The Inconspicuous Cysts

A previously healthy 40-year-old male, with a past medical history significant for latent tuberculosis s/p treatment 15 years ago, presented with blurry vision and progressively worsening headaches for 6 months. He was originally from Guatemala and moved to the US in 2001 (crossed the deserts through Mexico and Texas).

The Inconspicuous Cysts Lily Zhang MD Hong Jiang MD PhD, Folusakin Ayoade MD, Julio Diaz Perez MD No financial disclosures Case Presentation 40 yo M presents with blurred vision and headaches for 6 months • • • • PMHx: latent TB s/p treatment 15 years ago POHx: none PSHx: none Meds: none • Visual Acuity Exam – OD: 20/20 – OS: 20/25 • IOP 15/13 • Pupils 4->3 round, no APD OU • EOMs full OU • Anterior segment exam: normal OU MRI Brain + Orbits w/wo Contrast MRI Brain + Orbits w/wo Contrast Differential Diagnosis • Infectious meningitis, encephalitis • Inflammatory: sarcoidosis, lupus, Behcet’s, VKH • Infiltrative: leukemia, lymphoma, meningeal carcinomatosis Work up • Lumbar puncture – Opening pressure >40 – Glucose <2, TP 108, WBC 209, clear fluid, 56% neutrophils, 44% lymphs, 10% eosinophils • Chronic fungal meningitis – Coccidioides vs cryptococcus – CSF eosinophils – suggestive of fungal or parasitic – Additional hx: previous travel from Guatemala to Mexico and SW U.S. Lab Workup CSF Serum • • • • • • • • • HIV neg HepC neg COVID neg Blood cx neg Cryptococcal Ag neg AFB cx neg Mycology cx neg MTB sputum PCR neg VDRL neg • • • • • • RPR neg AGM neg Brucella AB neg Quantiferon neg Histo urine neg Coccidioides neg • • • • Culture neg VDRL neg Coccidioides neg Meningitis encephalitis panel neg • Fungitell neg Timeline VA OD 20/40, OS 20/25 (worse OD) Plan • Worsening despite empiric treatment for fungal meningitis • All testing negative to-date • High risk for permanent vision loss - decreasing vision and worsening visual field • Return to hospital for repeat LP and start acetazolamide 500mg bid • New loss of left hemibody sensation at T9-10 • LPs q48h with OP >50 • Additional CSF testing: cocci immunodiffusion, AFB cx, MTB PCR, bacterial & fungal cx, cytology & flow cytometry • Eventually has VPS placed with neurosurgery • Headaches and vision improved, discharged with continuing fluconazole Timeline • Suprapubic abdominal pain, urinary retention and generalized numbness and weakness over 2 weeks • Requiring a walker • Weight loss of 15lbs A definitive diagnostic procedure was performed... Spinal intradural biopsy - H&E 2x * ** Spinal intradural biopsy - H&E HP 20x Spinal intradural biopsy - Trichrome HP 20x Extra-parenchymal Neurocysticercosis (NCC) with arachnoiditis and spinal lesions resulting in papilledema, lower extremity weakness, and bladder dysfunction • Started on albendazole, praziquantel, prednisone with improvement in neurological symptoms Timeline VA 20/20 OU Spinal Cysticercosis • 0.7- 5.8% of cases and most are associated with intracranial lesions • No standard of treatment • Medical - Antiparasitic + corticosteroids – Multiple cysts – albendazole + praziquantel • Surgical - severe neurological deficits or for definitive histopathology for diagnosis • Combination – superior to surgery or medical treatment alone and highest chances of recovery Expert Discussion Neurocysticercosis Walsh Presentations: NANOS 2022 48TH Annual Meeting (Virtual and Live Conference) Austin, TX, USA February 12-17, 2022 Manraj Kanwal Singh Heran MD, FRCPC Division of Neuroradiology (VGH) Pediatric Interventional Radiology (BCCH) [e-mail] Neurocysticercosis • CNS involved in 60-90% of cysticercosis cases • Within the brain: subarachnoid spaces >cisterns > parenchyma > ventricles) • Parenchymal cysts often at