MS Diagnosis & Important Diagnostic Mimics

MS Diagnosis & Important Diagnostic Mimics Jeffrey M. Gelfand, MD, MAS, FAAN Associate Professor of Clinical Neurology University of California, San Francisco, MS and Neuroinflammation Center

National Multiple Sclerosis Society – Seattle (delivered virtually from San Francisco), June 2020 Disclosures

• Research support (to UCSF) from Genentech for a clinical trial; consulting for Biogen and Alexion; personal compensation for medical-legal consulting.

• Support to UCSF from the National MS Society for an Institutional Clinician Training Fellowship to train the next generation of specialists in MS care. UCSF MS and Neuroinflammation Center

Sandler Neurosciences Center

New Joan and Sanford I. Weill Neurosciences Building Future home of the MS and Neuroinflammation clinic (Jan 2021)

Owens St. Clinic Diagnosis of MS and Diagnostic Mimics Theses / Take Home Points:

1) MS is a clinical diagnosis established through skillful history, physical examination, diagnostic interpretation, and clinical reasoning.

2) MS diagnostic mimics are usually EITHER clinical OR MRI and only rarely true mimics of both. Sometimes the benefit of careful follow-up is needed to secure a final diagnosis, with attention to history, atypical clinical features, MRI review, and familiarity with relevant alternate diagnoses for the clinical syndrome.

-- About 1 million people with MS in the U.S., the highest numbers measured to date.

-- More common higher latitudes (North > South)

Wallin, et. al. Neurology, 2019 MS Around the World

Browne, et. al. Neurology 2014 Clinical Phenotypes of MS

Relapses (Attacks) Progression (Insidious worsening/disability )

- Acute inflammation / - Combinations of demyelination neurodegeneration (nerve loss), - T2/FLAIR (i.e. white incomplete myelin spots) and enhancing repair, “trapped” MRI lesions inflammation - Usually recover over - Atrophy (loss of Brain volume time but may have volume) on MRI some residual injury

Schlaeger, et. al. Annals of Neurology 2014 Measuring spinal cord volume Common MS presenting syndromes

• Optic neuritis (20% 1st symptom; 50% lifetime), typically unilateral • Myelitis (esp partial transverse myelitis) • Brainstem syndromes (including INO) • Weakness, spasticity, tonic spinal spasms • Sensory impairment (including Lhermitte’s symptom) • Imbalance • Cognitive impairment • Neurogenic bowel and bladder • Heat sensitivity (due to demyelination) • Fatigue • Neuropathic pain 2017 International Panel (”McDonald”) Criteria for MS -- RELAPSING Lancet Neurology 2017 Dissemination in space and time + “no better explanation for the clinical presentation” Attacks / Relapses Typical MRI lesions Additional Data Needed for MS dx 2 or more attacks 2 or more --

2 or more attacks 1 (if clear-cut historical evidence of another -- lesion in a distinct neuroanatomical localization) 2 or more attacks Just 1 Dissemination in Space with new attack elsewhere or new MRI lesion 1 attack 2 or more Dissemination in Time with new attack, new or subclinical enhancing MRI lesion, or CSF +OCBs 1 attack Just 1 Dissemination in Space with new attack elsewhere or MRI AND Dissemination in Time with new attack or MRI 2017 International Panel (”McDonald”) Criteria for MS – PRIMARY PROGRESSIVE Lancet Neurology 2017

Dissemination in space and time + “no better explanation for the clinical presentation”

Clinical Presentation + 2 or more of the following:

1 year or more of disability progression - One or more BRAIN MRI lesions typical of (independent of clinical relapse (i.e. slow, MS (periventricular, cortical or juxtacortical, insidious worsening over time) or infratentorial - Two or more SPINE MRI lesions *Can be retrospective (i.e. by history) or - CSF +OCBs prospective (by following pt over time) Updated Terminology to Describe MS Phenotype

