Clinico-Pathological Conference

Transcription

1 Disclosures Clinico-Pathological Conference Andrew W. Bollen DVM, MD Professor of Pathology, UCSF Betjemann- None Bollen- None Larimer- None John Betjemann MD Assistant Professor of Neurology, UCSF Phil Larimer MD, PhD Neurology Resident, UCSF Case: A 27 year old right-handed man presented with generalized convulsions. Review of systems: Fatigue for two weeks Allergies: None Medications: None Past medical history: None Family history: None Social: Denies alcohol, recreational drugs, smoking. Born in Mexico City. Works in agriculture in the central valley for 16 years. No travel outside of Mexico and California. No household pets but numerous stray cats in his apartment complex. No unpasteurized dairy exposure. No large animal exposure. Pesticide exposure. Exam: 37.0, 103, 97/50, 19/min, 95% on RA In no apparent distress No meningismus, no lymphadenopathy No cardiac murmurs, lungs clear bilaterally, abdomen soft Neurologic Exam: MS: Alert and oriented to self, place, date; speech fluent in Spanish, memory intact, follows commands briskly, left-sided visual neglect CN: Pupils equal and reactive to light, no papilledema OU, extraocular movements are intact without nystagmus, trace left nasolabial fold flattening with symmetric activation, facial sensation intact bilaterally, tongue and uvula are midline, no dysarthria Motor: No pronator drift, confrontational strength is without deficit Reflexes: Biceps, triceps, and patellar reflexes are symmetric and 1+, plantar responses are flexor bilaterally Sensation: Intact to vibration and temperature distally in all extremities Coordination: Normal finger-nose-finger bilaterally 1

2 Initial Labs CRP 5.2 CT head 5 cm FLAIR 5 cm T1 with gadolinium 5 cm 2

3 ADC 5 cm GRE 5 cm Labs (normal unless otherwise noted): CRP 5.2 CEA AFP CA 19-9 CA 125 Beta HCG TTE: Normal Computed tomography scans of the chest, abdomen, and pelvis as well as an ultrasound of the testicles did not reveal a primary neoplasm. CTA head/neck: normal RPR Serum cryptococcal antigen Serum cocci immunodiffusion and complement fixation HIV antibody and viral load CD4 228 EBV PCR Cysticercosis IgG Toxoplasmosis IgG, IgM, PCR CSF (HD#4): 5 WBC (98% lymphocytes), 0 RBC, glc 83, protein 30, LDH 14, CrAg, cocci complement fixation, india ink, AFB smear, cysticercosis IgG Blood/CSF bacterial/afb/fungal cultures: no growth Dexamethasone Vancomycin, Ceftriaxone Metronidazole Albendazole Therapies: Cefazolin Imipenem/cilastin TMP-SMX Cefipime Vancomycin Voriconazole Ambisome Hospital Day (transfer) 3

4 Clinical Course Scan at day 26 Seizure LP Brain Biopsy Fever Mild encephalopathy and ongoing headaches Vancomycin, Ceftriaxone Metronidazole Dexamethasone Albendazole Opiates for headache Cefazolin TMP-SMX Cefipime Voriconazole/Vancomycin Hospital Day (transfer) FLAIR T1 with GAD FLAIR T1 with GAD FLAIR T1 with GAD 4

5 FLAIR T1 with GAD FLAIR T1 with GAD FLAIR T1 with GAD FLAIR T1 with GAD 5

6 FLAIR T1 with GAD FLAIR T1 with GAD FLAIR T1 with GAD FLAIR T1 with GAD 6

7 FLAIR T1 with GAD FLAIR T1 with GAD UCSF Course FLAIR T1 with GAD He remained in coma with EEG demonstrating only diffuse slowing. Due to evidence of herniation on arrival, he was intubated and an EVD was placed. He had elevated intracranial pressure refractory to CSF diversion and medical management so had a decompressive hemicraniectomy on UCSF HD#3. He did not regain brainstem reflexes, was transitioned to comfort measures, and succumbed to his illness 35 days after initial presentation Brain Biopsy Seizure (inconclusive) Mild encephalopathy Hospital Day Fever Death Decompression EVD Intubated Coma