gray-white junction • Best diagnostic clue: Cyst with "dot" inside Orbital Cysticercosis • Can involve the intraocular structures or involve the orbital adnexa • Extraocular muscle involvement common • Best diagnostic clue: Cyst with "dot" inside PATH COMMENTARY ON ‘THE INCONSPICUOUS CYSTS’ NEUROCYSTICERCOSIS (NCC) • Cysticerci – larvae of tapeworm Taenia solium • Cysticercosis is the most common of all worm infections to affect the CNS • It has been estimated that in some countries, NCC is the most common brain space occupying lesion and most frequent identifiable cause of epilepsy • Due to ingestion of T. solium eggs which then burrow into the gut wall and disseminate through the body – muscle, heart, subcutis, eye and CNS within hours. • 2-3 months: oncosphere develops into a cysticercus which lives for years before dying NEUROCYSTICERCOSIS (NCC) • Most clinical sd are due to humoral and cellular response to the parasite when it dies • Described clinicopathological forms • Seizures, the presenting form in about 50–80 per cent, from parenchymal cysts. Multiple degenerating cysts may lead to an encephalitic form. • Leptomeningitis, often basal with hydrocephalus. It may be eosinophilic. • Intraventricular, the fourth ventricle being the most common. Cysts may be attached or floating free – obstruction of third ventricle may lead to sudden death. • Cerebrovascular, with endarteritis obliterans and thrombosis due to inflammation from an adjacent cyst and host reaction. • Spinal localization, which is rare, but may lead to arachnoiditis, with transverse myelitis or signs of a local mass lesion. Scolex of T. solium with four large suckers and rostellum containing two rows of hooks. www.cdc.gov ‘Racemose cyst’ occur in the subarachnoid space. Multiple grape-like bladders without a scolex. Kumar Yadav et al., J Parasit Dis. 2012 Apr; 36(1): 106–111. Velho et al., Internet J. Neurosurg., 7(1) Expert Dicussion for The Nidus of the Neuropathy Metronidazole Toxicity Walsh Presentations: NANOS 2022 48TH Annual Meeting (Virtual and Live Conference) Austin, TX, USA February 12-17, 2022 Manraj Kanwal Singh Heran MD, FRCPC Division of Neuroradiology (VGH) Pediatric Interventional Radiology (BCCH) [e-mail] Metronidazole Neurotoxicity • Not dependent upon dosage and duration of usage • No significant difference between oral and IV routes • Seizures • Diffuse encephalopathy • Acute/chronic cerebellar symptoms dysarthria, ataxia, dysmetria, etc. • Mechanism: unclear Metronidazole Neurotoxicity • Lesions typically bilateral and symmetric • Typically involves: dentate nuclei of cerebellum midbrain (periaqueductal region, red nucleus) splenium of corpus callosum dorsal brainstem (often around nuclei) inferior colliculi Metronidazole Neurotoxicity • Less common sites: subcortical white matter basal ganglia thalamus middle cerebellar peduncles inferior olivary nuclei Dentate Nucleus T2 Hyperintensity • Methyl bromide intoxication • Enteroviral encephalomyelitis • Maple syrup urine disease Imaging • • • • • T2 hyperintensity T1 hypointensity No enhancement No mass effect Many demonstrate restricted diffusion • Complete/near-complete resolution of changes after appropriate cessation of metronidazole …within weeks Wernicke Encephalopathy • • Thiamine deficiency Alcoholic versus non-alcoholic • Biggest mimic of metronidazole induced cerebellar toxicity • Affects dentate nuclei Clinical history/findings of alcoholism usually evident! Wernicke Encephalopathy • Also affects: Mamillary bodies Medial thalami Periaqueductal grey matter Methyl Bromide Toxicity • Rare • Fumigant gas or relevant industrial exposure • Imaging features closely resembling MIE: cerebellar dentate