Relapsing Progressive Clinically Isolated Syndrome (CIS) Primary Progressive (PP) Relapsing-Remitting Disease (RRMS) Secondary Progressive (SP) + + Active / Inactive Active / Inactive + With Progression / Without Progression

Lublin, et. al. International Advisory Committee on Clinical Trials, Neurology, 2014 “Active” Ongoing inflammatory-demyelinating disease – clinical relapse or MRI activity Updated FDA Definitions for “Relapsing Forms” of MS

- Clinically Isolated Syndrome - Relapsing-Remitting MS - Active Secondary Progressive MS

“Active” Ongoing inflammatory-demyelinating disease – clinical relapse or MRI activity “Silent Progression”

UCSF EPIC team – Cree, et. al. Ann Neuro 2018 - “Silent progression” (neurodegeneration) not from relapse

- Also called Progression Independent of Relapse Activity (PIRA)

- Preventing ”silent progression” is a priority treatment-wise

UCSF EPIC study, 12+ years of follow-up RIS vs CIS

Radiologically Isolated Syndrome / Preclinical MS – typical MRI findings of MS without relapse or disability progression.

Clinically Isolated Syndrome – A first clinical attack/episode of inflammatory-demyelinating disease. Differential diagnosis includes: Monophasic event, first attack of MS, first attack of an alternate/mimic diagnosis. Limits of McDonald (MS diagnostic) Criteria…

• “McDonald criteria were not developed to differentiate multiple sclerosis from other conditions but to identify multiple sclerosis or a high likelihood of the disease in patients with a typical clinically isolated syndrome once other diagnoses have been deemed unlikely” (Lancet Neurology 2017)

• Particular diagnostic caution with CIS and PPMS phenotypes

• Formal criteria do NOT currently include other helpful “paraclinical” diagnostics, such as electrophysiology (VEP, SSEPs) or retinal optical coherence tomography (SD-OCT) – in clinical practice these can be helpful to “build the case” for or against diagnosis MS Misdiagnosis Clinical Red flags for MS Diagnosis

• Prominent non-neurological (i.e. “systemic”) findings not accounted by a comorbid diagnosis

• First-ever relapse in patients >60 years old (can certainly occur but less commonly); PPMS phenotype in young patients (esp consider metabolic / genetic in ddx)

• Severe optic neuritis with poor visual recovery (?NMO, ischemic optic neuropathy, etc)

• Prominent non-CNS neuroanatomic localization on examination (neuropathy, myopathy)

• Prominent encephalopathy (cognitive symptoms are common in MS but not frank encephalopathy, ?ADEM including MOG, autoimmune encephalitis, many other causes)

• Seizures as a prominent presenting feature (occurs in few % of MS patients but less typical)

• Hyperacute (i.e. ”stroke-like”) presentations

References: Miller, et. al. Mult Scler 2008; Gelfand, JM. Handb Clinical Neurol, 2014 MRI Red flags for MS Diagnosis

- Nerve root or meningeal enhancement

- Persistent abnormal gadolinium enhancement of the same lesion for months to years (gad+ lesions in MS typically resolve in 1-2 months, longer for tumefactive lesions)

- Solitary lesions (thus need for dissemination in space)

- Unremarkable brain and spine MRI (in current era would expect to see some lesions in MS if good quality MRI) MS LETM - Longitudinally extensive transverse myelitis (LETM) → T2 hyperintensity extending >3 spinal vertebral bony levels (must distinguish this from extensive “skip” lesions in MS that may appear to coalesce; axial imaging review helpful) References: Miller, et. al. Mult Scler 2008; Gelfand, JM. Handb Clinical Neurol, 2014 CSF Red flags for MS Diagnosis

- CSF pleocytosis >50 WBCs

- Neutrophils or eosinophils on CSF differential

- Low CSF Glucose (infection, malignancy, sarcoidosis, rarely SLE or vasculitis)

