Difficult Diagnosis: Case History. 7 months prior, she happened to have undergone a C-spine MRI after a car accident
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1 Relevant Disclosures: None Difficult Diagnosis: Recent Advances in Neurology 2013 Jeffrey M. Gelfand, MD Assistant Professor UCSF Neuroinflammation and MS Center UCSF Department of Neurology Case History - 50 yo right-handed woman developed tingling in the hands and arms, followed 3 days later by excruciating pain radiating down arms/upper back - Ascending numbness in the feet, constipation, urinary urgency and right leg weakness 7 months prior, she happened to have undergone a C-spine MRI after a car accident T2 T2 7 months prior New Sagittal T2 New (sequential cuts) 1
2 Case History Pre-op (& Pre-steroids) 2.5 weeks post-op (still on dexamethasone taper) CSF with no oligoclonal bands, culture no growth, normal cytology and flow cytometry Brain MRI normal Started high dose oral dexamethasone by neurosurgery and underwent anterior cervical discectomy/fusion at C3-7 Arm pain resolved immediately post-operatively; numbness and weakness persisted T2 T2 Case History Case History Tapered steroids off completely over the next 6 weeks. Labs that were negative or normal: Anti-aquaporin-4 IgG (NMO antibody) ANA HTLV I/II ACE RPR HIV Symptoms and exam remained stable Repeat MRI showed slight worsening T2 at 2.5 months T1 Post at 2.5 months Repeat CSF exam: 7 WBC (93% lymphs, 7% monocytes); 1 RBC Total protein 41 mg/dl Glucose 56 mg/dl (serum was normal range) IgG index 0.5 No oligoclonal bands Imaging: Brain MRI again normal CT Chest/Abdomen/Pelvis with and without contrast unremarkable 2
3 She is referred for another opinion - General examination normal - Fine-finger movements and foot taps slightly slowed on the right. Mild spasticity in both legs. Mild pyramidal weakness right IP and HS (4/5). - Reflexes 3+ in UE and LE, plantar response flexor. - Light touch reduced about 50% in the left foot - 25-foot timed walk 4.5 seconds unassisted Audience Response Question #1 What do you recommend for this patient as the next step? A. Do no harm, repeat C-spine MRI in 3 months (assuming clinically stable) B. Referral to neurosurgery for spinal cord biopsy C. Bone marrow biopsy 26% D. PET Scan 23% 23% 21% E. Start appropriate immunosuppressive therapy for seronegative NMO (spectrum disorder) 4% 4% F. Start appropriate DMT for multiple sclerosis she has an atypical but classically-described variant) D o n o h a r m, r e... R e f e r r a l t o n e... B o n e m a r r o w b i... P E T S c a n S t a r t a p p r o p r i... S t a r t a p p r o p r i... FDG-PET 1) Multiple hot mediastinal and hilar lymph nodes Sarcoidosis 1) Abnormal uptake in the C- spine consistent with MRI findings 2) Right orbital lesion (abutting inferior rectus on subsequent MRI) Endobronchial ultrasound guided biopsy: Non-caseating granulomas consistent with sarcoidosis, no evidence of infection or malignancy PFTs: normal Stage 1 Sarcoidosis - Inflammatory disorder of unclear etiology characterized by noncaseating granulomas on histopathology - Commonly invoked in neurological differential diagnosis Non-caseating granuloma of sarcoidosis 3
4 Epidemiology - Sarcoidosis is most common in Northern European and African-American populations - Neurosarcoidosis ~1/100,000 person-years annual incidence in the U.K - Peak age at onset in 30s-40s (working age) Practical Framework for CNS Sarcoidosis Diagnosis Definite CNS Sarcoidosis CNS Biopsy, typical clinical syndrome & exclusion of other causes Probable Neurosarcoidosis Extra-CNS biopsy, typical clinical syndrome & exclusion of other causes Possible Neurosarcoidosis No pathology, typical clinical syndrome There are many steroid responsive, atypical CNS inflammatory syndromes that are not necessarily sarcoidosis UCSF CNS Sarcoidosis Experience Total CNS Sarcoidosis Definite Cases (CNS Biopsy) Probable Cases (Extra-CNS Biopsy) Age at neurological syndrome onset n=41 n=19 n=22 40 years (IQR 35 to 49), range years Female 51% Black White Non-Hispanic Known sarcoidosis at neuro syndrome onset Evidence of pulmonary sarcoidosis at time of neurological presentation Evidence of any extra-cns sarcoidosis at time of neurological presentation Whole Body PET provided diagnostic insight beyond conventional CT 41% 46% 5 (12%) 88% did NOT have known sarcoidosis at first neurological presentation! 