nuclei dorsal pons dorsal medulla splenium of corpus callosum cranial nerve nuclei Splenial T2 Hyperintensity • • • • • • • • • • • Marchiafava-Bignami disease Osmotic demyelination syndrome Anti-epileptic therapy (overdose or acute withdrawal) Acute infectious encephalitis Demyelinating diseases (ADEM, SLE, etc) Vitamin B12 deficiency Stroke Hypertensive encephalopathy PRES Hypoglycemia High altitude edema Splenial Hyperintensity and Restricted Diffusion (with reversal) Atypical Corpus Callosal Involvement Dentate Nuclei, Splenial, and Collicular Involvement Dentate Nuclei “Dentate, Red, and Facial Nuclei Resolution of Dentate Nuclear Hyperintensity PATH COMMENTARY ON ‘THE NIDUS OF THE NEUROPATHY’ METRONIDAZOL-INDUCED ENCEPHALOPATHY • Pathology not well studied • One autopsy case showed multifocal WM necrotic lesions – ?critical illness encephalopathy Pseudo Pseudotumor Cerebri Benard-Seguin E, Al-Ani A, Umansky D, Langdon K, Hazrati L, Midha R, de Robles P, Costello F, *No conflict of interest or financial disclosures. Financial Disclosures • No financial disclosures History and Examination • A 23-year-old female to male transgender patient. • BMI= 30 • 5-day history of nausea, vomiting and photophobia. • Daily transient visual obscuration. PMHx • Female to Male Transgender • Scoliosis Surgery at age 10. Meds • Testosterone qweekly injection • Prozac V -2.79 dB 20/25 20/25 CV øRAPD Full Full -3.08 dB Diagnosis: Papilledema secondary to hormone replacement therapy? Urgent MRI/MRV ordered Enhancement of CNVI Enhancement of the Interpeduncular cistern Enhancement of the Optic Chiasm Figure 2a. MRI Axial T1 Post Gadolinium Admitted to Hospital for Workup of Communicating Hydrocephalus and leptomeningeal enhancement Enhancement of Cervical Spine Figure 2b. Sagittal T1 Post Gadolinium Mild communicating hydrocephalus Figure 2c. Axial T1 Post Gadolinium Lumbar Puncture Atypical epithelioid Opening cells on flow Leukocytes: Traumatic Tap Pressure: 33 cytometry. 15 x 106/L cmHAFB Mycobacterial, 2O smear and culture, HSV and VZV, fungal culture, enterovirus, bacterial culture, Erythrocytes: Protein 3.10 HIV 6/L and syphilis normal. 28 000 x 10 g/L Live Content Slide When playing as a slideshow, this slide will display live content Poll: What is the next best step? Timeline Admitted for tonic-clonic seizures and started on Keppra. Readmitted to hospital for worsening symptoms. 1 month 2 weeks 7 months 6 months Right ventriculoperitoneal shunt inserted. Cerebral cortex and leptomeningeal biopsy showed dense connective tissue with increased cellularity. Patient referred to NeuroOphthalmology. V 20/40 20/20 CV Non recordable 8/10 R RAPD -29.001 dB -7.28 dB Bilateral Optic Atrophy with significant GCC-IPL thinning and visual field loss OD 72 “Just before my scoliosis surgery, they found a tumor (Pilocytic Astrocytoma) that they removed.” 73 Live Content Slide When playing as a slideshow, this slide will display live content Poll: What is the most likely diagnosis? Working Theory Pilocytic Astrocytoma resected in Latin America. Chronic Arachnoiditis caused by the following at the time of surgery: • Oil based myelogram • Pilocytic Astrocytoma hemorrhage • Infection • Hormonal therapy could have disrupted the homeostasis and pushed the patient into a state of elevated ICP. • • A repeat diagnostic procedure was performed… Repeat Biopsy of the leptomeninges and culture Culture Results • Positive for C. Acnes • Infectious disease believed this to be causing hardware infection. • Completed a 6 week course of Ceftriaxone 2g q12h. • No improvement noted. 