- Substantially elevated CSF total protein

- Absence of oligoclonal bands in adults with MS (about 80-95% of adults with MS have +OCBs so negative OCBs certainly occurs in true MS but less commonly so important to have other strong evidence; +OCBs >60% in children>12, <50% in children <12)

References: Miller, et. al. Mult Scler 2008; Gelfand, JM. Handb Clinical Neurol, 2014 Common reasoning pitfalls in MS Diagnosis

- Misinterpreting MRI lesions as consistent with MS when due to other causes (nonspecific, small vessel ischemic, leukoencephalopathy)

- Misattributing symptoms to MS when due to other causes (chronic migraine, systemic disease, functional neurological disorders)

- (Rarely) misinterpreting biopsy data (inflammatory demyelination on brain biopsy has differential, not just MS)

- Incomplete workup at time of CIS (first attack) or early RRMS stage → CSF helps to “rule out” other causes not just to “rule-in” MS

- Incomplete consideration of neurodegenerative / genetic / metabolic causes in atypical PPMS type presentations and especially if CSF OCB negative MS Misdiagnosis – Multicenter study from 4 MS specialty clinics. Evidence Base 66% of misdiagnosed patients had alternate diagnoses of: - Migraine - Fibromyalgia - Non-specific or non-localizing symptoms with MRI findings - Conversion or “psychogenic” disorder (what would now be called functional neurological disorders) - Neuromyelitis optica spectrum disease Solomon, et. al. Neurology, 2016 Root causes: inappropriate classification of clinical symptoms; overreliance on MRI

In MS specialty centers in Lebanon and Kuwait (Yamout, et. al. MSRD 2017), 30% of patients referred for suspected MS had an alternate diagnosis. Common alternate diagnoses: “psychogenic”, nonspecific white matter MRI abnormalities, NMOSD, migraine, systemic autoimmune disease.

In 2001-2003 at University of Colorado (Carmosino, et. al. Arch Neuro, 2005), of patients referred for possible MS, only 33% had MS as a final diagnosis. Major alternate diagnoses for abnormal MRI were nonspecific small vessel ischemic disease/hypertension, migraine. Also see review by Solomon, et. al. Neurology, 2019 Tumefactive Demyelinating Lesions (TDLs) Tumefactive Demyelinating Lesions (TDLs)

Cystic Incomplete Rim TDLs: Atypical inflammatory - demyelinating lesions >2 cm

-1-2/1000 cases of MS; also associated with “ADEM”, NMO, HIV, connective tissue disease or as a stand-alone Solid Nodular diagnosis

Relapse risk highly variable in literature; especially high if otherwise have MS

Of 31 biopsy-confirmed cases at UCSF, 2 Balo-Like Patchy were malignant diagnoses (glioma, lymphoma). Up to 50% with f/u relapsed, 3 with recurrent TDLs.

Tremblay, Villanueva-Meyer, Cha, Tihan and Gelfand, et. all. J Neurol Sci, 2017 Acute Disseminated Encephalomyelitis (ADEM) ADEM

• Polyfocal CNS inflammatory-demyelinating event • Classically with encephalopathy (which is atypical for MS) • Clasically monophasic (including no progression for 3 months) • MRI with brain lesions and often deep gray involvement; T1 hypointense lesions are rare in ADEM (but common in MS)

• Classically occurs in children but can also occur in adults • Anti-MOG disease (see next slides) is now known to cause a subset of cases

• TDLs (see previous slide) in isolation are not synonymous with “ADEM" Anti-MOG Oligodendrocytopathy Case – “ADEM”

• Woman in 50s with a 20-year history of relapsing-remitting myelitis and optic neuritis.

• Pleocytosis when symptomatic. NMO antibody negative. CSF with 0 oligoclonal bands.

