Clinicopathologic Conference Neurology Resident: Susan Sun Pathologist: Geoffrey

Clinicopathologic Conference Neurology Resident: Susan Sun Pathologist: Geoffrey

Clinicopathologic Conference Neurology Resident: Susan Sun Pathologist: Geoffrey Murdoch April 16, 2018 S B.H. 84 year old woman with history of atrial fibrillation, CAD s/p CABG, and bilateral carotid stenosis presenting with progressive cognitive decline over the span of 4 months Patient was previously fully independent and had been

primary caregiver for her husband before he passed away 9 months ago; her brother also passed away 5 months ago She developed anhedonia, fatigue, and anorexia started on citalopram for depression, found also with hypothyroidism She also had progressive memory impairment short term, forgets stories but not names or birthdates, repeats herself HPI Patient had several mechanical falls and was admitted 3

months ago at OSH workup revealed hyponatremia and urinary tract infection; citalopram was discontinued She was discharged home still functional doing her own bills She was re-admitted 2 months later acutely confused She was again hyponatremic and was again treated for UTI

Patient was given ativan to obtain MRI during this admission then became acutely agitated with visual hallucinations received multiple doses of antipsychotics HPI Afterwards patient was somnolent for ~72 hours mentation gradually improved but she remained unable to ambulate and never returned to prior cognitive baseline Renal was consulted thought hyponatremia was subacute syndrome of inappropriate antidiuretic hormone secretion Endocrinology was consulted to manage hypothyroidism uptitrated levothyroxine with no effect on mental status

HPI Her mental status continue to worsen and she was discharged now to dementia unit in a skilled nursing facility Since discharge, patient is wheelchair bound with fluctuating mental status with periods of lucidity and periods of lethargy, poor appetite, with 20 lb weight loss Family hence requested transfer for further evaluation Histories

PMH: paroxysmal atrial fibrillation, bilateral carotid artery stenosis, CAD, hypothyroidism, urinary retention PSH: CABG and MVR in 4/2012 FH: CAD, hypertension SH: no history of tobacco, alcohol, or illicit drug use Medications: NaCl 1g TID, lasix 20, lisinopril 10, metoprolol 25 BID, levothyroxine 75 mcg, aspirin 81, atorvastatin 20 General Exam Vitals: T 36.6C, 152/80, HR 98, RR 22, Sat 97% on RA General: no acute distress HEENT: normocephalic, atraumatic Neck: Supple Cardiovascular: RRR Respiratory: Normal work of breathing

Gastrointestinal: Non-distended Integumentary: warm, dry, and pink; scattered bruising Neurological Exam Mental Status: Awake, alert, not oriented to person, place, and time, inattentive, constantly looking up at the ceiling, nonsensical speech, occasionally responds to questions with "I don't know Cranial Nerves: VF full to BTT, PERRL, opsoclonus, hearing intact to conversational voice, face symmetric, SCM and shoulder shrug intact bilaterally, tongue midline Motor: Normal bulk. Diffuse paratonia. Fine postural tremor in bilateral upper extremities. Strength 5/5 throughout Reflexes: 3+ at biceps, triceps, brachioradialis, 2+ R patella,

unable to obtain L patella due to knee deformity, 2+ achilles. No clonus. Flexor plantar response bilaterally Sensory: intact to noxious stimuli throughout Cerebellar and Gait: unable to assess Previous Workup CMP only notable for Na 129, CBC wnl, RPR nonreactive, B12>1000, folate 12.5, ESR 13, ammonia <9 Thyroid ultrasound with small R thyroid cyst, RUQ ultrasound unremarkable, CXR normal HCT with chronic small vessel ischemic change MRI brain: slight narrowing of left ICA, flow void within the horizontal petrous portion of left ICA less clearly depicted, some attenuation of distal L M1 and proximal M2 TTE (12/2017): EF 55-59%, trace aortic regurgitation Current Workup CMP with Na of 132 and K of 2.8 otherwise normal CBC notable for WBC of 14.3 only Vitamin B1 <7, NH3 30, B12 1128, TSH 1.141

EKG sinus, CXR with no acute cardiopulmonary process EEG with diffuse theta-delta activity Pan CT: left atrial appendage thrombosis, dilated left atrium, mitral valve calcifications, T12 compression fracture Head CT Head CT

Head CT Hospital Course She was treated for Klebsiella UTI, started on IV thiamine, and heparin gtt for left atrial appendage thrombosis Patient had aspirated with subsequent respiratory failure on hospital day 5 and family transitioned to comfort care only Patient passed away 4 days later in the hospital family

did not want transfer to inpatient hospice and asked for autopsy MRI was never obtained due to her declining mental status and past severe paradoxical reaction to sedative-hypnotics Rapidly Progressive Dementia Progress from onset of symptoms to dementia in <1-2 years Vascular dural arteriovenous fistula, cerebral amyloid angiopathy, multiple infarcts, hypertensive encephalopathy, thalamic stroke (especially if bilateral - venous thrombosis) Dementia decline in more than one cognitive domain with functional impairment; 1ST Alzheimers, 2nd FTD, 3rd DLB MRI (diffuse white matter changes with dAVF, hemorrhages with surrounding FLAIR white matter changes from inflammation of CAA), conventional and noninvasive angiography Rare entities: cerebroretinal micoangiopathy with calcifications and cysts, subacute diencephalic angioencephalopathy (PRES)