78 Final Pathology Report (2.5 weeks after positive culture) Hematoxylin and eosin stain at various magnifications H&E x40 H&E x100 H&E x200 Immunohistochemistry S100 protein x100- Positive Olig2 x100- Positive MAP2 x100- Positive Synaptophysin x100- Positive GFAP x100- Negative Ki-67 x100 (proliferation index) 20% Positivity Molecular Genetics • -KIAA1549(exon15)/BRAF(exon9) fusion (Trusight) • PTEN p.P246L S • 1p19q co-deletion • Two copy gain of 1q Diagnostic for a Diffuse Leptomeningeal Glioneuronal Tumor Diffuse leptomeningeal glioneuronal tumors • Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare central nervous system (CNS) tumors • First added to the World Health Organization (WHO) classification of CNS tumors in 2016 • DLGNTs occur more in males and preferentially in children. • On neuroimaging: • Prominent leptomeningeal enhancement • Communicating hydrocephalus. • Reports of DLGNT erroneously being diagnosed as a Pilocytic astrocytoma. 83 DLGNT is a rare tumor that affects pediatric patients and young adults. Learning Points C. Acnes can cause hardware infection but is also a well known contaminant of OR specimens. Papilledema in a young obese female is not always IIH. Expert Discussion Radiology Walsh Presentations: NANOS 2022 48TH Annual Meeting (Virtual and Live Conference) Austin, TX, USA February 12-17, 2022 Manraj Kanwal Singh Heran MD, FRCPC Division of Neuroradiology (VGH) Pediatric Interventional Radiology (BCCH) [e-mail] PATH COMMENTARY ON ‘PSEUDO PSEUDOTUMOR CEREBRI’ DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOUR (DLGNT) • Glioneuronal neoplasm with oligodendrocyte-like cells • DLGNTs are rare, and data on incidence are not available • Affect mostly pediatric patients (median age at Dx 5 years) • Sporadic; no evidence of genetic predisposition or exposure to specific carcinogens. • Commonly involves the leptomeninges (spinal and post fossa), but rare pure parenchymal examples exist • CSF examination demonstrates elevated protein levels and cytology is often negative. Diagnosis usually requires a biopsy. WHO classification of CNS tumors, 5th ed. © A. Perry DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOUR (DLGNT) • Molecularly characterized by chromosome arm 1p deletion and a mitogen-activated protein kinase (MAPK) pathway gene alteration, most commonly KIAA1549::BRAF fusion (same as PA). • Most are well-differentiated low-grade lesions. Not enough data to assign grades. • Clinical courses reported to date have been similar to WHO CNS grade 2 or 3. DLGNTs may go through periods of stability or slow progression over many years, although often with considerable morbidity. • Main DDx are intraparenchymal astrocytic or oligodendroglial gliomas with leptomeningeal dissemination. • PAs not infrequently show leptomeningeal dissemination: • Strongly GFAP positive • No isolated 1p deletion “An Apple a Day” Joseph W. Fong, MD James C. O’Brien, MD Anil D. Patel, MD Financial Disclosures ▪ The authors have no relevant financial disclosures. CC: Double vision, facial pain ▪ 73-year-old Caucasian female with 4-month history of… – progressive binocular oblique diplopia – right upper eyelid ptosis – right-sided facial pain and paresthesias in V1/V2 distribution ▪ Prior diagnosis of idiopathic trigeminal neuralgia ▪ Reported no systemic symptoms Additional History ▪ Past Ocular History – Cataracts ▪ Medications – – – – Citalopram Alprazolam Glucosamine Multivitamin ▪ Past Medical History – Depression & anxiety – Ruptured ovarian cyst ▪ Family History – Non-contributory ▪ Allergies – NKDA ▪ Social History – – – – – Never smoker No alcohol No illicit substances Retired Single Exam ▪ BCVA – OD 20/40 – OS 20/25 ▪ IOP – OD 8 – OS 11 ▪ Pupils – 7mm/5mm → 7mm/3.5mm – No RAPD ▪ Visual Fields – Full to confrontation OU ▪ External