• Glucocorticoid toxicity. Responded well to IVIg previously. Relapses on MMF, azathioprine and Rituximab. FLAIR T1 post gadolinium Serum MOG positive at 1:10,000 (very high titer) MOG-Antibody Oligodendrocytopathy Literature rapidly expanding (i.e.): -- Optic neuritis, myelitis → “NMOSD-like” -- Parenchymal lesions, seizures, AMS → ”ADEM” Hacohen, JAMA Neuro, 2018 -- Conceptually, this is a human version of EAE

-- Can be monophasic (esp in children); when relapsing remitting titer appears to be high and predictive Ramanathan, JNNP, 2018 -- IVIG responsive, also Rituximab, AZA, MMF; poorer response to injection MS therapies Hyun, JNNP, 2017 -- Lab test clinically only recently commercially available in the U.S (2018). May be role for reinvestigating in “atypical” patients Hennes, Neurology, 2017

Hamid, JAMA Neuro, 2018 Water, JAMA Neuro, 2019 Evolving Paradigm of CNS Antibody Disorders

Neuronal Neuronal Intracellular Cell-Surface/Synaptic Astrocyte Myelin (Classical Paraneoplastic) (Autoimmune)

CRMP-5, Hu (ANNA-1), Yo (Purkinje cells), NMDA, VGKC-c/LGI-1/CASPR2, AMPA, AQP4 MOG (NMO or Ri, Ma, amphiphysin.... GABA-A, GABA-B, DPPX… (NMO) ADEM-like GFAP syndrome) (meningoencephalitis/myelitis)

Usually associated with cancer Sometimes cancer related but some Variable Not predominantly autoimmune, post-infectious (rare for NMO; reported with GFAP)

Cytotoxic T-cell Response; Antibody/complement mediated with T cell Antibody/complement Antibody and T Antibodies are probably an epiphenomenon of response mediated with T cell cell response tumoral autoimmunity response (for AQP4)

Frequently poor response to immunosuppression Usually good response to immunosuppression Good Good

*Note that Thyroid antibodies do not have a known antigenic target in the CNS Autoimmune Encephalitis with parenchymal T2 hyperintensities Case – Encephalopathy, seizures

• Man in his 30s with rapidly progressive encephalopathy, particularly abnormal behavior… then medically refractory seizures (localization related)

• CSF with 5 WBC, normal protein and glucose, normal IgG index, but with 8 OCBs GABA-A Encephalitis

Research based testing confirmed positive GABA- A antibodies in CSF (which can be hard to distinguish from GAD with existing clinical assays)

Final Diagnosis: Anti-GABA-A Autoimmune Encephalitis

FLAIR UCSF GABA-A Antibody Encephalitis

-- Median age 40, but wide age range (2.5 months to 62 years) -- Seizures, movement disorders, multifocal WM lesions -- Post/Peri-infectious in children; tumor (esp thymoma) associations in adults -- Relatively rare (26 cases over 3+ years in Spanish series) Spatola, et. al. Neurology, 2017

Late 50s, seizures and encephalopathy

CSF x1 with elevated protein CSF x 2 with 7 WBC

No malignancy identified

Evolving, muiltifocal MRI lesions over time.

Treatment with steroids, IVIG, PLEX, Rituximab

O’Connor, et. al. Submitted. Mayo/UCSF Compare with GABA-B Encephalitis (more classic LE) Severe Amnesia, Medically Refractory Seizures, No Malignancy

-- Median age 61 (range 16-77) -- Seizures, amnesia, AMS, rare opsoclonus- myoclonus or ataxia -- 50% SCLC / paraneoplastic Hoftberger, et. al. Neurology, 2013 Evolving Paradigm of CNS Antibody Disorders

Neuronal Neuronal Intracellular Cell-Surface/Synaptic Astrocyte Myelin (Classical Paraneoplastic) (Autoimmune)

Usually associated with cancer Sometimes cancer related but some Variable Not predominantly autoimmune, post-infectious (rare for NMO; reported with GFAP)

Frequently poor response to immunosuppression Usually good response to immunosuppression Good Good

*Note that Thyroid antibodies do not have a known antigenic target in the CNS Neuromyelitis Optica Spectrum Disorders (NMOSD) NMOSD Wingerchuk, et. al. Neurology, 2019