8 Approach and Overview RECENT ADVANCES IN NEUROLOGY CLINICO-PATHOLOGIC CONFERENCE Key points History Exam Evaluation Treatment Broad Differential Diagnosis (DDx) Further work up Diagnostic and treatment pearls Make a diagnosis John Betjemann, MD History and Exam- Key Points Young healthy man from Mexico working in agriculture Subacuteonset of fatigue, encephalopathy, headache and new seizure Exposure to stray cats Exam: left visual neglect, facial asymmetry Evaluation and Treatment- Key Points Labs LP: not consistent with meningitis but was performed after 4 days of steroids and Abx CD4= 228 Imaging: Initially multiple ring enhancing lesions with edema. New lesions on repeat scan despite treatment Treatment Steroids Polymicrobial, fungal, neurocysticercosis(ncc) 8

9 Differential Diagnosis Low CD4 Malignancy Lymphoma Multifocal CNS neoplasm/metastases Gliomatosis Cerebri Sarcoid Infarct/vasculitis Infection Pyogenic abscess Septic emboli Toxoplasmosis Fungi TB NCC Walker UA. Curr Opin Rheumatol 2006 Malignancy- CNS Lymphoma Pros Encephalopathy, focal deficits, and seizures Immunodeficiency Cons Age Usually more steroid responsive Imaging Malignancy-Multifocal glioma/cns metastases Pros Headache, seizures Imaging: ring enhancing masses, gray-white, with edema Cons Encephalopathy Age Lack of discernible primary Dramatic progression after 3 weeks Haldorsen IS. AJNR

10 Malignancy- Gliomatosis Cerebri Cons Age Usually more extensive radiographic involvement Freund M. et al. Eur Radiol Infection- Pyogenic Abscess Pros History and exam Ring enhancing lesions Cons (none of these exclude the possibility!) Lack of fever Negative blood cultures CSF classically with pleocytosis and elevated protein Septic emboli Negative TTE and blood Cx, lack of other embolic strokes and absence of hemosiderin on GRE Infection- Toxoplasmosis Pros Immunodeficiency Imaging: multiple ring enhancing lesions with edema Cons Not quite immunodeficient enough Negative serologies Majority are IgG positive PCR: 83% sens, 95% spec in CSF of AIDS-infected patients (similar in serum) (Alfonso Y, et al and MesquitaRT et al. 2010) Infection- Fungi Cryptococcus Usually immunocompromised Typically meningoencephalitis rather than discrete masslike lesions (cryptococcomas) CSF: elevated OP, pleocytosis(lymphocytic), low gluc, high prot. India ink, culture and CrAg(sens and spec 93-98)(Tanner DC et al. 1994) Aspergillosis Usually disseminated infection but can be local spread Coccidomycosis Typically a meningitis, but can have abscess formation CSF with lymphocytic pleocytosis 10

11 Infection- TB Infection- Neurocysticercosis Pros Imaging fits well with tuberculomas Low CD4 may serve as risk for TB or may be result of active TB CSF often nonspecific in tuberculomas Not treated empirically for TB Negative AFB smear and culture are not terribly helpful Cons Classically causes a meningitis +/- tuberculomas Not from a truly endemic area CT chest without malignancy, but evidence of remote TB? Pros Commonly presents with seizures and focal findings From an endemic area Cons Imaging not classic-not truly cystic, no calcification, and no scolex Serum Abtesting negative (up to 98% sensitive) (Del Brutto OH 2012) New lesions despite albendazole Neurosarcoid Can impact any portion of the CNS without systemic manifestations Imaging: can see enhancing parenchymal lesions but also often meningeal enhancement and cranial neuropathies Initial treatment involves steroids Vasculitis Many of the above conditions can be associated with a vasculitis Might somewhat explain the interval progression on MRIs 11

12 Further Diagnostic Considerations Dental exam: source of bacteremia and septic emboli Ophthalmologic exam: sarcoid, lymphoma PET scan: potential biopsy target Labs: Beta-D-glucan, galactomannan Diagnostic and Treatment Pearls CSF Timing: when possible LP prior to steroids and Abx For cytology, CSF should be analyzed within few hours For TB and lymphoma key is volume, volume, volume! Lymphoma: cytology sensitivity 2-32% (Scott BJ, 2013). Lower yield with small CF volume, processing delays and steroids TB: AFB smear~60%, PCR 56% sensitivity (Thwaites GE 2013) Steroids Alter imaging, decrease diagnostic yield (lymphoma) Diagnostic and Treatment Pearls Diagnosis Our CSF diagnostic testing is limited! What are we good at Viruses CrAg In many cases a negative test doesn t exclude the disease (lymphoma, TB) Steiner I, et al. EurJ Neuol Lymphoma Pyogenic abscess Tuberculosis Fungal abscess +/- vasculitis Neurosarcoid Neurocysticercosis Toxoplasmosis gliomatosis Metastatic/multifo cal glioma 12