and Slit Lamp Exam – 50% RUL ptosis – Decreased sensation R V1/V2 – 2+ nuclear sclerotic cataracts OU – Asymmetric PEE OD>OS ▪ Funduscopic Exam – Normal OU 50RXT / 10RHoT MRI Brain (T1 Coronal FSE Post Contrast) MRI Brain (T2 FLAIR Post Contrast) MRI Brain (T1 Axial FSE Post Contrast) MRI Brain (Axial FSPGR) Thoughts? ▪ Differential Diagnosis – Malignant neoplasia with perineural spread ▪ Squamous cell carcinoma ▪ Lymphoma – Benign neoplasia ▪ Meningioma ▪ Schwannoma – Inflammatory disorders ▪ IgG4-related disease ▪ Tolosa-Hunt Syndrome ▪ Sarcoidosis ▪ Craniotomy with biopsy and subtotal resection of tissue mass H&E 20x Biopsy of Trigeminal Mass Congo Red 20x Biopsy of Trigeminal Mass Congo Red 20x with polarized light Biopsy of Trigeminal Mass Amyloidosis ▪ Extracellular deposition of amorphous, heterogenous, abnormallyfolded protein in body tissues and organs ▪ Can occur as primary disease, inherited disease, or secondary disease: – Chronic inflammatory disease and rheumatoid arthritis: Amyloid A (AA) – Occult neoplastic disorders, such as Hodgkin lymphoma and multiple myeloma: Amyloid L (AL) – Chronic renal failure: beta2-M amyloid – Familial: Transthyretin (ATTR) and Gelsolin (AGel) – Alzheimer disease: Amyloid β (A β) ▪ There can be localized or systemic disease burden Kyle RA. Br J Haematol. 2001 Trigeminal Amyloidosis ▪ First reported in 1957, 17 cases overall ▪ Slow-growing masses exhibiting perineural spread ▪ Can mimic idiopathic trigeminal neuralgia picture ▪ Systemic work-up to rule out systemic amyloidosis – Complete blood count – Serum and urine protein electrophoresis – Serum and urine kappa and lambda light chains, urine kappa and lambda light chains – Chest X-ray – Electrocardiogram – CT scans of the chest, abdomen, pelvis – Nuclear bone scan and echocardiography – Abdominal fat pad biopsy Hashmi H, Dhanoa J, Manapuram S. Cureus. 2018 Gultasli N, van den Hauwe L, Bruneau M, et al. J Neuroradiol. 2012 Bookland MJ, Bagley C, Schwarz J, Burger PC, Brem H. Neurosurgery. 2007 The Cause: Smoldering Plasma Cell Myeloma ▪ Hematology/oncology consulted ▪ Bone marrow biopsy – 10-12% population of monoclonal cells ▪ PET-CT revealed numerous bony lytic lesions ▪ Started on combination therapy with lenalidomide, bortezomib, and dexamethasone ▪ Patient elected for palliative therapies rather than bone marrow suppression / transplant ▪ Continued on gabapentin 300 mg bid for management of trigeminal pain Take Home Points ▪ Include localized amyloid lesion in the differential diagnosis of trigeminal nerve and cavernous sinus lesions ▪ Prompt and extensive work up should be undertaken to investigate potential etiologies; localized vs systemic ▪ Localized amyloid lesions in the CNS are most commonly AL-subtype, therefore tailor work up accordingly Expert Discussion Cerebral Amyloidosis Walsh Presentations: NANOS 2022 48TH Annual Meeting (Virtual and Live Conference) Austin, TX, USA February 12-17, 2022 Manraj Kanwal Singh Heran MD, FRCPC Division of Neuroradiology (VGH) Pediatric Interventional Radiology (BCCH) [e-mail] Cerebral Amyloidoma • “Primary CNS Amyloidoma” • Localized form of amyloid deposit …deposition of insoluble glycoproteins • Distinct from systemic amyloidosis and amyloiod angiopathy Cerebral Amyloidoma • Much, much rarer than congophilic amyloid angiopathy • Usually solitary • May be multiple in 1/3 of cases …may have satellite lesions • Most often in supratentorial (and subcortical) white matter • Gasserian (Trigeminal) ganglion and nerve • Spinal and peripheral nerves • Spinal cord and meninges, most commonly thoracic region Imaging Features • • • • Patchy Hyperattenuating on NCCT Enhance avidly (due to amyloid involvement