Core Clinical Features

1. Optic neuritis If AQP4 IgG positive, 1 attack plus 2. Acute myelitis exclusion of alternate diagnoses 3. Area postrema syndrome: episode of otherwise unexplained hiccups or If AQP4 IgG negative, 2 attacks nausea and vomiting (one must be ON, LETM, area 4. Acute brainstem syndrome postrema syndrome), MRI, 5. Symptomatic narcolepsy or acute exclusion diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesion 6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions NMOSD Neurosarcoidosis Neurosarcoidosis MS

T2 T1 post gad T1 post gad NMOSD – Diencephalic - AQP4 IgG positive Evolving Paradigm of CNS Antibody Disorders

Neuronal Neuronal Intracellular Cell-Surface/Synaptic Astrocyte Myelin (Classical Paraneoplastic) (Autoimmune)

Usually associated with cancer Sometimes cancer related but some Variable Not predominantly autoimmune, post-infectious (rare for NMO; reported with GFAP)

Frequently poor response to immunosuppression Usually good response to immunosuppression Good Good

*Note that Thyroid antibodies do not have a known antigenic target in the CNS GFAP Astrocytopathy Case – Meningoencephalitis + Myelitis

• Man in 60s with meningoencephalitis and myelitis, rapidly progressive encephalopathy, headache, imbalance

FLAIR T1 Gad • CSFs with lymphocytic pleocytosis (6 WBC, 9 WBC), elevated protein, normal glucose, IgG index normal. 0 OCBs.

T2 T1 GAD

GFAP Autoimmune Astrocytopathy Flanagan, et. al. Annals of Neurology, 2017

- Meningoencephalitis +/- myelitis, rare disc edema - CSF testing most sensitive (vs serum); ”false” positive ~1% unaffected controls - Radial perivascular enhancement (not pathognomonic, caution re sarcoidosis, lymphoma…) Can have longitudinally extensive or short segment myelitis - Can coexist with other antibodies (NMDAR, AQP4, VGKC, etc), esp with teratoma - Rx with glucocorticoids, MMF, AZA, Rituximab – but need better data to guide treatment

CSF GFAP antibody positive Evolving Paradigm of CNS Antibody Disorders

Neuronal Neuronal Intracellular Cell-Surface/Synaptic Astrocyte Myelin (Classical Paraneoplastic) (Autoimmune)

Usually associated with cancer Sometimes cancer related but some Variable Not predominantly autoimmune, post-infectious (rare for NMO; reported with GFAP)

Frequently poor response to immunosuppression Usually good response to immunosuppression Good Good

*Note that Thyroid antibodies do not have a known antigenic target in the CNS Neurosarcoidosis Neurosarcoidosis

- “Sarcoma-like” appearance of sarcoidosis skin lesions described in the late 1800s (the root of the name “sarcoidosis”)

- Lungs (90%), skin (~15%), eye (10-30%), liver (20-30%) and lymph nodes (10-20%) are most commonly affected by sarcoidosis

- Neurological organ system involvement – neurosarcoidosis – in 5-15% of patients

- ~20% of neurosarcoidosis is “isolated” to the CNS in modern studies

Valeyre Lancet 2014; Iannuzzi NEJM 2007; Stern JAMA Neurology 2018 Case – Vision loss, hypopituitarism, cognitive impairment Brain Biopsy

First available 2.4 years later 2.7 years 3.3 years 4.1 years 8 years 9.25 years 9.67 years 9.75 years 9.9 years 10.8 years archived MRI, age 40 Corticosteroids + Azathioprine Infliximab Infliximab 5 mg/kg load 7 mg/kg then Q8 weeks Q6 weeks Blindness Hypopituitarism Cognitive Impairment Cognitive Problems Resolved

First available 2.4 years later 2.7 years 3.3 years 4.1 years 8 years 9.25 years 9.67 years 9.75 years 9.9 years 10.8 years archived MRI, age 40