24 (62%) 72% (28% truly had isolated neurosarcoidosis) 4/8 (50%) UCSF CNS Sarcoidosis Experience Serum ACE Elevated (>67) N=33 CSF ACE elevated N=19 CSF Pleocytosis (>5 WBC) N=31 CSF Protein elevation (>50) N=32 CSF Glucose Abnormally Low N=30 Oligoclonal bands Present (2 or more) None Matched (bands in serum and CSF) N=26 IgG index elevated N=23 Biopsy Proven CNS Sarcoidosis n=41 16% 16% 77% 69% 31% 29% 50% 21% 52% Gelfand, et. al, manuscript in preparation Gelfand, et. al, manuscript in preparation 4
5 Practical Approach to Diagnosis of CNS Sarcoidosis A chest CT with contrast is probably the most helpful test to survey for pulmonary involvement When the Chest CT is negative, a whole-body FDG-PET can be invaluable to identify sites of metabolically active disease, including hot but normal size lymph nodes (50% hit rate in our series) Image the entire neuroaxis for biopsy targets A tissue diagnosis is favored when the risk is acceptable ACE not that helpful for CNS disease CNS Sarcoidosis MRI Observations 1) Tends to seed within the CNS at favored neuroanatomic sites and can persist for months to years at a time with ongoing enhancement 1) Nodular/lobulated enhancement on MRI is a sign of active disease; often involves nearby meninges 2) Relapses tend to occur at sites of previous activity (Beware of new symptoms completely out of the blue!) Nodular enhancing appearance on MRI Syndrome: Optic Neuropathy FLAIR Nodular enhancing appearance on MRI Syndrome: Hypopituitarism T1 Post- Contrast T1 Post- Contrast Sagittal Coronal over time shows extension into periventricular meningeal spaces CNS Biopsy: FLAIR Noncaseating Granulomatous Inflammation T1 Post-Contrast 5
6 Nodular, infiltrative, lobulated contrast-enhancement Syndrome: Myelopathy A Decade of Brain Biopsy-Proven CNS Sarcoidosis: The disease extends and spreads through regional propagation Nasal Biopsy Brain Biopsy 12/2001 4/2003 7/2003 3/2004 1/ /2009 2/2011 7/2011 8/ / /2012 Corticosteroids + Azathioprine Blindness Hypopituitarism Infliximab 5 mg/kg load then Q8 weeks Cognitive Impairment Infliximab 7 mg/kg Q6 weeks Cognitive Problems Resolved T2 Axial 12/2001 4/2003 7/2003 3/2004 1/ /2009 2/2011 7/2011 8/ / /2012 T2 Sagittal CSF Exam: 9 WBC Glucose 50 Protein 81 CSF ACE<3 CSF Exam: 7 WBC Glucose 52 Protein 112 IgG Index OCBs CSF ACE <3 General rule is to treat organ system involvement from sarcoidosis as opposed to treating sarcoidosis as a standalone, systemic disease entity Our usual approach to disease modifying therapy for CNS Sarcoidosis 1) First-line therapy with glucocorticoids (start high and taper cautiously) 2) Second-line therapy with weekly oral methotrexate (up to 20 mg/week), azathioprine or mycophenolate 3) Infliximab (TNF-alpha inhibitor) 6
7 TNF-alpha inhibition in sarcoidosis 2 RCTs of infliximab in pulmonary sarcoid modest benefit in lung function 1 RCT of infliximab in extrapulmonary sarcoid reduced a composite disease severity score Small case series in CNS sarcoidosis report benefit Not all TNF-alpha inhibitors are the same some make sarcoidosis worse! Audience Response Question #2 What major neurological adverse effect is associated with TNF-alpha inhibitors? 1. Small fiber neuropathy 2. Demyelinating disease 3. Meningioma 4. Stroke 5. Reduction of seizure threshold S m a l l f i b e r n e... 40% 37% D e m y e l i n a t i n g... M e n i n g i o m a 1% S t r o k e 5% 16% R e d u c t i o n o f s... TNF-Alpha Inhibition is associated with demyelinating disease Dramatic Improvement within weeks of starting Infliximab after 6 years of unrelenting disease de des (ca2 = Infliximab) Neurology 1996 Journal of Rheumatology 2007 Neurology 1999 Lenercept made MS worse compared to placebo T2 T2 *After treatment with infliximab 7
8 Case resolution Our patient from today Baseline 3 months Start Infliximab + MTX 6 months 8 months Difficult Diagnosis: Recent Advances in Neurology 2013 Jeffrey M. Gelfand, MD Assistant Professor UCSF Neuroinflammation and MS Center UCSF Department of Neurology T2 T2 Relevant Disclosures: None 8
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