in blood vessel) No mass effect or perilesional edema • T1WI: hypo/iso/hyperintense (extent of amyloid protein) • T2WI: heterogeneous • May have finely irregular, radiating lines from edge of tumour …may resemble vascular lesion or infiltrative glioma Imaging Features • Slow growing, with usually a benign course …similar to indolent tumours • No mass effect or perilesional edema • T1WI: hypo/iso/hyperintense (extent of amyloid protein) • T2WI: heterogeneous • May have finely irregular, radiating lines from edge of tumour Cerebral Amyloidosis Cerebral Amyloidosis PATH COMMENTARY ON ‘AN APPLE A DAY’ AMYLOIDOSIS • Amyloid: Extracellular deposits of fibrillar proteins that result in tissue damage and functional compromise • Abnormal fibrils are produced by the aggregation of misfolded proteins (which are soluble in their normal configuration) • Fibrillar deposits bind a wide variety of proteoglycans and glycosaminoglycans and plasma proteins • The presence of abundant charged sugar groups give the deposits staining characteristics resembling starch (amylose) • Rudolph Virchow used the term amyloid because of the peculiar staining of corpora amylacea of the CNS with iodine. He preferred this term to the commonly used ‘lardaceous’ or ‘waxy’ expressions [Kyle, BJHaem, 2001;114(3); 529-538] AMYLOIDOSIS • More than 20 different proteins can aggregate to form continuous, nonbranching fibrils with a diameter of approximately 7.5 to 10 nm. • Ultrastructurally, these fibrils demonstrate a characteristic cross-βpleated sheet conformation. Robbins and Cotran pathologic basis of disease. Elsevier [2021] The Grey Area of White Matter Parker Bohm1, Angela Liu2, Robert Schmidt3, Leanne Stunkel1,2, Gregory P. Van Stavern1,2 1. Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO 2. Department of Neurology, Washington University in St. Louis, St. Louis, MO 3. Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO Frank B. Walsh Session North American Neuro-ophthalmology Society 48th Annual Meeting Disclosures • The authors have no relevant disclosures A 76 year-old man presented with two months of progressive confusion, vision loss, and left-sided weakness Past Medical History Basal cell carcinoma of the right forehead, excised months prior Deep vein thrombosis Type 2 diabetes mellitus Hypothyroidism Hypertension Coronary artery disease Medications • Apixaban 2.5 mg BID • Levothyroxine 150 mcg qd • Metformin 500 mg QID • Pantoprazole 40 mg qd • Nifedipine 60 mg ER qd • Triamterene 37.5 mg/HCTZ 25 mg qd • Citalopram 20 mg qd • Montelukast 10 mg qd • Vitamin D 50,000U weekly • Vitamin B12 5000 mcg qd Medical History Family History • Mother with stroke (70s) • Brother with Alzheimer’s (60s) Social History • Financial advisor • No illicit habits Allergies • None Exposures • No recent travel • No unusual hobbies or known animal exposure Clinical Course • Two months prior to neuro-ophthalmology evaluation, he was hospitalized for dyspnea • CT chest with contrast revealed mediastinal and hilar lymphadenopathy with extensive perihilar interstitial infiltrates • ACE 65 (10-55), p-ANCA + (repeat negative), ANA 1:160 Lung biopsy revealed non-necrotizing granulomas Corticosteroids were initiated for pulmonary sarcoidosis which improved his dyspnea Clinical Course • 1 month later, he was readmitted for dyspnea after corticosteroid taper and also complained of confusion. Prednisone 40mg was started on admission • The patient described recent difficulty reading and responding to text messages, but no problems with verbal communication • He felt like his symptoms had worsened as he tapered off corticosteroids, and he was feeling better after restarting corticosteroids • Neurologic