CSF Exam CSF Exam 9 WBC 7 WBC Glucose 50 Glucose 52 Protein 81 Protein 112 CSF ACE<3 IgG Index 0.9 4 OCBs Gelfand, Bradshaw, et. al. Neurology 2017 CSF ACE <3 The granuloma – Hallmark of Sarcoidosis H&E

Multinucleated Giant Cell

Leptomeninges, H&E, Neurosarcoidosis H&E CD68 (Macrophage) Neurosarcoidosis Consortium Consensus Diagnostic Criteria

JAMA Neurology Dec 2018

Bottom line: 1) Clinical syndrome consistent with neurosarcoidosis with confirmatory neurodiagnostics 2) Pathological evidence of sarcoidosis in the CNS/PNS (Definite) or elsewhere in the body (Probable) 3) Rigorous exclusion of other causes, particularly infection and malignancy Neurosarcoidosis – Clinical Pearls - 1 • Infiltrates within favored CNS sites

• Tends to spread locally (unlike MS) & often involves adjacent meninges

• Abnormal contrast enhancement -- most typically nodular/lobulated +/- perivenular, & often involving overlying meninges (pia), is a sign of active neurosarcoidosis

• CSF may show a pleocytosis, elevated protein, normal or low glucose, elevated IgG index, +OCBS (in ~25%)

• Causes a clinical syndrome that reflects the affected neuroanatomy Neurosarcoidosis: Optic Neuropathy

FLAIR

T1 Post-Contrast

T1 Post- Contrast

FLAIR CNS Biopsy: Noncaseating Granulomatous Inflammation T1 Post-Contrast Neurosarcoidosis Myelitis

7 months prior T2 T1 Post-Gadolinium (sequential cuts) T2 T1 Post (after MVA) 6 months later NMOSD Neurosarcoidosis Neurosarcoidosis MS

T2 T1 post gad T1 post gad Neurosarcoidosis – Clinical Pearls - 2 - “Relapses” tend to occur in anatomical sites of previous disease activity (unlike MS)

- Resolution of abnormal MRI enhancement is usually a good indicator of remission (whereas T2/FLAIR lesions can persist)

- CSF can be an important marker of disease activity even when the MRI is negative Evaluation of suspected neurosarcoidosis

• A chest CT with contrast is usually the most helpful test to survey for extra- neural involvement when there is a high pretest probability. Abd/Pelvis CT also helpful. Dilated eye exams and skin examination also valuable.

• When body CT is negative, a whole-body FDG-PET can be valuable to identify sites of metabolically active disease, including “hot” lymph nodes that can be normal in size (and thereby appear normal on CT)

• Survey the entire neuroaxis, as there can be distant, subclinical sites of disease involvement

• Tissue diagnosis is favored (pathological diagnosis) Whole body FDG-PET in sarcoidosis

Transbronchial biopsy: Non-caseating granulomas consistent with sarcoidosis Biomarkers - CNS Sarcoidosis (UCSF)

Biopsy Proven CNS Sarcoidosis N=53 Serum ACE Elevated (>67) 14% N=35

CSF ACE elevated 14% N=22

CSF Pleocytosis (>5 WBC) 80% N=44

CSF Protein elevation (>50) 73% N=44

CSF Glucose Abnormally Low 27% N=41

IgG index elevated 36% N=44

Gelfand, et. al., in preparation Low CSF Glucose (Hypoglycorrhachia) in Neurosarcoidosis

225 cases (115 “septic” and 110 infectious) meningitis from search of UCSF clinical laboratory data and EMR

Baud, et. al. Neurology Neuroimmunology 2017

- Low CSF glucose (<40 mg/dL) in 50.1% of infectious cases vs 10.4% of aseptic, nearly all of which were neurosarcoidosis (1 CNS vasculitis, 2 NMO); only 1 non-infectious case had a CSF <40 mg/dL

Be cautious attributing CSF glucose lower than 30 mg/dL (particularly <20) to neurosarcoidosis!

