including AKI requiring intermittent dialysis/CRRT, complete heart block, liver failure with jaundice and hypoglycemia, seizures, and refractory hypotension. She ultimately passed from refractory septic shock on 9/18/15.

15. Suspected Pathology Refractory Septic Shock – Changes related to global stagnant hypoxia (decreased blood flow) Gross: ◦ Acute: Congested and dusky with diffuse cerebral swelling  Possible softening and discoloration in the border zone territories of the cerebral hemispheres and cerebellum due to “watershed infarcts” Micro: ◦ 0-12 hours: no changes ◦ 12-24 hours: Pallor and vacuolation of the neuropil on low magnification. At higher power there will be neuronal shrinkage with cytoplasmic hypereosinophilia and nuclear pyknosis (“Red dead neurons”)

16. Suspected Pathology Lewy Body Dementia Gross: ◦ Diffuse atrophy with associated ventriculomegaly ex vacuo ◦ Loss of the pigmentation in the substantia nigra and locus coeruleus. Micro: ◦ Intracytoplasmic deposits of α -synuclein and ubiquetin (Lewy bodies) in the cortex, limbic system and brainstem nuclei. ◦ Lewy neurites ( α -synuclein immunoreactive dystrophic neurons)  Located in the CA2/CA3 region of the hippocampus, amygdala, nucleus basalis of Meynert, brain stem, olfactory bulb, intermediolateral column of the spinal cord, and autonomic ganglia ◦ Microvacuolation of the temporal cortex ◦ Possible AD pathology: diffuse and neuritic plaques, and neurofibrillary tangles.

17. Microscopy Frontal Cortex ◦ H&E H&E ◦ A  A  ◦ pTau pTau ◦ Tau Tau ◦ Bielschowsky Bielschowsky ◦ Alpha-Synuclein Alpha-Synuclein

18. Microscopy Basal Ganglia ◦ H&E H&E Hippocampus ◦ H&E H&E ◦ A  A  ◦ Tau Tau ◦ pTau pTau ◦ Gallayas Gallayas ◦ Bielschowsky Bielschowsky ◦ TDP43 TDP43 ◦ Alpha Synuclein Alpha Synuclein

19. Microscopy Substantia Nigra ◦ H&E H&E ◦ Alpha Synuclein Alpha Synuclein Optic Nerve ◦ H&E H&E