examination revealed a right homonymous hemianopia but was otherwise unremarkable MRI brain with and without contrast Clinical Course • CSF evaluation demonstrated isolated elevated protein of 77 • CSF ACE, IgG index, OCB, cytology WNL • MRI cervical spine showed two chronic nonenhancing cord lesions • Five doses of intravenous methylprednisolone 1g daily were administered; he was discharged on prednisone 20mg without improvement in neurologic symptoms Neuro-ophthalmology Consultation • Over the two weeks since discharge, he had developed worsening left hemiparesis, inability to read, and needed assistance with daily activities. He was able to watch television but had difficulty finding channels Pupils 3mm to 2mm OU; no APD Visual acuity sc 20/500 20/100 ph cc 20/90 PHNI Difficulty using occluder noted Color VF 0/11 OU right incongruous homonymous defects Motility moderately impaired smooth pursuit, frequent macro square-wave jerks, dysmetric saccades, extraocular movements seemingly mildly limited in all directions of gaze Stereo identified fly as a “person” Neuro-ophthalmology Consultation Slit lamp and dilated fundus examination was largely unremarkable Oriented to self, month, and year Able to state reason for visit was “visual impairment” Unable to draw a clock • There was no evidence of anterior visual pathway dysfunction, and examination was consistent with cortical visual impairment • Discussed broad differential diagnosis and possible further diagnostic tests • Within 1 week of evaluation, he was hospitalized due to falls, incontinence, and left hemiparesis • Examination revealed impaired short-term memory, alexia, left-sided neglect, left hemiparesis, left-sided hyperreflexia, and upgoing toes bilaterally Diagnostic testing • Negative HIV, RPR, SARS-CoV-2, blastomyces Ab, histoplasma Ab, hepatitis panel, quantiferon, CD4, C3, C4, anti-DS DNA, MOG, ANCA, monoclonal protein study, Cu, TSH • A1c 7.5%, CD8 57 (187-781), B12 2000 (230-1250) • CSF: 5 nucleated cells with 1131 rbc (tube 1), 0 nucleated cells (tube 4), protein 66, glucose 85 • Negative cultures, OCB, JC virus PCR, flow cytometry, cryptococcal antigen, autoimmune encephalopathy panel PET CT skull to thigh showed reduced FDG uptake corresponding with MRI brain lesions and no areas of increased FDG uptake Left Parietal Lobe Biopsy SV40 IHC – JC Virus Surrogate Marker In Situ Hybridization JC Virus Case Summary New biopsy-proven pulmonary sarcoidosis with worsening dyspnea, new confusion, and vision loss noted during initial steroid taper Brain biopsy revealed evidence of progressive multifocal leukoencephalopathy Abnormal spinal fluid and spinal lesions could be compatible with neurosarcoidosis Despite lack of long-term immunosuppression, JC virus was checked in CSF and was negative Empiric corticosteroids improved dyspnea but did not help other symptoms Worsening neurologic symptoms and neuroimaging prompted extensive work-up Progressive Multifocal Leukoencephalopathy • PML is an often fatal disease that causes lytic infection of glial cells caused by John Cunningham (JC) virus • As 60-80% of the general population exhibits JC virus seroconversion by the age of 70, the majority of cases of PML only occur in the setting of prolonged immunosuppression • HIV, hematologic malignancy, or exogenous immunosuppression • PML has been described in patients with inflammatory disorders such as sarcoidosis and systemic lupus erythematosus even prior to initiation of immunosuppression • These patients may have a lower viral load, reducing the sensitivity of CSF JC virus PCR Teaching Points • PML can occur in patients with inflammatory disease who have minimal or no exposure to exogenous