Examples of final diagnoses in patients referred to our clinic for suspected neurosarcoidosis with very low CSF glucose: Cryptococcus, immunocompetent histoplasmosis, others. CNS Vasculitis CNS Vasculitis • Primary (PACNS) vs secondary (systemic or infection)

• PACNS 2.4 cases/million (1/100,000 neurosarcoidosis), median age 50 but can affect any age

• Likely a common pathological final common pathway for several different primary pathologies (i.e. subset with angiographic abnormalities, some lymphocytic others granulomatous (<50% cases), even rare monogenic immunodeficiency associations)

• Diagnosis based on clinical syndrome, biopsy +/- angiogram (often supported by CSF)

• Caution with “beading” on angiography: RCVS, atherosclerosis, vasculopathy

References: Hajj-Ali, Calabrese, reviews and UTDOL Small Vessel CNS vasculitis (PACNS)

Cerebral angiogram normal

Brain Biopsy with necrotizing small vessel vasculitis Small Vessel CNS Vasculitis (PACNS)

Rapidly progressive encephalopathy, seizures, headache

CSF with lymphocytic pleocytosis

Small vessel lymphocytic vasculitis on neuropathology PACNS with brain and spinal cord involvement PACNS (Granulomatous)

FLAIR T1 Post Neuropsychiatric Systemic Lupus Erythematosus (NP-SLE) Neuropsychiatric SLE

• Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect any organ, including the nervous system.

• Primary NP-SLE vs secondary neuropsych manifestations (meds, infxn)

• Use of older terms like “lupus cerebritis” and “lupus sclerosis” is not encouraged due to pathological ambiguity

• 1/3-1/2 have NP-SLE but in many probably co-morbid pathology

• Exam: look for mucocutaneous disease (skin rashes, oral ulcerations, alopecia), musculoskeletal disease (inflammatory arthritis), or serositis (pleuritic chest pain, rubs)

• Labs: ANA, ENAs, cytopenias, low complement, APLAS

Gelfand and Yazdany, review, in preparation NP-SLE

• Stroke risk is high in SLE – 2x ischemic, 3x ICH, 4x SAH → risks include hypertension from renal disease, vasculopathy, accelerated athero, endocarditis (Libman-Sacks), only very rarely true vasculitis

• Acute confusional state / psychosis (1.5% of SLE within 3 years of diagnosis)

• Cognitive dysfunction 38% point prevalence in meta-analysis

Gelfand and Yazdany, review, in preparation APLAS

• Hypercoagulable disorder, recurrent arterial and venous thrombosis, can also have recurrent embryonic loss

• Associated with antiphospholipid antibodies (beta-2-glycoprotein, cardiolipin, lupus anticoagulant)

• In CNS typically manifests as clinical stroke-like events. MRI may have multifocal white matter lesions. CSF usually bland.

• Some patients with SLE have APLAS but not all APLAS patients have SLE CNS Sjogren’s CNS Neuro-Sjogren’s • Primary Sjogren’s: Chronic inflammation of exocrine glands

• “Extra-glandular” Sjogren’s neuro syndromes reported → PNS & CNS

• Cognitive deficits (attention, executive dysfunction, memory) in up to 80% of pts in some cohorts, but likely multifactorial as well as comorbid psychiatric disease

• Question of whether this is truly a manifestation of Sjogren’s vs associations with other pathology (i.e. 2 diseases or even 2 autoimmune diseases)

• Caution with story of “MS-like” variant of Sjogren’s (probably MS + Sjogren’s); many cases of “Sjogren’s myelitis” are now known to be NMOSD Leukodystrophy / Leukoencephalopathy / Genetic / Metabolic Leukodystrophy / Leukoencephalopathy / Genetic

• Long list of potential causes, including genetic, toxic, metabolic, infectious, vascular. Potential clues are imaging, polyneuropathy, progressive course

• Potential MS mimics (and can have +OCBs), may include adrenal leukodystrophy or AMN (VLCFA / ABCD1), metachromatic leukodystrophy (arylsulfatase), adolescent onset Krabbe’s (GALC gene), CADASIL (Notch3 gene), ALSP (CSF1R gene)

• NMOSD mimic: Biotinidase deficiency (late onset multiple carboxylase deficiency) in kids/teens with myelopathy attacks

Select References: Wolf, B. Neurol Clin Practice, 2017; Tomas J, et. al. BMJ Case Reports, 2015; van der Knaap MS, et. al. Lancet Neurology, 2019; Gelfand, et. al. Brain, 2020 Progressive myelopathy since teens. 3 LPs, one with 14 WBC, others bland. Delayed tibial SSEPS, normal median SSEP and VEPs. Brain MRI unremarkable.

*Brain MRI otherwise unremarkable, not shown Very Long Chain Fatty Acids (Blood)

“The amount of C26:0 and the ratios of C24/22 and C26/22 are higher than normal. Results are consistent with a defect in peroxisomal fatty acid oxidation, such as X-linked Adrenoleukodystrophy or Adrenomyeloneuropathy”

Confirmational testing showed mutation in ABCD1

Labs with mild adrenal insufficiency

Adrenomyeloneuropathy (AMN)

Upper C-spine ALSP – CSF1R

Gelfand, et. al. Brain 2020 CADASIL

Notch3 mutation

Headache (migraine), cognitive complaints (that can progress to dementia), sometimes with strokes or seizures MELAS

6 months later B12 or Copper Deficiency (subacute combined degeneration) • B12 deficiency most commonly presents neurologically with tingling, paresthesias, and neuropsychiatric complaints. Can progress to subacute combined degeneration of the spinal cord involving the dorsal column (vibration and position sense) and corticospinal (motor) pathways. Can also cause bilateral optic neuropathy. Macrocytosis/anemia. MMA, homocysteine, transholocobalamin.

• Copper Deficiency can cause a similar pattern. Sometimes associated with zinc toxicity (dentures) causing low copper CNS Infection Some CNS infectious considerations in MS ddx

• Lyme Disease (esp secondary neuroborreliosis) • Syphilis (specifically secondary or tertiary neurosyphilis; papillitis as an important phenotype of secondary syphilis) • HIV (can rarely be comorbid with MS) • HTLV1/2 / Tropical Spastic Paraparesis (Progressive, CSF inflammation, +HTLV antibodies and index and proviral load) • Schistosomiasis (esp thoracic/conus/cauda lesions, eosinophils) • Many causes of meningoencephalitis (clinical context is key)… PML in MS Progressive Multifocal Leukoencephalopathy (PML)

JC virus Malignancy Insidiously, relentlessly progressive L Hemiparesis

Brain biopsy showed noncaseating granulomatous inflammation c/w with neurosarcoidosis

Treated with chronic high dose oral steroids. Insidiously progressed.

Repeat brain biopsy: Lymphomoplasmacytic infiltrate with rare atypical cells c/w treated B-cell lymphoma

CNS Lymphoma Erdheim-Chester Disease / Histiocytosis

Gupta and Gelfand, et. al. JAMA Neurology 2019 Diagnosis of MS and Diagnostic Mimics Theses / Take Home Points:

1) MS is a clinical diagnosis established through skillful history, physical examination, diagnostic interpretation, and clinical reasoning.

3) Comorbid conditions do not necessarily imply mimicry. Occam’s Razor vs Hickam’s Dictum → “Patients can have as many diseases as they [darn] well please.” (MS + B12 / MS + SLE / etc) MS Diagnosis & Important Diagnostic Mimics Jeffrey M. Gelfand, MD, MAS, FAAN Associate Professor of Clinical Neurology University of California, San Francisco, MS and Neuroinflammation Center

National Multiple Sclerosis Society – Seattle (delivered virtually from San Francisco), June 2020