Rapidly Progressive Dementia Infectious: HSV encephalitis, HIV dementia, AIDS-related toxoplasmosis, progressive multifocal encephalopathy, Lyme, CNS Whipple disease, aspergillosis (immunocompromised), Subacute sclerosing panencephalitis, neurosyphilis, UTI, Pneumonia Serial CSF HSV PCRs, Tropheryma whippelii PCR, acute and convalescent viral titers, metagenomic deep sequencing

Toxic-Metabolic: lithium, lead, bismuth, mercury, B3, B1, B12 Organic mercury - concentric VF loss, paresthesia, and cerebellar ataxia; niacin dermatitis, diarrhea, dementia in malnourished pts Medication levels, heavy metal screening (24 hr urine, hair/nail) Cortical ribboning with hypoglycemia, rapidly corrected hypoNa Rapidly Progressive Dementia Autoimmune CNS vasculitis, CNS lupus, ADEM, SREAT, antibody-mediated encephalopathy

Autoimmune panel, tissue biopsy from an abnormal area Neurodegenerative Corticobasal degeneration, FTD, FTD-motor neuron disease, AD, DLB, prion disease CJD - CSF 14-3-3, total tau, and neuron-specific enolase are markers of rapid neuronal injury; confirm with real-time quaking-induced conversion assay - detects prion seeding activity uses recombinant prion protein to induce aggregation Rapidly Progressive Dementia

Neoplastic CNS lymphoma, intravascular lymphoma CNS lymphoma multifocal lesions with irregular enhancement in immunosuppression; uniform enhancement in immunocompetent patients; CSF 2 microglobulin large volume CSF analysis; EBV DNA in HIV cases Steroids are lymphocytoxic hence would affect biopsy yield Systemic/Seizures sarcoidosis, MELAS, epilepsy, nonconvulsive status epilepticus, subdural hematoma

Rapidly Progressive Dementia Primary CNS Lymphoma (PCNSL) 4% of all CNS malignancy diagnosed each year 4 cases per million persons per year Rare variant of extranodal non-Hodgkin lymphoma

Immunodeficiency is the only established risk factor Can involve any part of the neuroaxis Intracranial lesion(s), diffuse leptomeningeal and periventricular lesions, vitreous/uveal deposits, spinal lesions, nerve seeking lymphoma (neurolymphomatosis) Primary Cerebral Lymphoma

Presenting symptoms in immunocompetent patients Personality changes occur manifesting as depression, apathy, psychosis, memory impairment, confusion, and hallucinations 70% focal neurological deficits, 43% neuropsychiatric symptoms, 33% signs of increased ICP, 14% seizures, 4% ocular symptoms Develops slowly and most often associated with lesions involving periventricular white matter, frontal lobes, and corpus callosum

Visual hallucinations occur with lesions involving visual pathway, brainstem, and with ocular and leptomeningeal involvement PCNSL Variants Leptomeningeal involvement seen in up to 40% of patients with primary cerebral lymphoma at time of diagnosis Primary leptomeningeal lymphoma is rare and patient present with signs and symptoms of multilevel involvement of the neuroaxis cranial neuropathies, radiculopathies 15-25% of patients with PCNSL have ocular involvement

Involves posterior segment of eye with subsequent uveitis, exudative retinal detachment, PCNSL Variants Primary spinal involvement in less than 1% of PCNSL Discrete intramedullary nodules in PCNSL, extradural nodules or diffuse leptomeningeal involvement in systemic lymphoma Can present as progressive myelopathy (100%), mostly lower cervical or upper thoracic, B symptoms (64%), back pain (64%), and lower motor neuron signs on exam (43%) Nerve root involvement hallmark of poorly localized

severe pain in the absence of parenchymal lesions or lymphoma seen in the CSF (can spare the meninges) Peripheral (60%), spinal (48%), cranial (45%), plexus (40%) Diagnostic Evaluation Establish extent of disease and restriction to the CNS General exam including lymph nodes and testicular exam

Testicular lymphoma has predilection to spread to CNS Contrasted MRI or CT; CSF analysis and slit lamp exam Solitary lesions in 50-70% of immunocompetent patients Periventricular > frontal > parietal > temporal > occipital Isodense to hyperdense on CT, isointense to hypointense on T2 Diagnostic Evaluation CSF cytology positive in 40% of cases; complementary with PCR for rearranged

immunoglobulin heavy-chain genes Stereotactic needle biopsy if no ocular or CSF involvement 80-85% aggressive diffuse large cell subtypes, almost all B cell CT c/a/p, testicular ultrasound, mammogram, and bone marrow biopsy to evaluate for occult systemic disease References Batchelor T, Loeffler JS. Clinical presentation, pathologic

features, and diagnosis of primary central nervous system lymphoma. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on April 15, 2018.) Gerstner ER, Batchelor TT. Primary central nervous system lymphoma. Arch Neurol. 2010; 67(3): 2917. Geschwind MD. Rapidly progressive dementia. Continuum (Minneap Minn). 2016; 22(2 Dementia): 510-37. Rubenstein JL, Gupta NK, Mannis GN, LaMarre A K, Treseler P. How I treat CNS lymphomas. Blood. 2013; 122(14): 2318-30.

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