immunosuppression • A negative CSF JC virus PCR does not exclude the diagnosis of PML • Histopathologic confirmation of non-caseating granulomas outside of nervous system tissue may be suggestive of neurosarcoidosis, but even criteria for “probable neurosarcoidosis” require rigorous exclusion of other causes as well as MRI, CSF, or electrodiagnostic data typical of granulomatous inflammation of the nervous system Acknowledgements • Dr. Van Stavern, Dr. Stunkel, Dr. Shepherd from the Washington University neuro-ophthalmology division • Drs Robert Schmidt, Angela Liu, and the entire inpatient neurology, ophthalmology and neurosurgery teams caring for this patient Expert Discussion PML Walsh Presentations: NANOS 2022 48TH Annual Meeting (Virtual and Live Conference) Austin, TX, USA February 12-17, 2022 Manraj Kanwal Singh Heran MD, FRCPC Division of Neuroradiology (VGH) Pediatric Interventional Radiology (BCCH) [e-mail] Rituximab IRIS High b value DWI PATH COMMENTARY ON ‘THE GREY AREA OF WHITE MATTER’ PROGRESSIVE MULTIFOC AL LEUKOENCEPHALOPATHY (PML) • JC virus, first cultured in 1971, is a Polyomavirus. • The human Polyomaviridae include simian virus 40 (SV40), BK polyomavirus (BKV) and JC polyomavirus (JCV). Only JCV is associated with significant CNS disease. • PML is largely restricted to hosts with immunodeficiency of any cause, including genetic disorders, iatrogenic immunosuppression and chronic inflammatory and infectious diseases. • Surprisingly, PML is relatively unusual in patients receiving a bone marrow transplant. • Once in the CNS parenchyma, JC virus is produced in oligodendrocytes (consequent demyelination) and cerebellar granule cells. Astrocytes do not produce JC virus, but infection of these cells leads to their morphological transformation and bizarre appearance. • Productive infection of cerebellar granule cells by JCV can cause subacute or chronic cerebellar dysfunction, including gait ataxia, dysarthria, and incoordination. • JCV–induced loss of granule cells is relatively common and can be found with or without typical demyelinating lesions. PML PATHOLOGY • Macroscopy : • Multiple foci of grey discoloration best seen in juxtacortical or deeper WM • Pitting/gelatinous softening of the lesions, confluent areas may cavitate • Microscopy: • Affects predominantly white matter but any part of the CNS can be involved • Loss of myelin with axonal sparing. In larger lesions can have considerable loss of axons. • Numerous foamy macrophages, particularly in active lesions. • In classic PML, the inflammatory infiltrate consists almost exclusively of macrophages, with only scanty lymphocytes. • Lesions in patients with IRIS can show intense inflammation and necrosis. • Oligodendrocytes at the margins of the lesions have enlarged nuclei filled with homogeneous, amphophilic or basophilic material. • Adjacent astrocytes show enlarged, hyperchromatic, bizarrely shaped nuclei and abundant eosinophilic cytoplasm - resemble malignant astrocytes SV40 IHC PML • Cerebellar granule cells infected by JCV show large vesicular nuclei and central nucleoli. • JC virus can be confirmed by electron microscopy, immunohistochemistry and in situ hybridization. • EM shows numerous intranuclear viral particles in oligos. Virus particles are rarely, if ever, detected in astrocytes. • Recovery from PML seems to depend on the development of a JC virus-specific CD8+ cytotoxic T-cell response. • In patients who have been successfully treated, the resolution of PML may leave foci of chronic demyelination, gliosis and variable lymphocytic inflammation without any detectable viral inclusions - ‘burnt-out’ PML (requires clinicopathological correlations) JC ISH