13 Tuberculosis References Tuberculoma/Tubercular abscess RipamontiD, et al. Clin Infect Dis Walker UA, Warnatz K. Idiopathic CD4 lymphocytopenia. Curr Opin Rheumatol 2006;18: Haldorsen IS, Espeleand A, Larsson E-M. Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. AJNR 2011; 32: Freund M, et al. CT and MRI findings in gliomatosis cerebri: a neuroradiologic and neuropathologic review of diffuse infiltrating brain neoplasms. Eur Radiol. 2001;11: Alfonso Y, et al. Molecular diagnosis of Toxoplasma gondiiinfection in cerebrospinal fluid from AIDS patients. Cerebrospinal Fluid Res 2009;6: Mesquita RT et al. Molecular diagnosis of cerebral toxoplasmosis: comparing markers that determine toxoplasma gondii by PCR in peripheral blood from HIV-infected patients. Braz J Infect Dis 2010;14: Tanner DC, et al. Comparison of commercial kits for detection of cryptococcal antigen. J ClinMicrobiol. 1994;32: Del BruttoOH. Diagnostic criteria for neurocysticercosis revisited. Pathogens and Global Health 2012;106: Scott BJ, et al. A systematic approach to the diagnosis of suspected central nervous system lymphoma. Jama Neurol 2013;70: Thwaites GE, et al. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol 2013;12: Steiner I, et al. EFNS-ENS guidelines for the use of PCR technology for the diagnosis of infections of the nervous system. Eur J Neuol. 2012;19: Ripamonti D, et al. New times for an old disease: intracranial mass lesions caused by mycobacterium tuberculosis in 5 HIV-negative African immigrants. ClinInfect Dis 2004;39:e35-e45. Recent Advances in Neurology Case: Neuropathology Andrew Bollen MD, DVM Department of Anatomic Pathology Neuropathology Division University of California San Francisco 100X 13

14 400X 200X 100X 200X 14

15 100X 200X 400X AFB-400X 15

16 40X 200X 400X AFB-400X 16

17 40X 200X 400X PAS-400X 17

18 PAS-400X 100X 200X 400X 18

19 PAS-400X 40X 100X 200X 19

20 40X GMS-200X Clinical presentation of CNS TB Accounts for 1% of TB cases world wide. Occurs during primary infection in children or late reactivation infection in (often immunocompromised) adults. Tuberculous meningitis From rupture of a subependymal tubercle into the subarachnoid space. Complicated by vasculitis and hydrocephalus Three phases Prodromal: 2-3 weeks of malaise, headache, low-grade fever Meningitic: Meningismus, vomiting, confusion, focal signs Paralytic: Coma and seizures Death is usually with 5-8 weeks of symptom onset if untreated CSF has a high protein and low glucose with mild pleocytosis Intracranial tuberculoma Signs of systemic illness or meningeal inflammation are rare CSF unremarkable Tuberular arachnoiditis Radiological findings in CNS TB Tuberculous meningitis Hydrocephalus or infarcts from arteritis on CT head Meningeal enhancement (typically basal) or pahcymeningitis on MRI Intracranial tuberculoma T1 isointense with ring enhancement Surrounded by T2 hyerintense vasogenic edema Not diffusion restricted Tuberular arachnoiditis Matted lumbar nerve roots Reviewed in Indian J Radiol Imaging. 2009; 19:

21 Sensitivity of diagnostic tests in CNS TB Tuberculous meningitis CSF acid fast bacilli (AFB) smear has sensitivity of 10-91% (dependent the method) CSF AFB culture has 11-83% sensitivity CSF enzyme-linked immuno assay (ELISA) has 52-92% sensitivity CSF antigen assays have 38-94% sensitivity CSF PCR assays have % sensitivity Intracranial tuberculoma CSF studies are not sensitivce MRI and pathological biopsy are most diagnostic Must maintain a high clinical suspicion! Reviewed in Clin Microbiol Rev. 2008; 21: